3rd dose for the non-immunocompromised – is it necessary?

13th November 2021, Dr Chee L Khoo

booster shots?

The success of mass vaccination is demonstrated by the dramatic reduction in case numbers and deaths from Covid-19 infections since the introduction of the covid-19 vaccines worldwide. Countries such as UK, USA, Israel and Singapore started and completed their campaign very early in 2021. Their success has been challenged by the increasing breakthrough in those countries since June 2021. There can be many potential causes to the breakthroughs – the emergence of the delta variant, the possible waning of immunity conferred by the vaccine after 6 months or the premature relaxation of the lockdown measures in those countries. Unfortunately, they all happened at about the same time.

Thus, the evidence on the waning effectiveness of the vaccines is rather conflicting. Several studies investigating the effectiveness of the BNT162b2 vaccine (Pfizer–BioNTech) against the beta (B.1.351)(1,2) and delta (B.1.617.2) (3-5) variants showed only modest rates of breakthrough infection and disease, whereas other studies showed higher rates (6,7).

If the major cause of the breakthrough spikes in cases is related to the rapid waning of immune response after 6 months (especially with the Pfizer Comirnaty vaccine), then a booster dose after 6 months should curtail the outbreak. Is there evidence that the immune response against the delta variant wanes after 6 months?

Israel began a mass vaccination campaign against Covid-19 in December 2020 by administering 2 doses of BNT162b2 vaccines. More than half the adult population received two doses of vaccine within 3 months. By May 2021, infection rates had decreased to a few dozen cases daily, most of which were in unvaccinated persons or in persons returning from abroad. However, the number of positive polymerase-chain-reaction (PCR) tests rose exponentially in June 2021, with a substantial number of infections being reported in vaccinated persons. Genetic analysis showed that as of June 2021, more than 98% of the positive cases in Israel were attributed to the delta variant (16).

In a very novel study, Goldberg et al compare rates of confirmed SARS-CoV-2 infection and severe Covid-19 among persons vaccinated during different time periods (8). Data on all residents of Israel who had been fully vaccinated before June 1, 2021, and who had not been infected before the study period were extracted from the Israeli Ministry of Health database on September 2, 2021. They focused on infections that had been documented in the period from July 11 through 31, 2021 (study period), removing from the data all confirmed cases that had been documented before that period. The end date was just after Israel had initiated a campaign regarding the use of a booster vaccine (third dose). The study period happened to coincide with the school summer vacation. They removed from the analysis all residents who had returned from abroad in July.

The Analysis

To examine the effect of waning immunity during the period when the delta variant was predominant, they compared the rate of confirmed infections (per 1000 persons) during the study period (July 11 to 31, 2021) among persons who became fully vaccinated during various periods.  Among 5,279,926 fully vaccinated adults, they had data on 4,791,398 persons for the main analysis. 3,426 had a positive PCR test and 403 had severe Covid-19.

A comparison of the rate of confirmed infection among persons vaccinated at different times revealed a clear increase in the rate as the time from vaccination increased in all age groups, with and without correction for measured confounding factors. The rate of confirmed infection among persons 60 years of age or older who became fully vaccinated in the second half of January was 1.6 times as high as that among persons in the same age group who became fully vaccinated in March.

Among persons 60 years of age or older who were fully vaccinated in the second half of January, the rate was 3.3 confirmed infections per 1000 persons during the study period, as compared with 2.2 confirmed infections per 1000 persons who became fully vaccinated in the second half of February and 1.7 confirmed infections per 1000 persons fully vaccinated in the second half of March.

Previous serologic studies in Israel have shown a correlated time-dependent reduction in neutralisation titres (9,10) which might be the biologic mechanism governing the observed waning immunity, and thus support the finding in this population-based research.

The findings from this study is also consistent with the follow-up study of the participants in the phase 2–3 randomised trial of the BNT162b2 vaccine which showed a reduction in vaccine efficacy from 96% (from 7 days – 2 months post second dose) to 84% (4 – 7 months post second dose) (11). Preliminary reports of waning effectiveness of the same vaccine have come from a health maintenance organisation in Israel (12) and from the United States (13) and a decrease in vaccine-induced neutralisation titres during the first 6 months after receipt of the second dose of vaccine has been reported (9).

In summary, there appears to be a waning of the effectiveness of the Pfizer BNT162b2 vaccine a few months after the second dose that warrants a booster shot. We don’t have data on the effectiveness of the AZ vaccine. We can confidently encourage our patients to come forward when they are due for their 6-month booster.


  1. Mor O, Zuckerman NS, Hazan I, et al. BNT162b2 vaccination efficacy is margin[1]ally affected by the SARS-CoV-2 B.1.351 variant in fully vaccinated individuals. July 19, 2021 (https://papers.ssrn.com/ sol3/papers.cfm?abstract_id=3878825). preprint.
  2. Abu-Raddad LJ, Chemaitelly H, Butt AA, et al. Effectiveness of the BNT162b2 Covid-19 vaccine against the B.1.1.7 and B.1.351 variants. N Engl J Med 2021;385: 187-9.
  3. Lopez Bernal J, Andrews N, Gower C, et al. Effectiveness of Covid-19 vaccines against the B.1.617.2 (delta) variant. N Engl J Med 2021;385:585-94.
  4. Sheikh A, McMenamin J, Taylor B, Robertson C. SARS-CoV-2 delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness. Lan[1]cet 2021;397:2461-2.
  5. Pouwels KB, Pritchard E, Matthews PC, et al. Effect of delta variant on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK. Nat Med 2021 October 14 (Epub ahead of print).
  6. Tang P, Hasan MR, Chemaitelly H, et al. BNT162b2 and mRNA-1273 COVID-19 vaccine effectiveness against the Delta (B.1.617.2) variant in Qatar. August 11, 2021 (https://www.medrxiv.org/content/ 10.1101/2021.08.11.21261885v1). preprint.
  7. Puranik A, Lenehan PJ, Silvert E, et al. Comparison of two highly-effective mRNA vaccines for COVID-19 during periods of Alpha and Delta variant prevalence. Au[1]gust 21, 2021 (https://www.medrxiv.org/ content/10.1101/2021.08.06.21261707v3). preprint.
  8. Goldberg Y, Mandel M, Bar-On YM, Bodenheimer O, Freedman L, Haas EJ, Milo R, Alroy-Preis S, Ash N, Huppert A. Waning Immunity after the BNT162b2 Vaccine in Israel. N Engl J Med. 2021 Oct 27. doi: 10.1056/NEJMoa2114228. Epub ahead of print. PMID: 34706170.
  9. Khoury DS, Cromer D, Reynaldi A, et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med 2021;27:1205-11
  10. Wall EC, Wu M, Harvey R, et al. Neu[1]tralising antibody activity against SARS[1]CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 vaccination. Lancet 2021;397: 2331-3.
  11. Thomas SJ, Moreira ED Jr, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine through 6 months. N Engl J Med. DOI: 10.1056/NEJMoa2110345.
  12. Mizrahi B, Lotan R, Kalkstein N, et al. Correlation of SARS-CoV-2 breakthrough infections to time-from-vaccine; prelimi[1]nary study. July 31, 2021 (https://www .medrxiv.org/content/10.1101/2021.07.29 .21261317v1). preprint.
  13. Puranik A, Lenehan PJ, O’Horo JC, et al. Durability analysis of the highly effec[1]tive BNT162b2 vaccine against COVID-19. September 7, 2021 (https://www.medrxiv .org/content/10.1101/2021.09.04 .21263115v1)
  14. Nextstrain: real-time tracking of patho[1]gen evolution (https://nextstrain.org/