FDA Struggles to Find Way Forward on COVID-19 Vaccine
‘The best we can with the knowledge we have at hand’
Vaccine advisors to the Food and Drug Administration (FDA) face a tight timeline and a host of unknowns as they try to prepare for an expected winter surge of COVID-19, all the while acknowledging that any plan forward could be dashed by the emergence of a new variant of the pandemic virus. Such was the tone during a long day of discussions at an April 6, 2022, meeting of the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC).
With the general expectation that COVID-19 will surge again in the fall and winter of 2022-2023, there was a sense of urgency to determine what type of vaccine could be ready given the demands of production and distribution. There was some consensus that a bivalent or multivalent vaccine should be pursued, conferring broader protection against more COVID-19 variants. However, the daunting timeline of such an effort means the reality could be another booster shot, although few see that as a path out of the pandemic.
“What really keeps me up at night is the knowledge that we can’t [just] keep boosting and that we’re going to have vaccine exhaustion,” said Peter Marks, MD, PhD, director of the FDA Center for Biologics Evaluation & Research. “I don’t mean immune exhaustion. I’m talking about the physical exhaustion of people [about] getting boosted.”
If a new vaccine is pursued, the safety and efficacy appraisal would have to be done in the near-term, making clinical trial data less likely to be available than some surrogate measures of immunity. The consensus was that this was not ideal, in a meeting where few things were.
“We would love to have a correlate of protection, but we don’t have it,” said Arnold Monto, MD, acting chair of VRBPAC. “We realize that clinical trial data will be necessary, but we might have to use surrogates if that becomes necessary. Our focus is on preventing hospitalization and death.”
Wary of increasing public confusion by taking a scatter-shot approach, some suggested the committee ultimately should unite in recommending whatever vaccine components are decided upon to all manufacturers.
“I will put my foot forward proposing that we have a unified approach to vaccination and strain content for the vaccines offered here in the U.S.,” said committee member Michael Nelson, MD, PhD. “I think it’ll be important, seeing the confusion that’s already occurred with the launch of vaccines that have been approved and put out through emergency use authorization to the public.”
Advocating a more intentional framework, Nelson advised only making vaccine changes when “we feel confident it is going to substantially lead to a longer duration of baseline immunity. I think that we need to use our predictive models and perhaps pivot to a multivalent approach that includes some baseline immunity from historically evidence-based strains. Then, intentionally and cautiously, fold in additional variants that may provide a longer range approach to sustained immunity, both on the humoral and cellular side.”
Winter Is Coming
To meet a winter surge, shots would need to be administered beginning in October or November of this year “to protect against a wave that could come at the highest time that we were at risk for any kind of respiratory viruses as we are going inside again,” Marks said.
Some models show people with two doses of messenger ribonucleic acid (mRNA) vaccines, and even some that have received three shots, could be at risk, he added. A fourth shot, or second booster, for people aged 50 years and older, and those who are immunocompromised recently was approved by the FDA and recommended by the Centers for Disease Control and Prevention (CDC).
However, this approach may have diminishing returns, as evidenced by a recent Israeli study in recipients of a fourth dose of the Pfizer mRNA vaccine: “Protection against confirmed infection appeared short-lived, whereas protection against severe illness did not wane during the study period,” the authors concluded.1
In summarizing the committee’s discussion, Monto said, “We don’t feel comfortable with multiple boosters every eight weeks. [We] would love to see an annual vaccination, similar to influenza, but realize that the evolution of the virus will dictate how we respond in terms of additional vaccine doses.”
Maintaining at least an 80% protection against hospitalization and death is the goal of any new iteration of the vaccine, which will be complemented by the continuing development of antivirals and other therapeutics, he said.
“We realize you can’t prevent everything, especially with an evolving virus, and the need for revaccination will really be dictated by the virus more than by us,” Monto said.
In that regard, Nelson cited the rapid emergence of Omicron to underscore the lean options if another variant of concern suddenly appears. The variant was discovered on Nov. 26, 2021, in Africa, and the first case appeared in the United States in early December, he noted.
“To make a decision on a change in vaccination, and to launch it in time to prevent that disease, would not have occurred with the Omicron variant, specifically,” Nelson said. “Had we pivoted all our vaccines to that particular variant, we would be at risk of not only missing the waves, but perhaps being so antigenically distinct from others that will come, we may have missed the boat in providing baseline advancement in immune protection.”
The FDA is committed to improving vaccines, and research is ongoing on “mucosal vaccines, pan-coronavirus vaccines, but we’re not going to get there for this coming year,” Marks said. “This is really trying to do the best we can with the knowledge we have at hand, which is something that we’ve had to do a fair amount of over the past two years as a public health agency.”
Indeed, there are so many variables and open questions that, at one point, VRPAC member Oveta Fuller, PhD, called for more public understanding of how complex the task is before the FDA and the committee. “We’re in uncharted territory,” she said. “I don’t think the public really understands how complex it is, and I don’t even think we have understood, until a number of things came up today. We don’t know what will happen with the strains that come up, but we do know that the current vaccines do protect well, as long as there’s a reasonable time of boost, against hospitalizations and death. And that’s really, really important. We’re going to have to learn as we go.”
Indeed, this served as timely reminder that the vaccines have effectively staved off serious infections, and there is the sentiment in some corners that they may just hold up in this regard.
That said, the committee must think forward even without all the answers, said committee member Ofer Levy, MD, PhD, who reminded that two years ago, “We had nothing, and any vaccine that had some safety and even modest efficacy would have been a godsend.”
“Right now, we have to deal with what’s in front of us. The main platform in the coming year will be the mRNA vaccines — and thank god we have them,” Levy continued. “There’s a lot of different types of work to be done here and yes, we want to keep our eye on what’s practical, but we also want to be ambitious toward the future. Because maybe in a year, year and a half, or two years, we can have something even better. We’re going to get there by working together in a systematic way.”
While new vaccines are in the future, it still is somewhat striking how many millions of Americans have not been immunized at all, have suboptimal dosing, or are declining the boosters.
“We still need to get more people vaccinated,” said committee member Hank Bernstein, DO, MHCM, FAAP. “It seems quite obvious that those who are vaccinated do better than those [who] are unvaccinated when we look at all of the outcomes,” “I think it’s imperative of us to clearly communicate to the public what we’re thinking and what our overall aim is. I would suggest it is to prevent severe disease, hospitalization, and death more than just infection prevention.”
The panel also discussed meeting more frequently in the coming months and having other federal agencies help determine any new vaccine.
“There’s so many things that are changing and things we don’t know,” Fuller said. “The virus is changing, and we don’t know what will happen. We have models that help us predict, and we have surveillance that helps us look at what is happening. We have waning immunity. We also don’t know the systemic effects of COVID. We still have long COVID, and, clearly, we still have rare but very real vaccine effects.”
To that latter point, the continuing and frequent vaccination of people for COVID-19 may exacerbate the side effects and adverse events, she added. The argument still holds that the disease outcomes are much worse than those caused by the vaccines.
“We know COVID can lead to death and hospitalizations, and we know the current vaccines protect against that, but we need people to understand that that’s not the end-all, that’s not the magic formula,” Fuller said. “There’s some risk involved, but the risk of the disease — by multiple times — is much worse than the risk of the vaccine. This is not a perfect system.”
There was discussion of eventually establishing something like the ongoing surveillance and seasonal production used to create an annual influenza vaccine.
“Even though we’ve got a well-established process that works really well for influenza, there’s so much more unpredictability and unknowns [with COVID] that it is an imperfect model,” said committee member Melinda Wharton, MD, MPH, associate director for vaccine policy at the CDC. “It doesn’t seem like it’s feasible to create a type-specific vaccine in a time frame that would allow it to be used for a rapidly circulating variant like Omicron did, so it does feel to me like the strategy that ultimately is going to be most effective for us is how to use the vaccine technologies that are currently available to hopefully create broader protection that will provide protection against a variety of variants, given that we can’t really predict what’s going to circulate.”
- Bar-On YM, Goldberg Y, Mandel M, et al. Protection by a fourth dose of BNT162b2 against omicron in Israel. N Engl J Med 2022; Apr 5. doi: 10.1056/NEJMoa2201570. [Online ahead of print].
Vaccine advisors to the Food and Drug Administration face a tight timeline and a host of unknowns as they try to prepare for an expected winter surge of COVID-19, all the while acknowledging that any plan forward could be dashed by the emergence of a new variant of the pandemic virus.
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