Vaccines

Having oral sex with more than 10 previous partners was associated with a 4.3 times’ greater likelihood of developing human papillomavirus (HPV)–related oropharyngeal cancer, according to new findings.

The study also found that having more partners in a shorter period (i.e., greater oral sex intensity) and starting oral sex at a younger age were associated with higher odds of having HPV-related cancer of the mouth and throat.

The new study, published online on Jan. 11 in Cancer, confirms previous findings and adds more nuance, say the researchers.

Previous studies have demonstrated that oral sex is a strong risk factor for HPV-related oropharyngeal cancer, which has increased in incidence in recent decades, particularly cancer of the base of the tongue and palatine and lingual tonsils.

“Our research adds more nuance in our understanding of how people acquire oral HPV infection and HPV-related oropharyngeal cancer,” said study author Gypsyamber D’Souza, PhD, professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health, Baltimore. “It suggests that risk of infection is not only from the number of oral sexual partners but that the timing and type of partner also influence risk.”

The results of the study do not change the clinical care or screening of patients, Dr. D’Souza noted, but the study does add context for patients and providers in understanding, “Why did I get HPV-oropharyngeal cancer?” she said.

“We know that people who develop HPV-oropharyngeal cancer have a wide range of sexual histories, but we do not suggest sexual history be used for screening, as many patients have low-risk sexual histories,” she said. “By chance, it only takes one partner who is infected to acquire the infection, while others who have had many partners by chance do not get exposed, or who are exposed but clear the infection.”
 

Reinforces the need for vaccination

Approached for comment, Joseph Califano, MD, physician-in-chief at the Moores Cancer Center and director of the Head and Neck Cancer Center at the University of California, San Diego, noted that similar data have been published before. The novelty here is in the timing and intensity of oral sex. “It’s not new data, but it certainly reinforces what we knew,” he said in an interview.

These new data are not going to change monitoring, he suggested. “It’s not going to change how we screen, because we don’t do population-based screening for oropharyngeal cancer,” Dr. Califano said.

“It does underline the fact that vaccination is really the key to preventing HPV-mediated cancers,” he said.

He pointed out that some data show lower rates of high-risk oral HPV shedding by children who have been appropriately vaccinated.

“This paper really highlights the fact we need to get people vaccinated early, before sexual debut,” he said. “In this case, sexual debut doesn’t necessarily mean intercourse but oral sex, and that’s a different concept of when sex starts.”

These new data “reinforce the fact that early exposure is what we need to focus on,” he said.
 

Details of the new findings

The current study by Dr. D’Souza and colleagues included 163 patients with HPV-related oropharyngeal cancer who were enrolled in the Papillomavirus Role in Oral Cancer Viral Etiology (PROVE) study. These patients were compared with 345 matched control persons.

All participants completed a behavioral survey and provided a blood sample. For the patients with cancer, a tumor sample was obtained.

The majority of participants were male (85% and 82%), were aged 50-69 years, were currently married or living with a partner, and identified as heterosexual. Case patients were more likely to report a history of sexually transmitted infection than were control participants (P = .003).

Case patients were more likely to have ever performed oral sex compared to control persons (98.8% vs 90.4%; P < .001) and to have performed oral sex at the time of their sexual debut (33.3% of case patients vs 21.4% of control persons; P = .004; odds ratio [OR], 1.8).

Significantly more case patients than control persons reported starting oral sex before they were 18 years old (37.4% of cases vs. 22.6% of controls; P < .001; OR, 3.1), and they had a greater number of lifetime oral sex partners (44.8% of cases and 19.1% of controls reported having more than 10 partners; P < .001; OR, 4.3).

Intensity of oral sexual exposure, which the authors measured by number of partners per 10 years, was also significantly higher among cases than controls (30.8% vs 11.1%; P < .001; OR, 5.6).

After adjustment for confounders (such as the lifetime number of oral sex partners and tobacco use), ever performing oral sex (adjusted odds ratio [aOR], 4.4), early age of first oral sex encounter (20 years: aOR, 1.8), and oral sex intensity (aOR, 2.8) all remained significantly associated with increased odds of HPV-oropharyngeal cancer.

The type of sexual partner, such as partners who were older (OR, 1.7) and having a partner who engaged in extramarital sex (OR, 1.6), were also associated with increased odds of developing HPV-oropharyngeal cancer. In addition, seropositivity for antibodies to HPV16 E6 (OR, 286) and any HPV16 E protein (E1, E2, E6, E7; OR, 163) were also associated with increased odds of developing the disease.

The study was supported by the National Institute of Dental and Craniofacial Research and the National Institute on Deafness and Other Communication Disorders. Dr. D’Souza and Dr. Califano have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Having oral sex with more than 10 previous partners was associated with a 4.3 times’ greater likelihood of developing human papillomavirus (HPV)–related oropharyngeal cancer, according to new findings.

The study also found that having more partners in a shorter period (i.e., greater oral sex intensity) and starting oral sex at a younger age were associated with higher odds of having HPV-related cancer of the mouth and throat.

The new study, published online on Jan. 11 in Cancer, confirms previous findings and adds more nuance, say the researchers.

Previous studies have demonstrated that oral sex is a strong risk factor for HPV-related oropharyngeal cancer, which has increased in incidence in recent decades, particularly cancer of the base of the tongue and palatine and lingual tonsils.

“Our research adds more nuance in our understanding of how people acquire oral HPV infection and HPV-related oropharyngeal cancer,” said study author Gypsyamber D’Souza, PhD, professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health, Baltimore. “It suggests that risk of infection is not only from the number of oral sexual partners but that the timing and type of partner also influence risk.”

The results of the study do not change the clinical care or screening of patients, Dr. D’Souza noted, but the study does add context for patients and providers in understanding, “Why did I get HPV-oropharyngeal cancer?” she said.

“We know that people who develop HPV-oropharyngeal cancer have a wide range of sexual histories, but we do not suggest sexual history be used for screening, as many patients have low-risk sexual histories,” she said. “By chance, it only takes one partner who is infected to acquire the infection, while others who have had many partners by chance do not get exposed, or who are exposed but clear the infection.”
 

Reinforces the need for vaccination

Approached for comment, Joseph Califano, MD, physician-in-chief at the Moores Cancer Center and director of the Head and Neck Cancer Center at the University of California, San Diego, noted that similar data have been published before. The novelty here is in the timing and intensity of oral sex. “It’s not new data, but it certainly reinforces what we knew,” he said in an interview.

These new data are not going to change monitoring, he suggested. “It’s not going to change how we screen, because we don’t do population-based screening for oropharyngeal cancer,” Dr. Califano said.

“It does underline the fact that vaccination is really the key to preventing HPV-mediated cancers,” he said.

He pointed out that some data show lower rates of high-risk oral HPV shedding by children who have been appropriately vaccinated.

“This paper really highlights the fact we need to get people vaccinated early, before sexual debut,” he said. “In this case, sexual debut doesn’t necessarily mean intercourse but oral sex, and that’s a different concept of when sex starts.”

These new data “reinforce the fact that early exposure is what we need to focus on,” he said.
 

Details of the new findings

The current study by Dr. D’Souza and colleagues included 163 patients with HPV-related oropharyngeal cancer who were enrolled in the Papillomavirus Role in Oral Cancer Viral Etiology (PROVE) study. These patients were compared with 345 matched control persons.

All participants completed a behavioral survey and provided a blood sample. For the patients with cancer, a tumor sample was obtained.

The majority of participants were male (85% and 82%), were aged 50-69 years, were currently married or living with a partner, and identified as heterosexual. Case patients were more likely to report a history of sexually transmitted infection than were control participants (P = .003).

Case patients were more likely to have ever performed oral sex compared to control persons (98.8% vs 90.4%; P < .001) and to have performed oral sex at the time of their sexual debut (33.3% of case patients vs 21.4% of control persons; P = .004; odds ratio [OR], 1.8).

Significantly more case patients than control persons reported starting oral sex before they were 18 years old (37.4% of cases vs. 22.6% of controls; P < .001; OR, 3.1), and they had a greater number of lifetime oral sex partners (44.8% of cases and 19.1% of controls reported having more than 10 partners; P < .001; OR, 4.3).

Intensity of oral sexual exposure, which the authors measured by number of partners per 10 years, was also significantly higher among cases than controls (30.8% vs 11.1%; P < .001; OR, 5.6).

After adjustment for confounders (such as the lifetime number of oral sex partners and tobacco use), ever performing oral sex (adjusted odds ratio [aOR], 4.4), early age of first oral sex encounter (20 years: aOR, 1.8), and oral sex intensity (aOR, 2.8) all remained significantly associated with increased odds of HPV-oropharyngeal cancer.

The type of sexual partner, such as partners who were older (OR, 1.7) and having a partner who engaged in extramarital sex (OR, 1.6), were also associated with increased odds of developing HPV-oropharyngeal cancer. In addition, seropositivity for antibodies to HPV16 E6 (OR, 286) and any HPV16 E protein (E1, E2, E6, E7; OR, 163) were also associated with increased odds of developing the disease.

The study was supported by the National Institute of Dental and Craniofacial Research and the National Institute on Deafness and Other Communication Disorders. Dr. D’Souza and Dr. Califano have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Having oral sex with more than 10 previous partners was associated with a 4.3 times’ greater likelihood of developing human papillomavirus (HPV)–related oropharyngeal cancer, according to new findings.

The study also found that having more partners in a shorter period (i.e., greater oral sex intensity) and starting oral sex at a younger age were associated with higher odds of having HPV-related cancer of the mouth and throat.

The new study, published online on Jan. 11 in Cancer, confirms previous findings and adds more nuance, say the researchers.

Previous studies have demonstrated that oral sex is a strong risk factor for HPV-related oropharyngeal cancer, which has increased in incidence in recent decades, particularly cancer of the base of the tongue and palatine and lingual tonsils.

“Our research adds more nuance in our understanding of how people acquire oral HPV infection and HPV-related oropharyngeal cancer,” said study author Gypsyamber D’Souza, PhD, professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health, Baltimore. “It suggests that risk of infection is not only from the number of oral sexual partners but that the timing and type of partner also influence risk.”

The results of the study do not change the clinical care or screening of patients, Dr. D’Souza noted, but the study does add context for patients and providers in understanding, “Why did I get HPV-oropharyngeal cancer?” she said.

“We know that people who develop HPV-oropharyngeal cancer have a wide range of sexual histories, but we do not suggest sexual history be used for screening, as many patients have low-risk sexual histories,” she said. “By chance, it only takes one partner who is infected to acquire the infection, while others who have had many partners by chance do not get exposed, or who are exposed but clear the infection.”
 

Reinforces the need for vaccination

Approached for comment, Joseph Califano, MD, physician-in-chief at the Moores Cancer Center and director of the Head and Neck Cancer Center at the University of California, San Diego, noted that similar data have been published before. The novelty here is in the timing and intensity of oral sex. “It’s not new data, but it certainly reinforces what we knew,” he said in an interview.

These new data are not going to change monitoring, he suggested. “It’s not going to change how we screen, because we don’t do population-based screening for oropharyngeal cancer,” Dr. Califano said.

“It does underline the fact that vaccination is really the key to preventing HPV-mediated cancers,” he said.

He pointed out that some data show lower rates of high-risk oral HPV shedding by children who have been appropriately vaccinated.

“This paper really highlights the fact we need to get people vaccinated early, before sexual debut,” he said. “In this case, sexual debut doesn’t necessarily mean intercourse but oral sex, and that’s a different concept of when sex starts.”

These new data “reinforce the fact that early exposure is what we need to focus on,” he said.
 

Details of the new findings

The current study by Dr. D’Souza and colleagues included 163 patients with HPV-related oropharyngeal cancer who were enrolled in the Papillomavirus Role in Oral Cancer Viral Etiology (PROVE) study. These patients were compared with 345 matched control persons.

All participants completed a behavioral survey and provided a blood sample. For the patients with cancer, a tumor sample was obtained.

The majority of participants were male (85% and 82%), were aged 50-69 years, were currently married or living with a partner, and identified as heterosexual. Case patients were more likely to report a history of sexually transmitted infection than were control participants (P = .003).

Case patients were more likely to have ever performed oral sex compared to control persons (98.8% vs 90.4%; P < .001) and to have performed oral sex at the time of their sexual debut (33.3% of case patients vs 21.4% of control persons; P = .004; odds ratio [OR], 1.8).

Significantly more case patients than control persons reported starting oral sex before they were 18 years old (37.4% of cases vs. 22.6% of controls; P < .001; OR, 3.1), and they had a greater number of lifetime oral sex partners (44.8% of cases and 19.1% of controls reported having more than 10 partners; P < .001; OR, 4.3).

Intensity of oral sexual exposure, which the authors measured by number of partners per 10 years, was also significantly higher among cases than controls (30.8% vs 11.1%; P < .001; OR, 5.6).

After adjustment for confounders (such as the lifetime number of oral sex partners and tobacco use), ever performing oral sex (adjusted odds ratio [aOR], 4.4), early age of first oral sex encounter (20 years: aOR, 1.8), and oral sex intensity (aOR, 2.8) all remained significantly associated with increased odds of HPV-oropharyngeal cancer.

The type of sexual partner, such as partners who were older (OR, 1.7) and having a partner who engaged in extramarital sex (OR, 1.6), were also associated with increased odds of developing HPV-oropharyngeal cancer. In addition, seropositivity for antibodies to HPV16 E6 (OR, 286) and any HPV16 E protein (E1, E2, E6, E7; OR, 163) were also associated with increased odds of developing the disease.

The study was supported by the National Institute of Dental and Craniofacial Research and the National Institute on Deafness and Other Communication Disorders. Dr. D’Souza and Dr. Califano have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

On December 11, 2020, the US Food and Drug Administration (FDA) delivered the holiday gift America was waiting for—approval of the first COVID-19 vaccine. Following the recommendation of its expert advisory panel, the FDA issued its opening emergency use authorization (EUA) for the Pfizer and BioNTech product to be distributed and administered across the country.¹ A week after that historic announcement, the FDA issued an EUA to Moderna for a second COVID-19 vaccine.²

An EUA is a misunderstood concept that, like the development of the vaccine itself, appears almost like a magical federal deliverance to a nation at a time when almost every other public health effort has floundered. An EUA is a regulatory process to enable a public health emergency response with medical countermeasures including not only vaccines, but also medications. Earlier in 2020, hydroxychloroquine and remdesivir each received EUAs for treating patients with COVID-19.³ The EUA for hydroxychloroquine was later revoked when more data raised concerns for its efficacy.⁴ EUAs do not mean the drugs are experimental or that everyone receiving them is participating in a research trial; however, for the sake of safety and science, data continue to be collected and analyzed. Issuance of an EUA indicates that after rigorous examination and an independent advisory board review of data submitted by the manufacturer, the FDA has determined the product and situation meet key criteria: (1) There is a public health emergency that threatens health and life and requires expedited procedures; (2) there are no extant approved products able to treat or prevent the disease; and (3) the known and potential benefits of the product outweigh the known and potential risks.⁵

The public and even the professional press have celebrated the arrival of this technologic triumph over a virus that had vanquished staggering numbers of lives and livelihoods. Much of the media coverage aptly chose the word “hope” to capture the significance of this unprecedented accomplishment for which so many millions yearned. A Google search for “hope” on the morning of December 20, yielded 339,000,000 results. For example, a headline especially salient for Federal Practitioner readers from the New York Times read, “‘A Shot of Hope’ What the Vaccine is like for Frontline Doctors and Nurses.”⁶

I want to briefly argue why even though I believe hope in and for the vaccine is desperately needed if we are to survive this long, dark winter, trust in the vaccine can actually usher in the warmth of economic recovery and the light of saved lives. Trust is crucial in 3 main areas if the awe-inspiring hope of the vaccine the EUAs codify is to be fulfilled. The venerable moral and civic virtue of trust has been trivialized and commercialized mostly mentioned in advertising for insurance or real estate companies. Medical virtue-ethicists Edmund Pellegrino and David Thomasma describe trust as the binding force that keeps civilization intact. “Trust is ineradicable in human relationships. Without we could not live in society or attain even the rudiments of a fulfilling life, they explain. “Without trust we could not anticipate the future, and we would therefore be paralyzed into inaction. Yet to trust and entrust is to become vulnerable and dependent on the good will and motivations of those we trust. Trust, ineradicable as it is, is also always problematic.”⁷

The first area where that trust is the hardest to secure is in the federal government, the actions and messages of which have seemed so inconstant, unjust, and deceptive to many. For enough citizens to roll up their sleeves, they must believe the outgoing and the incoming administrations and legislators can make rational plans translated into sound public health policy that place the good of humanity above other interests and then mobilize the resources of the country to deliver that good with consistency, fairness, and transparency.

The second area is trust in medical science. Long before COVID-19, American attitudes toward vaccines reflected reasonable fears and ridiculous conspiracy theories—both of which are serious obstacles to the breadth of immunization required to achieve herd immunity. Ordinary people must believe that the health care professionals and scientists at the Centers for Disease Control and Prevention and the FDA will never compromise safety for political expediency. Recent polls have shown an increase in the percentage of the population willing to consider vaccination. A December Gallop poll found that 63% of Americans were willing to be vaccinated for COVID-19.⁸ To raise those numbers high enough to approach herd immunity will require Americans to believe that the scientists who discover the vaccines and the companies that develop them have placed people above profit and ranked the safety of society above individual scientific renown.

Groups that have been the historic objects of exploitation in research and contemporary disparities in health care understandably have more distrust of science and medicine. While public health officials insist that they have developed a system of vaccine distribution that is equitable and prioritizes the sick and old and those who care for them before the rich and powerful, we should not be surprised that our communication of this assurance is viewed with skepticism. As a recent Medscape article advised, public health officials may need to rely on, “trusted messengers” to help some communities to “overcome vaccine hesitancy.”⁹

Third we must trust in our fellow citizens to maintain the public health measures of social distancing and mask wearing even after there is widespread vaccination. If we are to reap the benefits of a safe and effective vaccine, we must be a community of immunity, not just isolated inoculated individuals. We as health care practitioners must do all we can to educate the public that the adverse reactions to the vaccine so prominently featured in the media are expected with any new and complex biological product and do not signal risk that outweighs the deadliness of the virus.¹⁰

Fourth, and finally, we must trust in ourselves as health care professionals and administrators. We in the DoD, VA, and PHS have the knowledge and skills to endure the onslaught of pain and suffering we will all experience in one way or another in these next long months. We must believe that our courage and compassion can turn a vaccine into vaccinations sufficient to relieve the COVID-19 siege of our hospitals and intensive care units. When that day comes, hope will have been a plan we could trust. 

On December 11, 2020, the US Food and Drug Administration (FDA) delivered the holiday gift America was waiting for—approval of the first COVID-19 vaccine. Following the recommendation of its expert advisory panel, the FDA issued its opening emergency use authorization (EUA) for the Pfizer and BioNTech product to be distributed and administered across the country.¹ A week after that historic announcement, the FDA issued an EUA to Moderna for a second COVID-19 vaccine.²

An EUA is a misunderstood concept that, like the development of the vaccine itself, appears almost like a magical federal deliverance to a nation at a time when almost every other public health effort has floundered. An EUA is a regulatory process to enable a public health emergency response with medical countermeasures including not only vaccines, but also medications. Earlier in 2020, hydroxychloroquine and remdesivir each received EUAs for treating patients with COVID-19.³ The EUA for hydroxychloroquine was later revoked when more data raised concerns for its efficacy.⁴ EUAs do not mean the drugs are experimental or that everyone receiving them is participating in a research trial; however, for the sake of safety and science, data continue to be collected and analyzed. Issuance of an EUA indicates that after rigorous examination and an independent advisory board review of data submitted by the manufacturer, the FDA has determined the product and situation meet key criteria: (1) There is a public health emergency that threatens health and life and requires expedited procedures; (2) there are no extant approved products able to treat or prevent the disease; and (3) the known and potential benefits of the product outweigh the known and potential risks.⁵

The public and even the professional press have celebrated the arrival of this technologic triumph over a virus that had vanquished staggering numbers of lives and livelihoods. Much of the media coverage aptly chose the word “hope” to capture the significance of this unprecedented accomplishment for which so many millions yearned. A Google search for “hope” on the morning of December 20, yielded 339,000,000 results. For example, a headline especially salient for Federal Practitioner readers from the New York Times read, “‘A Shot of Hope’ What the Vaccine is like for Frontline Doctors and Nurses.”⁶

I want to briefly argue why even though I believe hope in and for the vaccine is desperately needed if we are to survive this long, dark winter, trust in the vaccine can actually usher in the warmth of economic recovery and the light of saved lives. Trust is crucial in 3 main areas if the awe-inspiring hope of the vaccine the EUAs codify is to be fulfilled. The venerable moral and civic virtue of trust has been trivialized and commercialized mostly mentioned in advertising for insurance or real estate companies. Medical virtue-ethicists Edmund Pellegrino and David Thomasma describe trust as the binding force that keeps civilization intact. “Trust is ineradicable in human relationships. Without we could not live in society or attain even the rudiments of a fulfilling life, they explain. “Without trust we could not anticipate the future, and we would therefore be paralyzed into inaction. Yet to trust and entrust is to become vulnerable and dependent on the good will and motivations of those we trust. Trust, ineradicable as it is, is also always problematic.”⁷

The first area where that trust is the hardest to secure is in the federal government, the actions and messages of which have seemed so inconstant, unjust, and deceptive to many. For enough citizens to roll up their sleeves, they must believe the outgoing and the incoming administrations and legislators can make rational plans translated into sound public health policy that place the good of humanity above other interests and then mobilize the resources of the country to deliver that good with consistency, fairness, and transparency.

The second area is trust in medical science. Long before COVID-19, American attitudes toward vaccines reflected reasonable fears and ridiculous conspiracy theories—both of which are serious obstacles to the breadth of immunization required to achieve herd immunity. Ordinary people must believe that the health care professionals and scientists at the Centers for Disease Control and Prevention and the FDA will never compromise safety for political expediency. Recent polls have shown an increase in the percentage of the population willing to consider vaccination. A December Gallop poll found that 63% of Americans were willing to be vaccinated for COVID-19.⁸ To raise those numbers high enough to approach herd immunity will require Americans to believe that the scientists who discover the vaccines and the companies that develop them have placed people above profit and ranked the safety of society above individual scientific renown.

Groups that have been the historic objects of exploitation in research and contemporary disparities in health care understandably have more distrust of science and medicine. While public health officials insist that they have developed a system of vaccine distribution that is equitable and prioritizes the sick and old and those who care for them before the rich and powerful, we should not be surprised that our communication of this assurance is viewed with skepticism. As a recent Medscape article advised, public health officials may need to rely on, “trusted messengers” to help some communities to “overcome vaccine hesitancy.”⁹

Third we must trust in our fellow citizens to maintain the public health measures of social distancing and mask wearing even after there is widespread vaccination. If we are to reap the benefits of a safe and effective vaccine, we must be a community of immunity, not just isolated inoculated individuals. We as health care practitioners must do all we can to educate the public that the adverse reactions to the vaccine so prominently featured in the media are expected with any new and complex biological product and do not signal risk that outweighs the deadliness of the virus.¹⁰

Fourth, and finally, we must trust in ourselves as health care professionals and administrators. We in the DoD, VA, and PHS have the knowledge and skills to endure the onslaught of pain and suffering we will all experience in one way or another in these next long months. We must believe that our courage and compassion can turn a vaccine into vaccinations sufficient to relieve the COVID-19 siege of our hospitals and intensive care units. When that day comes, hope will have been a plan we could trust. 

On December 11, 2020, the US Food and Drug Administration (FDA) delivered the holiday gift America was waiting for—approval of the first COVID-19 vaccine. Following the recommendation of its expert advisory panel, the FDA issued its opening emergency use authorization (EUA) for the Pfizer and BioNTech product to be distributed and administered across the country.¹ A week after that historic announcement, the FDA issued an EUA to Moderna for a second COVID-19 vaccine.²

An EUA is a misunderstood concept that, like the development of the vaccine itself, appears almost like a magical federal deliverance to a nation at a time when almost every other public health effort has floundered. An EUA is a regulatory process to enable a public health emergency response with medical countermeasures including not only vaccines, but also medications. Earlier in 2020, hydroxychloroquine and remdesivir each received EUAs for treating patients with COVID-19.³ The EUA for hydroxychloroquine was later revoked when more data raised concerns for its efficacy.⁴ EUAs do not mean the drugs are experimental or that everyone receiving them is participating in a research trial; however, for the sake of safety and science, data continue to be collected and analyzed. Issuance of an EUA indicates that after rigorous examination and an independent advisory board review of data submitted by the manufacturer, the FDA has determined the product and situation meet key criteria: (1) There is a public health emergency that threatens health and life and requires expedited procedures; (2) there are no extant approved products able to treat or prevent the disease; and (3) the known and potential benefits of the product outweigh the known and potential risks.⁵

The public and even the professional press have celebrated the arrival of this technologic triumph over a virus that had vanquished staggering numbers of lives and livelihoods. Much of the media coverage aptly chose the word “hope” to capture the significance of this unprecedented accomplishment for which so many millions yearned. A Google search for “hope” on the morning of December 20, yielded 339,000,000 results. For example, a headline especially salient for Federal Practitioner readers from the New York Times read, “‘A Shot of Hope’ What the Vaccine is like for Frontline Doctors and Nurses.”⁶

I want to briefly argue why even though I believe hope in and for the vaccine is desperately needed if we are to survive this long, dark winter, trust in the vaccine can actually usher in the warmth of economic recovery and the light of saved lives. Trust is crucial in 3 main areas if the awe-inspiring hope of the vaccine the EUAs codify is to be fulfilled. The venerable moral and civic virtue of trust has been trivialized and commercialized mostly mentioned in advertising for insurance or real estate companies. Medical virtue-ethicists Edmund Pellegrino and David Thomasma describe trust as the binding force that keeps civilization intact. “Trust is ineradicable in human relationships. Without we could not live in society or attain even the rudiments of a fulfilling life, they explain. “Without trust we could not anticipate the future, and we would therefore be paralyzed into inaction. Yet to trust and entrust is to become vulnerable and dependent on the good will and motivations of those we trust. Trust, ineradicable as it is, is also always problematic.”⁷

The first area where that trust is the hardest to secure is in the federal government, the actions and messages of which have seemed so inconstant, unjust, and deceptive to many. For enough citizens to roll up their sleeves, they must believe the outgoing and the incoming administrations and legislators can make rational plans translated into sound public health policy that place the good of humanity above other interests and then mobilize the resources of the country to deliver that good with consistency, fairness, and transparency.

The second area is trust in medical science. Long before COVID-19, American attitudes toward vaccines reflected reasonable fears and ridiculous conspiracy theories—both of which are serious obstacles to the breadth of immunization required to achieve herd immunity. Ordinary people must believe that the health care professionals and scientists at the Centers for Disease Control and Prevention and the FDA will never compromise safety for political expediency. Recent polls have shown an increase in the percentage of the population willing to consider vaccination. A December Gallop poll found that 63% of Americans were willing to be vaccinated for COVID-19.⁸ To raise those numbers high enough to approach herd immunity will require Americans to believe that the scientists who discover the vaccines and the companies that develop them have placed people above profit and ranked the safety of society above individual scientific renown.

Groups that have been the historic objects of exploitation in research and contemporary disparities in health care understandably have more distrust of science and medicine. While public health officials insist that they have developed a system of vaccine distribution that is equitable and prioritizes the sick and old and those who care for them before the rich and powerful, we should not be surprised that our communication of this assurance is viewed with skepticism. As a recent Medscape article advised, public health officials may need to rely on, “trusted messengers” to help some communities to “overcome vaccine hesitancy.”⁹

Third we must trust in our fellow citizens to maintain the public health measures of social distancing and mask wearing even after there is widespread vaccination. If we are to reap the benefits of a safe and effective vaccine, we must be a community of immunity, not just isolated inoculated individuals. We as health care practitioners must do all we can to educate the public that the adverse reactions to the vaccine so prominently featured in the media are expected with any new and complex biological product and do not signal risk that outweighs the deadliness of the virus.¹⁰

Fourth, and finally, we must trust in ourselves as health care professionals and administrators. We in the DoD, VA, and PHS have the knowledge and skills to endure the onslaught of pain and suffering we will all experience in one way or another in these next long months. We must believe that our courage and compassion can turn a vaccine into vaccinations sufficient to relieve the COVID-19 siege of our hospitals and intensive care units. When that day comes, hope will have been a plan we could trust. 

REFERENCES

1. Oliver SE, Gargano JW, Marin M; et al. The Advisory Committee on Immunization Practices’ interim recommendation for use of Pfizer-BioNTech COVID-19 vaccine—United States, December 2020. MMWR Morbid Mortal Wkly Rep. 2020;69:1922-1924. Accessed January 13, 2021. www.cdc.gov/mmwr/volumes/69/wr/mm6950e2.htm
2. 2. Oliver SE, Gargano JW, Marin M; et al. The Advisory Committee on Immunization Practices’ interim recommendation for use of Moderna COVID-19 vaccine—United States, December 2020. MMWR Morbid Mortal Wkly Rep. 2021;69:1653-1656. Accessed January 13, 2021. www.cdc.gov/mmwr/volumes/69/wr/mm695152e1.htm
3. CDC. COVID-19 vaccines: update on allergic reactions, contraindications, and precautions [webinar]. December 30, 2020. Accessed January 6, 2021. https://emergency.cdc.gov/coca/calls/2020/callinfo_123020.asp
4. CDC. What clinicians need to know about the Pfizer-BioNTech and Moderna COVID-19 vaccines [webinar]. December 18, 2020. Accessed January 6, 2021. https://emergency.cdc.gov/coca/calls/2020/callinfo_121820.asp
5. CDC COVID-19 Response Team; Food and Drug Administration. Allergic reactions including anaphylaxis after receipt of the first dose of Pfizer-BioNTech COVID-19 vaccine—United States, December 14-23, 2020. MMWR Morb Mortal Wkly Rep. ePub: January 6, 2021. Accessed January 13, 2021. www.cdc.gov/mmwr/volumes/70/wr/mm7002e1.htm

REFERENCES

1. Oliver SE, Gargano JW, Marin M; et al. The Advisory Committee on Immunization Practices’ interim recommendation for use of Pfizer-BioNTech COVID-19 vaccine—United States, December 2020. MMWR Morbid Mortal Wkly Rep. 2020;69:1922-1924. Accessed January 13, 2021. www.cdc.gov/mmwr/volumes/69/wr/mm6950e2.htm
2. 2. Oliver SE, Gargano JW, Marin M; et al. The Advisory Committee on Immunization Practices’ interim recommendation for use of Moderna COVID-19 vaccine—United States, December 2020. MMWR Morbid Mortal Wkly Rep. 2021;69:1653-1656. Accessed January 13, 2021. www.cdc.gov/mmwr/volumes/69/wr/mm695152e1.htm
3. CDC. COVID-19 vaccines: update on allergic reactions, contraindications, and precautions [webinar]. December 30, 2020. Accessed January 6, 2021. https://emergency.cdc.gov/coca/calls/2020/callinfo_123020.asp
4. CDC. What clinicians need to know about the Pfizer-BioNTech and Moderna COVID-19 vaccines [webinar]. December 18, 2020. Accessed January 6, 2021. https://emergency.cdc.gov/coca/calls/2020/callinfo_121820.asp
5. CDC COVID-19 Response Team; Food and Drug Administration. Allergic reactions including anaphylaxis after receipt of the first dose of Pfizer-BioNTech COVID-19 vaccine—United States, December 14-23, 2020. MMWR Morb Mortal Wkly Rep. ePub: January 6, 2021. Accessed January 13, 2021. www.cdc.gov/mmwr/volumes/70/wr/mm7002e1.htm

REFERENCES

1. Oliver SE, Gargano JW, Marin M; et al. The Advisory Committee on Immunization Practices’ interim recommendation for use of Pfizer-BioNTech COVID-19 vaccine—United States, December 2020. MMWR Morbid Mortal Wkly Rep. 2020;69:1922-1924. Accessed January 13, 2021. www.cdc.gov/mmwr/volumes/69/wr/mm6950e2.htm
2. 2. Oliver SE, Gargano JW, Marin M; et al. The Advisory Committee on Immunization Practices’ interim recommendation for use of Moderna COVID-19 vaccine—United States, December 2020. MMWR Morbid Mortal Wkly Rep. 2021;69:1653-1656. Accessed January 13, 2021. www.cdc.gov/mmwr/volumes/69/wr/mm695152e1.htm
3. CDC. COVID-19 vaccines: update on allergic reactions, contraindications, and precautions [webinar]. December 30, 2020. Accessed January 6, 2021. https://emergency.cdc.gov/coca/calls/2020/callinfo_123020.asp
4. CDC. What clinicians need to know about the Pfizer-BioNTech and Moderna COVID-19 vaccines [webinar]. December 18, 2020. Accessed January 6, 2021. https://emergency.cdc.gov/coca/calls/2020/callinfo_121820.asp
5. CDC COVID-19 Response Team; Food and Drug Administration. Allergic reactions including anaphylaxis after receipt of the first dose of Pfizer-BioNTech COVID-19 vaccine—United States, December 14-23, 2020. MMWR Morb Mortal Wkly Rep. ePub: January 6, 2021. Accessed January 13, 2021. www.cdc.gov/mmwr/volumes/70/wr/mm7002e1.htm

A proposal to delay administration of the second dose of COVID-19 vaccines – suggested as a strategy to boost the number of people who get some degree of protection from a single immunization with the Pfizer/BioNTech or Moderna vaccines – is inciting a strong debate among clinicians and public health officials.

Proponents argue that getting some degree of protection to a greater number of Americans is worthwhile, particularly as case numbers and hospitalizations continue to rise and with the emergence of a more contagious variant.

Opponents raise concerns about diverting from the two-dose schedule evaluated in clinical trials, including a lack of data on long-term protection from a single dose. They also suggest a longer interval between dosing could increase resistance of SARS-CoV-2 virus.

It is time to consider delaying the second dose, Robert M. Wachter, MD, at the University of California San Francisco, and Ashish Jha, MD, MPH, at Brown University in Providence, R.I., wrote in an opinion piece in The Washington Post Jan. 3. 

The two experts state that supply constraints, distribution bottlenecks, and hundreds of thousands of new infections daily prompted them to change their stance on administering COVID-19 vaccines according to the two-dose clinical trial regimen. Furthermore, they cited a study in the New England Journal of Medicine that suggests 80%-90% efficacy for preventing SARS-CoV-2 infection following one dose of the Moderna vaccine. 

Not everyone agrees one dose is a good idea. “Clinical trials with specific schedules for vaccine dosing – that’s the whole basis of the scientific evidence,” Maria Elena Bottazzi, PhD, associate dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, said in an interview.

After one dose “the immune system is learning, but it’s not ideal. That’s why you need the second dose,” Dr. Bottazzi said. “I appreciate the urgency and the anxiety ... but the data support [that] clinical efficacy requires two doses.”

Another proposed strategy to extend the current supply of COVID-19 vaccines to more Americans involves splitting the current dosage of the Moderna vaccine in half. Officials in the United States and the United Kingdom are reportedly considering this approach. In the United States, the Food and Drug Administration would have to approve any dosing change.
 

Agreeing to disagree

Dr. Wachter shared a link to his opinion piece on Twitter, stating that “We both came to this view because of the slow rollout & the new variant. But it’s a tough call and reasonable people will disagree.”

As predicted, the tweet elicited a number of strong opinions.

“There are no correct answers but there’s data deficiency, plenty of fodder and need for healthy, intellectual debate. That wouldn’t be occurring if there was an ample supply of vaccines,” Eric Topol, MD, director of the Scripps Translational Science Institute and editor-in-chief of Medscape, tweeted on Jan. 3.

“If the problem were with the supply of the vaccine, one might make an argument for focusing on 1st dose. But the problem is in distribution of the vaccine & giving actual doses,” John Grohol, PsyD, tweeted.

“Right now we don’t have a supply issue, we have a distribution issue,” Angela Shen, ScD, MPH, a research scientist in the Vaccine Education Center at Children’s Hospital of Philadelphia, said in an interview. Emergency use authorization for the Johnson & Johnson and other COVID-19 vaccines in development could further boost available supplies, she added.

“The clinical trials studied two doses,” Dr. Shen said. “We don’t have data that one dose is going to have lasting protection.” 
 

Does new variant change equation?

Dr. Wachter and Dr. Jha, in their editorial, cited a quote from former boxing champion Mike Tyson: “Everybody has a plan until they’ve been punched in the mouth.” ‘Punches’ such as the new variant, the high number of cases and deaths in the United States, and other problems prompted them to advocate for the delayed dosing strategy.

“Appreciate the concern for the new variant – I think it’s worth noting that we’re punching ourselves in the mouth with the slow vaccine rollout, which is the first problem to solve,” Jake Quinton, MD, an internist at UCLA Health in Los Angeles, noted on Twitter.

 

Vaccine and public resistance raised

“I agree with the problem but not with the proposed solution, which is guesswork not based on data,” the Jan Grimm Lab at Memorial Sloan Kettering Cancer Center in New York responded to Dr. Wachter and Dr. Jha on Twitter. “There ARE data though that show that 1 shot alone did not elicit sufficient T-cell nor antibody response. This might also lead to mutations resistant to the vaccines. Dangerous!”

Other physicians took to Twitter to point out that changing the recommendations at this point could further erode public confidence in COVID-19 immunization. For example, Deirdre Habermehl, MD, wrote, “We’ve spent months telling the public the best route is to follow the science and now without data think a course correction based on a guesstimate is ok? Public confidence is low enough and the real issue is logistics at this point.”

Dr. Shen and Dr. Bottazzi have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A proposal to delay administration of the second dose of COVID-19 vaccines – suggested as a strategy to boost the number of people who get some degree of protection from a single immunization with the Pfizer/BioNTech or Moderna vaccines – is inciting a strong debate among clinicians and public health officials.

Proponents argue that getting some degree of protection to a greater number of Americans is worthwhile, particularly as case numbers and hospitalizations continue to rise and with the emergence of a more contagious variant.

Opponents raise concerns about diverting from the two-dose schedule evaluated in clinical trials, including a lack of data on long-term protection from a single dose. They also suggest a longer interval between dosing could increase resistance of SARS-CoV-2 virus.

It is time to consider delaying the second dose, Robert M. Wachter, MD, at the University of California San Francisco, and Ashish Jha, MD, MPH, at Brown University in Providence, R.I., wrote in an opinion piece in The Washington Post Jan. 3. 

The two experts state that supply constraints, distribution bottlenecks, and hundreds of thousands of new infections daily prompted them to change their stance on administering COVID-19 vaccines according to the two-dose clinical trial regimen. Furthermore, they cited a study in the New England Journal of Medicine that suggests 80%-90% efficacy for preventing SARS-CoV-2 infection following one dose of the Moderna vaccine. 

Not everyone agrees one dose is a good idea. “Clinical trials with specific schedules for vaccine dosing – that’s the whole basis of the scientific evidence,” Maria Elena Bottazzi, PhD, associate dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, said in an interview.

After one dose “the immune system is learning, but it’s not ideal. That’s why you need the second dose,” Dr. Bottazzi said. “I appreciate the urgency and the anxiety ... but the data support [that] clinical efficacy requires two doses.”

Another proposed strategy to extend the current supply of COVID-19 vaccines to more Americans involves splitting the current dosage of the Moderna vaccine in half. Officials in the United States and the United Kingdom are reportedly considering this approach. In the United States, the Food and Drug Administration would have to approve any dosing change.
 

Agreeing to disagree

Dr. Wachter shared a link to his opinion piece on Twitter, stating that “We both came to this view because of the slow rollout & the new variant. But it’s a tough call and reasonable people will disagree.”

As predicted, the tweet elicited a number of strong opinions.

“There are no correct answers but there’s data deficiency, plenty of fodder and need for healthy, intellectual debate. That wouldn’t be occurring if there was an ample supply of vaccines,” Eric Topol, MD, director of the Scripps Translational Science Institute and editor-in-chief of Medscape, tweeted on Jan. 3.

“If the problem were with the supply of the vaccine, one might make an argument for focusing on 1st dose. But the problem is in distribution of the vaccine & giving actual doses,” John Grohol, PsyD, tweeted.

“Right now we don’t have a supply issue, we have a distribution issue,” Angela Shen, ScD, MPH, a research scientist in the Vaccine Education Center at Children’s Hospital of Philadelphia, said in an interview. Emergency use authorization for the Johnson & Johnson and other COVID-19 vaccines in development could further boost available supplies, she added.

“The clinical trials studied two doses,” Dr. Shen said. “We don’t have data that one dose is going to have lasting protection.” 
 

Does new variant change equation?

Dr. Wachter and Dr. Jha, in their editorial, cited a quote from former boxing champion Mike Tyson: “Everybody has a plan until they’ve been punched in the mouth.” ‘Punches’ such as the new variant, the high number of cases and deaths in the United States, and other problems prompted them to advocate for the delayed dosing strategy.

“Appreciate the concern for the new variant – I think it’s worth noting that we’re punching ourselves in the mouth with the slow vaccine rollout, which is the first problem to solve,” Jake Quinton, MD, an internist at UCLA Health in Los Angeles, noted on Twitter.

 

Vaccine and public resistance raised

“I agree with the problem but not with the proposed solution, which is guesswork not based on data,” the Jan Grimm Lab at Memorial Sloan Kettering Cancer Center in New York responded to Dr. Wachter and Dr. Jha on Twitter. “There ARE data though that show that 1 shot alone did not elicit sufficient T-cell nor antibody response. This might also lead to mutations resistant to the vaccines. Dangerous!”

Other physicians took to Twitter to point out that changing the recommendations at this point could further erode public confidence in COVID-19 immunization. For example, Deirdre Habermehl, MD, wrote, “We’ve spent months telling the public the best route is to follow the science and now without data think a course correction based on a guesstimate is ok? Public confidence is low enough and the real issue is logistics at this point.”

Dr. Shen and Dr. Bottazzi have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A proposal to delay administration of the second dose of COVID-19 vaccines – suggested as a strategy to boost the number of people who get some degree of protection from a single immunization with the Pfizer/BioNTech or Moderna vaccines – is inciting a strong debate among clinicians and public health officials.

Proponents argue that getting some degree of protection to a greater number of Americans is worthwhile, particularly as case numbers and hospitalizations continue to rise and with the emergence of a more contagious variant.

Opponents raise concerns about diverting from the two-dose schedule evaluated in clinical trials, including a lack of data on long-term protection from a single dose. They also suggest a longer interval between dosing could increase resistance of SARS-CoV-2 virus.

It is time to consider delaying the second dose, Robert M. Wachter, MD, at the University of California San Francisco, and Ashish Jha, MD, MPH, at Brown University in Providence, R.I., wrote in an opinion piece in The Washington Post Jan. 3. 

The two experts state that supply constraints, distribution bottlenecks, and hundreds of thousands of new infections daily prompted them to change their stance on administering COVID-19 vaccines according to the two-dose clinical trial regimen. Furthermore, they cited a study in the New England Journal of Medicine that suggests 80%-90% efficacy for preventing SARS-CoV-2 infection following one dose of the Moderna vaccine. 

Not everyone agrees one dose is a good idea. “Clinical trials with specific schedules for vaccine dosing – that’s the whole basis of the scientific evidence,” Maria Elena Bottazzi, PhD, associate dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, said in an interview.

After one dose “the immune system is learning, but it’s not ideal. That’s why you need the second dose,” Dr. Bottazzi said. “I appreciate the urgency and the anxiety ... but the data support [that] clinical efficacy requires two doses.”

Another proposed strategy to extend the current supply of COVID-19 vaccines to more Americans involves splitting the current dosage of the Moderna vaccine in half. Officials in the United States and the United Kingdom are reportedly considering this approach. In the United States, the Food and Drug Administration would have to approve any dosing change.
 

Agreeing to disagree

Dr. Wachter shared a link to his opinion piece on Twitter, stating that “We both came to this view because of the slow rollout & the new variant. But it’s a tough call and reasonable people will disagree.”

As predicted, the tweet elicited a number of strong opinions.

“There are no correct answers but there’s data deficiency, plenty of fodder and need for healthy, intellectual debate. That wouldn’t be occurring if there was an ample supply of vaccines,” Eric Topol, MD, director of the Scripps Translational Science Institute and editor-in-chief of Medscape, tweeted on Jan. 3.

“If the problem were with the supply of the vaccine, one might make an argument for focusing on 1st dose. But the problem is in distribution of the vaccine & giving actual doses,” John Grohol, PsyD, tweeted.

“Right now we don’t have a supply issue, we have a distribution issue,” Angela Shen, ScD, MPH, a research scientist in the Vaccine Education Center at Children’s Hospital of Philadelphia, said in an interview. Emergency use authorization for the Johnson & Johnson and other COVID-19 vaccines in development could further boost available supplies, she added.

“The clinical trials studied two doses,” Dr. Shen said. “We don’t have data that one dose is going to have lasting protection.” 
 

Does new variant change equation?

Dr. Wachter and Dr. Jha, in their editorial, cited a quote from former boxing champion Mike Tyson: “Everybody has a plan until they’ve been punched in the mouth.” ‘Punches’ such as the new variant, the high number of cases and deaths in the United States, and other problems prompted them to advocate for the delayed dosing strategy.

“Appreciate the concern for the new variant – I think it’s worth noting that we’re punching ourselves in the mouth with the slow vaccine rollout, which is the first problem to solve,” Jake Quinton, MD, an internist at UCLA Health in Los Angeles, noted on Twitter.

 

Vaccine and public resistance raised

“I agree with the problem but not with the proposed solution, which is guesswork not based on data,” the Jan Grimm Lab at Memorial Sloan Kettering Cancer Center in New York responded to Dr. Wachter and Dr. Jha on Twitter. “There ARE data though that show that 1 shot alone did not elicit sufficient T-cell nor antibody response. This might also lead to mutations resistant to the vaccines. Dangerous!”

Other physicians took to Twitter to point out that changing the recommendations at this point could further erode public confidence in COVID-19 immunization. For example, Deirdre Habermehl, MD, wrote, “We’ve spent months telling the public the best route is to follow the science and now without data think a course correction based on a guesstimate is ok? Public confidence is low enough and the real issue is logistics at this point.”

Dr. Shen and Dr. Bottazzi have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The Centers for Disease Control and Prevention has issued updated guidance for people with underlying medical conditions who are considering getting the coronavirus vaccine.

scyther5/thinkstock

“Adults of any age with certain underlying medical conditions are at increased risk for severe illness from the virus that causes COVID-19,” the CDC said in the guidance, posted on Dec. 26. “mRNA COVID-19 vaccines may be administered to people with underlying medical conditions provided they have not had a severe allergic reaction to any of the ingredients in the vaccine.” 

Both the Pfizer and Moderna vaccines use mRNA, or messenger RNA.

The CDC guidance had specific information for people with HIV, weakened immune systems, and autoimmune conditions such as Guillain-Barré syndrome (GBS) and Bell’s palsy who are thinking of getting the vaccine.

People with HIV and weakened immune systems “may receive a COVID-19 vaccine. However, they should be aware of the limited safety data,” the CDC said.

There’s no information available yet about the safety of the vaccines for people with weakened immune systems. People with HIV were included in clinical trials, but “safety data specific to this group are not yet available at this time,” the CDC said.

Cases of Bell’s palsy, a temporary facial paralysis, were reported in people receiving the Pfizer and Moderna vaccines in clinical trials, the Food and Drug Administration said Dec. 17. 

But the new CDC guidance said that the FDA “does not consider these to be above the rate expected in the general population. They have not concluded these cases were caused by vaccination. Therefore, persons who have previously had Bell’s palsy may receive an mRNA COVID-19 vaccine.”

Researchers have determined the vaccines are safe for people with GBS, a rare autoimmune disorder in which the body’s immune system attacks nerves just as they leave the spinal cord, the CDC said.

“To date, no cases of GBS have been reported following vaccination among participants in the mRNA COVID-19 vaccine clinical trials,” the CDC guidance said. “With few exceptions, the independent Advisory Committee on Immunization Practices general best practice guidelines for immunization do not include a history of GBS as a precaution to vaccination with other vaccines.”

For months, the CDC and other health authorities have said that people with certain medical conditions are at an increased risk of developing severe cases of COVID-19.

A version of this article first appeared on Medscape.com.

The Centers for Disease Control and Prevention has issued updated guidance for people with underlying medical conditions who are considering getting the coronavirus vaccine.

scyther5/thinkstock

“Adults of any age with certain underlying medical conditions are at increased risk for severe illness from the virus that causes COVID-19,” the CDC said in the guidance, posted on Dec. 26. “mRNA COVID-19 vaccines may be administered to people with underlying medical conditions provided they have not had a severe allergic reaction to any of the ingredients in the vaccine.” 

Both the Pfizer and Moderna vaccines use mRNA, or messenger RNA.

The CDC guidance had specific information for people with HIV, weakened immune systems, and autoimmune conditions such as Guillain-Barré syndrome (GBS) and Bell’s palsy who are thinking of getting the vaccine.

People with HIV and weakened immune systems “may receive a COVID-19 vaccine. However, they should be aware of the limited safety data,” the CDC said.

There’s no information available yet about the safety of the vaccines for people with weakened immune systems. People with HIV were included in clinical trials, but “safety data specific to this group are not yet available at this time,” the CDC said.

Cases of Bell’s palsy, a temporary facial paralysis, were reported in people receiving the Pfizer and Moderna vaccines in clinical trials, the Food and Drug Administration said Dec. 17. 

But the new CDC guidance said that the FDA “does not consider these to be above the rate expected in the general population. They have not concluded these cases were caused by vaccination. Therefore, persons who have previously had Bell’s palsy may receive an mRNA COVID-19 vaccine.”

Researchers have determined the vaccines are safe for people with GBS, a rare autoimmune disorder in which the body’s immune system attacks nerves just as they leave the spinal cord, the CDC said.

“To date, no cases of GBS have been reported following vaccination among participants in the mRNA COVID-19 vaccine clinical trials,” the CDC guidance said. “With few exceptions, the independent Advisory Committee on Immunization Practices general best practice guidelines for immunization do not include a history of GBS as a precaution to vaccination with other vaccines.”

For months, the CDC and other health authorities have said that people with certain medical conditions are at an increased risk of developing severe cases of COVID-19.

A version of this article first appeared on Medscape.com.

The Centers for Disease Control and Prevention has issued updated guidance for people with underlying medical conditions who are considering getting the coronavirus vaccine.

scyther5/thinkstock

“Adults of any age with certain underlying medical conditions are at increased risk for severe illness from the virus that causes COVID-19,” the CDC said in the guidance, posted on Dec. 26. “mRNA COVID-19 vaccines may be administered to people with underlying medical conditions provided they have not had a severe allergic reaction to any of the ingredients in the vaccine.” 

Both the Pfizer and Moderna vaccines use mRNA, or messenger RNA.

The CDC guidance had specific information for people with HIV, weakened immune systems, and autoimmune conditions such as Guillain-Barré syndrome (GBS) and Bell’s palsy who are thinking of getting the vaccine.

People with HIV and weakened immune systems “may receive a COVID-19 vaccine. However, they should be aware of the limited safety data,” the CDC said.

There’s no information available yet about the safety of the vaccines for people with weakened immune systems. People with HIV were included in clinical trials, but “safety data specific to this group are not yet available at this time,” the CDC said.

Cases of Bell’s palsy, a temporary facial paralysis, were reported in people receiving the Pfizer and Moderna vaccines in clinical trials, the Food and Drug Administration said Dec. 17. 

But the new CDC guidance said that the FDA “does not consider these to be above the rate expected in the general population. They have not concluded these cases were caused by vaccination. Therefore, persons who have previously had Bell’s palsy may receive an mRNA COVID-19 vaccine.”

Researchers have determined the vaccines are safe for people with GBS, a rare autoimmune disorder in which the body’s immune system attacks nerves just as they leave the spinal cord, the CDC said.

“To date, no cases of GBS have been reported following vaccination among participants in the mRNA COVID-19 vaccine clinical trials,” the CDC guidance said. “With few exceptions, the independent Advisory Committee on Immunization Practices general best practice guidelines for immunization do not include a history of GBS as a precaution to vaccination with other vaccines.”

For months, the CDC and other health authorities have said that people with certain medical conditions are at an increased risk of developing severe cases of COVID-19.

A version of this article first appeared on Medscape.com.

The human papillomavirus (HPV) vaccine, recommended by the Centers for Disease Control and Prevention for the prevention of HPV-associated genital warts and neoplasia, appears to be an effective and perhaps underappreciated treatment of existing cutaneous warts, according to expert speaking at the annual Coastal Dermatology symposium, held virtually.

The value of HPV vaccine for treating any cutaneous HPV-associated warts, not just genital lesions, has been suggested repeatedly in case reports and small studies, but a recently published review provides strong evidence that this is a practical clinical strategy, according to Theodore Rosen, MD, professor of dermatology at Baylor College of Medicine, Houston.

“Clearly, if you have someone, particularly a youngster, and you’re having trouble getting rid of their warts and they are age 9 years or above – and they need the vaccine anyhow – that’s a win-win proposition,” Dr. Rosen said.

The current nonavalent HPV vaccine is approved for individuals from age 9 to age 45. Although the CDC recommends routine vaccination at age 11 or 12 years, it allows earlier vaccination within the label.

The recently published and updated evidence of a benefit from treatment comes from a systematic literature review. For the review, 63 articles were drawn from the PubMed and Cochrane databases. The studies yielded 4,439 patients with cutaneous warts at the time they received the HPV vaccine or who specifically received vaccine as a treatment strategy.

As has been suggested previously in the case series and in a limited number of prospective studies, the majority of warts, including cutaneous warts and anogenital warts, resolved following vaccine administration.

“Mostly these were common warts, plantar warts, and flat warts,” Dr. Rosen said, but the paper also reported successful treatment of recurrent respiratory papillomatosis, squamous cell carcinomas, and basal cell carcinomas.

Case reports and small studies associating HPV vaccine with successful resolution of warts are easy to find in the literature. For example, 60% of patients achieved a complete response and 30% a partial response to HPV vaccine in one small prospective study of 26 patients with genital warts. Following vaccination, no recurrences were observed after a median follow-up of more than 8 months.

In the review paper, most of the cases involved patients who received the quadrivalent HPV vaccine, Dr. Rosen noted. Only one received the updated nonavalent vaccine, which, in addition to protection against the 6, 11, 16, and 18 subtypes extends protection to subtypes 31, 33, 45, 52, and 58.

“You would expect the nonavalent vaccine to provide the same protection. It is the same vaccine. It just offers activity against more subtypes,” Dr. Rosen said at the meeting, jointly presented by the University of Louisville and Global Academy for Medical Education. He reported that he personally has used the nonavalent vaccine successfully to treat a cutaneous wart.

The nonavalent vaccine can be administered in just two doses for those who receive the first dose before age 15. In others, it is given in three doses at 1- to 2-month intervals, according to Dr. Rosen. He said the efficacy for preventing genital warts and most HPV-related neoplasia exceeds 90%, although it is lower for penile and anal cancer. The protection extends for at least 10 years, but he said that he believes that it is likely to be longer.

“The HPV vaccine is really, really safe,” Dr. Rosen said. Besides injection-site reactions, the most common adverse event is syncope. For this reason, patients are advised to stay seated for 30 minutes after administration.

There is some evidence for cross-immunity for HPV subtypes not covered by the vaccine, particularly among children, Dr. Rosen commented. Citing the review article, he said that, although almost all HPV-associated warts resolve in children when treated with the vaccine, response is somewhat lower in adolescents and further reduced in adults.

In an interview, the senior author of the recent literature review, Natasha A. Mesinkovska, MD, PhD, associate professor of dermatology, University of California, Irvine, agreed with Dr. Rosen about the value of HPV vaccine for patients not responding to conventional therapies for HPV-related cutaneous warts.

“I think HPV vaccine is an excellent option for those patients, even older ones at 45 years of age if cost is not an issue,” she said. She did offer a caveat. In a recent statement from the International Papillomavirus Society (IPVS) on a world shortage of HPV vaccine, it was estimated that supplies might be limited for the next 3-5 years.

Given this shortage, “obtaining them currently may prove to be difficult,” she cautioned.

This publication and Global Academy for Medical Education are owned by the same parent company.

The human papillomavirus (HPV) vaccine, recommended by the Centers for Disease Control and Prevention for the prevention of HPV-associated genital warts and neoplasia, appears to be an effective and perhaps underappreciated treatment of existing cutaneous warts, according to expert speaking at the annual Coastal Dermatology symposium, held virtually.

The value of HPV vaccine for treating any cutaneous HPV-associated warts, not just genital lesions, has been suggested repeatedly in case reports and small studies, but a recently published review provides strong evidence that this is a practical clinical strategy, according to Theodore Rosen, MD, professor of dermatology at Baylor College of Medicine, Houston.

“Clearly, if you have someone, particularly a youngster, and you’re having trouble getting rid of their warts and they are age 9 years or above – and they need the vaccine anyhow – that’s a win-win proposition,” Dr. Rosen said.

The current nonavalent HPV vaccine is approved for individuals from age 9 to age 45. Although the CDC recommends routine vaccination at age 11 or 12 years, it allows earlier vaccination within the label.

The recently published and updated evidence of a benefit from treatment comes from a systematic literature review. For the review, 63 articles were drawn from the PubMed and Cochrane databases. The studies yielded 4,439 patients with cutaneous warts at the time they received the HPV vaccine or who specifically received vaccine as a treatment strategy.

As has been suggested previously in the case series and in a limited number of prospective studies, the majority of warts, including cutaneous warts and anogenital warts, resolved following vaccine administration.

“Mostly these were common warts, plantar warts, and flat warts,” Dr. Rosen said, but the paper also reported successful treatment of recurrent respiratory papillomatosis, squamous cell carcinomas, and basal cell carcinomas.

Case reports and small studies associating HPV vaccine with successful resolution of warts are easy to find in the literature. For example, 60% of patients achieved a complete response and 30% a partial response to HPV vaccine in one small prospective study of 26 patients with genital warts. Following vaccination, no recurrences were observed after a median follow-up of more than 8 months.

In the review paper, most of the cases involved patients who received the quadrivalent HPV vaccine, Dr. Rosen noted. Only one received the updated nonavalent vaccine, which, in addition to protection against the 6, 11, 16, and 18 subtypes extends protection to subtypes 31, 33, 45, 52, and 58.

“You would expect the nonavalent vaccine to provide the same protection. It is the same vaccine. It just offers activity against more subtypes,” Dr. Rosen said at the meeting, jointly presented by the University of Louisville and Global Academy for Medical Education. He reported that he personally has used the nonavalent vaccine successfully to treat a cutaneous wart.

The nonavalent vaccine can be administered in just two doses for those who receive the first dose before age 15. In others, it is given in three doses at 1- to 2-month intervals, according to Dr. Rosen. He said the efficacy for preventing genital warts and most HPV-related neoplasia exceeds 90%, although it is lower for penile and anal cancer. The protection extends for at least 10 years, but he said that he believes that it is likely to be longer.

“The HPV vaccine is really, really safe,” Dr. Rosen said. Besides injection-site reactions, the most common adverse event is syncope. For this reason, patients are advised to stay seated for 30 minutes after administration.

There is some evidence for cross-immunity for HPV subtypes not covered by the vaccine, particularly among children, Dr. Rosen commented. Citing the review article, he said that, although almost all HPV-associated warts resolve in children when treated with the vaccine, response is somewhat lower in adolescents and further reduced in adults.

In an interview, the senior author of the recent literature review, Natasha A. Mesinkovska, MD, PhD, associate professor of dermatology, University of California, Irvine, agreed with Dr. Rosen about the value of HPV vaccine for patients not responding to conventional therapies for HPV-related cutaneous warts.

“I think HPV vaccine is an excellent option for those patients, even older ones at 45 years of age if cost is not an issue,” she said. She did offer a caveat. In a recent statement from the International Papillomavirus Society (IPVS) on a world shortage of HPV vaccine, it was estimated that supplies might be limited for the next 3-5 years.

Given this shortage, “obtaining them currently may prove to be difficult,” she cautioned.

This publication and Global Academy for Medical Education are owned by the same parent company.

The human papillomavirus (HPV) vaccine, recommended by the Centers for Disease Control and Prevention for the prevention of HPV-associated genital warts and neoplasia, appears to be an effective and perhaps underappreciated treatment of existing cutaneous warts, according to expert speaking at the annual Coastal Dermatology symposium, held virtually.

The value of HPV vaccine for treating any cutaneous HPV-associated warts, not just genital lesions, has been suggested repeatedly in case reports and small studies, but a recently published review provides strong evidence that this is a practical clinical strategy, according to Theodore Rosen, MD, professor of dermatology at Baylor College of Medicine, Houston.

“Clearly, if you have someone, particularly a youngster, and you’re having trouble getting rid of their warts and they are age 9 years or above – and they need the vaccine anyhow – that’s a win-win proposition,” Dr. Rosen said.

The current nonavalent HPV vaccine is approved for individuals from age 9 to age 45. Although the CDC recommends routine vaccination at age 11 or 12 years, it allows earlier vaccination within the label.

The recently published and updated evidence of a benefit from treatment comes from a systematic literature review. For the review, 63 articles were drawn from the PubMed and Cochrane databases. The studies yielded 4,439 patients with cutaneous warts at the time they received the HPV vaccine or who specifically received vaccine as a treatment strategy.

As has been suggested previously in the case series and in a limited number of prospective studies, the majority of warts, including cutaneous warts and anogenital warts, resolved following vaccine administration.

“Mostly these were common warts, plantar warts, and flat warts,” Dr. Rosen said, but the paper also reported successful treatment of recurrent respiratory papillomatosis, squamous cell carcinomas, and basal cell carcinomas.

Case reports and small studies associating HPV vaccine with successful resolution of warts are easy to find in the literature. For example, 60% of patients achieved a complete response and 30% a partial response to HPV vaccine in one small prospective study of 26 patients with genital warts. Following vaccination, no recurrences were observed after a median follow-up of more than 8 months.

In the review paper, most of the cases involved patients who received the quadrivalent HPV vaccine, Dr. Rosen noted. Only one received the updated nonavalent vaccine, which, in addition to protection against the 6, 11, 16, and 18 subtypes extends protection to subtypes 31, 33, 45, 52, and 58.

“You would expect the nonavalent vaccine to provide the same protection. It is the same vaccine. It just offers activity against more subtypes,” Dr. Rosen said at the meeting, jointly presented by the University of Louisville and Global Academy for Medical Education. He reported that he personally has used the nonavalent vaccine successfully to treat a cutaneous wart.

The nonavalent vaccine can be administered in just two doses for those who receive the first dose before age 15. In others, it is given in three doses at 1- to 2-month intervals, according to Dr. Rosen. He said the efficacy for preventing genital warts and most HPV-related neoplasia exceeds 90%, although it is lower for penile and anal cancer. The protection extends for at least 10 years, but he said that he believes that it is likely to be longer.

“The HPV vaccine is really, really safe,” Dr. Rosen said. Besides injection-site reactions, the most common adverse event is syncope. For this reason, patients are advised to stay seated for 30 minutes after administration.

There is some evidence for cross-immunity for HPV subtypes not covered by the vaccine, particularly among children, Dr. Rosen commented. Citing the review article, he said that, although almost all HPV-associated warts resolve in children when treated with the vaccine, response is somewhat lower in adolescents and further reduced in adults.

In an interview, the senior author of the recent literature review, Natasha A. Mesinkovska, MD, PhD, associate professor of dermatology, University of California, Irvine, agreed with Dr. Rosen about the value of HPV vaccine for patients not responding to conventional therapies for HPV-related cutaneous warts.

“I think HPV vaccine is an excellent option for those patients, even older ones at 45 years of age if cost is not an issue,” she said. She did offer a caveat. In a recent statement from the International Papillomavirus Society (IPVS) on a world shortage of HPV vaccine, it was estimated that supplies might be limited for the next 3-5 years.

Given this shortage, “obtaining them currently may prove to be difficult,” she cautioned.

This publication and Global Academy for Medical Education are owned by the same parent company.

Respiratory syncytial virus vaccine development has progressed rapidly in recent years, and there is hope that an efficacious vaccine soon may be approved.

Dr. Craig Lyerla/CDC

Louis Bont, MD, PhD, provided an overview of the most recent developments in the complex respiratory syncytial virus (RSV) vaccine landscape at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

RSV imposes significant burden worldwide, with 33 million patients, 3 million hospitalizations, and at least 120,000 deaths, reported Dr. Bont of the Wilhelmina Children’s Hospital, University Medical Centre, Utrecht, the Netherlands. Of those deaths, more than 50% are in infants younger than 5 months, and “about 99% of the children dying from RSV live in low- and middle-income countries.”

“There are high-risk populations, such as children with prematurity, congenital heart disease, lung disease, and Down syndrome, but about 73% of all children who are hospitalized for RSV infection were previously healthy children,” Dr. Bont explained. “So, we need to find a solution for all children to prevent RSV infection.”

As observed by Nienke Scheltema in a Lancet Global Health article, population distributions of RSV infection mortality show that, regardless of whether children have comorbidities or they are previously healthy, most children die at a very young age, Dr. Bont explained. These data suggest “that a maternal vaccine or an antibody prophylaxis approach from birth onwards or during the first RSV season is the solution for the problem.”

The path to developing an RSV vaccine has now narrowed its focus onto a structural element of RSV, the prefusion F protein. This shift started with the discovery by Jason McLellan (Science, 2013 [two papers]) that there are two variants of the RSV F-fusion protein: the very stable postfusion conformation and the prefusion active conformation, a metastable protein that exists for a “fraction of a second,” Dr. Bont said.

“The interesting thing is that epitopes that are visible at the prefusion, metastable state … induce highly neutralizing antibodies, whereas epitopes at the postfusion conformation do not,” Dr. Bont explained. “So, by stabilizing the prefusion state, we start inducing neutralizing antibodies that will protect against severe RSV infection, and this is the basic concept of all the vaccine developments currently ongoing.”

These RSV vaccine developments fall into five approach types: live-attenuated or chimeric vaccines, vector-based vaccines, monoclonal antibodies, particle-based vaccines, and subunit or protein-based vaccines.

One breakthrough, which was presented at last year’s ESPID meeting, is the monoclonal antibody nirsevimab. In addition to being nine times more potent than the broadly used antibody palivizumab, it is also more stable; whereas many antibodies have a half-life of 3 weeks, nirsevimab has a half-life of 100 days. “The idea is that a single injection at the start of the RSV season protects children in the first RSV season of their life, a dangerous episode for them.” Dr. Bont explained. The originators, AstraZeneca and Sanofi Pasteur, have “the vision that every child on this planet should receive a single injection with this antibody in the first season,” he explained.

Studies of nanoparticle-based maternal vaccines have also revealed interesting results: Although a phase 3 trial investigating such vaccines didn’t achieve its primary endpoint, “interestingly, 15% of all RSV infections were mild, and only 2% were very severe and leading to hypoxemia,” Dr. Bont noted. “But if we look at vaccine efficacy, we see the opposite – the vaccine was not very efficacious to prevent mild disease, but very efficacious to prevent severe hypoxemia; actually, this is exactly what you would like to see in a vaccine.”

Investigations into live-attenuated and vector-based vaccines have been promising as well, Dr. Bont shared. Studies of live-attenuated vaccines suggest they have a future and that we can move onto their next phase of clinical development, and a study investigating adenoviral vector-based vaccines has demonstrated safety, efficacy, and immunogenicity, though it has also shown that we should anticipate some side effects when using them.

Simple subunit vaccines for RSV are also being explored – a study of DS-Cav1, a stabilized prefusion F subunit protein candidate vaccine, has shown that it has a superior functional profile, compared with previous pre-F subunit vaccines. However, it seemed to be more efficacious against strains of RSV A than strains of RSV B, the dominant strain.

Dr. Bont also discussed exciting work by Sesterhenn et al., in which they used a computer-based program to develop their own vaccine. Using their in-depth knowledge of the RSV prefusion F protein and a computer program, Sesterhenn et al. developed a trivalent vaccine, produced it, and showed – both in vitro and in monkeys – that such vaccines can work up to the level of preclinical in vivo experiments.

“We can now make vaccines behind our computer,” Dr. Bont declared. “And the system doesn’t only work for RSV vaccines, but also for other pathogens – as long as you have an in-depth molecular knowledge of the target epitope,” he added.

Joanne Wildenbeest, MD, PhD, at the Utrecht University, the Netherlands commented: “Lower respiratory tract infections due to RSV are among the leading causes of death worldwide in children under the age of 5, especially young infants. The recent advances in the development of a vaccine and passive immunization are important steps towards the goal to reduce childhood mortality due to RSV worldwide. Since RSV-related mortality is mainly seen in developing countries it is important that, once a vaccine has been approved, it will also be made easily available to these countries.”

Dr. Bont reported the following disclosures: ReSViNET (a nonprofit foundation); investigator-initiated studies with the Bill & Melinda Gates Foundation, AbbVie, MedImmune, and MeMed; participation with Pfizer, Regeneron, and Janssen; and consultancy with GlaxoSmithKline, Ablynx, Novavax, and Janssen.

Respiratory syncytial virus vaccine development has progressed rapidly in recent years, and there is hope that an efficacious vaccine soon may be approved.

Dr. Craig Lyerla/CDC

Louis Bont, MD, PhD, provided an overview of the most recent developments in the complex respiratory syncytial virus (RSV) vaccine landscape at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

RSV imposes significant burden worldwide, with 33 million patients, 3 million hospitalizations, and at least 120,000 deaths, reported Dr. Bont of the Wilhelmina Children’s Hospital, University Medical Centre, Utrecht, the Netherlands. Of those deaths, more than 50% are in infants younger than 5 months, and “about 99% of the children dying from RSV live in low- and middle-income countries.”

“There are high-risk populations, such as children with prematurity, congenital heart disease, lung disease, and Down syndrome, but about 73% of all children who are hospitalized for RSV infection were previously healthy children,” Dr. Bont explained. “So, we need to find a solution for all children to prevent RSV infection.”

As observed by Nienke Scheltema in a Lancet Global Health article, population distributions of RSV infection mortality show that, regardless of whether children have comorbidities or they are previously healthy, most children die at a very young age, Dr. Bont explained. These data suggest “that a maternal vaccine or an antibody prophylaxis approach from birth onwards or during the first RSV season is the solution for the problem.”

The path to developing an RSV vaccine has now narrowed its focus onto a structural element of RSV, the prefusion F protein. This shift started with the discovery by Jason McLellan (Science, 2013 [two papers]) that there are two variants of the RSV F-fusion protein: the very stable postfusion conformation and the prefusion active conformation, a metastable protein that exists for a “fraction of a second,” Dr. Bont said.

“The interesting thing is that epitopes that are visible at the prefusion, metastable state … induce highly neutralizing antibodies, whereas epitopes at the postfusion conformation do not,” Dr. Bont explained. “So, by stabilizing the prefusion state, we start inducing neutralizing antibodies that will protect against severe RSV infection, and this is the basic concept of all the vaccine developments currently ongoing.”

These RSV vaccine developments fall into five approach types: live-attenuated or chimeric vaccines, vector-based vaccines, monoclonal antibodies, particle-based vaccines, and subunit or protein-based vaccines.

One breakthrough, which was presented at last year’s ESPID meeting, is the monoclonal antibody nirsevimab. In addition to being nine times more potent than the broadly used antibody palivizumab, it is also more stable; whereas many antibodies have a half-life of 3 weeks, nirsevimab has a half-life of 100 days. “The idea is that a single injection at the start of the RSV season protects children in the first RSV season of their life, a dangerous episode for them.” Dr. Bont explained. The originators, AstraZeneca and Sanofi Pasteur, have “the vision that every child on this planet should receive a single injection with this antibody in the first season,” he explained.

Studies of nanoparticle-based maternal vaccines have also revealed interesting results: Although a phase 3 trial investigating such vaccines didn’t achieve its primary endpoint, “interestingly, 15% of all RSV infections were mild, and only 2% were very severe and leading to hypoxemia,” Dr. Bont noted. “But if we look at vaccine efficacy, we see the opposite – the vaccine was not very efficacious to prevent mild disease, but very efficacious to prevent severe hypoxemia; actually, this is exactly what you would like to see in a vaccine.”

Investigations into live-attenuated and vector-based vaccines have been promising as well, Dr. Bont shared. Studies of live-attenuated vaccines suggest they have a future and that we can move onto their next phase of clinical development, and a study investigating adenoviral vector-based vaccines has demonstrated safety, efficacy, and immunogenicity, though it has also shown that we should anticipate some side effects when using them.

Simple subunit vaccines for RSV are also being explored – a study of DS-Cav1, a stabilized prefusion F subunit protein candidate vaccine, has shown that it has a superior functional profile, compared with previous pre-F subunit vaccines. However, it seemed to be more efficacious against strains of RSV A than strains of RSV B, the dominant strain.

Dr. Bont also discussed exciting work by Sesterhenn et al., in which they used a computer-based program to develop their own vaccine. Using their in-depth knowledge of the RSV prefusion F protein and a computer program, Sesterhenn et al. developed a trivalent vaccine, produced it, and showed – both in vitro and in monkeys – that such vaccines can work up to the level of preclinical in vivo experiments.

“We can now make vaccines behind our computer,” Dr. Bont declared. “And the system doesn’t only work for RSV vaccines, but also for other pathogens – as long as you have an in-depth molecular knowledge of the target epitope,” he added.

Joanne Wildenbeest, MD, PhD, at the Utrecht University, the Netherlands commented: “Lower respiratory tract infections due to RSV are among the leading causes of death worldwide in children under the age of 5, especially young infants. The recent advances in the development of a vaccine and passive immunization are important steps towards the goal to reduce childhood mortality due to RSV worldwide. Since RSV-related mortality is mainly seen in developing countries it is important that, once a vaccine has been approved, it will also be made easily available to these countries.”

Dr. Bont reported the following disclosures: ReSViNET (a nonprofit foundation); investigator-initiated studies with the Bill & Melinda Gates Foundation, AbbVie, MedImmune, and MeMed; participation with Pfizer, Regeneron, and Janssen; and consultancy with GlaxoSmithKline, Ablynx, Novavax, and Janssen.

Respiratory syncytial virus vaccine development has progressed rapidly in recent years, and there is hope that an efficacious vaccine soon may be approved.

Dr. Craig Lyerla/CDC

Louis Bont, MD, PhD, provided an overview of the most recent developments in the complex respiratory syncytial virus (RSV) vaccine landscape at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

RSV imposes significant burden worldwide, with 33 million patients, 3 million hospitalizations, and at least 120,000 deaths, reported Dr. Bont of the Wilhelmina Children’s Hospital, University Medical Centre, Utrecht, the Netherlands. Of those deaths, more than 50% are in infants younger than 5 months, and “about 99% of the children dying from RSV live in low- and middle-income countries.”

“There are high-risk populations, such as children with prematurity, congenital heart disease, lung disease, and Down syndrome, but about 73% of all children who are hospitalized for RSV infection were previously healthy children,” Dr. Bont explained. “So, we need to find a solution for all children to prevent RSV infection.”

As observed by Nienke Scheltema in a Lancet Global Health article, population distributions of RSV infection mortality show that, regardless of whether children have comorbidities or they are previously healthy, most children die at a very young age, Dr. Bont explained. These data suggest “that a maternal vaccine or an antibody prophylaxis approach from birth onwards or during the first RSV season is the solution for the problem.”

The path to developing an RSV vaccine has now narrowed its focus onto a structural element of RSV, the prefusion F protein. This shift started with the discovery by Jason McLellan (Science, 2013 [two papers]) that there are two variants of the RSV F-fusion protein: the very stable postfusion conformation and the prefusion active conformation, a metastable protein that exists for a “fraction of a second,” Dr. Bont said.

“The interesting thing is that epitopes that are visible at the prefusion, metastable state … induce highly neutralizing antibodies, whereas epitopes at the postfusion conformation do not,” Dr. Bont explained. “So, by stabilizing the prefusion state, we start inducing neutralizing antibodies that will protect against severe RSV infection, and this is the basic concept of all the vaccine developments currently ongoing.”

These RSV vaccine developments fall into five approach types: live-attenuated or chimeric vaccines, vector-based vaccines, monoclonal antibodies, particle-based vaccines, and subunit or protein-based vaccines.

One breakthrough, which was presented at last year’s ESPID meeting, is the monoclonal antibody nirsevimab. In addition to being nine times more potent than the broadly used antibody palivizumab, it is also more stable; whereas many antibodies have a half-life of 3 weeks, nirsevimab has a half-life of 100 days. “The idea is that a single injection at the start of the RSV season protects children in the first RSV season of their life, a dangerous episode for them.” Dr. Bont explained. The originators, AstraZeneca and Sanofi Pasteur, have “the vision that every child on this planet should receive a single injection with this antibody in the first season,” he explained.

Studies of nanoparticle-based maternal vaccines have also revealed interesting results: Although a phase 3 trial investigating such vaccines didn’t achieve its primary endpoint, “interestingly, 15% of all RSV infections were mild, and only 2% were very severe and leading to hypoxemia,” Dr. Bont noted. “But if we look at vaccine efficacy, we see the opposite – the vaccine was not very efficacious to prevent mild disease, but very efficacious to prevent severe hypoxemia; actually, this is exactly what you would like to see in a vaccine.”

Investigations into live-attenuated and vector-based vaccines have been promising as well, Dr. Bont shared. Studies of live-attenuated vaccines suggest they have a future and that we can move onto their next phase of clinical development, and a study investigating adenoviral vector-based vaccines has demonstrated safety, efficacy, and immunogenicity, though it has also shown that we should anticipate some side effects when using them.

Simple subunit vaccines for RSV are also being explored – a study of DS-Cav1, a stabilized prefusion F subunit protein candidate vaccine, has shown that it has a superior functional profile, compared with previous pre-F subunit vaccines. However, it seemed to be more efficacious against strains of RSV A than strains of RSV B, the dominant strain.

Dr. Bont also discussed exciting work by Sesterhenn et al., in which they used a computer-based program to develop their own vaccine. Using their in-depth knowledge of the RSV prefusion F protein and a computer program, Sesterhenn et al. developed a trivalent vaccine, produced it, and showed – both in vitro and in monkeys – that such vaccines can work up to the level of preclinical in vivo experiments.

“We can now make vaccines behind our computer,” Dr. Bont declared. “And the system doesn’t only work for RSV vaccines, but also for other pathogens – as long as you have an in-depth molecular knowledge of the target epitope,” he added.

Joanne Wildenbeest, MD, PhD, at the Utrecht University, the Netherlands commented: “Lower respiratory tract infections due to RSV are among the leading causes of death worldwide in children under the age of 5, especially young infants. The recent advances in the development of a vaccine and passive immunization are important steps towards the goal to reduce childhood mortality due to RSV worldwide. Since RSV-related mortality is mainly seen in developing countries it is important that, once a vaccine has been approved, it will also be made easily available to these countries.”

Dr. Bont reported the following disclosures: ReSViNET (a nonprofit foundation); investigator-initiated studies with the Bill & Melinda Gates Foundation, AbbVie, MedImmune, and MeMed; participation with Pfizer, Regeneron, and Janssen; and consultancy with GlaxoSmithKline, Ablynx, Novavax, and Janssen.

COVID-19 vaccines should not be withheld from people who are pregnant or lactating and want to be vaccinated, despite a lack of safety data in these populations, according to guidance from the Centers for Disease Control and Prevention, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine.

Thye Aun Ngo/Fotolia.com

Pregnant women who opt not to receive the vaccine should be supported in that decision as well, a practice advisory from ACOG recommends.

“Pregnant women who experience fever following vaccination should be counseled to take acetaminophen,” the advisory notes.

In addition, women do not need to avoid pregnancy after receiving the Pfizer-BioNTech COVID-19 vaccine, according to the CDC’s interim clinical considerations for its use. The U.S. Food and Drug Administration issued an emergency use authorization for the vaccine on Dec. 11.

Although investigators excluded pregnant women from clinical trials, experts believe that mRNA vaccines, which are not live vaccines, “are unlikely to pose a risk for people who are pregnant” and “are not thought to be a risk to the breastfeeding infant,” the CDC notes.

Meanwhile, women who are pregnant may be at greater risk of severe COVID-19, even though the absolute risk of severe illness is low. COVID-19 also may increase the risk of adverse pregnancy outcomes, such as preterm birth, although the data have been mixed with some studies finding an association and others not.

“If pregnant people are part of a group that is recommended to receive a COVID-19 vaccine (e.g., health care personnel), they may choose to be vaccinated,” the CDC advises. “A conversation between the patient and their clinical team may assist with decisions regarding the use of vaccines approved under EUA for the prevention of COVID-19. While a conversation with a health care provider may be helpful, it is not required prior to vaccination.”
 

Acknowledging side effects and uncertainty

ACOG’s advisory reiterates that approach. The group notes that, based on the mRNA vaccine’s mechanism of action and its safety and efficacy in clinical trials, “it is expected that the safety and efficacy profile of the vaccine for pregnant individuals would be similar to that observed in nonpregnant individuals ... That said, there are no safety data specific to mRNA vaccine use in pregnant or lactating individuals and the potential risks to a pregnant individual and the fetus are unknown.” 

In clinical trials, most participants experienced mild influenza-like symptoms following vaccination, including injection site reactions, fatigue, chills, muscle and joint pain, and headache. Among participants aged 18-55 years, fever greater than 38°C occurred in 3.7% of participants after the first dose and in 15.8% after the second dose. Most symptoms resolved within a few days. 

Women who are pregnant should treat fever with acetaminophen because “fever has been associated with adverse pregnancy outcomes,” according to the ACOG guidance. “Acetaminophen has been proven to be safe for use in pregnancy and does not appear to impact antibody response to COVID-19 vaccines.” Patients may treat other vaccine side effects, such as injection-site soreness with acetaminophen as well.

When counseling patients, clinicians should explain that side effects are a normal part of developing antibodies to protect against COVID-19. “Regardless of their decision,” the group says, “these conversations provide an opportunity to remind patients about the importance of other prevention measures such as hand washing, physical distancing, and wearing a mask.”
 

More data expected

Data from developmental and reproductive toxicity studies in animals are expected soon, the CDC said. In addition, the manufacturer is following clinical trial participants who became pregnant during the study. 

Women who are pregnant and their physicians should weigh factors such as the extent of COVID-19 transmission in the community, the patient’s risk of contracting COVID-19, risks of COVID-19 to the patient and fetus, vaccine efficacy and side effects, and the lack of data about COVID-19 vaccination during pregnancy.

The Society for Maternal-Fetal Medicine recommends that pregnant and lactating women have access to COVID-19 vaccines in general and has advocated for the inclusion of women who are pregnant or lactating in vaccine trials. The society has suggested that health care professionals “counsel their patients that the theoretical risk of fetal harm from mRNA vaccines is very low.” It published resources this week for physicians and patients focused on COVID-19 vaccination and pregnancy.

In a review published online Dec. 10 in the American Journal of Obstetrics & Gynecology MFM, Amanda M. Craig, MD, of Duke University Health System in Durham, N.C., and coauthors note that there “is a theoretical risk for fetal harm from any untested medical intervention and this is no different for COVID-19 vaccines.”

“Pregnant individuals should be given the opportunity, along with their obstetric provider, to weigh the potential risk of severe maternal disease against the unknown risk of fetal exposure, and make an autonomous decision about whether or not to accept vaccine until pregnancy safety data are available,” they write.

A version of this article first appeared on Medscape.com.

COVID-19 vaccines should not be withheld from people who are pregnant or lactating and want to be vaccinated, despite a lack of safety data in these populations, according to guidance from the Centers for Disease Control and Prevention, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine.

Thye Aun Ngo/Fotolia.com

Pregnant women who opt not to receive the vaccine should be supported in that decision as well, a practice advisory from ACOG recommends.

“Pregnant women who experience fever following vaccination should be counseled to take acetaminophen,” the advisory notes.

In addition, women do not need to avoid pregnancy after receiving the Pfizer-BioNTech COVID-19 vaccine, according to the CDC’s interim clinical considerations for its use. The U.S. Food and Drug Administration issued an emergency use authorization for the vaccine on Dec. 11.

Although investigators excluded pregnant women from clinical trials, experts believe that mRNA vaccines, which are not live vaccines, “are unlikely to pose a risk for people who are pregnant” and “are not thought to be a risk to the breastfeeding infant,” the CDC notes.

Meanwhile, women who are pregnant may be at greater risk of severe COVID-19, even though the absolute risk of severe illness is low. COVID-19 also may increase the risk of adverse pregnancy outcomes, such as preterm birth, although the data have been mixed with some studies finding an association and others not.

“If pregnant people are part of a group that is recommended to receive a COVID-19 vaccine (e.g., health care personnel), they may choose to be vaccinated,” the CDC advises. “A conversation between the patient and their clinical team may assist with decisions regarding the use of vaccines approved under EUA for the prevention of COVID-19. While a conversation with a health care provider may be helpful, it is not required prior to vaccination.”
 

Acknowledging side effects and uncertainty

ACOG’s advisory reiterates that approach. The group notes that, based on the mRNA vaccine’s mechanism of action and its safety and efficacy in clinical trials, “it is expected that the safety and efficacy profile of the vaccine for pregnant individuals would be similar to that observed in nonpregnant individuals ... That said, there are no safety data specific to mRNA vaccine use in pregnant or lactating individuals and the potential risks to a pregnant individual and the fetus are unknown.” 

In clinical trials, most participants experienced mild influenza-like symptoms following vaccination, including injection site reactions, fatigue, chills, muscle and joint pain, and headache. Among participants aged 18-55 years, fever greater than 38°C occurred in 3.7% of participants after the first dose and in 15.8% after the second dose. Most symptoms resolved within a few days. 

Women who are pregnant should treat fever with acetaminophen because “fever has been associated with adverse pregnancy outcomes,” according to the ACOG guidance. “Acetaminophen has been proven to be safe for use in pregnancy and does not appear to impact antibody response to COVID-19 vaccines.” Patients may treat other vaccine side effects, such as injection-site soreness with acetaminophen as well.

When counseling patients, clinicians should explain that side effects are a normal part of developing antibodies to protect against COVID-19. “Regardless of their decision,” the group says, “these conversations provide an opportunity to remind patients about the importance of other prevention measures such as hand washing, physical distancing, and wearing a mask.”
 

More data expected

Data from developmental and reproductive toxicity studies in animals are expected soon, the CDC said. In addition, the manufacturer is following clinical trial participants who became pregnant during the study. 

Women who are pregnant and their physicians should weigh factors such as the extent of COVID-19 transmission in the community, the patient’s risk of contracting COVID-19, risks of COVID-19 to the patient and fetus, vaccine efficacy and side effects, and the lack of data about COVID-19 vaccination during pregnancy.

The Society for Maternal-Fetal Medicine recommends that pregnant and lactating women have access to COVID-19 vaccines in general and has advocated for the inclusion of women who are pregnant or lactating in vaccine trials. The society has suggested that health care professionals “counsel their patients that the theoretical risk of fetal harm from mRNA vaccines is very low.” It published resources this week for physicians and patients focused on COVID-19 vaccination and pregnancy.

In a review published online Dec. 10 in the American Journal of Obstetrics & Gynecology MFM, Amanda M. Craig, MD, of Duke University Health System in Durham, N.C., and coauthors note that there “is a theoretical risk for fetal harm from any untested medical intervention and this is no different for COVID-19 vaccines.”

“Pregnant individuals should be given the opportunity, along with their obstetric provider, to weigh the potential risk of severe maternal disease against the unknown risk of fetal exposure, and make an autonomous decision about whether or not to accept vaccine until pregnancy safety data are available,” they write.

A version of this article first appeared on Medscape.com.

COVID-19 vaccines should not be withheld from people who are pregnant or lactating and want to be vaccinated, despite a lack of safety data in these populations, according to guidance from the Centers for Disease Control and Prevention, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine.

Thye Aun Ngo/Fotolia.com

Pregnant women who opt not to receive the vaccine should be supported in that decision as well, a practice advisory from ACOG recommends.

“Pregnant women who experience fever following vaccination should be counseled to take acetaminophen,” the advisory notes.

In addition, women do not need to avoid pregnancy after receiving the Pfizer-BioNTech COVID-19 vaccine, according to the CDC’s interim clinical considerations for its use. The U.S. Food and Drug Administration issued an emergency use authorization for the vaccine on Dec. 11.

Although investigators excluded pregnant women from clinical trials, experts believe that mRNA vaccines, which are not live vaccines, “are unlikely to pose a risk for people who are pregnant” and “are not thought to be a risk to the breastfeeding infant,” the CDC notes.

Meanwhile, women who are pregnant may be at greater risk of severe COVID-19, even though the absolute risk of severe illness is low. COVID-19 also may increase the risk of adverse pregnancy outcomes, such as preterm birth, although the data have been mixed with some studies finding an association and others not.

“If pregnant people are part of a group that is recommended to receive a COVID-19 vaccine (e.g., health care personnel), they may choose to be vaccinated,” the CDC advises. “A conversation between the patient and their clinical team may assist with decisions regarding the use of vaccines approved under EUA for the prevention of COVID-19. While a conversation with a health care provider may be helpful, it is not required prior to vaccination.”
 

Acknowledging side effects and uncertainty

ACOG’s advisory reiterates that approach. The group notes that, based on the mRNA vaccine’s mechanism of action and its safety and efficacy in clinical trials, “it is expected that the safety and efficacy profile of the vaccine for pregnant individuals would be similar to that observed in nonpregnant individuals ... That said, there are no safety data specific to mRNA vaccine use in pregnant or lactating individuals and the potential risks to a pregnant individual and the fetus are unknown.” 

In clinical trials, most participants experienced mild influenza-like symptoms following vaccination, including injection site reactions, fatigue, chills, muscle and joint pain, and headache. Among participants aged 18-55 years, fever greater than 38°C occurred in 3.7% of participants after the first dose and in 15.8% after the second dose. Most symptoms resolved within a few days. 

Women who are pregnant should treat fever with acetaminophen because “fever has been associated with adverse pregnancy outcomes,” according to the ACOG guidance. “Acetaminophen has been proven to be safe for use in pregnancy and does not appear to impact antibody response to COVID-19 vaccines.” Patients may treat other vaccine side effects, such as injection-site soreness with acetaminophen as well.

When counseling patients, clinicians should explain that side effects are a normal part of developing antibodies to protect against COVID-19. “Regardless of their decision,” the group says, “these conversations provide an opportunity to remind patients about the importance of other prevention measures such as hand washing, physical distancing, and wearing a mask.”
 

More data expected

Data from developmental and reproductive toxicity studies in animals are expected soon, the CDC said. In addition, the manufacturer is following clinical trial participants who became pregnant during the study. 

Women who are pregnant and their physicians should weigh factors such as the extent of COVID-19 transmission in the community, the patient’s risk of contracting COVID-19, risks of COVID-19 to the patient and fetus, vaccine efficacy and side effects, and the lack of data about COVID-19 vaccination during pregnancy.

The Society for Maternal-Fetal Medicine recommends that pregnant and lactating women have access to COVID-19 vaccines in general and has advocated for the inclusion of women who are pregnant or lactating in vaccine trials. The society has suggested that health care professionals “counsel their patients that the theoretical risk of fetal harm from mRNA vaccines is very low.” It published resources this week for physicians and patients focused on COVID-19 vaccination and pregnancy.

In a review published online Dec. 10 in the American Journal of Obstetrics & Gynecology MFM, Amanda M. Craig, MD, of Duke University Health System in Durham, N.C., and coauthors note that there “is a theoretical risk for fetal harm from any untested medical intervention and this is no different for COVID-19 vaccines.”

“Pregnant individuals should be given the opportunity, along with their obstetric provider, to weigh the potential risk of severe maternal disease against the unknown risk of fetal exposure, and make an autonomous decision about whether or not to accept vaccine until pregnancy safety data are available,” they write.

A version of this article first appeared on Medscape.com.

Although there is an effective vaccine against Bordetella pertussis, whooping cough remains a leading cause of death. Cases are increasing, and scientists face challenges in developing new vaccines.

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

In a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Dimitri Diavatopoulos, PhD, associate professor at the Radboud University Medical Centre Nijmegen, the Netherlands, summarized the pertussis vaccination problem and what the Pertussis Correlates of Protection Europe (PERISCOPE) project seeks to achieve. Dr. Diavatopoulos has a longstanding interest in pertussis and immunity and will soon take over as the scientific coordinator of PERISCOPE.

Pertussis is a highly contagious infectious disease that causes uncontrollable coughing. The disease begins with an atypical cough and rhinorrhea before entering a paroxysmal stage characterized by cyanosis, lymphocytosis, vomiting, and whoops. Generally, fever is absent and coughing increases at night. Finally, after weeks to months, the patient enters a convalescent stage. The World Health Organization estimates that there are 16 million pertussis cases annually and approximately 195,000 deaths in children. Most cases are caused by Bordetella pertussis and are preventable by vaccination.

In the United States, following the introduction of a national immunization program using a whole-cell vaccine in the 1950s, cases fell significantly. After a lag phase, the adoption of an acellular vaccine in the United States in 1997 and the Netherlands in 2005 – usually in combination with diphtheria and tetanus via DTaP – saw an increase in case numbers. Dr. Diavatopoulos stated that control is no longer as good, compared with other infectious diseases prevented by the MMR vaccine, such as mumps, measles, and rubella.

In the face of increasing numbers, how do we move to the next generation of vaccines to improve control? There are several barriers to licensure, including the following:

• Universal recommendation for pertussis prevention means that more than 90% of the population will have received DTaP (usually in combination with polio and Haemophilus influenzae B) and be protected for several years after vaccination.

• Because DTaP vaccines are only efficacious for a limited time, the problem is not immediately apparent.

• Pertussis epidemics are cyclical, occurring every 3-5 years. These peaks and troughs complicate the development of epidemiological studies.

What this means is that large-scale Phase III efficacy studies, in which disease is used as the endpoint, are not feasible. Also, formal correlates of protection have not been identified.

The PERISCOPE Project started in March 2016 and is designed to respond to some of these issues. Funding is made available by a public private consortium involving the Bill & Melinda Gates foundation, the European Union, and European Federation of Pharmaceutical Industries and Associations (EFPIA) partners, and in this case, GlaxoSmithKline and Sanofi Pasteur. In total, there are 22 partners in this project.

The strategic objectives of this partnership include the following:

• Foster expertise and increase capacity in Europe to evaluate new pertussis vaccines both in clinical and preclinical models.

• Identify early biomarkers of long-lasting protective immunity to pertussis in humans. (This step will accelerate and de-risk clinical development of next generation pertussis vaccines.)

• Investigate the impact of maternal vaccination on infant response to pertussis vaccination.

The problem is that there is no one single study design that addresses all questions about the pertussis vaccine. For example, in PERISCOPE, the results of preclinical studies using the baboon or mouse models and addressing disease and colonization endpoints or immunogenicity do not perfectly model human infection and disease.

By comparison, controlled human infection studies provide information on colonization but not disease endpoints. Such studies, however, do provide information on immunogenicity endpoints. Also available are booster vaccination studies and infant vaccination studies providing data on immunogenicity, as well as safety information.

Finally, there are patient studies, such as household contact studies where immunogenicity can be correlated to disease endpoints. From these studies, it will be seen that what is needed is integration of evidence from clinical and preclinical studies to support a new vaccine registration.

PERISCOPE addresses these issues by developing novel, functional antibody and cellular assays and employing cutting-edge methods to characterize innate immune responses and cell-mediated systemic and mucosal immunity. PERISCOPE combines two major industrial partners with public researchers from academic and public health institutes and small and medium-sized enterprises with expertise in clinical trials, vaccinology, immunology, molecular microbiology, challenge models, and bioinformatics.

Andrew Gorringe, PhD, from Public Health England and the Research and Development Institute at Porton Down, Wiltshire, England, said, “Vaccines have greatly reduced the incidence of pertussis, but it remains the most prevalent ‘vaccine preventable’ disease. This is an exciting period for pertussis vaccine research as we find new ways to understand the immunity that protects from both infection and disease. The PERISCOPE project provides a collaborative environment that combines expertise across Europe to provide a route to the development of new, more effective vaccines.”

GSK and Sanofi Pasteur have cofunded the PERISCOPE Project. Dr. Diavatopoulos made no other financial disclosures.

Although there is an effective vaccine against Bordetella pertussis, whooping cough remains a leading cause of death. Cases are increasing, and scientists face challenges in developing new vaccines.

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

In a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Dimitri Diavatopoulos, PhD, associate professor at the Radboud University Medical Centre Nijmegen, the Netherlands, summarized the pertussis vaccination problem and what the Pertussis Correlates of Protection Europe (PERISCOPE) project seeks to achieve. Dr. Diavatopoulos has a longstanding interest in pertussis and immunity and will soon take over as the scientific coordinator of PERISCOPE.

Pertussis is a highly contagious infectious disease that causes uncontrollable coughing. The disease begins with an atypical cough and rhinorrhea before entering a paroxysmal stage characterized by cyanosis, lymphocytosis, vomiting, and whoops. Generally, fever is absent and coughing increases at night. Finally, after weeks to months, the patient enters a convalescent stage. The World Health Organization estimates that there are 16 million pertussis cases annually and approximately 195,000 deaths in children. Most cases are caused by Bordetella pertussis and are preventable by vaccination.

In the United States, following the introduction of a national immunization program using a whole-cell vaccine in the 1950s, cases fell significantly. After a lag phase, the adoption of an acellular vaccine in the United States in 1997 and the Netherlands in 2005 – usually in combination with diphtheria and tetanus via DTaP – saw an increase in case numbers. Dr. Diavatopoulos stated that control is no longer as good, compared with other infectious diseases prevented by the MMR vaccine, such as mumps, measles, and rubella.

In the face of increasing numbers, how do we move to the next generation of vaccines to improve control? There are several barriers to licensure, including the following:

• Universal recommendation for pertussis prevention means that more than 90% of the population will have received DTaP (usually in combination with polio and Haemophilus influenzae B) and be protected for several years after vaccination.

• Because DTaP vaccines are only efficacious for a limited time, the problem is not immediately apparent.

• Pertussis epidemics are cyclical, occurring every 3-5 years. These peaks and troughs complicate the development of epidemiological studies.

What this means is that large-scale Phase III efficacy studies, in which disease is used as the endpoint, are not feasible. Also, formal correlates of protection have not been identified.

The PERISCOPE Project started in March 2016 and is designed to respond to some of these issues. Funding is made available by a public private consortium involving the Bill & Melinda Gates foundation, the European Union, and European Federation of Pharmaceutical Industries and Associations (EFPIA) partners, and in this case, GlaxoSmithKline and Sanofi Pasteur. In total, there are 22 partners in this project.

The strategic objectives of this partnership include the following:

• Foster expertise and increase capacity in Europe to evaluate new pertussis vaccines both in clinical and preclinical models.

• Identify early biomarkers of long-lasting protective immunity to pertussis in humans. (This step will accelerate and de-risk clinical development of next generation pertussis vaccines.)

• Investigate the impact of maternal vaccination on infant response to pertussis vaccination.

The problem is that there is no one single study design that addresses all questions about the pertussis vaccine. For example, in PERISCOPE, the results of preclinical studies using the baboon or mouse models and addressing disease and colonization endpoints or immunogenicity do not perfectly model human infection and disease.

By comparison, controlled human infection studies provide information on colonization but not disease endpoints. Such studies, however, do provide information on immunogenicity endpoints. Also available are booster vaccination studies and infant vaccination studies providing data on immunogenicity, as well as safety information.

Finally, there are patient studies, such as household contact studies where immunogenicity can be correlated to disease endpoints. From these studies, it will be seen that what is needed is integration of evidence from clinical and preclinical studies to support a new vaccine registration.

PERISCOPE addresses these issues by developing novel, functional antibody and cellular assays and employing cutting-edge methods to characterize innate immune responses and cell-mediated systemic and mucosal immunity. PERISCOPE combines two major industrial partners with public researchers from academic and public health institutes and small and medium-sized enterprises with expertise in clinical trials, vaccinology, immunology, molecular microbiology, challenge models, and bioinformatics.

Andrew Gorringe, PhD, from Public Health England and the Research and Development Institute at Porton Down, Wiltshire, England, said, “Vaccines have greatly reduced the incidence of pertussis, but it remains the most prevalent ‘vaccine preventable’ disease. This is an exciting period for pertussis vaccine research as we find new ways to understand the immunity that protects from both infection and disease. The PERISCOPE project provides a collaborative environment that combines expertise across Europe to provide a route to the development of new, more effective vaccines.”

GSK and Sanofi Pasteur have cofunded the PERISCOPE Project. Dr. Diavatopoulos made no other financial disclosures.

Although there is an effective vaccine against Bordetella pertussis, whooping cough remains a leading cause of death. Cases are increasing, and scientists face challenges in developing new vaccines.

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

In a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Dimitri Diavatopoulos, PhD, associate professor at the Radboud University Medical Centre Nijmegen, the Netherlands, summarized the pertussis vaccination problem and what the Pertussis Correlates of Protection Europe (PERISCOPE) project seeks to achieve. Dr. Diavatopoulos has a longstanding interest in pertussis and immunity and will soon take over as the scientific coordinator of PERISCOPE.

Pertussis is a highly contagious infectious disease that causes uncontrollable coughing. The disease begins with an atypical cough and rhinorrhea before entering a paroxysmal stage characterized by cyanosis, lymphocytosis, vomiting, and whoops. Generally, fever is absent and coughing increases at night. Finally, after weeks to months, the patient enters a convalescent stage. The World Health Organization estimates that there are 16 million pertussis cases annually and approximately 195,000 deaths in children. Most cases are caused by Bordetella pertussis and are preventable by vaccination.

In the United States, following the introduction of a national immunization program using a whole-cell vaccine in the 1950s, cases fell significantly. After a lag phase, the adoption of an acellular vaccine in the United States in 1997 and the Netherlands in 2005 – usually in combination with diphtheria and tetanus via DTaP – saw an increase in case numbers. Dr. Diavatopoulos stated that control is no longer as good, compared with other infectious diseases prevented by the MMR vaccine, such as mumps, measles, and rubella.

In the face of increasing numbers, how do we move to the next generation of vaccines to improve control? There are several barriers to licensure, including the following:

• Universal recommendation for pertussis prevention means that more than 90% of the population will have received DTaP (usually in combination with polio and Haemophilus influenzae B) and be protected for several years after vaccination.

• Because DTaP vaccines are only efficacious for a limited time, the problem is not immediately apparent.

• Pertussis epidemics are cyclical, occurring every 3-5 years. These peaks and troughs complicate the development of epidemiological studies.

What this means is that large-scale Phase III efficacy studies, in which disease is used as the endpoint, are not feasible. Also, formal correlates of protection have not been identified.

The PERISCOPE Project started in March 2016 and is designed to respond to some of these issues. Funding is made available by a public private consortium involving the Bill & Melinda Gates foundation, the European Union, and European Federation of Pharmaceutical Industries and Associations (EFPIA) partners, and in this case, GlaxoSmithKline and Sanofi Pasteur. In total, there are 22 partners in this project.

The strategic objectives of this partnership include the following:

• Foster expertise and increase capacity in Europe to evaluate new pertussis vaccines both in clinical and preclinical models.

• Identify early biomarkers of long-lasting protective immunity to pertussis in humans. (This step will accelerate and de-risk clinical development of next generation pertussis vaccines.)

• Investigate the impact of maternal vaccination on infant response to pertussis vaccination.

The problem is that there is no one single study design that addresses all questions about the pertussis vaccine. For example, in PERISCOPE, the results of preclinical studies using the baboon or mouse models and addressing disease and colonization endpoints or immunogenicity do not perfectly model human infection and disease.

By comparison, controlled human infection studies provide information on colonization but not disease endpoints. Such studies, however, do provide information on immunogenicity endpoints. Also available are booster vaccination studies and infant vaccination studies providing data on immunogenicity, as well as safety information.

Finally, there are patient studies, such as household contact studies where immunogenicity can be correlated to disease endpoints. From these studies, it will be seen that what is needed is integration of evidence from clinical and preclinical studies to support a new vaccine registration.

PERISCOPE addresses these issues by developing novel, functional antibody and cellular assays and employing cutting-edge methods to characterize innate immune responses and cell-mediated systemic and mucosal immunity. PERISCOPE combines two major industrial partners with public researchers from academic and public health institutes and small and medium-sized enterprises with expertise in clinical trials, vaccinology, immunology, molecular microbiology, challenge models, and bioinformatics.

Andrew Gorringe, PhD, from Public Health England and the Research and Development Institute at Porton Down, Wiltshire, England, said, “Vaccines have greatly reduced the incidence of pertussis, but it remains the most prevalent ‘vaccine preventable’ disease. This is an exciting period for pertussis vaccine research as we find new ways to understand the immunity that protects from both infection and disease. The PERISCOPE project provides a collaborative environment that combines expertise across Europe to provide a route to the development of new, more effective vaccines.”

GSK and Sanofi Pasteur have cofunded the PERISCOPE Project. Dr. Diavatopoulos made no other financial disclosures.

With increasing whooping cough numbers, developing an effective new vaccine against Bordetella pertussis is a priority. Results from the multifactorial PERISCOPE Project will help scientists and clinicians move forward.

MarianVejcik/Getty Images

Dominic Kelly, PhD, talked about vaccine-induced immunity and provided an overview of ongoing clinical trials in the PERISCOPE (Pertussis Correlates of Protection Europe) project in a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. Dr. Kelly, a pediatrician at the Children’s Hospital in Oxford and a member of the Oxford Vaccines Group, leads one of the studies in the project looking at infant vaccination.

Dr. Kelly began his presentation by showing a figure depicting where vaccine-induced immunity fits into the larger suite of clinical studies. These studies involve mouse models, human challenge models, and infection patients. A key theme is the use of a core group of immunoassays across all studies, with the hope that they will allow effective cross comparisons.

Dr. Kelly stated, “If we find a correlate of protection in the challenge model, we can then interpret the vaccine studies in the light of that because we are using standardized constant immunoassays.”

The assays being used depend in part on the specific study and the volume of blood available. They will generally include Bordetella-specific antibody and functional antibody assays, as well as interesting studies collecting mucosal samples from infants and adults to look at serological responses. Also under examination are a range of enzyme-linked immune absorbent spot, flow cytometry, and culture techniques looking at Memory B cells, T cells, and gene expression.

Complementing these assay studies, PERISCOPE includes a series of clinical investigations designed to throw light on three areas of interest, described below:

First, researchers hope to gain a better understanding regarding the effects of the original whole cell vaccine versus the current acellular variety. The former uses an inactivated version of the whole organism. Epidemiological studies, animal data, and experience in the field demonstrate that whole-cell vaccination results in a broad, long-lasting, and effective immune response.

By comparison, the acellular pertussis vaccine consists of between three and five protein components, which are purified from cultured Bordetella pertussis. While it is an effective vaccine, its effects are less durable; routine use in some countries is associated with cyclical outbreaks of increasing severity.

A second issue for researchers involved in the PERISCOPE project concerns the effects of maternal immunization. In the United Kingdom in 2012, for example, an increasing number of cases were noted 6-7 years after adoption of an acellular vaccine for routine vaccination in the 2nd-3rd trimester of pregnancy. Vaccination appears to effectively control neonatal disease, but whether this influences infant immune responses and long-term control of pertussis for a population is unknown.

Finally, the group is interested in the effects of an acellular booster across all age groups. While the effects may be short-lived, the booster is a potential strategy for controlling a population by repeated boosting of immunity. This is another area where using novel immunoassays may aid better understanding.

To find answers, the consortium has established four studies: the Gambia Pertussis study (GaPs) in Gambia and AWARE, the sister study to GaPs in the United Kingdom, addressing the acellular pertussis versus cellular pertussis question; the Pertussis Maternal Immunization Study in Finland (MIFI) addressing maternal immunization; and the Booster against Pertussis (BERT) study across three countries (U.K., the Netherlands, and Finland) looking at acellular booster across age groups.
 

Gambia pertussis study

GaPs is the largest single study in the project and is being run at the Medical Research Council–funded London School of Tropical Medicine center in Gambia. Beate Kampmann, MD, PhD, of Imperial College London, England, is the project lead. It is due to complete in 2022. GaPs seeks to enroll 600 mother/infant pairs and randomize the mothers to either an acellular pertussis booster in pregnancy or a tetanus toxoid control vaccine. Infants are subsequently randomized to an acellular or whole-cell pertussis schedule of primary immunization. The vaccine doses are being given at 2, 3, and 4 months. The primary endpoint is a serological finding being measured at 9 months of age, when the infant would usually receive yellow fever, measles, and rubella vaccination.

GaPs has a number of pathways. Within each of the four arms generated by the two randomizations, the maternal randomization and the infant randomization, there are five subgroups. They are designed to study time points in subgroups A and B after the first dose in more detail, looking at the innate immune responses using gene expression. It will enable researchers to study adaptive immune responses to T cells and B cells after the second dose of vaccine. By employing a range of subgroups, the team can explore the immune profile using the assays referred to above. Such information should provide new insights into the differences between acellular and whole-cell vaccines.
 

The AWARE study

AWARE is the sister study to GaPs and looks at the acellular/whole pertussis issue. Because many developed countries, such as the United Kingdom, have established maternal immunization programs, it is not possible to randomize mothers. Consequently, researchers have opted to recruit infants of mothers who have received an acellular vaccine in pregnancy and randomize them to either an acellular schedule of primary immunization or a whole-cell schedule.

The selected vaccine is ComVac5 from Bharat Biotech. This whole-cell vaccine differs from that used in Gambia. An early obstacle for AWARE has been seeking permission to import a non-conventional vaccine into Europe. It has delayed the anticipated end date to 2023. Participating infants will receive a two-dose schedule at 2 and 4 months of age per their randomization; then, both groups will go on to receive an acellular pertussis booster at 12 months. At all time points, the team will sample blood for cells and serum, as well as mucosal fluid from the nose. Because the mucosal surface is where the action is, this approach will likely generate new data around antibody responses.
 

The MIFI

The Pertussis Maternal Immunization Study in Finland is being run by Jussi Mertsola, of the University of Turku, Finland, and Qiushui He, of the National Public Health Institute, Turku. It is due to complete in late 2021. Where, in the United Kingdom, researchers are unable to randomize mothers because of the current guidelines, researchers in Finland do not have a maternal immunization program to consider. MIFI will randomize 80 mothers, 40 to immunization with acellular pertussis and 40 to a control group. Dr. Kelly stated that whole cell vaccines are not available for use in Finland. Participants will receive a two-dose schedule at 3 and 5 months. Blood samples will then be taken to compare the serological and cellular responses, which will help researchers understand the effects of maternal immunization. In addition, there will be sampling of mucosal fluid using a device that collects a standardized aliquot of fluid.
 

The BERT study

The final clinical element of PERISCOPE presented by Dr. Kelly was the Booster against Pertussis study. This study is near completion. It seeks to examine the use of an acellular booster across different age groups and three countries: the United Kingdom, the Netherlands, and Finland. The study is being coordinated by Guy Berbers, PhD, at the National Institute for Public Health and the Environment in the Netherlands.

BERT comprises four cohorts (A, B, C, D) of different ages: 7-10 years (36 participants), 11-15 years (36 participants), mid-adult (25 participants), and older age (25 participants). After receiving an acellular booster, participants will undergo intense sampling. Sampling will take place immediately after immunization at day 7 and look at adaptive effects, then again at day 28 and day 365.

Because some participants will have already received whole cell or acellular vaccination, this approach will allow researchers to look at the effects of priming (i.e., how long the B cell/T cell antibody responses last).

Involving different countries across Europe ensures wide applicability of results, but also allows researchers to compare the effects of very different immunization histories.

At the end of this ESPID session, Dimitri Diavatopoulos, PhD, assistant professor at the Radboud University Medical Centre Nijmegen, the Netherlands, commented that a future problem in studying pertussis vaccines and their potential clinical application is that most vaccination schedules now involve combination products. Obtaining a stand-alone vaccination may prove difficult, and there may be resistance if it complicates current vaccination programs.

Dr. Kelly acknowledged funding for the PERISCOPE project from GlaxoSmithKline and Pasteur Sanofi.

With increasing whooping cough numbers, developing an effective new vaccine against Bordetella pertussis is a priority. Results from the multifactorial PERISCOPE Project will help scientists and clinicians move forward.

MarianVejcik/Getty Images

Dominic Kelly, PhD, talked about vaccine-induced immunity and provided an overview of ongoing clinical trials in the PERISCOPE (Pertussis Correlates of Protection Europe) project in a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. Dr. Kelly, a pediatrician at the Children’s Hospital in Oxford and a member of the Oxford Vaccines Group, leads one of the studies in the project looking at infant vaccination.

Dr. Kelly began his presentation by showing a figure depicting where vaccine-induced immunity fits into the larger suite of clinical studies. These studies involve mouse models, human challenge models, and infection patients. A key theme is the use of a core group of immunoassays across all studies, with the hope that they will allow effective cross comparisons.

Dr. Kelly stated, “If we find a correlate of protection in the challenge model, we can then interpret the vaccine studies in the light of that because we are using standardized constant immunoassays.”

The assays being used depend in part on the specific study and the volume of blood available. They will generally include Bordetella-specific antibody and functional antibody assays, as well as interesting studies collecting mucosal samples from infants and adults to look at serological responses. Also under examination are a range of enzyme-linked immune absorbent spot, flow cytometry, and culture techniques looking at Memory B cells, T cells, and gene expression.

Complementing these assay studies, PERISCOPE includes a series of clinical investigations designed to throw light on three areas of interest, described below:

First, researchers hope to gain a better understanding regarding the effects of the original whole cell vaccine versus the current acellular variety. The former uses an inactivated version of the whole organism. Epidemiological studies, animal data, and experience in the field demonstrate that whole-cell vaccination results in a broad, long-lasting, and effective immune response.

By comparison, the acellular pertussis vaccine consists of between three and five protein components, which are purified from cultured Bordetella pertussis. While it is an effective vaccine, its effects are less durable; routine use in some countries is associated with cyclical outbreaks of increasing severity.

A second issue for researchers involved in the PERISCOPE project concerns the effects of maternal immunization. In the United Kingdom in 2012, for example, an increasing number of cases were noted 6-7 years after adoption of an acellular vaccine for routine vaccination in the 2nd-3rd trimester of pregnancy. Vaccination appears to effectively control neonatal disease, but whether this influences infant immune responses and long-term control of pertussis for a population is unknown.

Finally, the group is interested in the effects of an acellular booster across all age groups. While the effects may be short-lived, the booster is a potential strategy for controlling a population by repeated boosting of immunity. This is another area where using novel immunoassays may aid better understanding.

To find answers, the consortium has established four studies: the Gambia Pertussis study (GaPs) in Gambia and AWARE, the sister study to GaPs in the United Kingdom, addressing the acellular pertussis versus cellular pertussis question; the Pertussis Maternal Immunization Study in Finland (MIFI) addressing maternal immunization; and the Booster against Pertussis (BERT) study across three countries (U.K., the Netherlands, and Finland) looking at acellular booster across age groups.
 

Gambia pertussis study

GaPs is the largest single study in the project and is being run at the Medical Research Council–funded London School of Tropical Medicine center in Gambia. Beate Kampmann, MD, PhD, of Imperial College London, England, is the project lead. It is due to complete in 2022. GaPs seeks to enroll 600 mother/infant pairs and randomize the mothers to either an acellular pertussis booster in pregnancy or a tetanus toxoid control vaccine. Infants are subsequently randomized to an acellular or whole-cell pertussis schedule of primary immunization. The vaccine doses are being given at 2, 3, and 4 months. The primary endpoint is a serological finding being measured at 9 months of age, when the infant would usually receive yellow fever, measles, and rubella vaccination.

GaPs has a number of pathways. Within each of the four arms generated by the two randomizations, the maternal randomization and the infant randomization, there are five subgroups. They are designed to study time points in subgroups A and B after the first dose in more detail, looking at the innate immune responses using gene expression. It will enable researchers to study adaptive immune responses to T cells and B cells after the second dose of vaccine. By employing a range of subgroups, the team can explore the immune profile using the assays referred to above. Such information should provide new insights into the differences between acellular and whole-cell vaccines.
 

The AWARE study

AWARE is the sister study to GaPs and looks at the acellular/whole pertussis issue. Because many developed countries, such as the United Kingdom, have established maternal immunization programs, it is not possible to randomize mothers. Consequently, researchers have opted to recruit infants of mothers who have received an acellular vaccine in pregnancy and randomize them to either an acellular schedule of primary immunization or a whole-cell schedule.

The selected vaccine is ComVac5 from Bharat Biotech. This whole-cell vaccine differs from that used in Gambia. An early obstacle for AWARE has been seeking permission to import a non-conventional vaccine into Europe. It has delayed the anticipated end date to 2023. Participating infants will receive a two-dose schedule at 2 and 4 months of age per their randomization; then, both groups will go on to receive an acellular pertussis booster at 12 months. At all time points, the team will sample blood for cells and serum, as well as mucosal fluid from the nose. Because the mucosal surface is where the action is, this approach will likely generate new data around antibody responses.
 

The MIFI

The Pertussis Maternal Immunization Study in Finland is being run by Jussi Mertsola, of the University of Turku, Finland, and Qiushui He, of the National Public Health Institute, Turku. It is due to complete in late 2021. Where, in the United Kingdom, researchers are unable to randomize mothers because of the current guidelines, researchers in Finland do not have a maternal immunization program to consider. MIFI will randomize 80 mothers, 40 to immunization with acellular pertussis and 40 to a control group. Dr. Kelly stated that whole cell vaccines are not available for use in Finland. Participants will receive a two-dose schedule at 3 and 5 months. Blood samples will then be taken to compare the serological and cellular responses, which will help researchers understand the effects of maternal immunization. In addition, there will be sampling of mucosal fluid using a device that collects a standardized aliquot of fluid.
 

The BERT study

The final clinical element of PERISCOPE presented by Dr. Kelly was the Booster against Pertussis study. This study is near completion. It seeks to examine the use of an acellular booster across different age groups and three countries: the United Kingdom, the Netherlands, and Finland. The study is being coordinated by Guy Berbers, PhD, at the National Institute for Public Health and the Environment in the Netherlands.

BERT comprises four cohorts (A, B, C, D) of different ages: 7-10 years (36 participants), 11-15 years (36 participants), mid-adult (25 participants), and older age (25 participants). After receiving an acellular booster, participants will undergo intense sampling. Sampling will take place immediately after immunization at day 7 and look at adaptive effects, then again at day 28 and day 365.

Because some participants will have already received whole cell or acellular vaccination, this approach will allow researchers to look at the effects of priming (i.e., how long the B cell/T cell antibody responses last).

Involving different countries across Europe ensures wide applicability of results, but also allows researchers to compare the effects of very different immunization histories.

At the end of this ESPID session, Dimitri Diavatopoulos, PhD, assistant professor at the Radboud University Medical Centre Nijmegen, the Netherlands, commented that a future problem in studying pertussis vaccines and their potential clinical application is that most vaccination schedules now involve combination products. Obtaining a stand-alone vaccination may prove difficult, and there may be resistance if it complicates current vaccination programs.

Dr. Kelly acknowledged funding for the PERISCOPE project from GlaxoSmithKline and Pasteur Sanofi.

With increasing whooping cough numbers, developing an effective new vaccine against Bordetella pertussis is a priority. Results from the multifactorial PERISCOPE Project will help scientists and clinicians move forward.

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Dominic Kelly, PhD, talked about vaccine-induced immunity and provided an overview of ongoing clinical trials in the PERISCOPE (Pertussis Correlates of Protection Europe) project in a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. Dr. Kelly, a pediatrician at the Children’s Hospital in Oxford and a member of the Oxford Vaccines Group, leads one of the studies in the project looking at infant vaccination.

Dr. Kelly began his presentation by showing a figure depicting where vaccine-induced immunity fits into the larger suite of clinical studies. These studies involve mouse models, human challenge models, and infection patients. A key theme is the use of a core group of immunoassays across all studies, with the hope that they will allow effective cross comparisons.

Dr. Kelly stated, “If we find a correlate of protection in the challenge model, we can then interpret the vaccine studies in the light of that because we are using standardized constant immunoassays.”

The assays being used depend in part on the specific study and the volume of blood available. They will generally include Bordetella-specific antibody and functional antibody assays, as well as interesting studies collecting mucosal samples from infants and adults to look at serological responses. Also under examination are a range of enzyme-linked immune absorbent spot, flow cytometry, and culture techniques looking at Memory B cells, T cells, and gene expression.

Complementing these assay studies, PERISCOPE includes a series of clinical investigations designed to throw light on three areas of interest, described below:

First, researchers hope to gain a better understanding regarding the effects of the original whole cell vaccine versus the current acellular variety. The former uses an inactivated version of the whole organism. Epidemiological studies, animal data, and experience in the field demonstrate that whole-cell vaccination results in a broad, long-lasting, and effective immune response.

By comparison, the acellular pertussis vaccine consists of between three and five protein components, which are purified from cultured Bordetella pertussis. While it is an effective vaccine, its effects are less durable; routine use in some countries is associated with cyclical outbreaks of increasing severity.

A second issue for researchers involved in the PERISCOPE project concerns the effects of maternal immunization. In the United Kingdom in 2012, for example, an increasing number of cases were noted 6-7 years after adoption of an acellular vaccine for routine vaccination in the 2nd-3rd trimester of pregnancy. Vaccination appears to effectively control neonatal disease, but whether this influences infant immune responses and long-term control of pertussis for a population is unknown.

Finally, the group is interested in the effects of an acellular booster across all age groups. While the effects may be short-lived, the booster is a potential strategy for controlling a population by repeated boosting of immunity. This is another area where using novel immunoassays may aid better understanding.

To find answers, the consortium has established four studies: the Gambia Pertussis study (GaPs) in Gambia and AWARE, the sister study to GaPs in the United Kingdom, addressing the acellular pertussis versus cellular pertussis question; the Pertussis Maternal Immunization Study in Finland (MIFI) addressing maternal immunization; and the Booster against Pertussis (BERT) study across three countries (U.K., the Netherlands, and Finland) looking at acellular booster across age groups.
 

Gambia pertussis study

GaPs is the largest single study in the project and is being run at the Medical Research Council–funded London School of Tropical Medicine center in Gambia. Beate Kampmann, MD, PhD, of Imperial College London, England, is the project lead. It is due to complete in 2022. GaPs seeks to enroll 600 mother/infant pairs and randomize the mothers to either an acellular pertussis booster in pregnancy or a tetanus toxoid control vaccine. Infants are subsequently randomized to an acellular or whole-cell pertussis schedule of primary immunization. The vaccine doses are being given at 2, 3, and 4 months. The primary endpoint is a serological finding being measured at 9 months of age, when the infant would usually receive yellow fever, measles, and rubella vaccination.

GaPs has a number of pathways. Within each of the four arms generated by the two randomizations, the maternal randomization and the infant randomization, there are five subgroups. They are designed to study time points in subgroups A and B after the first dose in more detail, looking at the innate immune responses using gene expression. It will enable researchers to study adaptive immune responses to T cells and B cells after the second dose of vaccine. By employing a range of subgroups, the team can explore the immune profile using the assays referred to above. Such information should provide new insights into the differences between acellular and whole-cell vaccines.
 

The AWARE study

AWARE is the sister study to GaPs and looks at the acellular/whole pertussis issue. Because many developed countries, such as the United Kingdom, have established maternal immunization programs, it is not possible to randomize mothers. Consequently, researchers have opted to recruit infants of mothers who have received an acellular vaccine in pregnancy and randomize them to either an acellular schedule of primary immunization or a whole-cell schedule.

The selected vaccine is ComVac5 from Bharat Biotech. This whole-cell vaccine differs from that used in Gambia. An early obstacle for AWARE has been seeking permission to import a non-conventional vaccine into Europe. It has delayed the anticipated end date to 2023. Participating infants will receive a two-dose schedule at 2 and 4 months of age per their randomization; then, both groups will go on to receive an acellular pertussis booster at 12 months. At all time points, the team will sample blood for cells and serum, as well as mucosal fluid from the nose. Because the mucosal surface is where the action is, this approach will likely generate new data around antibody responses.
 

The MIFI

The Pertussis Maternal Immunization Study in Finland is being run by Jussi Mertsola, of the University of Turku, Finland, and Qiushui He, of the National Public Health Institute, Turku. It is due to complete in late 2021. Where, in the United Kingdom, researchers are unable to randomize mothers because of the current guidelines, researchers in Finland do not have a maternal immunization program to consider. MIFI will randomize 80 mothers, 40 to immunization with acellular pertussis and 40 to a control group. Dr. Kelly stated that whole cell vaccines are not available for use in Finland. Participants will receive a two-dose schedule at 3 and 5 months. Blood samples will then be taken to compare the serological and cellular responses, which will help researchers understand the effects of maternal immunization. In addition, there will be sampling of mucosal fluid using a device that collects a standardized aliquot of fluid.
 

The BERT study

The final clinical element of PERISCOPE presented by Dr. Kelly was the Booster against Pertussis study. This study is near completion. It seeks to examine the use of an acellular booster across different age groups and three countries: the United Kingdom, the Netherlands, and Finland. The study is being coordinated by Guy Berbers, PhD, at the National Institute for Public Health and the Environment in the Netherlands.

BERT comprises four cohorts (A, B, C, D) of different ages: 7-10 years (36 participants), 11-15 years (36 participants), mid-adult (25 participants), and older age (25 participants). After receiving an acellular booster, participants will undergo intense sampling. Sampling will take place immediately after immunization at day 7 and look at adaptive effects, then again at day 28 and day 365.

Because some participants will have already received whole cell or acellular vaccination, this approach will allow researchers to look at the effects of priming (i.e., how long the B cell/T cell antibody responses last).

Involving different countries across Europe ensures wide applicability of results, but also allows researchers to compare the effects of very different immunization histories.

At the end of this ESPID session, Dimitri Diavatopoulos, PhD, assistant professor at the Radboud University Medical Centre Nijmegen, the Netherlands, commented that a future problem in studying pertussis vaccines and their potential clinical application is that most vaccination schedules now involve combination products. Obtaining a stand-alone vaccination may prove difficult, and there may be resistance if it complicates current vaccination programs.

Dr. Kelly acknowledged funding for the PERISCOPE project from GlaxoSmithKline and Pasteur Sanofi.