The Current COVID-19 Booster-Shot Strategy is Not Sustainable, Says FDA’s Expert Panel

While the currently available COVID-19 vaccines remain effective in protecting people from serious disease, public health experts still face a handful of important questions about the shots and their ability to continue to protect against the virus in coming years. Will a new version of the vaccine be more effective? How long does protection last? Are boosters the only way to extend that protection? Is there a better, more coordinated way to give vaccines and boosters to maximize immunity in the face of an ever-changing virus?

Those were the discussion topics that the U.S. Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee addressed in a day-long virtual meeting on April 6. The 28-member committee of independent experts reviewed the available data on vaccine effectiveness and tried to lay the foundation for maximizing the effect of vaccines in curbing COVID-19.

Because public health experts at the Centers for Disease Control and Prevention (CDC) and regulators at the FDA are still learning about how the virus works, and what type of immunity is needed to control it, the U.S.’s vaccination strategy has relied on a game of catch-up: chasing after waves of infections first with the primary vaccinations and then with booster doses to keep those waves from cresting and overwhelming the health care system with sick patients.

For now, the vaccination schedule is a complicated algorithm depending on which vaccine people get, as well as their age and health status.

The Pfizer-BioNTech mRNA vaccine, for example, is approved as a primary vaccination, meaning two doses, for adults 16 and over, and allowed under emergency use authorization for children five years to 15 years old. An additional booster dose is recommended for anyone over age 12, but for children 5 to 11, the booster is only advised for those with weakened immune systems. The Moderna mRNA vaccine is approved for people 18 and over as a two-dose primary vaccination, and for a third, booster dose for this age groups as well. The Johnson&Johnson-Janssen vaccine is authorized as a single primary vaccination with a second booster dose for adults 18 and older.

The FDA also recently authorized a second booster dose (fourth shot) of both Pfizer-BioNTech’s and Moderna’s vaccines for people over age 50 and those with compromised immune systems.

The complex guidelines in part led the FDA to call its committee together in order to come up with a more systematic and effective vaccination strategy moving forward. Currently, 70% of the U.S. population that is eligible to get vaccinated has received their primary immunization—two doses of mRNA vaccines from Pfizer-BioNTech or Moderna, or one dose from Johson&Johnson-Janssen. Only about 50% of this group has received a booster dose.

In addition to the confusing recommendations, studies show that the immunity provided by the vaccines, including the boosters, wanes. The panel heard from CDC scientists, who reported that in studies in which blood serum from people who are fully vaccinated with their primary doses was mixed with the Omicron variant, there was a 25-fold drop in antibodies that could neutralize that variant; among those who were boosted, there was still a 6-fold drop in that neutralization activity.

That means the current booster strategy isn’t sustainable, so the committee discussed ways to establish a more structured plan for studying vaccine effectiveness and making decisions about whether, and when to change the shots or boosters.

One strategy they discussed was the influenza model: With the annual flu shot, an expert panel of scientists invited by the World Health Organization analyze data on the genetics of circulating influenza viruses as well as how much disease they cause. They then recommend which strains of influenza should be included in the annual shot, and health departments in various countries generally follow this advice when making their annual flu vaccines.

That model isn’t entirely applicable to SARS-CoV-2, since researchers don’t fully understand its genetic changes and what they might mean for causing human disease. The variants that have morphed from the original virus so far, including Alpha, Beta, Delta and Omicron, do not represent any pattern or predictable progression from one set of mutations to the next. That’s very different from the influenza virus, which generally does change in broadly predictable ways.

In addition, while most flu vaccines are built the same way, by growing the desired influenza strains in chicken eggs and then generating specific flu proteins to include in the shots, there’s a range of approaches used in COVID-19 vaccines, with some relying on mRNA, some on recombinant viral proteins, and still others on viral vectors to deliver viral messages to the immune system.

Further, with COVID-19, it isn’t clear that an annual vaccine like the influenza approach would make sense, But what would drive that change isn’t entirely obvious either. “The issue of how we decide when the vaccine needs to be modified, and what is going to be the threshold where we say so much escape from vaccine immunity requires a change—that’s such a difficult question to answer,” said Dr. Cody Meissner, director of pediatric infectious disease at Tufts Medical Center, and one of the FDA committee members.

Such decisions would have to be made using data that may not be the gold standard that the committee members would ideally like to see, for practical reasons. If new versions of the vaccines are needed that target different variants, those vaccines would still need to go through safety and clinical testing. Ideally, that would come from months-long studies of people who have been vaccinated and then exposed to the virus, to see if they get infected, and if they do, how sick they get.

But, for example, to have enough new shots ready for a wave of cases in the fall, they would have to be tested and manufactured by May or June. So the committee members discussed the possibility of using the sort of lab-based studies that have driven the authorizations and approvals to date, in which scientists test blood from people vaccinated and measure how well the antibodies the shots produced can neutralize the virus.

Such studies are underway. One that the committee will watch closely is COVAIL, recently launched by the National Institute of Allergy and Infectious Diseases. The trial, which will investigate different booster doses—and versions—of Moderna’s mRNA COVID-19 shots, involves 600 participants at 24 sites across the US. All of the volunteers have been vaccinated with two doses of the Moderna shot, and one booster dose. They will be assigned to one of six different boosters:

“Could we come up with a strategy where we are not chasing variants but could make a vaccine that targets a cocktail of variants?” says Dr. Nadine Rouphael, professor of medicine and executive director of the Hope Clinic at the Emory Vaccine Center, and co-chair of the COVAIL study. “The idea behind COVAIL is to take the available variant vaccines, either alone or in combination, and try to see how the immune responses they generate compare against the [original] vaccine.” Rouphael expects early results sometime this summer. Other similar studies involving Pfizer-BioNTech’s mRNA vaccine are also under way and will provide results in a few months as well.

The current policy of responding to COVID-19 waves with another booster dose “will not get us what we ultimately want, which is basically a vaccine that is more durable and more cross-protective,” says Rouphael. Most of the panel members agreed that a vaccine that targets multiple strains at once, which could also provide longer lasting immunity, might be the logical next step in the COVID-19 vaccination strategy.

The committee also stressed that rather than waiting for the pharmaceutical companies to dictate what shots they are developing, as has been the case so far, the FDA should play a more active role. “Now we have the manufacturers coming to us with proposals for how to evaluate the composition and strain of the vaccines,” said Jerry Weir, director of viral products in the FDA’s Office of Vaccines Research. “What about the idea that we better coordinate in advance what studies need to be done to inform strain selection?”

The committee charged the FDA with providing them as much information on studies like COVAIL, and the genetic changes in SARS-CoV-2 that scientists are tracking, in order to make more informed decisions about what the next step in the COVID-19 vaccine campaign will be. “What keeps me up at night is the knowledge that we can’t keep boosting. We’re going to have vaccine exhaustion, and I’m not talking about immune exhaustion but physical exhaustion from people who won’t get boosted,” said Dr. Peter Marks, director of the Center for Biologics Evaluation and Research at the FDA. “We want people to remain confident in the safety and effectiveness of all COVID-19 vaccines. Our goal is to stay ahead of future variants and outbreaks to ensure we do our best to reduce the toll of disease and death due to COVID-19 on our population.”