Objective To evaluate the effectiveness of heterologous and homologous covid-19 vaccine regimens with and without boosting in preventing covid-19 related infection, hospital admission, and death. Design Living systematic review and network meta-analysis. Data sources World Health Organization covid-19 databases, including 38 sources of published studies and preprints. Study selection Randomised controlled trials, cohort studies, and case-control studies. Methods 38 WHO covid-19 databases were searched on a weekly basis from 8 March 2022. Studies that assessed the effectiveness of heterologous and homologous covid-19 vaccine regimens with or without a booster were identified. Studies were eligible when they reported the number of documented, symptomatic, severe covid-19 infections, covid-19 related hospital admissions, or covid-19 related deaths among populations that were vaccinated and unvaccinated. The primary measure was vaccine effectiveness calculated as 1−odds ratio. Secondary measures were surface under the cumulative ranking curve (SUCRA) scores and the relative effects for pairwise comparisons. The risk of bias was evaluated by using the risk of bias in non-randomised studies of interventions (ROBINS-I) tool for all cohort and case-control studies. The Cochrane risk of bias tool (version 2; ROB-2) was used to assess randomised controlled trials. Results The first round of the analysis comprised 53 studies. 24 combinations of covid-19 vaccine regimens were identified, of which a three dose mRNA regimen was found to be the most effective against asymptomatic and symptomatic covid-19 infections (vaccine effectiveness 96%, 95% credible interval 72% to 99%). Heterologous boosting using two dose adenovirus vector vaccines with one mRNA vaccine has a satisfactory vaccine effectiveness of 88% (59% to 97%). A homologous two dose mRNA regimen has a vaccine effectiveness of 99% (79% to 100%) in the prevention of severe covid-19 infections. Three dose mRNA is the most effective in reducing covid-19 related hospital admission (95%, 90% to 97%). The vaccine effectiveness against death in people who received three doses of mRNA vaccine remains uncertain owing to confounders. In the subgroup analyses, a three dose regimen is similarly effective in all age groups, even in the older population (≥65 years). A three dose mRNA regimen works comparably well in patients who are immunocompromised and those who are non-immunocompromised. Homologous and heterologous three dose regimens are effective in preventing infection by covid-19 variants (alpha, delta, and omicron). Conclusion An mRNA booster is recommended to supplement any primary vaccine course. Heterologous and homologous three dose regimens work comparably well in preventing covid-19 infections, even against different variants. The effectiveness of three dose vaccine regimens against covid-19 related death remains uncertain. Systematic review registration This review was not registered. The protocol is included in the supplementary document. Readers’ note This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.

Background An optimised standard experimental setup across different hospitals is urgently needed to ensure consistency in nucleic acid test results for SARS-CoV-2 detection. A standard comparison across different nucleic acid tests and their optimal experimental setups is not present. We assessed the performance of three common nucleic acid tests, namely digital PCR (dPCR), quantitative PCR (qPCR), and loop-mediated isothermal amplification (LAMP), to detect SARS-CoV-2 in clinical settings. Methods In this systematic review and meta-analysis we compared sensitivity and specificity of qPCR, dPCR, and LAMP and their performances when different experimental setups (namely specimen type used, use of RNA extraction, primer–probe sets, and RNA extraction methods) are applied. We searched PubMed, BioRxiv, MedRxiv, SciFinder, and ScienceDirect for studies and preprints published between Feb 29 and Dec 15, 2020. Included dPCR, qPCR, and LAMP studies using any type of human specimens should report the number of true-positive, true-negative, false-positive, and false-negative cases with Emergency Use Authorization (EUA)-approved PCR assays as the comparator. Studies with a sample size of less than ten, descriptive studies, case studies, reviews, and duplicated studies were excluded. Pooled sensitivity and specificity were computed from the true and false positive and negative cases using Reitsma's bivariate random-effects and bivariate latent class models. Test performance reported in area under the curve (AUC) of the three nucleic acid tests was further compared by pooling studies with similar experimental setups (eg, tests that used RNA extracted pharyngeal swabs but with either the open reading frame 1ab or the N primer). Heterogeneity was assessed and reported in I 2 and τ 2 . Findings Our search identified 1277 studies of which we included 66 studies (11 dPCR, 32 qPCR, and 23 LAMP) with 15 017 clinical samples in total in our systematic review and 52 studies in our meta-analysis. dPCR had the highest pooled diagnostic sensitivity (94·1%, 95% CI 88·9–96·6, by Reitsma's model and 95·8%, 54·9–100·0, by latent class model), followed by qPCR (92·7%, 88·3–95·6, and 93·4%, 60·9–99·9) and LAMP (83·3%, 76·9–88·2, and 86·2%, 20·7–99·9), using EUA-approved PCR kits as the reference standard. LAMP was the most specific with a pooled estimate of 96·3% (93·8–97·8) by Reitsma's model and 94·3% (49·1–100·0) by latent class model, followed by qPCR (92·9%, 87·2–96·2, and 93·1%, 47·1–100·0) and dPCR (78·5%, 57·4–90·8, and 73·8%, 0·9–100·0). The overall heterogeneity was I 2 0·5% (τ 2 2·79) for dPCR studies, 0% (4·60) for qPCR studies, and 0% (3·96) for LAMP studies. AUCs of the three nucleic acid tests were the highest and differed the least between tests (ie, AUC>0·98 for all tests) when performed with RNA extracted pharynge...

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