By Marie Rosenthal, MS

The FDA’s Vaccines and Related Biological Products Advisory Committee voted against recommending a booster of the COVID-19 vaccine (Comirnaty, Pfizer-BioNTech) in people ages 16 years and older. 

Instead, the committee recommended the booster for those ages 65 and older and people who are at high risk for serious disease. Before adjourning, the members provided clarification about whom they thought should also receive a booster—those at occupational risk for COVID-19.

Peter Marks, MD, PhD, the director of the Center for Biologics Evaluation and Research (CBER) at the FDA, reminded the committee that the FDA did not have to follow the guidance but appreciated the clarification. It sounded as if the FDA will take a broad approach regarding which occupations should receive a booster. Dr. Marks specifically mentioned first responders and teachers, in addition to the health care workers that the committee thought should be included.

The messenger RNA (mRNA) vaccine, Comirnaty, is the only COVID-19 vaccine that has FDA approval versus an emergency use authorization (EUA), which is the legal authority for the distribution of the Moderna mRNA and Johnson & Johnson adenovirus vaccines.

Pfizer and BioNTech sought a Supplemental Biologics License Application (BLA) for a third dose of their vaccine for people ages 16 years and older.

“The emergence of the highly transmissible delta variant of SARS-CoV-2 has led to considerations of the potential need for boosters in fully vaccinated individuals,” explained Marion Gruber, PhD, the director of the FDA’s Office of Vaccines Research and Review, CBER. “Data from post-authorization effectiveness studies conducted suggest that the currently U.S.-authorized or licensed vaccines remain effective in protecting against severe disease; however, some data suggest that effec-tiveness may be waning.” 

She added that some experts are concerned that declining neutralizing antibody titers and reduced efficacy against symptomatic disease could signal decreases in the effectiveness against severe disease. (Dr. Gruber was among the signatories of an editorial in the Lancet that argued against booster doses at this time [2021 Sep 13. doi:10.1016/SO140-6736[21]02046-8], but she did not express her concerns at the meeting. However, she did announce her retirement from the FDA, and several news reports claimed that she retired because she thought the CDC and the COVID response team had overstepped their remit when they announced that the White House was preparing for boosters before the issue was considered by the FDA.)

Sarah Oliver, MD, MPH, an epidemic intelligence officer at the CDC’s Division of Viral Disease, National Center for Immunization and Respiratory Diseases, gave an update on the pandemic and what was at stake.

“To date, over 41 million cases have been reported in the United States,” she said, reminding everyone that this surge is second only to the surge seen in the winter of 2020. The current seven-day moving average is around 145,000 new cases and 1,300 deaths per day. The surge is primarily occurring among unvaccinated people. Unvaccinated people ages 18 to 49 years are 23 times more likely, those 50 to 64 are 22 times more likely, and those 65 and older are 13 times more likely to be hospitalized for COVID-19 than their peers who are vaccinated, she said.

But the real concern of everyone, including Pfizer-BioNTech, is the delta variant, which now accounts for 99% of all U.S. COVID-19 infections, because it is twice as transmissible as the other SARS-CoV-2 strains, and there is concern that immunity wanes after several months. “Pre-delta VE [vaccine effectiveness] estimates are high,” Dr. Oliver said. “VE against infection ranged from 72% to 97%, and against hospitalization from 84% to 97%.” 

Since delta became the predominant circulating strain, VE against infection ranges from 39% to 84% and against hospitalizations from 75% to 95%, she said.

“COVID-19 vaccines continue to maintain high protection against severe disease, hospitalization and death,” Dr. Oliver said, “but protection against infection, including asymptomatic infections, has been lower in recent months.” 

Argument in Favor of Boosters

Data presented earlier in the day, particularly from Israel, gave a compelling argument for booster doses. However, the committee was concerned about a lack of data in younger people who are at increased risk for vaccine-associated myocarditis.

“Post-authorization data demonstrate increased risks of myocarditis and pericarditis, particularly within seven days following the second dose of Comirnaty. The observed risk is higher among males under 40 years of age than among females and older males. The observed risk is highest in males 16 to 17 years of age,” Dr. Gruber said, who added that it was not “known whether there will be an increased risk of myocarditis or pericarditis or other adverse reactions after a booster dose of Comirnaty.”

Israel began vaccinating its population in January and “reached high levels of population-wide immunity about three months before most countries,” explained Sharon Elroy Preiss, MD, MPH, MBA, the director of public health services, Ministry of Health, Israel. 

Then delta hit the country, and they started seeing a rapid increase in cases even though more than 60% of the population was fully vaccinated. In one month, they saw a 10-fold increase in cases, and by May, waning immunity was seen in all age groups, Dr. Preiss said.

Even a seemingly modest 12 percentage point decline in effectiveness could translate into a fivefold increase in severe cases among the vaccinated, she explained. 

The country began administering boosters on July 30, and more than 2.8 million booster doses have been given, mostly to older adults, but also younger people. Following the third dose, they saw a sharp decline in severe cases. Dr. Preiss said they have not seen any adverse events that were different from the first two doses of vaccine, and there were fewer in every category after the third dose. There was only one report of myocarditis in a 30-year-old man, she said. However, she said younger people have only just started getting the third dose in Israel, so adverse events in the adolescent group may not be complete.

However, Dr. Preiss said the booster dose “dampened the severe cases in the fourth wave.”

Pfizer’s presented data on just more than 300 adults who received the booster and extrapolated the basis for a third dose from older adults to those 16 and 17, which the committee did not agree with.

Many members of the committee wanted more data about the myocarditis effects that were seen in adolescents and young adults after the primary series, and they were uncomfortable recommending a booster for that age group without more data. 

It was fairly clear before the vote that the panel was not going to recommend the requested action, and Dr. Marks told them they could vote on the question and if rejected, reword the recommendation—which is what they did. However, the second vote was taken based on the EUA for the Pfizer-BioNTech vaccine rather than the BLA, although it was never explained why that was done.

Committee member, Paul Offit, MD, a pediatric infectious disease doctor at Children’s Hospital in Philadelphia summed it up nicely. “I think the stated goal of this vaccine by people like [CDC Director] Rochelle Wolinsky and others has been to protect against serious illness and the data that were presented by Sarah Oliver …  show that these vaccines do exactly that.”

These studies are consistent with the fact that protection against serious illness is mediated by memory B cells, which have been shown to be induced by two doses of mRNA vaccines and are long-lived. It's clear, however, that the third dose of mRNA vaccines increases the titer of virus-specific neutralizing antibodies, and will likely decrease the incidence of symptomatic infection, which is associated with contagiousness, he explained. 

“So then the question becomes what will be the impact of that on the arc of the pandemic, which may not be all that much? I mean, certainly we all agree that if we want to impact this pandemic we need to vaccinate the unvaccinated,” Dr. Offit said. “We're being asked to approve this as a three-dose vaccine for people 16 years of age and older, without any clear evidence that the third dose for younger person, when compared with an elderly person is a value. 

“If it's not of value, then the risks may outweigh the benefits. And we know that the 16 to 29 year old is at higher risk for myocarditis. 

“While I would probably support a three-dose recommendation for those over 60 or 65, I really have trouble supporting this as written for anyone of greater than, or equal to 16,” Dr. Offit said.

In the end, the committee said it could see the rationale for boosting the immunity of people at high risk for severe disease and health care workers who are sorely needed in the hospital rather than at home recovering from a mild COVID-19 infection.