Delayed second dose compared to the normal treatment for vaccination against Covid-19

The clinical trials of the vaccines Pfizer – BioNTech and Moderna had two injections given 3 to 4 weeks apart. Both vaccines had approximately 95% efficacy after the second dose – an impressive finding.^1-2

Under normal circumstances, the vaccines should be used according to the test protocols. The current circumstances – a slow rollout of vaccines, a limited vaccine supply and the recent emergence of more contagious SARS-CoV-2 variants that threaten to surpass our vaccination program – are anything but normal. This may be a case where the risks of strict compliance with the plan outweigh the risks of adapting it.

Some argue that any deviation from the protocol used in the clinical trials is unscientific. But the argument is based on too narrow a definition of science. In both trials, the cases in the placebo and active vaccine groups started to deviate approximately 10 days after the first dose, with increasing vaccine efficacy. By the day of the second dose injection, the effectiveness of the first dose was somewhere between 80 and 90%.^1.2

Why should you delay the second dose of vaccine? First, with Covid-19 currently killing about 3,000 people a day in the United States, we face an important consideration: we use our limited vaccination capacity to protect people who received a first dose of about 85% (after dose) increase one) to 95% (after dose two) by administering a second dose? Or do we use the same ability to take a similar number of people from an unprotected state to one in which they are 80 to 90% protected? One model shows that the expected number of Covid-19 cases will be significantly lower if more people receive a first dose, even if it costs postponing the second dose.³

Secondly, we have recently seen the appearance of several viral variants, with one (B.1.1.7, also called the British variant) being about 50% more contagious than the native coronavirus.⁴ This variant quickly became the largest tribe in England, and the Centers for Disease Control and Prevention (CDC) now predicts the same for the United States in the next six weeks.⁵ This prospect increases the need to vaccinate the population, especially those at high risk, more quickly.

Are there any possible risks of delaying the second dose? Certainly. It is possible that the second dose will be less effective if given later, although few scientists believe that this will be the case.⁶ Immunity may begin to decline between the first dose and a delayed second dose, although the rarity of recurrent infections is likely to mean that immunity, at least those caused by native infection, lasts longer than three months.⁷ Some people may forget to return after a longer delay for their second dose, but a reminder system that works for a return within 3 to 4 weeks should work a month or two later. It is possible that some people will become confused by a change in the vaccination schedule, and the confusion may lead them to evade the vaccination altogether or believe that they only need a single dose. The likelihood of this is difficult to quantify, although it can probably be addressed with a strong message campaign. Finally, some experts have warned that partial vaccination leading to a less robust immune response may increase the risk of mutations, which, as we have seen, may lead to variants with more problematic traits.⁸ It is also difficult to quantify.

Although the strategy of a delayed second dose carries risks, the benefits of giving many more people a first dose sooner deserve strong consideration of the strategy, especially since the shortage of vaccines is likely to ease by late spring. On 30 December 2020, the United Kingdom approved the delayed second dose approach.⁶ And on January 21, 2021, the CDC released its guidance on the timing of the second dose, saying for the first time that a delay of up to 6 weeks after dose one would be acceptable.⁹ This move to a more flexible approach seems sensible.

While it is always comforting to stick to the plan, our current Covid-19 crisis presents a classic case in which the plan – by protecting too few people too slowly, in the face of a growing threat – could be the riskier option. be. Of course, any discrepancy in the protocol should be studied carefully and quickly, and second doses should be administered immediately as the vaccine supply increases.

Public health leaders need to make the best decisions they can with the available science, and the balance between population health, social and economic concerns, and the need to maintain public confidence. Decision-making data is rarely available when needed, but the “retrospect-o-scope” is always ready to evaluate decisions made. US science agencies (the National Institutes of Health, the FDA and the CDC) as well as vaccine developers are committed to making Covid-19 vaccine recommendations guided by science.

My recommendation is that at the moment in the United States we should not delay the second dose of mRNA vaccine after the intervals evaluated for their emergency authorization. Although the immune response to the first dose is unlikely to decrease rapidly, it is incomplete, and there are no data to indicate how long a second dose can be delayed without compromising effectiveness. We do not even know the duration of the immunity produced by the two-dose regimen, or how the dose timing affects the immunity in elderly and immunocompromised persons responsible for most hospitalizations and deaths. If a second dose is significantly delayed, these people may simultaneously be inadequately protected and impede progress in alleviating the increase in hospitalizations.

Populations that are essential for social and economic functioning, such as frontline health care workers and other essential workers, must have the assurance that if they are vaccinated, they can expect a high level of protection and work more safely. The delay of a second dose may not provide the insurance and may have an adverse effect on their future willingness to work or to be vaccinated.

Some models have suggested that the use of a less effective vaccine or the postponement of a second dose to give the first doses to more people will end the pandemic sooner.^10.11 However, these models do not take into account the possible deterioration of the immune response or the effect of such decisions on the acceptance of vaccines. Many people are skeptical about vaccines, fearing that the speed of development will need to turn around and that political pressure has influenced vaccine recommendations. Suddenly, the dosing recommendations change the public’s confidence in serious dangers and hamper willingness to be vaccinated. Cases of Covid-19 have already occurred in vaccine recipients, as seen in phase 3 trials, which will raise questions about the strategy for the delayed second dose and will erode confidence in the explosion of the vaccine. If these breakthrough cases occur more frequently before the second, delayed dose, confidence will be further impaired, which will eventually delay the end of the pandemic and social and economic recovery.

The presence of SARS-CoV-2 variants implies that the virus is under evolutionary pressure. Some have postulated – though speculatively – that the inhibitory levels of antibody response before a second dose, if widespread, may contribute to the choice of antigenic variants that may escape current vaccines.¹² Although we now know how to make Covid-19 vaccines, the design, testing, manufacture and administration of a vaccine at a new variant will take time and it will be challenging.

At present our country is not able to administer the doses it has quickly. The supply constraints are likely to ease within a month or two, as manufacturing becomes more efficient and other vaccines are likely to be available. Meanwhile, vaccines are not the only tool to destroy this pandemic. In the short term, adherence to basic public health measures is expected to save 1.5 times as many lives as vaccines.¹³ As we increase vaccination, I would strongly encourage us to use science to quickly evaluate alternative approaches to expanding vaccine supply (e.g. delayed second dose, half dose and use of dose saver aids) to raise critical questions answer. for now and in anticipation of new, vaccine-resistant strains.

Dr. Lurie is a strategic advisor at the Coalition for Epidemic Preparedness Innovations (CEPI). The views expressed do not represent those of CEPI.

This article was published on February 17, 2021 on NEJM.org.