In September, the US Food and Drug Administration (FDA) dealt a blow to President Biden's sweeping plan to dispense third dose COVID-19 vaccines to all adults, instead authorising the Pfizer–BioNTech vaccine only for people aged 65 or older and those at high risk of severe disease or occupational exposure. Similar recommendations have been implemented in the UK for individuals who are immunosuppressed as well as all people aged 50 years or older. Israel has been the most aggressive in pursuing third vaccine doses, now offering them to everyone older than 12 years and requiring a third vaccine dose to obtain a green pass allowing entry to restaurants, gyms, and other indoor venues. But with vast swathes of the global population yet to receive a single dose, the morality of an aggressive push for booster doses has been widely questioned.
Indeed, the 55–70% vaccine coverage among adults in the USA, UK, and EU stands in sharp contrast to the other world regions—only 4% of the population of Africa has been vaccinated, and more than 50 countries worldwide failed to meet the WHO target of fully vaccinating at least 10% of their populations by the end of September, 2021. 80% of the roughly 5·5 billion doses of vaccine administered so far have gone to high-income and upper-middle-income countries. Of more than a billion doses of vaccine that high-income countries have pledged to donate, less than 15% have been delivered so far. In view of these stark realities, WHO Director General Tedros Adhanom Ghebreyesus has now called for a global moratorium on booster doses until the end of 2021, to allow every country to vaccinate at least 40% of their populations. But many high-income countries are pressing forward nonetheless.
Beyond ethical questions around global vaccine equity, it is not yet clear whether booster doses are really needed for most of the population. For patients who are immunocompromised, particularly those taking B-cell-depleting agents and certain other drugs, accumulating data show that vaccine-generated antibody and T-cell responses are often much lower than in non-immunosuppressed recipients. In one study, only half of patients taking anti-CD20 drugs generated antibodies against the SARS-CoV-2 spike protein after full vaccination, compared with 100% of healthy vaccinees. Emerging data suggest that a third dose can help to boost the immune response in such patients—in a recent case series, 80% of patients with autoimmune diseases who had no detectable antibody response to the first two doses of vaccine responded well to a third dose. As such, the recommendation for third vaccine doses in patients who are immunocompromised has been welcomed by many rheumatologists.
Third vaccine doses given more broadly, however, seem premature in view of the available data. A recent Viewpoint in The Lancet stressed that policies for administering booster doses to already-vaccinated populations must be based on a careful consideration of benefits and risks and must be informed by careful, balanced, and public scrutiny of available data rather than by politics. With clear evidence that full vaccination (ie, two doses) is more than 90% effective in protecting against severe illness and hospitalisation—including against the more transmissible delta variant—the authors conclude that “even if some gain can ultimately be obtained from boosting, it will not outweigh the benefits of providing initial protection to the unvaccinated.”
Much of the dialogue around the need for third vaccine doses is centred on evidence that antibody responses wane in the months after vaccination and so-called breakthrough infections. But evidence is lacking to suggest that higher levels of circulating antibodies necessarily equate to better protection, and no study has yet shown convincing evidence for waning protection against severe infection over time. It is also worth noting that diminishing antibody levels largely reflects the natural progression of the immune response; as the immediate threat is contained, immune cells shift away from active defences (eg, antibody production) and toward development of immune memory, with antigen-experienced cells poised to rapidly respond to repeat attack. What's more, an over-emphasis on waning immunity and breakthrough infections downplays the robust effectiveness of full vaccination and could be counterproductive to efforts to improve vaccine uptake.
As more data accumulate and more of the world's population receives the primary vaccine, priorities will rightfully pivot to questions around administration of routine booster vaccines and the best way to formulate them. Until then, vaccinating the world should remain the priority.
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