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ObjectiveTo compare the efficacy of COVID 19 vaccines between those with immunocompromised medical conditions and those who are immunocompetentDesignSystematic review and meta-analysisData sourcesPubMed, EMBASE, CENTRAL, CORD-19 and WHO COVID-19 research databases were searched for eligible comparative studies published between 1 December 2020 and 3 September 2021. ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched in September 2021 to identify registered yet unpublished or ongoing studies.Study selectionProspective observational studies which compared the efficacy of COVID-19 vaccination between those with immunocompromising medical conditions and those who were immunocompetent were included. Two reviewers independently screened for potentially eligible studies.Data extractionThe primary outcomes of interest were cumulative incidence of seroconversion after first and second doses of COVID vaccination. Secondary outcomes included SARS-CoV-2 antibody titre level after first and second doses of COVID-19 vaccination. After duplicate data abstraction, a frequentist random effects meta-analysis was conducted. Risk of bias was assessed using the ROBINS-I tool. Certainty of evidence was assessed using the GRADE approach.ResultsAfter screening 3283 studies, 42 studies that met our inclusion criteria were identified. 18 immunocompromised cohorts from 17 studies reported seroconversion in immunocompromised patients compared to healthy controls after the first dose and 30 immunocompromised cohorts in 28 studies reporting data after the second dose.Among immunocompromised groups, in incremental order, transplant recipients had the lowest pooled risk ratio of 0.06 (95%CI: 0.04 to 0.09, I^2=0%, p=0.81) (GRADE=Moderate) followed by haematological cancer patients at 0.36 (95%CI: 0.21 to 0.62, I^2 = 89%, pAfter the second dose, the lowest pooled risk ratio was again seen in transplant recipients at 0.29 (95%CI: 0.21 to 0.40, I^2=91%, pConclusionSeroconversion rates and serological titres are significantly lower in immunocompromised patients with transplant recipients having the poorest outcomes. Additional strategies on top of the conventional 2-dose regimen will likely be warranted, such as a booster dose of the vaccine.Systematic review registrationPROSPERO CRD42021272088