For several months, America has been in the vaccine-booster phase of the COVID-19 pandemic. Various aspects of booster policy have been controversial and/or confusing, and the public response to the need for boosters has been mixed. But what is the best way to continue to provide the sensible majority who trust in the life-saving COVID-19 vaccines with the best protection in the coming months to years? At times, it seems as if some folks believe “a dose a day keeps the doctor away.” And a meme is now circulating of a “Pfizer Loyalty Card,” offering a free pizza after dose nine. While droll, might that actually happen? (Dose nine, that is).
While the strong protective efficacy of the mRNA vaccines was certainly not predicted early on in the global vaccine program, a basic understanding of vaccine immunology allowed us to predict that protective antibody titers would inevitably wane over a 6-month period and could be restored with a booster dose (see Figure 3).
The Early Booster Debates
In summer 2021, data from Israel triggered discussions among policymakers, scientists, and company executives about the need for boosters in the U.S. The vaccine booster concept wasn’t — or shouldn’t have been — inherently controversial, particularly for individuals at high risk for COVID-19 complications. However, there were doubts about the arguably premature timing of, and rationale for, a broadly based boosting program. Arguments were also raised about using those doses in under-vaccinated countries instead, both on moral grounds and to prevent the emergence of even more troubling variants (e.g., Omicron…). Other debates centered on whether the goal was to protect against mild infections (which vaccines typically don’t do) or severe disease and death. These discussions generally faded away once it became clear that protection against severe infections was diminishing significantly for older individuals, and that fully vaccinated people could still transmit their infections to others. In addition, anxious members of the vaccine-embracing public, including members of the media, put pressure on the Biden administration. A vaccine boost became something that Jane Public and Ronnie Reporter wanted, and, frankly, expected.
Americans can now be boosted 5 months after their initial two mRNA vaccine doses of Moderna or Pfizer. The far fewer recipients of the Johnson & Johnson (J&J) vaccine are also being boosted, most opting for an mRNA dose as that provides a stronger antibody response.
But what’s next? Already, Israel is rolling out a fourth Pfizer dose and is therefore well on the way to handing over a slice of pizza. Should we do the same here, and if so, when? In the hope that any policy decisions will be science-based, I will review some of the knowns and unknowns. Whatever knowledge I possess has been significantly boosted by helpful discussions with world-class immunologist colleagues.
Determining the Right Booster Schedule
Most agree that dose three (i.e., the first boost) should not be given too early. The period between the second and third dose is critical to the maturation of the immune response and establishment of immunological memory. As the quantity of antibodies in the blood declines, their quality increases, including their ability to counter variants. While there is no “magic moment” for dose three, the original CDC recommendation for a 6-month gap for both mRNA vaccines and the recent revisions to 5 months are both about right.
But what about dose four and onwards? Is there a point when it is certainly needed? Here, we don’t have hard data, although there are early indications from Israel that the antibody responses to Pfizer dose three are now dropping. That should not be a surprise, based in part on decades of experience with attempts at an HIV-1 vaccine. As but one illustrative example, an HIV-1 “spike protein” vaccine was given seven times to humans over a 30-month period. After the first two immunizations, every subsequent one triggered a rapid rise in antibody levels, followed by a gradual decline at a similar rate each time. The titer pattern over time looked like saw teeth. In the period between boosts, the antibody levels didn’t disappear but the boosted peak levels weren’t much higher each time — there were ever diminishing returns to the potency of each booster dose.
Perhaps we will see something different with the SARS-CoV-2 spike protein, and maybe the mRNA delivery method will be the charm — but I wouldn’t bet the farm on a dramatically different outcome to our experiences with the HIV-1 spike protein. In other words, boosting is likely to increase protective antibody levels in the short term but probably won’t be truly sustained (T-cell responses, which help to prevent severe disease, also wane but more slowly). If the pandemic persists, fairly regular boosting may therefore be needed, akin to the annual flu vaccines.
However, this scenario also invites more questions about the intervals between doses: the HIV-1 vaccine study discussed above used a 6-month interval between the later doses, probably because prior experience showed that was when the boosted titers dropped back to near baseline. The Israelis, however, are now giving the fourth Pfizer vaccine dose about 4 months after the third. Is that too soon for comfort? Well, for sure, it should be no sooner than that…and most immunologists I talked to favor a longer interval. Given the cost and logistics, some important decisions will need to be made soon.
Our political and public health leaders have much to consider, and will need to decide whether there is a need to sustain a high level of protection against SARS-CoV-2 infection and mild COVID-19.
Will We Keep Boosting…Forever?
What about the future? There is nothing inherently problematic with giving regular, sensibly spaced vaccine doses from an immunology perspective. Different COVID-19 vaccines can clearly be mixed when given sequentially. A recent HIV-1 vaccine study in monkeys involved nine doses of mRNAs, proteins, and protein-nanoparticles over a ~14-month period in a heroic attempt to broaden the neutralizing antibody response (the major obstacle to a successful HIV-1 vaccine). Next-generation, more potent COVID-19 vaccines may eventually play an important role. We’ll also need to explore alternative ways to deliver vaccines, whether based on immunology or emerging technology. What happens should be dictated by the trajectory of the pandemic, including the evolution of yet more variants. So far, despite vaccine manufacturers going ahead with their own plans, the case for variant-specific vaccines has been weak. Although, it’s possible the need for them may change in the coming months as Omicron continues to spread.
Boosting J&J Vaccine Recipients
Additional complications are at play too: What’s the right approach to boosting J&J vaccine recipients? They can receive a second dose 2 months after the first, but in most cases that dosing interval is many months longer (and, as noted, most opted for an mRNA boost at that point). When should they receive a third dose? For the mRNA vaccines, the critical period for immunological quality improvements is the ~6-month interval between doses two and three (see above), but when does that happen for the J&J vaccine? In the long and rather random interval between doses one and two? After dose two? Or both? Could a third dose in the near future be too soon for comfort? Having more data would help.
Factoring in Natural Immunity
We also need to consider how to — or whether to — factor in immune responses induced by vaccine breakthrough infections, which are becoming increasingly common. Although breakthrough Omicron infections are generally not severe, the viral antigens will surely trigger a boosting effect in vaccine-primed immune systems — some members of the public are now embracing this idea. And we know that vaccinating previously infected people generates particularly strong immune responses (“hybrid immunity“). We can expect a lot of data on this topic in the next month or so, but for now we have to speculate.
But what happens when vaccination precedes infection? Should a two-dose vaccine recipient who is then Omicron-infected receive a further vaccine dose and, if so, when? Similarly, what happens if a triply vaccinated person becomes infected? Given how mutated the Omicron spike-protein is, an infection with this variant is likely to trigger the production of antibodies that have a lesser impact on new variants that more closely resemble the ones that circulated in 2020-2021. They would, however, be better poised to counter any variants that emerge from the Omicron lineage, as would Omicron-based vaccine boosters. In short, we need to determine how to factor in the combination of vaccination and infection history, and also how the pandemic may further evolve, to devise an optimal boosting approach. There are important scenarios that policymakers and serious immunologists must ponder soon. Otherwise, far-reaching decisions will be taken on the fly, which is never ideal.
The U.S. is blessed with an abundance of COVID-19 vaccines and world-class scientists. Our complex scenarios merit the most qualified experts to figure out the best paths forward. I, for one, look forward to reading what might emerge. I need that guidance to answer with greater confidence the questions I am frequently asked by friends, colleagues, and random members of the public. “Winging it” is becoming as tiresome as it is tiring.
John P. Moore, PhD, is a professor of Microbiology and Immunology at Weill Cornell Medicine in New York City.
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