Safety of COVID-19 booster dose: is the juice worth the squeeze?

In this issue of The Lancet Infectious Diseases, Dan Yamin and colleagues' Article1Yamin D Yechezkel M Arbel R et al.Safety of monovalent and bivalent BNT162b2 mRNA COVID-19 vaccine boosters in at-risk populations in Israel: a large-scale, retrospective, self-controlled case series study.Lancet Infect Dis. 2023; (published online June 20.)https://doi.org/10.1016/S1473-3099(23)00207-4Google Scholar used a self-controlled case series design to evaluate the safety of COVID-19 vaccine boosters. The authors compared mRNA monovalent and bivalent boosters (ie, third to fifth doses) of the mRNA monovalent and bivalent (mainly used as a fifth dose) boosters by comparing a 28-day post-booster period (and a sensitivity analysis period up to 42 days post booster) with a 28-day baseline period that ended 7 days before vaccination. The analysis was focused primarily on individuals categorised as being at high risk of susceptibility to severe COVID-19, and was limited to analysis of only those patients hospitalised for 29 medical conditions (collectively termed as non-COVID-19 hospitalisations) that are potential adverse events associated with COVID-19 vaccination. Overall, the study found no indication that booster doses of mRNA COVID-19 vaccine were associated with an elevated risk of non-COVID-19 hospitalisation. Nevertheless, following the first booster dose, the rate of hospitalisation of vaccinated individuals increased for thrombocytopenia (absolute excess rate per 100 000 vaccinated individuals 2·6), seizures (2·2), myocarditis (0·7), although the population size under surveillance might have been suboptimal to evaluate for difference in risk for rare potential serious adverse events such as Guillain-Barré syndrome and central venous thrombosis. The use of a self-controlled case series design has advantages over case-control or large cohort study designs, which would require cases to be matched with appropriate controls or the measurement of confounding factors.2Andrews N Epidemiological designs for vaccine safety assessment: methods and pitfalls.Biologicals. 2012; 40: 389-392Crossref PubMed Scopus (0) Google Scholar Additionally, the self-controlled case series design accounts for non-time varying confounders (eg, genetic related conditions, socioeconomic status, or other non-time varying confounders including being an at-risk individual), which are immeasurable or have yet to be considered. Yamin and colleagues excluded events of interest that culminated in deaths, premised on deceased people who had not been boosted being ineligible for the analysis, and a sensitivity analysis that includes such deaths should be done. The limitations of the study include the assumption that the decision to receive a booster dose was independent of the occurrence of an adverse event. This view might not hold true if previous adverse events related to COVID-19 vaccination deter an individual from receiving subsequent vaccinations; how this factor could affect the findings should be considered. Other essentials of a self-controlled case series design include accurate ascertainment of exposure, ascertainment of case, and date of onset of event. The case ascertainment might vary depending on the clinician and be subject to additional bias if the clinician is aware of a patient's vaccination history. Also, the focus on only reporting on hospitalised cases of the events under consideration, and the issue of the population size under surveillance not being powered to identify risk differences for event rates lower than 1 per 10 000, warrants caution when interpreting the full risk–benefit ratio of booster doses of COVID-19 vaccines. Notably, a second dose of BNT162b2 was reported to have prevented an estimated 89 COVID-19 hospitalisations per 100 000 population in Israel among individuals older than 60 years of age, when the B.1.1.529 (Omicron) variant of concern was dominant.3Arbel R Sergienko R Friger M et al.Effectiveness of a second BNT162b2 booster vaccine against hospitalization and death from COVID-19 in adults aged over 60 years.Nat Med. 2022; 28: 1486-1490Crossref PubMed Scopus (48) Google Scholar WHO's Scientific Advisory Group of Experts on Immunization recommended on March 24, 2023, that additional booster doses of COVID-19 vaccine should be given 6–12 months after the most recent dose only to high-priority groups (defined similarly to the Israeli definition used in the study) during 2023.4WHOSAGE updates COVID-19 vaccination guidance. News release.https://www.who.int/news/item/28-03-2023-sage-updates-covid-19-vaccination-guidanceDate: March 28, 2023Date accessed: April 26, 2023Google Scholar The risk–benefit ratio of booster doses needs to be contextualised against the persistent dominance of the highly transmissible and relatively neutralising antibody-evasive omicron sublineages that have dominated globally since the evolution of the BA.1 variant of concern in November, 2021.5Kopsidas I Karagiannidou S Kostaki EG et al.Global distribution, dispersal patterns, and trend of several omicron subvariants of SARS-CoV-2 across the globe.Trop Med Infect Dis. 2022; 7: 373Crossref Scopus (5) Google Scholar, 6Ao D He X Hong W Wei X The rapid rise of SARS-CoV-2 omicron subvariants with immune evasion properties: XBB.1·5 and BQ.1·1 subvariants.MedComm (2020). 2023; 4: e239Google Scholar The global dissemination of omicron has been associated with widespread infection-induced immunity, including serological evidence of infection in 63·9% of individuals infected or reinfected during the initial BA.1-dominant wave in South Africa.7Madhi SA Kwatra G Myers JE et al.Sustained low incidence of severe and fatal COVID-19 following widespread infection induced immunity after the omicron (BA.1) dominant in Gauteng, South Africa: an observational study.Viruses. 2023; 15: 597Crossref PubMed Scopus (0) Google Scholar A systematic review and meta-analysis done by WHO's Serotracker Team reported that, by April 2022, the proportion of the population who were sero-positive was 89·8% globally, and as of June 2022, seropositivity (inclusive of vaccine-induced immunity) was 96·1% in Europe, 100% in the Americas and 99·0% in the Western Pacific.8WHO Department of Immunization and Biologicals (IVB)SAGE meeting slide decks; COVID-19—session 4: roadmap for COVID-19 vaccination in the era of omicron. Strategic Advisory Group of Experts (SAGE) on Immunization hybrid meeting March 20–23, 2023, WHO Geneva, Switzerland.https://www.who.int/news-room/events/detail/2023/03/20/default-calendar/sage_meeting_march_2023Date accessed: April 27, 2023Google Scholar The combination of infection-induced and vaccine-induced immunity, referred to as hybrid immunity, reportedly provides 97·4% (95% CI 91·4–99·2) protection against COVID-19 hospital admission or severe disease caused by omicron and its sublineages, up to 12 months after the primary series of vaccine alone. This protection is higher than that from previous infection or vaccination alone. Similarly, protection from hybrid immunity against omicron-related COVID-19 hospital admission or severe disease is projected to be 95·3% (95% CI 81·9–98·9) for up to at least 6 months after the first booster vaccine that follows the most recent SARS-CoV-2 infection or preceding vaccine dose.9Bobrovitz N Ware H Ma X et al.Protective effectiveness of previous SARS-CoV-2 infection and hybrid immunity against the omicron variant and severe disease: a systematic review and meta-regression.Lancet Infect Dis. 2023; 23: 556-567Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar Consequently, the added value of a booster dose warrants interrogation, including in the context of vaccinated high-risk groups who could remain susceptible to severe COVID-19. The risk–benefit ratio was factored into the WHO recommendation not to advocate for further booster doses during 2023 in individuals outside of the high-priority group.4WHOSAGE updates COVID-19 vaccination guidance. News release.https://www.who.int/news/item/28-03-2023-sage-updates-covid-19-vaccination-guidanceDate: March 28, 2023Date accessed: April 26, 2023Google Scholar In summary, Yamin and colleagues' study showed no increase in the risk of adverse events after additional booster doses of COVID-19 vaccine. Nevertheless, the absence of data on non-hospitalised adverse events that could be associated with severe additional morbidity, and the limited power of the study to identify events occurring in fewer than 1 in 10 000 people, warrant consideration when making decisions about recommendations for booster doses of COVID-19 vaccines. Such consideration is especially important in the context of the entrenched dominance of omicron sublineages, which have reduced rates of hospitalisation and infection fatality risk (0·03%),7Madhi SA Kwatra G Myers JE et al.Sustained low incidence of severe and fatal COVID-19 following widespread infection induced immunity after the omicron (BA.1) dominant in Gauteng, South Africa: an observational study.Viruses. 2023; 15: 597Crossref PubMed Scopus (0) Google Scholar and widespread hybrid immunity with lasting protection against severe disease. SAM received grant funds paid to his institution related to COVID-19 vaccines from The Bill and Melinda Gates Foundation and the South African Medical Research Council, and funds for clinical trials of COVID-19 vaccines from Novavax. AI declares no competing interests. Safety of monovalent and bivalent BNT162b2 mRNA COVID-19 vaccine boosters in at-risk populations in Israel: a large-scale, retrospective, self-controlled case series studyThis study provides the necessary vaccine safety assurances for at-risk populations to receive timed roll-out booster vaccinations. These assurances could reduce vaccine hesitancy and increase the number of at-risk individuals who opt to become vaccinated, and thereby prevent the severe outcomes associated with COVID-19. Full-Text PDF