In a plot showing the cumulative population-based rate of hospitalizations among vaccinated and unvaccinated people between January and July, the vaccinated line hardly budges, while the unvaccinated line soars upward. According to an unpublished paper presenting that data, the cumulative hospitalization rates in unvaccinated people were 17 times higher than in vaccinated people.
“From what I have seen, there is currently weak evidence at best to support the use of boosters in all people,” Richterman said.
Observational Study Challenges
A constant challenge for public health officials is how to best interpret many of the observational studies evaluating vaccine or booster effectiveness over time, given that the groups being compared are often very different from one another beyond whether they received a shot or not, or at what time.
Even some studies that seem relatively straightforward may not necessarily show what they claim to show.
Take the New York study, which found a decline in vaccine effectiveness against infection over time that many have interpreted as evidence of waning immunity. What’s curious about that data, Dowdy told us, is that while there’s a decline in vaccine effectiveness in younger people and the population as a whole, there isn’t a drop in people over the age of 65 (see figure 1).
“People who got the shot first and whose immune system should be the least strong — we’re not seeing any reduction in the effectiveness of the vaccine over time,” he said. “It would suggest that there is not strong waning of immunity over time, at least in those data.”
Instead, what might be happening, Dowdy said, is that younger people changed their behavior over the summer, while older people did not. “The natural explanation for this is that those people are getting exposed more frequently, more intensively over time,” he said.
Those additional exposures can overwhelm even a great vaccine, Dowdy said, likening the inoculation to an umbrella that works perfectly well in a rainstorm but is less useful in a hurricane. “It doesn’t mean that the umbrella is less effective, it just means you’re getting [more] exposed,” he said.
That’s not to say that there isn’t any waning immunity occurring or that it won’t happen, Dowdy said. But it underscores how difficult it can be to interpret some of the epidemiological data.
The immunology data also back the notion that in healthy people, the vaccines are holding steady against severe COVID-19, if not always against infection or more mild illness.
“We see antibodies going down, but we know that these vaccines make very good T cell responses and B cell responses that very likely protect from serious disease,” E. John Wherry, an immunologist at the University of Pennsylvania who has been studying the immune responses of vaccinated people, told us.
High levels of so-called neutralizing antibodies are needed to prevent infection entirely, or what’s known as sterilizing immunity. But if those decline, which is normal, there are still immune cells around to ward off illness — namely, the B cells that make antibodies and the T cells that assist in that process and can also kill infected cells to limit the spread of a virus in a body.
Both cell types need time to kick into gear when a person is first infected or first vaccinated, but with a second exposure, the cells can re-engage, proliferate and more quickly mount an immune response than before — preventing a person from falling very ill.
“Severe disease occurs when the virus begins to replicate unchecked in the lungs and the immune system misfires in efforts to control it,” Deepta Bhattacharya, an immunologist at the University of Arizona College of Medicine, told us. “Fortunately, the lungs are much more accessible to antibodies than is the upper respiratory tract, which is where the virus first enters. Moreover, because the virus hits the upper respiratory tract first, it buys memory B and T cells time to get going too before the lung becomes accessible to the virus. So for these reasons, protection against severe disease is expected to be maintained for far longer than protection against all infections.”
All of this is why immunologists suspect boosters might not be needed for a while yet.
“We could have protection against severe disease for a year, two years, three years,” said CHOP’s Offit, who nevertheless said boosters were likely eventually. “We’ll see.”
It’s also why Offit doesn’t buy the administration’s argument that fading vaccine immunity against infection or mild disease necessarily presages dwindling effectiveness against severe disease. “I think it’s built on a false premise,” he said.
Bhattacharya similarly said that he thought it would be “years” before a booster is needed to increase protection against severe disease. But if the goal is to prevent infection, then it might take annual boosters to keep antibody levels high.
A Benefit to Boosting Now?
The experts we spoke with agreed that giving third doses of the mRNA vaccines now could very well be somewhat helpful, but likely only to a limited degree — and would not be as advantageous as immunizing unvaccinated people.
“Boosting would almost certainly raise the concentration of antibodies for a while. How much clinical benefit we would see is much harder to predict,” Bhattacharya told us in an email. “Given that most estimates place the current 2-dose regimen at ~80+% effectiveness against symptomatic infections, there is not a ton of room to improve.”
“The real question is whether booster shots enhance memory,” said Dowdy. “If so, they could boost immunity for a longer period of time. But we have no evidence one way or the other on that. And also no compelling evidence that immunity from the initial vaccine series has waned to the extent that a booster is needed.”
While on the surface the Israeli studies suggest boosters might have a large impact, those effects have so far been observed only for a short period of time, and it remains unknown how long they might last.
“It would be very surprising if a third dose of a vaccine that we already know is effective didn’t decrease risk of infection by some amount over the short-term,” Richterman said. But, he added, the extra dose “probably doesn’t decrease it to the degree that these observational studies from Israel suggest because of large differences in exposure risk / behaviors between those getting the booster and those who did not.”
Richterman was especially dubious of the booster preprint that claimed a 10-fold reduction in the risk for severe COVID-19, which he said was “essentially uninterpretable” because it had a design flaw known as immortal time bias. Because outcomes weren’t counted for the boosted group until 12 days after getting the booster, he said, that group likely had less follow-up than the unboosted group, biasing the results in favor of boosters. “It takes on average 5 days from diagnosis to develop severe infection, oftentimes much longer,” he said, “so you can imagine that the boosted group has probably in many cases not even had the chance to have this outcome.”
It should be more clear what effect boosters have once the results are in from Pfizer/BioNTech’s phase 3 randomized controlled trial, he said.
Dowdy also cautioned against relying too heavily on the Israeli experience. Noting that the population of the country is about the same as the state of Michigan — and the U.S. would be unlikely to make national policy based on one state — he said, “we should be similarly hesitant to formulate national policy on data from a country the size of Israel.”
Another potential boon of boosters is their impact on reducing transmission of the coronavirus. But many scientists are skeptical that boosters will do much to bring the pandemic to a close.
“I doubt this would have a dramatic impact on the trajectory of the pandemic,” Bhattacharya said. “We know that vaccinated breakthrough infections can transmit, but the major drivers of the pandemic are still transmission from and to the unvaccinated.”
“The problem right now is not that we need to boost people who are already vaccinated. The problem is we need to vaccinate people who aren’t vaccinated,” said Offit. “The vaccine’s working, but it doesn’t work if we don’t give it.”
Relative to vaccinating new people, booster shots would be expected to be only incrementally helpful in reducing transmission and mitigating the pandemic, Richterman said. “Keep in mind that 1% of the low-income world has been vaccinated. If we want to end the pandemic, that is where the work must be done,” he added.
For its part, the Biden administration says it can “do both” — provide boosters to Americans while also helping other countries get first and second jabs. Officials have emphasized that the U.S. is the global leader in vaccine donations and announced on Sept. 2 that the government would be investing nearly $3 billion to scale up domestic vaccine manufacturing. Critics, however, say more should be done.
Beyond the ethics of working toward vaccine equity, Dowdy said a case could be made that even from a purely self-serving perspective, the U.S. should focus on helping to administer first and second doses, rather than rolling out booster shots to its own population, as that would limit circulation of the virus overall and help prevent the emergence of more transmissible or dangerous viral variants.
To Boost or Not to Boost?
Ultimately, the decision to boost is “one that’s going to have to be made in the face of imperfect evidence,” said Dowdy. The administration is in the difficult situation of trying to balance waiting for enough evidence against the risk of a surge in cases.
“I feel like the data right now to support any decisions are pretty weak,” he said. “But that’s also the nature of this. There’s no way that we’re going to be able to make the decision with great data without seeing a spike in cases.”
Several scientists said many questions remain about the best way to do a COVID-19 booster, including the number, spacing between doses and whether it’s advantageous to boost with a variant-specific vaccine or mix and match with different vaccines.
“I think that’s going to require more complicated studies to sort out,” Wherry said of the possibility of altering the timing of the doses or using mix-and-matched shots. “And I don’t know that we’re going to get to the bottom of that in the current pandemic situation.”
As for what happens next with the administration’s booster plan, we’ll learn more in the coming weeks as the FDA and CDC make recommendations and potentially release more research.
Editor’s note: SciCheck’s COVID-19/Vaccination Project is made possible by a grant from the Robert Wood Johnson Foundation. The foundation has no control over FactCheck.org’s editorial decisions, and the views expressed in our articles do not necessarily reflect the views of the foundation. The goal of the project is to increase exposure to accurate information about COVID-19 and vaccines, while decreasing the impact of misinformation.