key: cord-0692009-xpmmjfuq
authors: Reddy, K Srinath
title: Boosters appear effective, but are they always needed?
date: 2021-10-29
journal: Lancet
DOI: 10.1016/s0140-6736(21)02388-6
sha: 583e99877a0b6e591b982daffb6c0de5f3919681
doc_id: 692009
cord_uid: xpmmjfuq

nan

High efficacy rates of the mRNA vaccines against symptomatic COVID-19, reported from clinical trials, kindled hope that they would prevent all infections caused by SARS-CoV-2. Currently approved vaccines provide high levels of protection against serious illness, but do not confer mucosal immunity to resist entry of the virus into the respiratory tract. When mostly mild breakthrough infections were reported from different countries, 1-3 concern arose that individuals with a fast fading immune response to the standard vaccination schedule might experience serious illness if infected. 1 While severe illness requiring hospitalisation is now seen mostly in unvaccinated or incompletely vaccinated individuals, 1 vaccine-rich countries are developing and implementing policies for administering an additional so-called booster dose. 4 There is no consensus in any geography on when, for whom, and for which vaccines a booster dose is needed at present. Several public health experts have questioned a general need for boosters. 5 Beyond declining antibody concentrations, proponents of booster doses have cited real-life evidence of protection against breakthrough infections in Israel. 6 As clinical trials of booster dose efficacy would be difficult to conduct at this stage of the pandemic, evidence about protection is valuable.

A large population study by Noam Barda and colleagues, in The Lancet, reports a natural experiment on booster doses in Israel. 6 Different rates of severe breakthrough infections of COVID-19 were studied, comparing matched pairs of individuals who received either two or three doses of Pfizer-BioNTech's BNT162b2 mRNA vaccine. 6 The study had 728 321 such pairs, each of which had individuals appropriately matched for age, sex, and sociodemographic and clinical characteristics. The study population comprised mostly Jewish individuals (87%) and 51% were female.

In a well designed study using clinically relevant endpoints, the authors report a 85% reduction (95% CI 73-94) in the incidence of COVID-19-related admission to hospital, 76% reduction (49-94) in severe disease, and 94% reduction (72-100) in COVID-19-related deaths, when the three-dose group was compared to the two-dose group. Israel, with its brisk adult immunisation programme and robust data linkages, offered an excellent study population.

Such observational studies need to account for the influence of confounding variables. The authors are confident that the benefit of the third dose is real, as observed in the adjusted analysis. Some questions remain. Why did individuals who received only two doses delay the third dose? Did they not perceive a need for it, feeling sufficiently protected by two doses? If so, did they stop following the norms of appropriate behaviour during a COVID-19 pandemic, thus placing themselves at greater risk of breakthrough infections? Were the individuals who opted for the third dose more committed to protective behaviours? Some recipients of two doses who did not experience a breakthrough infection also made it into the three-dose group. Did these individuals have protective attributes that would have protected them even without the third dose? Although such questions are of scientific interest, the observed result of third dose protection appears credible, based on the logical study design.

How generalisable are these results? The study included recipients of the BNT162b2 vaccine, which delivers a lower antigen dose than Moderna's mRNA-1273 vaccine. 7 The US Centers for Disease Control Prevention report from a case-control analysis that the mRNA-1273 vaccine showed a decline in efficacy from 93% to 92%, after 120 days from the completion of vaccination, in contrast to a decline from 91% to 77% for BNT162b2. 7 A report on a Kaiser Permanente population indicates that effectiveness of the BNT162b2 vaccine against the delta (B.1.617.2) variant fell to 53% (95% CI 39-64) 4 months after the second dose, although effectiveness against admission to hospital remained high at 93% (84-96) up to 6 months. 8 Other reports from Israel and Qatar indicate speedily declining protection. 2, 3 Although these reports strengthen the case for a booster dose of BNT162b2, there is no evidence yet to suggest that global policies related to other vaccines should be influenced by this experience.

The present study included individuals aged at least 16 years, with a median age of 52 years (IQR 37-68). Third-dose vaccine effectiveness against admission to hospital and severe disease was similar between males and females, and between individuals aged 40-69 years and at least 70 years; however, for individuals aged 16-39 years, the rate of these severe outcomes was too small for meaningful estimation. Even if older individuals, with a rapidly waning immune response, are candidates for a booster shot, Barda and colleagues' findings do not extend to younger age groups, especially those aged 12-30 years.

Booster doses may also bring safety concerns. Israel has reported cases of myocarditis and pericarditis as rare events after mRNA vaccines. A study from Israel has reported a higher risk of myocarditis after the second dose, with a rate ratio of 2·35 (95% CI 1·10-5·02) compared with unvaccinated individuals. 9 Is the benefit to risk ratio of the third dose different for older and younger individuals? Concerns exist regarding vaccine-induced thrombotic thrombocytopenia in younger recipients of virus vector vaccines. 10 We await data on the safety of third-dose boosters with different vaccines.

Vaccine inequity across countries is a matter of global concern. 11 If the practice of administering a third dose to all individuals older than 12 years becomes established in vaccine-rich countries, it can aggravate supply shortages for other countries. In this scenario, under-vaccinated populations could generate the conditions for the emergence of new variants, which might not only be more infectious but also exhibit greater immune escape, and those variants might enter vaccine-rich countries to trigger fresh waves of infection. That is not the kind of natural experiment the world would like to see. As countries discharge their responsibility to protect vulnerable individuals in their populations, they must ensure adequate supply to other countries. Global policy must weigh the risks of adopting booster doses ad libitum across the world at this stage of the pandemic. I declare no competing interests.

K Srinath Reddy ksrinath.reddy@phfi.org

Vaccine breakthrough infections: the possibility of getting COVID-19 after getting vaccinated

Waning of BNT162b2 vaccine protection against SARS-CoV-2 infection in Qatar

Waning immune humoral response to BNT162b2 COVID-19 vaccine over 6 months

EU regulator backs mRNA vaccine booster for people with weak immunity

Considerations in boosting COVID-19 vaccine immune responses

Effectiveness of a third dose of the BNT162b2 mRNA COVID-19 vaccine for preventing severe outcomes in Israel: an observational study

Comparative effectiveness of Moderna

Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study

Myocarditis after BNT162b2 mRNA vaccine against COVID-19 in Israel

SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia