— The safety and effectiveness data should prompt CDC to update its policy

by Michael Daignault, MD, and Monica Gandhi, MD, MPH 

On Friday, February 4, the Advisory Committee on Immunization Practices (ACIP) quietly acknowledged the rapidly accumulating body of evidence supporting an extended interval between the first and second dose of a two-dose COVID-19 vaccine series. ACIP members weighed the benefits of extending the interval between doses of the two mRNA vaccines — currently 3 weeks for Pfizer (Comirnaty) and 4 weeks for Moderna (Spikevax) — to 8 weeks, based on both effectiveness and safety data. Updating the guidelines would represent a seismic policy shift in this country.

We welcome the long-overdue recognition of this evidence-based approach already endorsed by multiple other countries including Canada, India, the U.K., and other countries in Europe. Although the two-dose series of the Pfizer vaccine was studied at an interval of 3 weeks and the Moderna vaccine at an interval of 4 weeks, the companies were aware of the urgent global need for an effective COVID-19 vaccine while designing these interval strategies. Except for rabies, no other vaccine is given at a dosing interval of 3 weeks. In fact, a principle of vaccinology is that priming the immune system with the first dose generates good responses to second doses of most vaccines for at least 6 months or more.

There are three main lines of evidence for extending the COVID-19 vaccine dosing interval: 1) immunologic; 2) vaccine effectiveness studies; and 3) safety studies regarding the low risk of myocarditis with mRNA vaccines.

Immunologic Research

Many immunologic studies have shown higher SARS-CoV-2 antibody levels from extending the time between doses. Beyond the many studies showing a higher antibody response, several have shown that increasing the interval between doses amplifies the cellular immune response, which is important for durability. One important immunologic study verified that extending the interval of the Pfizer vaccine from 3 to 6 weeks not only increased antibody levels, but also, enriched T cells against COVID-19. T cells amplify the body’s response to a virus, help recruit cells to attack the pathogen, and generally protect us from severe disease. COVID-specific T cells protect us against variants, including omicron. Another study of healthcare workers verified the increased antibody response from extending the interval from 3-4 weeks to 6-8 weeks with Pfizer, and also showed a 7-fold increase in the magnitude of the B-cell response. B cells triggered by the vaccines are able to produce new antibodies if they ever see the virus, even if it has mutated.

Vaccine Effectiveness in the Real World

In terms of vaccine effectiveness in real-world settings, the bulk of research is from countries that, early on in their vaccine rollout, opted to accelerate population coverage with a single dose in the face of limited supply of both the Pfizer/BioNTech and Oxford/AstraZeneca vaccines and the rapidly spreading alpha (B.1.1.7) variant. The interval between the first and second doses was extended up to 12 weeks and 16 weeks, in the U.K. and Canada respectively, to accomplish that goal, and with the anticipation that doing so would extend the longevity of protection. Data from Quebec verified that extending the interval of the Pfizer vaccine from 3 to 8 weeks increased vaccine effectiveness from 82% to 92% in real-world settings. The National Advisory Committee on Immunization in Canada (counterpart to the U.S. ACIP) recognized the increased effectiveness of the extended interval dosing in its formal guidelines.

Safety

In the context of unanimously approving Moderna’s vaccine, ACIP members discussed the rate of myocarditis/pericarditis in those who received both Pfizer and Moderna vaccines. The rates are extremely low (67.5 and 46.8 cases per million, respectively for Moderna and Pfizer) and the vast majority of cases are self-limiting with full recovery.

Notably, the risk of these side effects is highest after the second dose. A pre-print study of 19.7 million doses of Pfizer and Moderna vaccine given to participants in Canada demonstrated a significantly lower risk of myocarditis/pericarditis in those who were vaccinated on an extended 8-week dosing schedule. Although the quantified risk of myocarditis/pericarditis is much higher with actual infection from COVID-19 than from mRNA vaccines, fear of this rare side effect has stopped some adults from getting vaccinated and prevented many parents from vaccinating their children. Nationally, only 28% of children 5 to 11 years old had received at least one dose of COVID-19 vaccine as of mid-January.

Therefore, a growing consensus for an extended interval of 8 weeks represents a “sweet spot” to both reduce this risk and address the concerns of unvaccinated adults and/or their children.

We do recognize that an extended interval between doses may not be an option for everyone, particularly high-risk groups like the elderly, those with multiple comorbid conditions, or those with moderate to severe immunocompromised conditions. This approach might also be unfavorable when disease prevalence is high.

Many of us have already advised our own patients and family members to strongly consider an extended interval between the first and the second doses. An official policy change from the CDC would go a long way to restore the public’s trust in the organization’s guidance. It would also send a strong signal to the public that our vaccine guidance is a continually evolving, data-based scientific process to ensure the most robust benefit while minimizing harm. For the millions of Americans who remain unvaccinated and who are perhaps overwhelmed by the daunting task of needing three vaccine doses to be up-to-date, an extended interval schedule could be more appealing and assuage their hesitancy.

We strongly recommend that ACIP further discuss the benefits of an 8-week extended dosing interval for a two-dose vaccine series and formally adopt this policy at their next meeting.

Michael Daignault, MD, is an emergency physician at Providence Saint Joseph Medical Center in Burbank, California. Monica Gandhi, MD, MPH, is a professor of medicine in the school of medicine at University of California, San Francisco.

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