Publication date: Dec 05, 2024

Limited studies have been conducted on the safety and effectiveness of heterologous COVID-19 vaccine boosting in lower income settings, especially those with high-HIV prevalence. , The Sisonke Heterologous mRNA-1273 boost after prime with Ad26. COV2. S (SHERPA) trial evaluated a mRNA-1273 boost after Ad26. COV2. S priming in South Africa. SHERPA was a single-arm, open-label, phase 3 study nested in the Sisonke implementation trial of 500000 healthcare workers (HCWs). Sisonke participants were offered mRNA-1273 boosters between May and November 2022, when Omicron sub-lineages were circulating. Adverse events (AE) were self-reported, and co-primary endpoints (SARS-CoV-2 infections and COVID-19 hospitalizations or deaths) were collected through national databases. We used Cox regression models with booster status as a time-varying covariate to determine the relative vaccine effectiveness (rVE) of the mRNA-1273 booster among SHERPA versus unboosted Sisonke participants. Of 11248 SHERPA participants in the rVE analysis cohort (79. 3% female, median age 41), 45. 4% had received one and 54. 6% two Ad26. COV2. S doses. Self-reported comorbidities included HIV (18. 7%), hypertension (12. 9%) and diabetes (4. 6%). In multivariable analysis including 413161 unboosted Sisonke participants, rVE of the booster was 59% (95%CI 29-76%) against SARS-CoV-2 infection: 77% (95%CI 9-94%) in the one-Ad26. COV2. S dose group and 52% (95%CI 13-73%) in the two-dose group. Severe COVID-19 was identified in 148 unboosted Sisonke participants, and only one SHERPA participant with severe HIV-related immunosuppression. Of 11798 participants in the safety analysis, 228 (1. 9%) participants reported 575 reactogenicity events within 7 days of the booster (most commonly injection site pain, malaise, myalgia, swelling, induration and fever). More reactogenicity events were reported among those with prior SARS-CoV-2 infections (adjusted odds ratio [aOR] 2. 03, 95%CI 1. 59-2. 59) and less among people living with HIV (PLWH) (aOR 0. 49, 95%CI 0. 34-0. 69). There were 115 unsolicited adverse events (AEs) within 28 days of vaccination. No related serious AEs were reported. In an immunogenicity sub-study, mRNA-1273 increased binding and neutralizing antibody titres and spike-specific T-cell responses 4 weeks after boosting regardless of the number of prior Ad26. COV2. S doses, or HIV status, and generated Omicron spike-specific cross-reactive responses. mRNA-1273 boosters after one or two Ad26. COV2. S doses were well-tolerated, safe and effective against Omicron SARS-CoV-2 infections among HCWs and PLWH. Trial registration: The SHERPA study is registered in the Pan African Clinical Trials Registry (PACTR): PACTR202310615330649 and the South African National Clinical Trial Registry (SANCTR): DOH-27-052022-5778.

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