Yes, some people will need a fourth shot. But most won’t.

Pressure is building to approve a fourth dose of the coronavirus vaccine in the United States, which is facing another potential wave of infections. Already, the two major vaccine makers have asked the Food and Drug Administration to sign off on another booster shot, recognizing that the vaccines’ effectiveness wanes over time. All this talk has raised a depressing possibility: Will we all have to keep getting shots every few months forever into the future?

The answer, thankfully, appears to be no. The evidence suggests that most people won’t need a fourth dose. Immunocompromised people and the elderly, who are at risk of severe breakthrough infections, will probably need another shot – and may need to keep getting them until a more long-lasting vaccine is made available. But for most people, the immunity conferred by the first round of vaccines and natural infection will be enough to keep us safe.

How can we be sure? We know that the vaccines generate antibodies against SARS-CoV-2, the virus that causes covid-19, but that these antibodies can be less effective against new variants like omicron. Even if those antibodies are boosted with an extra shot, their effectiveness will wane several months later. Luckily, the vaccines also generate something called cellular immunity, which is longer-lasting, and protect against severe disease in a more enduring fashion.

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Antibody-producing memory B cells – generated by the vaccines or as a result of a prior infection – have been shown to recognize the virus, including its variants. Although we do not know how long these memory B cells last, survivors of the 1918 influenza pandemic were able to produce antibodies from memory B cells when their blood was exposed to the same strain nine decades later. The vaccines also trigger the production of T cells.

While B cells serve as memory banks to produce antibodies when needed, T cells amplify the body’s response to a virus and help recruit cells to attack the pathogen directly. Memory T cells generated by covid-19 infection may last a lifetime, according to a study that examined participants with varying degrees of initial disease severity. Memory T cells generated in individuals who survived a different coronavirus infection in 2003 were shown in a recent paper to last at least 17 years.

During the omicron variant surge this winter, we did see a greater chance of re-infection compared with previous variants – but not in severe disease across the general population. A study from Qatar showed that a history of natural infection protected against mild re-infection with previous variants 90% of the time, but that protection declined to 56% against omicron. Two vaccines protected against mild re-infection 89% of the time against the delta variant, but that protection declined to 36% against omicron in a Canadian study. This is probably because the omicron variant was able to evade antibodies. In both studies, however, protection against severe disease endured, probably mediated by cellular immunity.

The increase in antibodies from a vaccine boost may last only a short period, around four months, according to one study by the Centers for Disease Control and Prevention. But this boost will be necessary for certain groups to maintain protection against severe disease, including the immunocompromised, older people and those with multiple risk factors. This is because B cells typically take two to four days to make neutralizing antibodies, which may be too long to wait for those who are more susceptible to severe disease. In another recent CDC study, those who were severely immunocompromised (for instance, patients on B cell-depleting therapies or solid organ transplant recipients) and those older than 75 with four comorbidities were found to be susceptible to severe breakthrough infections. Immunocompromised individuals have already been approved for a fourth shot, and those who are older with other medical conditions should obviously be next in line.

But there is little evidence that a fourth shot would be beneficial for the rest of the U.S. population. A recent study in the New England Journal of Medicine showed that a fourth shot in health care workers did not improve the effectiveness of the vaccine or reduce viral loads.

In the future, instead of using an mRNA or DNA vaccine that exposes us only to part of the virus (the spike protein, which is mutated across all the variants), we may need a vaccine booster that exposes us to the entire virus. Whole virus vaccines may be more protective against variants with multiple mutations in the spike protein. Vaccines given inside the nose can help boost antibodies at nasal surfaces, which will help with curbing viral transmission.

For now, the vaccines we have are doing a good job of preventing severe illness in most people. Vulnerable people should start getting a fourth shot to shore up their defenses. For everyone else, though, it makes little sense to give more booster shots.

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Dr. Monica Gandhi. Photo: uscf.edu

Monica Gandhi, an infectious-diseases specialist, is a professor of medicine at the University of California, San Francisco.

 

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