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Review 1: "Waning immunity of the BNT162b2 vaccine: A nationwide study from Israel"

Reviewer: Sergio I. Valdés-Ferrer (Salvador Zubirán National Institute of Health Sciences and Nutrition) | 📒📒📒◻️◻️

Published onMar 16, 2022
Review 1: "Waning immunity of the BNT162b2 vaccine: A nationwide study from Israel"
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key-enterThis Pub is a Review of
Waning immunity of the BNT162b2 vaccine: A nationwide study from Israel

ABSTRACTBackgroundStarting December 2020, Israel began a mass vaccination campaign against coronavirus administering the Pfizer BNT162b2 vaccine, which led to a sharp curtailing of the outbreak. After a period with almost no SARS-CoV-2 infections, a resurgent COVID-19 outbreak initiated mid June 2021. Possible reasons for the breakthrough were reduced vaccine effectiveness against the Delta variant, and waning immunity. The aim of this study was to quantify the extent of waning immunity using Israel’s national-database.MethodsData on all PCR positive test results between July 11-31, 2021 of Israeli residents who became fully vaccinated before June 2021 were used in this analysis. Infection rates and severe COVID-19 outcomes were compared between individuals who were vaccinated in different time periods using a Poisson regression, stratifying by age group and adjusting for possible confounding factors.ResultsThe rates of both documented SARS-CoV-2 infections and severe COVID-19 exhibit a statistically significant increase as time from second vaccine dose elapsed. Elderly individuals (60+) who received their second dose in March 2021 were 1.6 (CI: [1.3, 2]) times more protected against infection and 1.7 (CI: [1.0, 2.7]) times more protected against severe COVID-19 compared to those who received their second dose in January 2021. Similar results were found for different age groups.ConclusionsThese results indicate a strong effect of waning immunity in all age groups after six months. Quantifying the effect of waning immunity on vaccine effectiveness is critical for policy makers worldwide facing the dilemma of administering booster vaccinations.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.



BNT162b2, a highly effective mRNA vaccine, has played a critical role in controlling SARS-CoV-2 infection, particularly in reducing severe COVID-19. Despite its effectiveness, limited information exists about the length of protection conferred by BNT162b2. Physicians, healthcare organizations, and a growing public sector have been wondering if the effect of BNT162b2 is sustained or if periodic boosters will be required. A few studies have so far assessed this issue. A recently published extension study among participants of a multi-national randomized clinical trial indicates that, while there is a gradual decline in circulating neutralizing anti-COVID antibody levels, BNT162b2 is highly effective in reducing SARS-CoV-2 infection, and in particular severe COVID-19, after a six-month follow-up period1. To further address this, Goldberg et al. 2 evaluated a publicly available nationwide database of ~4.8 million people fully vaccinated with BNT162b2 in Israel. The authors analyzed all cases of PCR-confirmed SARS-CoV-2 infection occurring in a 20-day interval (July 11-31, 2021), a period of a high incidence of new cases in Israel driven mainly by the Delta variant. Authors observed that BNT162b2 offered strong protection across the study period; however, the rate of new infections, as well as severe ones seemed to be directly associated with the time from vaccination, with those with more distant vaccines being at higher risk of new SARS-CoV-2 infections; for instance, those receiving the vaccine in May (two months before the evaluated interval) were at least twice as protected against SARS-CoV-2 as those who were immunized in February (five months before the evaluated interval). A similar time-graded effect was observed regarding severe COVID-19, but regardless of the age group, protection was above 86% independently of age bracket or time from vaccination.

First of all, their results are encouraging regarding sustained protection from breakthrough infections (i.e., protection against mild and severe COVID-19 is still robust several months after immunizations). However, a few questions linger: the decrease in the effectiveness of BNT162b2 as a factor of time can surely reflect waning immunity, but based on available data, other factors may interfere with seemingly obvious but misleading interpretations. A recent study among healthcare workers from UCSD vaccinated with mRNA vaccines showed consistent effectiveness of mRNA vaccines above 90% in March-June, 2021; the effectiveness dropped to 65.5% in July 2021 as the Delta variant became the dominant SARS-CoV-2 strain.3 A similar trend was observed in Israel in the evaluated interval. Viral variants of concern, Delta and otherwise, may escape the effect of vaccines via mutations in the spike protein, increasing viral affinity -and infectivity- for host receptors, evading host recognition by evading T- and B-cell immune memory, or increasing virulence and disease severity, to name a few potential mechanisms4. Hence, viral factors may also play a role in the observed reduction in vaccine effectiveness. If a virus has already escaped the effect of a given vaccine, it’s anyone’s guess if a booster will improve its immune recognition and demise.

Another potential confounder is that younger populations were likelier to have received the vaccine later than older populations; younger people develop a more robust and longer-lasting response to vaccines than older ones5, including other coronaviruses6, something already reported with BNT162b27–9. Altogether, those observations suggest that time may not be the only driver in the apparent time-dependent waning effectiveness of BNT162b2.

The evidence derived from the study is potentially informative, but more data will be needed before taking public health measures. Nonetheless, these real-world data broaden our understanding of the dynamics of vaccine effectiveness. As in any other population-based study, confirmations from different genetic backgrounds, comorbid conditions, and so on are needed to confirm or refute these findings and, in turn, generate public-health recommendations; however, this is a solid step in that direction. Finally, the study followed international ethical and research standards and was approved by the local regulatory authorities.

This work suggests that BNT162b2-induced immunity wanes as a factor of time. At this moment, data does not support the widespread use of third dose (booster) shots; public health measures must be based on several factors, including the (obvious) need of expanding the global proportion of fully vaccinated people and boosting those at higher risk of vaccine failure (e.g., the elderly and immunocompromised)  before boosting a lucky few.10,11

1. Thomas SJ, Moreira ED, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine through 6 Months. N Engl J Med 2021;1–13. 

2. Goldberg Y, Mandel M, Bar-On YM, et al. Waning immunity of the BNT162b2 vaccine: A nationwide study from Israel. 2021;1–21. Available from:

3. Keehner J, Horton LE, Binkin NJ, et al. Resurgence of SARS-CoV-2 Infection in a Highly Vaccinated Health System Workforce. N Engl J Med [Internet] 2021;February(Coorespondance):2008–9. Available from:

4. Kupferschmidt K. Evolving threat. Science (80- ) [Internet] 2021;373(6557):844–9. Available from:

5. Del Giudice G, Goronzy JJ, Grubeck-Loebenstein B, et al. Fighting against a protean enemy: immunosenescence, vaccines, and healthy aging. npj Aging Mech Dis [Internet] 2018;4(1):1–8. Available from:

6. van Ginkel FW, Padgett J, Martinez-Romero G, Miller MS, Joiner KS, Gulley SL. Age-dependent immune responses and immune protection after avian coronavirus vaccination. Vaccine [Internet] 2015;33(23):2655–61. Available from:

7. Müller L, Andrée M, Moskorz W, et al. Age-dependent immune response to the Biontech / Pfizer BNT162b2 COVID-19 vaccination. medRxiv  Prepr Serv Heal Sci 2021;0–14. 

8. Terpos E, Trougakos IP, Apostolakou F, et al. Age-dependent and gender-dependent antibody responses against SARS-CoV-2 in health workers and octogenarians after vaccination with the BNT162b2 mRNA vaccine. Am J Hematol 2021;96(7): E257–9. 

9. Schwarz T, Tober-Lau P, Hillus D, et al. Delayed antibody and T-cell response to BNT162b2 vaccination in the elderly, Germany. Emerg Infect Dis 2021;27(8):2174–8. 

10. Krause PR, Fleming TR, Peto R, et al. Considerations in boosting COVID-19 vaccine immune responses. Lancet [Internet] 2021;6736(21):21–4. Available from:

11. Wagner CE, Saad-Roy CM, Morris SE, et al. Vaccine nationalism and the dynamics and control of SARS-CoV-2. Science (80- ) 2021;7364:e. 

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