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.

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.

Trends of Randomized Clinical Trials Citing Prior Systematic Reviews, 2007-2021.

Importance: Systematic reviews can help to justify a new randomized clinical trial (RCT), inform its design, and interpret its results in the context of prior evidence. Objective: To assess trends and factors associated with citing (a marker of the use of) prior systematic reviews in RCT reports. Design, Setting, and Participants: This cross-sectional study investigated 737 Cochrane reviews assessing health interventions to identify 4003 eligible RCTs, defined as those included in an updated version but not in the first version of a Cochrane review and published 2 years after the first version of the Cochrane review was published. Main Outcomes and Measures: The primary outcome was the citation of prior systematic reviews, Cochrane or others, as determined by screening references of eligible RCTs. Factors that may be associated with the citation of prior systematic reviews were also examined. Results: Among 4003 eligible RCTs, 1241 studies (31.0%) cited Cochrane reviews, 1698 studies (42.4%) cited prior non-Cochrane reviews, and 2265 studies (56.6%) cited either type of systematic review or both; 1738 RCTs (43.4%) cited no systematic reviews. The percentage of RCTs citing prior Cochrane reviews, non-Cochrane reviews, and either or both types of review increased from 28 studies (15.3%), 46 studies (25.1%), and 65 studies (35.5%) of 183 RCTs before 2008 to 42 studies (40.8%), 65 studies (64.1%), and 73 studies (71.8%) of 102 RCTs since 2020, respectively; the annual increases were 1.9% (95% CI, 1.4%-2.3%), 3.3% (95% CI, 2.9%-3.7%), and 3.0% (95% CI, 2.5%-3.5%), respectively. The proportion of RCTs citating prior systematic reviews varied considerably across clinical specialties, ranging from 28 of 106 RCTs (26.4%) in ophthalmology to 386 of 553 RCTs (69.8%) in psychiatry (P < .001). RCTs with 100 participants or more (risk ratio [RR], 1.16; 95% CI, 1.03-1.30), nonindustry funding (RR, 1.43; 95% CI, 1.27-1.61), and authors from high-income countries (RR, 1.10; 95% CI, 1.03-1.17) were more likely to cite systematic reviews than those with fewer than 100 participants, industry funding, and authors from low- and middle-income countries, respectively. A journal requirement to cite systematic reviews was not associated with the likelihood of citing a systematic review. Conclusions and Relevance: This study found that the citation of prior systematic reviews in RCT reports improved over time, but approximately 40% of RCTs failed to do so. These findings suggest that reference to prior evidence for initiating, designing, and reporting RCTs should be further emphasized to assure clinical relevance, improve methodological quality, and facilitate interpretation of new results.