Two Doses or One? COVID-19 Vaccine Regimens

• The effectiveness of the Pfizer and Moderna vaccines is based on the results of clinical trials that gave two doses of vaccine 3 or 4 weeks apart.
• The clinical trials did not give us information about different approaches to administering these vaccines (e.g., giving only one dose or spacing out the two doses beyond 3 or 4 weeks).
• Until we have more research about their efficacy, we should plan to give these vaccines as two doses at the scheduled times 3 or 4 weeks apart.

In this January of political crisis and surging COVID-19 cases and deaths, we are in the remarkably fortunate situation of having two safe and effective COVID-19 vaccines authorized for emergency use by the U.S. Food and Drug Administration. While the rollout has been frustratingly slow thus far, these vaccines and others under study hold our best promise of pandemic control. They are bright spots in an otherwise enormously difficult moment for our country and the world. Both products, the Pfizer-BioNTech and the Moderna vaccines, are based on novel mRNA technology, and both were shown to be highly effective in large clinical trials in preventing COVID-19 illness and severe COVID-19 disease. Both were studied as two-dose regimens. The Pfizer vaccine is given as two doses 21 days apart, and the Moderna vaccine is given as two doses 28 days apart. The two products work remarkably similarly as two-dose vaccines.

With both vaccines, the goal was to be well above the antibody levels of persons who recovered from the natural SARS-CoV-2 infection. In other words, if we could immunize to antibody levels above natural immunity, we would consider the vaccines to be successful. The Phase I trials of these vaccines showed that it took two doses of mRNA to get above these natural levels. And this is the basis for the two dose regimens that were eventually tested, and shown to be so effective.

Both scientific papers on the Pfizer and Moderna vaccines show results that say the vaccines seem to start working 10-12 days after the first dose. These trends, which show protection versus placebo, are extended out for the next four months, with increasing protection. The data after 21 days for the Pfizer vaccine or after 28 days for the Moderna vaccine, however, show the results of the second dose, since everyone in these trials received two doses. Whether high levels of prevention were achieved or sustained with just the first dose is unknown. The trials measured the efficacy of two doses, not one.

Vaccine regimens are selected based on empirical studies of immune responses, first in animals, and then eventually, if the products pass safety and immune response tests, in human volunteers. Both the dose (how much of a vaccine is given) and the regimen (one, two, or three doses, and how far apart) are carefully selected based on these kinds of studies. Then, we go into the field with our best estimate of dose and regimen, and study how the vaccines work in real people with real exposures to the diseases we are trying to prevent. In the case of the mRNA COVID-19 vaccines, what we studied was two-dose regimens, spaced by 3 or 4 weeks. That is what we know from the data from the vaccine efficacy trials.

Though we are learning more about these products every day, as safety data continue to be gathered from the volunteers in the trials, as more and more people are immunized, and as we understand the ‘real world’ logistical challenges of using these products. But the pressure to get more people immunized is driving some decision-makers to move toward single-dose use of these products, or to stop withholding vaccines – as U.S. Department of Health and Human Services Secretary Azar announced this week – impacting the certainty of available second doses for all who have had their first doses. President-Elect Biden has also stated he would press for release of all available doses and no longer withhold vaccine for those second doses. Neither is suggesting that one dose is enough – but both approaches are gambling that product manufacturing will keep up with demand, and that by extension it would be acceptable to have some persons vaccinated with second doses after longer windows than the current FDA-approved 21 or 28 days.

To be clear, the findings from the clinical trials in tens of thousands of volunteers is that these are two-dose regimens with quite tight time intervals between doses. Everything else is speculation. Until we have the empirical evidence to suggest it would not reduce safety or efficacy to make a change in the dosing and regimen, two spaced doses are what has shown such high efficacy in the trials. While there is great urgency to accelerate the COVID-19 vaccine rollout, and to immunize more Americans who want and need these vaccines, there are real risks to the effectiveness of these vaccines in changing anything about their current recommended and authorized use.

A corollary of the 2-dose response to the mRNA vaccines that is also increasingly being asked is how closely to 21 or 28 days does one need to be to give the second dose? The answer is another unknown, but in general, waiting for a boost is often associated with higher responses. So getting a boost at 2 months, while unproven, would compare well with other vaccine platforms and will likely be fine. The key issue with delaying the second vaccination is really how good and how long a first vaccination alone will work. That answer too is unknown and so getting the second vaccination is, from a policy point of view, imperative.

With the AstraZeneca Oxford vaccine candidate, the trials in the U.S., UK and elsewhere have also studied two-dose regimens. This two-dose regimen was what the UK approved for Emergency Use Authorization of the AstraZeneca product in December 2020. But again, some decision-makers in the UK are now pressing for use of this vaccine as a single-dose vaccine, arguing that it will be more beneficial to immunize more people with one dose than a smaller number of people receiving full immunization. There is a purported balance of greater coverage of the vaccines versus full protection for fewer people. But this too is a problematic framing of the issues. We don’t know that one dose is effective, or for how long. Having a large number of people partially protected, particularly during periods of high COVID-19 transmission, could end up benefiting variants of the viruses that can bypass the weak or partial protection from incomplete immunizations. The combination of partial protection and releasing of social distancing precautions could end up undermining the effort to control this pandemic. A decision of this gravity has to be made based on empirical data from human vaccine trials, not on modeling or other speculative approaches, and certainly not on political considerations or expediency.

The current COVID-19 vaccines that we have developed so quickly are precious resources, and we must use them wisely and protect their efficacy. This calls for fidelity to the science, ongoing and rigorous research, and the great patience that COVID-19 has demanded of us all. We need to ramp up immunizations as quickly as is humanly possible, and we need to get many more vaccines into people’s arms. But for a two-dose vaccine regimen, that means getting two doses, spaced apart as our data suggest, to ensure that people are truly protected.