Over the last week, the topic of COVID-19 booster shots -- a third dose of mRNA vaccine for healthy Americans -- has been thrust into the spotlight. The surgeon general, CDC director, Anthony Fauci, MD, and President Biden have announced that they wish for boosters to be available by late September for healthy adults who are 8 months out from their original two-dose series. While this will be contingent on an FDA evaluation to determine the "," a clear path forward has already been set. And just like everything else throughout the course of the pandemic, the choice has been made with a dearth of data and an abundance of political pressure.
Diminishing vaccine effectiveness supposedly makes the case for boosters. But there are two big questions here: First, what is current vaccine effectiveness? And second, what justifies boosters? Let's consider these in turn.
What Is Vaccine Effectiveness Now?
We have to be honest, many vaccine effectiveness studies are poorly done. All studies compare the rate of getting a breakthrough infection among vaccinated people against the rate of infection in unvaccinated people. But there are some issues with this approach. First, as time goes on, more unvaccinated people have had and recovered from COVID-19 (and these individuals may be less likely to go on to get a shot). This means that their risk of getting COVID-19 a second time is far less than the typical unvaccinated person who has never been sick. Even if vaccines "work" as well as before, this factor alone will result in the appearance of diminishing vaccine effectiveness.
Second, the order of vaccination in all nations is non-random. The folks who got vaccinated first are often the oldest and most vulnerable people with frailty and senescent immune systems. Vaccine effectiveness after 6 months, 8 months, and 12 months increasingly compares older, frailer people who got vaccinated first against unvaccinated people. These older people may always have a slightly higher risk of breakthrough infections. This bias will also give the false appearance of diminishing vaccine effectiveness.
A third consideration: We're looking at vaccine effectiveness, but for what? People don't want to get severely ill from SARS-CoV-2 and don't want to die, but it might be too much to ask that vaccines prevent the nucleotide sequence of SARS-CoV-2 from ever being in your nose. In other words, vaccine effectiveness against severe disease may be much higher than vaccine effectiveness against asymptomatic or mild infection. This matters a great deal -- if the vaccines continue to be highly effective against risk of severe illness and death, is it really worth boosting people in the U.S. right now?
And putting this all together, the do, in fact, still show high protection against severe disease and death.
What Justifies Boosters?
No matter what vaccine effectiveness is against preventing COVID-19 illness generally, the important question for boosters is whether they further lower the risk of severe disease or death. The only way to show this is through randomized controlled trials of the size and duration to measure that outcome. It is entirely possible that vaccine effectiveness is not perfect over time, or slightly lower than initial trials, but it's also possible that boosters do not further reduce the risk of SARS-CoV-2. Only trials can answer this.
While emerging data from Israel boosters may diminish the risk for COVID-19 infection and severe illness in people 60 and older, the data are not based on the types of studies we need. Pfizer to the FDA to support their boosters, with phase III trial data forthcoming. But again, the data may be insufficient if severe outcomes are not captured.
Moreover, we have to consider the risk of new, compounding, and worse toxicity. Randomized trials and close observation will be needed to exclude worse safety signals, particularly increases in myocarditis and pericarditis. These rare adverse events are more common after the second mRNA dose -- will they be even more common after dose three?
In short, diminished vaccine effectiveness does not make the case for boosters. A reduction in severe outcomes makes the case for boosters, but we have no such data to date.
Global Equity
There's also the ethical question of how a wealthy nation can give its inhabitants a third dose when there are literally billions of vulnerable older people around the world who have not gotten any doses. The World Health Organization not to do this, and history will judge us poorly if we pursue this. It is a human rights violation to direct limited mRNA supply and capabilities to third doses in the U.S. when the world remains vulnerable. Moreover, it is self-defeating. We are not safe from global variants.
Take a Step Back
Decisions about boosters have to be based in science and made by vaccine regulators. They should not be subject to the pressure of manufacturers, politicians, or political appointees. They should not be rushed. On Sunday television, Surgeon General Vivek Murthy, MD, was specifically asked if the third shot was safe. His response: ""
Excuse me? We don't know that to be true, and yet, our top medical and public health experts are ? Drug safety expert Walid Gellad, MD, MPH, : "It was irresponsible to push for boosters in healthy people before safety review."
Two days after the White House's announcement, two people with knowledge of the FDA's deliberation told The Washington Post that the agency was investigating myocarditis signal with the . Canadian data suggest the risk may be 2.5 times that of Pfizer's vaccine. The timing of this internal information leaking to reporters naturally leads me to wonder if reviewers in the agency are attempting to counteract political pressure, and create space to conduct a thorough review of booster data.
Boosters are an important medical question. Their approval must have a favorable safety and efficacy profile. Only randomized trials measuring severe disease can show that.
is a hematologist-oncologist and associate professor of medicine at the University of California San Francisco, and author of .
Disclosures
Prasad has relationships with Arnold Ventures, UnitedHealthcare, eviCore, and New Century Health.