Intended for healthcare professionals

CCBYNC Open access

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

BMJ 2022; 377 doi: (Published 31 May 2022) Cite this as: BMJ 2022;377:e069989
  1. Wing Ying Au, masters student1 2,
  2. Peter Pak-Hang Cheung, assistant professor1 2
  1. 1Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China
  2. 2Department of Chemical Pathology, Chinese University of Hong Kong, Hong Kong, China
  1. Correspondence to: P P-H Cheung ppcheung{at}
  • Accepted 27 April 2022
  • Final version accepted 15 November 2022


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 ( When citing this paper please consider adding the version number and date of access for clarity.


  • Contributors: PPHC conceived and supervised the study. WYA and PPHC initiated and designed the study plan. WYA and PPHC performed the search, independently screened search results and extracted data from eligible studies. WYA and PPHC exchanged data extraction results and resolved disagreement through discussion. WYA performed the statistical analysis. WYA and PPHC wrote the manuscript. We confirm that both authors had full access to all data in the study and final responsibility for publishing it. WYA and PPHC accessed and verified the data. WYA and PPHC are study guarantors. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: This work was supported by the Chinese University of Hong Kong Department of Chemical Pathology’s Faculty Startup Fund and the University Grants Committee’s Collaborative Research Fund (C6036-21GF to PPHC). The funder had no role in study design or the collection, analysis, interpretation of data, writing of the manuscript, or decision to submit the article for publication.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: support from the Chinese University of Hong Kong for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • The lead authors affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

  • Dissemination to participants and related patient and public communities: We will disseminate the results to clinicians, patients, governmental organisations, and agencies through social media and press releases.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

Data availability statement

Raw data in this systematic review with meta-analysis are extracted from published and preprint studies available on the internet. Our processed data for network meta-analysis and R codes on GitHub (

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:

View Full Text