Effectiveness of heterologous and homologous covid-19 vaccine regimens: living systematic review with network meta-analysis

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 to 31 July 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 second iteration of the analysis comprised 63 studies. 25 combinations of covid-19 vaccine regimens were identified, of which three doses of mRNA vaccine were found to be 93% (95% credible interval 70% to 98%) effective against asymptomatic or symptomatic covid-19 infections for non-delta or non-omicron related infections. Heterologous boosting using two dose adenovirus vector vaccines with one dose mRNA vaccine showed a vaccine effectiveness of 94% (72% to 99%) against non-delta or non-omicron related asymptomatic or symptomatic infections. Three doses of mRNA vaccine were found to be the most effective in reducing non-delta or non-omicron related hospital admission (96%, 82% to 99%). The vaccine effectiveness against death in people who received three doses of mRNA vaccine remains uncertain owing to confounders. The estimate for a four dose mRNA vaccine regimen was of low certainty, as only one study on the effectiveness of four doses could be included in this update. More evidence on four dose regimens will be needed to accurately assess the effectiveness of a fourth vaccine dose. For people with delta or omicron related infection, a two dose regimen of an adenovirus vector vaccine with one dose of mRNA booster was 77% (42% to 91%) effective against asymptomatic or symptomatic covid-19 infections, and a three dose regimen of a mRNA vaccine was 93% (76% to 98%) effective against covid-19 related hospital admission. 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. This version is update 1 of the original article published on 31 May 2022 (BMJ 2022;377:e069989), and previous versions can be found as data supplements (https://www.bmj.com/content/377/bmj-2022-069989/related). When citing this paper please consider adding the version number and date of access for clarity.