Food and Drug Administration advisory committee meetings tend to be staid, albeit important, events typically watched by a few dozen company representatives, scientists, investors and patient advocates.
But next week's hearing on coronavirus vaccine studies will be set against the backdrop of a presidential election 12 days later that could turn on the White House's response to the pandemic, likely making it a closely-watched affair of historic proportions.
The agency is expecting an audience of tens of thousands even though the outside experts convened remotely won't be asked to make a specific recommendation on approving a shot.
Two experimental vaccines, developed by Pfizer and Moderna, are nearing data readouts that, if positive, could support an emergency authorization. The companies almost certainly won't have anything to show the FDA in time for the Oct. 22 meeting, but the advisory committee still will have plenty to discuss.
Late-stage clinical trials enrolling hundreds of thousands of volunteers are underway. The outside experts comprising the advisory committee will be asked what additional research must be done to assess the shots' safety and effectiveness. In particular, the discussion could focus on the use of vaccines in under-studied or at-risk populations, safety evaluations for any granted emergency authorization and the likely durability of any protective benefit shown.
"The vaccine is going to hopefully go into hundreds of millions of people in this country and billions around the world," Thomas Russo, infectious diseases chief at the University of Buffalo, said in an interview. "These trials are just a fraction of that. What if there's a serious adverse reaction that occurs 1 in a million or 5 in a million?
Advisory committee documents, voting questions and panel rosters are typically published 48 hours ahead of meetings, making Oct. 20 a date to keep in mind for further clues on the FDA's views on coronavirus vaccines.
In the meantime, here are five important questions that could feature at next week's meeting.
How will vaccine safety be monitored following an emergency clearance? After a full approval?
The first vaccines likely to gain an emergency use authorization this fall will have, at best, eight months of safety data across early-, mid- and late-stage tests. For those pivotal studies, used to support an FDA OK, participants will have been followed for at most four months if November estimates of an emergency clearance hold.
Agency leaders have been specific about how much data will make them comfortable to authorize a vaccine for emergency use: two months or more of safety data for at least half of the volunteers in a trial. But the FDA will still want to keep evaluating safety to make sure there are no adverse events that might prompt them to withdraw the authorization. The two-month safety mark set by the agency is based on knowledge that most vaccine-related adverse events fall within that time frame.
In its guidance on applying for an emergency use authorization, or EUA, the agency said drugmakers will need to have a plan for monitoring side effects to support continued public use of their vaccines. Moreover, the FDA said issuance of an EUA is not grounds to stop blinded follow-up for safety and efficacy, so vaccine manufacturers will need to plan to monitor for months or years afterward. The expert advisers on the panel will likely be asked for input on good strategies for continued safety follow-up.
How long will immunity last and how would it be measured?
One of the bigger disputes of the SARS-CoV-2 pandemic is how long immunity, either from infection or vaccines, will last. Patients infected with the coronaviruses that caused SARS and MERS had measurable immune responses that ranged between one and three years.
Yet, with the first confirmed re-infection in a U.S. patient reported this week, the question will remain at the top of the agenda, especially as regulators and policymakers consider the possibility that a vaccine protecting against COVID-19 may need to be given annually along with one for influenza.
AstraZeneca CEO Pascal Soriot, whose company is developing a leading vaccine candidate, is among those who have acknowledged that boosters will need to be part of the long-term strategy for vaccination. The advisory committee will likely be asked how best to measure waning immunity, which will need to include ways of adjusting data collection to account for volunteers who withdraw from trials to receive any vaccine that's authorized.
How will vaccine-induced enhanced respiratory disease be monitored?
One of the foremost concerns of vaccine experts is the risk hastily tested coronavirus shots may lead to a condition known as vaccine-induced enhanced respiratory disease, or ERD. When this occurs, weakened antibodies actually help viruses enter cells, exacerbating the condition vaccination was meant to prevent.
Distinguishing between COVID-19 and ERD would require identifying biomarkers, such as certain types of white blood cells that are associated with allergic response and proteins involved in immune signaling, said Paul Offit, director of the Vaccine Education Center at Children's Hospital of Philadelphia, in an email.
The FDA's guidelines state that, for the purposes of an emergency clearance, five or more cases of severe COVID-19 in the placebo arm of a Phase 3 trial would ease concerns about ERD. Five or more cases in volunteers who received a vaccine, on the other hand, would be a sign for researchers to look more closely at the possibility of ERD.
Has enough data been collected on vulnerable groups?
As with most clinical trials, initial coronavirus vaccine studies in the U.S. enrolled mostly White volunteers, leaving out more vulnerable groups, like people over the age of 60 or people who identify as Black, Hispanic or Latino. The early studies also generally looked first at healthy adults under the age of 60, with no other illnesses.
For a vaccine to be effective in curbing the spread of COVID-19, however, vulnerable groups, who have been disproportionately affected by the disease, must be equally protected.
With that goal in mind, Moderna recently slowed enrollment into its large vaccine study to ensure greater representation among those who identify as Black, Hispanic or Latino, and Pfizer added 14,000 patients to its trial to ensure greater diversity among participants.
"We have proven that you can effectively enroll if you have community engagement," said Larry Corey, a virologist at Fred Hutchinson Cancer Research Center and co-head of the National Institutes of Health's COVID-19 Prevention Trials Network, in an interview. But "we won't know anything until we actually see the results. Enrolling doesn't mean that the trial is finished. We need to demonstrate efficacy."
The elderly and patients with comorbidities are also at high risk of COVID-19 complications, making data from those groups of high interest as well.
How other populations like children and pregnant women, who are excluded from the leading Phase 3 trials, will be studied could also be a topic of discussion. Testing vaccines in school-age children is important given their potential role in community transmission, while trials in pregnant women will likely need to be conducted to study possible birth defect risks.
Will future vaccine trials need to measure COVID-19 cases, or will immune response data be enough?
Even if two or three vaccines gain authorization or approval over the next few months, drug developers will want to improve on the first to launch.
But in such a scenario, enrolling in a study massive numbers of volunteers, as many as half of whom could end up receiving a placebo, may grow difficult. The FDA's own guidance on vaccine approval states that, once the first ones gain approval based on prevention of COVID-19, there may be a sufficient benchmark for subsequent vaccines to be cleared on so-called "surrogate" endpoints, like a well-characterized immune response. That will only be the case, however, if the vaccine in question is of a similar type to ones previously approved.
The FDA may want advice from its outside experts on when to use surrogate endpoints, which ones to use and what circumstances may support their use.
Ben Fidler contributed reporting.