key: cord-0937986-t3o4fsuz
authors: Petrelli, Fausto; Luciani, Andrea; Borgonovo, Karen; Ghilardi, Mara; Parati, Maria Chiara; Petrò, Daniela; Lonati, Veronica; Pesenti, Angelo; Cabiddu, Mary
title: Third dose of SARS‐CoV‐2 vaccine: A systematic review of 30 published studies
date: 2022-02-12
journal: J Med Virol
DOI: 10.1002/jmv.27644
sha: 5122eae2ce6713b97cf4e96c54bc01c39927d7f2
doc_id: 937986
cord_uid: t3o4fsuz

We analyzed published studies on the efficacy and safety of the third dose of the COVID‐19 vaccine in various general population settings. We conducted systematic searches of PubMed and EMBASE for series published in the English language through November 15, 2021, using the search terms “third” or “booster” or “three” and “dose” and “COVID‐19” or “SARS‐CoV‐2.” All articles were selected according to the MOOSE guidelines. The seroconversion risk after third doses was descriptively expressed as a pooled rate ratio ([seroconversion rate after the third dose]/[seroconversion rate after the second dose]). The search returned 30 studies that included a total of 2 734 437 vaccinated subjects. In more than 2 700 000 Israeli patients extracted from the general population, the reduction in the risk of infection ranged from 88% to 92%. Conversion rates for IgG anti‐spike ranged from 95% to 100%. In cancer or immunocompromised patients, mean IgG seroconversion was 39.4% before and 66.6% after third doses. A third dose seems necessary to protect against all COVID‐19 infection, severe disease, and death risk.

("COVID-19" or "SARS-CoV-2"). Studies were included if they reported the efficacy of the third dose in terms of infection rates and/ or mortality. Seroconversion rates before and after booster were also reported. Both observational and retrospective studies and clinical trials were analyzed. References of eligible studies were also screened for any other potential publication suitable for inclusion in this review.

Data were extracted from two reviewers (F. P. and M. C.). Information extracted regarded type of study, year and country of origin, type and number of boosted patients, type of initial two-dose vaccine received, type and timing of third doses, median anti-spike IgG titers before and after the booster, seroconversion rates, effectiveness, and safety. Descriptive statistic was used to explain results. The primary immunogenicity outcome of anti-spike IgG was reported for each study before and after the third dose. In particular, the ratio of seroconversion rates after third and second doses (rate ratios) where this value was not reported directly. Other outcomes were infection rates and mortality due to COVID-19. Informed consent was not necessary in this paper because it provides a review of the literature. The risk of bias was evaluated with Nottingham-Ottawa Scale.

The search process identified 30 studies (Table 1; Supporting Informations S1, S2, and S3), including four population-based observational studies from Israel, one retrospective analysis of the US Phase 1-3 trials in which 23 patients received third doses of the Pfizer-BioNTech vaccine after the recommendation released by health authorities, one Chinese Phase 1-2 study in which patients were randomized to two different vaccine doses (or placebo), an additional cohort of 80 subjects from two previous trials who received third doses of the Astra Zeneca vaccine. Two studies that reported safety data alone were excluded. A third study reported relative viral loads of Delta-variant in unvaccinated and boosted subjects was not included. Twenty-one publications were retrospective or prospective case series in different high-risk populations (hemodialyzed, transplant, or cancer patients). Finally, two other series reported effects in health care workers and volunteers. Only seven studies reported the rate of infections as the outcome. The others reported seroconversion rates after the third dose and IgG titers before and after the third dose, as well as safety data ( 

In more than 2 700 000 Israeli patients extracted from the general population, the reduction in the risk of infection ranged from 88% to 92%.

Conversion rates for IgG anti-spike ranged from 95% to 100%, including a non-mRNA Chinese vaccine (ZF2001) assessed in a Phase 2 study by Yang et al. These were studies in the uninfected population that received two previous doses of anti-COVID vaccines.

In cancer patients or the immunocompromised (e.g., transplant recipients), mean IgG seroconversion was 39.4% before and 66.6% after third dose administration (rate ratio IgG titers of pre-and postthird-dose vaccination 1.69).

Safety was usually satisfactory with no serious adverse effects and usually mild to moderate local and general side effects (adverse events are reported in Table 2 ).

The overall risk of bias was moderate-good for all studies except three publications that scored 5 with NOS score (see Table 1 for details). 

Author No -(-) EUROIMMUN anti-S1 IgG assay or Roche Elecsys anti-RBD pan-Ig assay -(9 days) EUROIMMUN anti-S1

IgG assay or Roche Elecsys anti-RBD pan-Ig assay In conclusion, a third-dose booster seems necessary, despite not providing complete protection at all against the risk of COVID-19 infection, severe disease, and death. We confirmed the efficacy of mRNA vaccine boosters for the general population not previously exposed to COVID-19 infection, particularly in those over 40 years of age with few or no comorbidities (from one large observational study conducted in Israel), in those over 60 (from over 1 million vaccinated patients in the real-world Israeli population), in those over 18 (from a retrospective cohort study of >800 000 Israeli subjects), and those at risk for severe COVID-19 because of comorbidities (from several small studies conducted in transplant, hemodialyzed, or oncologic patients).

In particular, a weaker immune response may occur in these frail patients compared to the response in healthy subjects (median increase of 70% in seroconversion rates). However, how long the increased antibody response from the third dose will last remains uncertain.

Continuous monitoring of the vaccines' effectiveness is also warranted.

Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial

Covid-19 vaccinations: a comprehensive review of their safety and efficacy in special populations

Protection of BNT162b2 vaccine booster against Covid-19 in Israel

SARS-CoV-2 vaccine protection and deaths among US veterans during 2021

Articles neutralising antibody titres as predictors of protection against SARS-CoV-2 variants and the impact of boosting: a meta-analysis

Safety monitoring of an additional dose of COVID-19 vaccine-United States

Reactogenicity of a third BNT162b2 mRNA COVID-19 vaccine among immunocompromised individuals and seniors-a nationwide survey

SUPPORTING INFORMATION Additional supporting information may be found in the online version of the article at the publisher's website. How to cite this article

The authors declare no conflict of interest.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

http://orcid.org/0000-0001-9639-4486