Opinion: Instead of debating ‘first-shot’ vs. ‘set-aside’ vaccine approaches, hospitals’ study should compare them

The FDA authorizations of two Covid-19 vaccines so far specify two-shot regimens, spaced three weeks apart for the Pfizer/BioNTech vaccine and four weeks apart for the Moderna vaccine. But because these vaccines will likely be in short supply for many months, some experts have proposed using available vaccine doses under a “first-shot” strategy: give as many people as possible their first dose of the vaccine and then deliver the second booster shot when supplies catch up.

The approach would be different from the current “set-aside” approach in the U.S., where one dose of booster is reserved in parallel with each first shot delivered.

Proponents of the first-shot approach have their reasons. When compared to trial participants who received a placebo, rates of Covid-19 among those who received either the Pfizer/BioNTech or Moderna vaccine began to fall dramatically 10 days after the first shot. In addition, many more people can be vaccinated sooner with the first-shot strategy, helping ease current supply constraints.

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But the set-aside approach is on firm ground, too. The only rigorous long-term protection and safety data are for the two-shot schedule.

There are two ways to resolve this question: We can debate it on social media or we can go get more data. I believe we should do the latter, and propose that academic nonprofit hospitals in the U.S. immediately start a study of their own employees.

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The data this study would generate could clarify whether the seemingly intuitive first-shot approach has downsides when compared to the stricter set-aside strategy by focusing on two questions: How long does immunity from the first shot last? And how well does the booster work when it is delayed (no one has yet proposed just a single shot with no booster)?

Here’s how the study would work: Every employee gets a first shot, as many already have. Then, before the second-shot booster, employees — with their consent, of course — are randomized to a second shot according to the FDA authorized schedule or to a placebo shot of saline. (Because vaccines are being drawn up within hospitals, the placebo could be made in the pharmacy and all other levels of blinding can be preserved). Participants would be tested weekly for the infection and cases of clinical Covid-19 would be recorded.

The primary endpoint would be differential rates of clinical Covid-19 beginning a week after the second shot is administered. Secondary endpoints would include rates of asymptomatic carriers. Hospitals would follow a common protocol, but the data could be housed within each hospital and shared only at the time of analyses.

When rates start to diverge, which would answer the first question, all placebo recipients would receive a booster, producing data with varying time between first shot and booster that could help answer the second question to some extent.

This study starts out with many embedded advantages. For one, it would be conducted in facilities that have deep expertise and experience in running clinical trials; some often run hundreds of them simultaneously. The employees of these institutions are knit together by a shared commitment to improving health, and by a shared understanding that clinical research is the backbone of scientific inquiry.

I believe enrollment would be a breeze. (I know I would volunteer when it is my turn.) All of these hospitals have testing, tracing, and other systems in place for monitoring infection and disease among their staff, loss to follow-up on the study endpoints would be exceedingly rare, and rates of Covid-19 are unfortunately persistently high in hospitals.

Finally, because randomization takes place before the second shot, even the very first recipients of the shot from a week or two ago can enroll, and would show leadership that would enhance the likelihood that future participants sign up and hesitant hospitals join in.

I can’t wait to see the participants’ signed consent forms posted on Twitter. At the current pace of vaccination, if a meaningful number of hospitals dive in and achieve even modest consent rates, this study could enroll 30,000 participants in a handful of weeks and start generating insights in a few months. If we move on this question, and I can’t think of a more important one to prioritize, preliminary data could be in hand by March.

Perhaps that seems too long to wait, but let’s be realistic about the pace of vaccination today, which will be continuing throughout 2021 at least. Each time a new batch of the Pfizer or Moderna vaccines becomes available we will face the same question the first-shotters and set-asiders are debating now: Do we use that next batch to boost the one-time vaccine recipients or get another group of unprotected individuals started?

Each time we elect the latter strategy, the time interval between the first shot and the booster will widen. When, then, do we change course? We could wait until we have overwhelming supply, but given the global need that won’t be any time soon. Or we could change course when the data tell us the immunity from the first shot is waning to a level where the booster is the best next use of the vaccine.

Clinical studies cost money. But if we can dole out billions to companies to develop vaccines, then we should be ready to dole out millions to study how they are best used to control the pandemic. The large academic hospitals that would conduct this study have current NIH funding, and adding supplements to existing grants is a relatively quick process that has been used throughout the pandemic to support Covid-19-related research. That these hospitals will internalize the financial benefits of ending the pandemic sooner and are granted tax-exempt status because their research mission includes improving the health of their communities are other reasons they should be eager to participate.

I anticipate that some will object that running a study like this is unethical because we know the two-shot regimen is effective. But the core ethical axiom of clinical research is that participants can choose to internalize reasonable risks if the knowledge they generate by doing so can provide meaningful benefits to others.

There will also be concerns that the experience and outcomes among health care workers will poorly generalize to other populations, such as the elderly and infirm. But this concern is mitigated by the fact that vaccine performance in health care workers is itself important, that health care workers are a diverse cross section of society, and that the clinical trials of the vaccines have shown similar performance across sub-groups.

Let me put it another way: Hospitals, for the sake of your workers and for all of us, please get your IRBs going.

Peter B. Bach is a physician at Memorial Sloan Kettering Cancer Center in New York City, where he directs the Drug Pricing Lab.

Source: STAT