Efficacy of SARS-CoV-2 vaccines and the dose-response relationship with three major antibodies: a systematic review and meta-analysis of randomised controlled trials

Abstract

Background: The efficacy of SARS-CoV-2 vaccines in preventing severe COVID-19 illness and death is uncertain due to the rarity of data in individual trials. How well the antibody concentrations can predict the efficacy is also uncertain. We aimed to assess the efficacy of these vaccines in preventing SARS-CoV-2 infections of different severities and the dose-response relationship between the antibody concentrations and efficacy.

Methods: We did a systematic review and meta-analysis of randomised controlled trials (RCTs). We searched PubMed, Embase, Scopus, Web of Science, Cochrane Library, WHO, bioRxiv, and medRxiv for papers published between Jan 1, 2020 and Sep 12, 2022. RCTs on the efficacy of SARS-CoV-2 vaccines were eligible. Risk of bias was assessed using the Cochrane tool. A frequentist, random-effects model was used to combine efficacy for common outcomes (ie, symptomatic and asymptomatic infections) and a Bayesian random-effects model was used for rare outcomes (ie, hospital admission, severe infection, and death). Potential sources of heterogeneity were investigated. The dose-response relationships of neutralising, spike-specific IgG and receptor binding domain-specific IgG antibody titres with efficacy in preventing SARS-CoV-2 symptomatic and severe infections were examined by meta-regression. This systematic review is registered with PROSPERO, CRD42021287238.

Findings: 28 RCTs (n=286 915 in vaccination groups and n=233 236 in placebo groups; median follow-up 1-6 months after last vaccination) across 32 publications were included in this review. The combined efficacy of full vaccination was 44·5% (95% CI 27·8-57·4) for preventing asymptomatic infections, 76·5% (69·8-81·7) for preventing symptomatic infections, 95·4% (95% credible interval 88·0-98·7) for preventing hospitalisation, 90·8% (85·5-95·1) for preventing severe infection, and 85·8% (68·7-94·6) for preventing death. There was heterogeneity in the efficacy of SARS-CoV-2 vaccines against asymptomatic and symptomatic infections but insufficient evidence to suggest whether the efficacy could differ according to the type of vaccine, age of the vaccinated individual, and between-dose interval (p>0·05 for all). Vaccine efficacy against symptomatic infection waned over time after full vaccination, with an average decrease of 13·6% (95% CI 5·5-22·3; p=0·0007) per month but can be enhanced by a booster. We found a significant non-linear relationship between each type of antibody and efficacy against symptomatic and severe infections (p<0·0001 for all), but there remained considerable heterogeneity in the efficacy, which cannot be explained by antibody concentrations. The risk of bias was low in most studies.

Interpretation: The efficacy of SARS-CoV-2 vaccines is higher for preventing severe infection and death than for preventing milder infection. Vaccine efficacy wanes over time but can be enhanced by a booster. Higher antibody titres are associated with higher estimates of efficacy but precise predictions are difficult due to large unexplained heterogeneity. These findings provide an important knowledge base for interpretation and application of future studies on these issues.

Funding: Shenzhen Science and Technology Programs.

Figure 1

Study selection RCTs=randomised controlled trials.

Figure 2

Forest plot for efficacy of full vaccination of SARS-CoV-2 vaccines on preventing infections according to severity of infection and type of vaccine Vaccine efficacy for individual studies was calculated with continuity correction by adding 0·5 to zero-count cells. CrI=credible interval.

Figure 2

Forest plot for efficacy of full vaccination of SARS-CoV-2 vaccines on preventing infections according to severity of infection and type of vaccine Vaccine efficacy for individual studies was calculated with continuity correction by adding 0·5 to zero-count cells. CrI=credible interval.

Figure 2

Forest plot for efficacy of full vaccination of SARS-CoV-2 vaccines on preventing infections according to severity of infection and type of vaccine Vaccine efficacy for individual studies was calculated with continuity correction by adding 0·5 to zero-count cells. CrI=credible interval.

Figure 3

Differences in efficacy of different SARS-CoV-2 full vaccinations on preventing infections of different severity, according to vaccine type Error bars show 95% CI for asymptomatic and symptomatic infection and 95% credible interval for hospital admission, severe infection, and death. Data on asymptomatic infection were not available for DNA vaccine and recombinant protein vaccine; data on hospitalisation were not available for DNA vaccine and mRNA vaccine; data on deaths were not available for DNA vaccine.

Figure 4

Change of vaccine efficacy in preventing symptomatic infection after full vaccination Error bars show 95% CI.

Figure 5

Dose–response relationship of three SARS-CoV-2 antibodies with efficacy of full vaccination for preventing symptomatic infections (A–C) and severe infections (D–F) An example of prediction. Thiruvengadam and colleagues showed that the neutralising antibody titres 61 days after the second vaccine dose of ChAdOx1 nCoV-19 (adenovirus-vectored vaccine) were 599·4 (95% CI 376·9–953·2), which converts to an SMD of 3·96. Using the formula efficacy=(1–e^{–0·2804×SMD})×100%, an efficacy of 67·1% for preventing symptomatic infection is obtained, which is close to the efficacy estimate of 63·1% given in the study. Where n₁ is the number of trials providing both efficacy and antibody data and n₂ is the number of trials providing efficacy data only, with corresponding antibody data reported in previous phase trials: (A) n₁=13, n₂=14; (B) n₁=9, n₂=8; (C) n₁=6, n₂=8; (D) n₁=9, n₂=13; (E) n₁=6, n₂=8; (F) n₁=5, n₂=6. RBD=receptor binding domain. SMD=standardised mean difference.