Garrett NTapley AHudson ADadabhai SZhang BMgodi NMAndriesen JTakalani AFisher LHKee JJMagaret CAVillaran MHural JAndersen-Nissen EFerarri GMiner MDLe Roux BWilkinson ELessells Rde Oliveira TOdhiambo JShah PPolakowski LYacovone MSamandari TChirenje ZElyanu PJMakhema JKamuti ENuwagaba-Biribonwoha HBadal-Faesen SBrumskine WCoetzer SDawson RDelany-Moretlwe SDiacon AHFry SGill KMEbrahim Hoosain ZAHosseinipour MCInambao MInnes CInnes SKalonji DKasaro MKassim PKayange NKilembe WLaher FMalahleha MMaluleke VLMboya GMcHarry KMitha EMngadi KMda PMoloantoa TMutuluuza CKNaicker NNaicker VNana ANanvubya ANchabeleng MOtieno WPotgieter ELPotloane DPunt ZSaid JSingh YTayob MSVahed YWabwire DOMcElrath MJKublin JGBekker LGGilbert PBCorey LGray GEHuang YKotze P2025-05-232025-Feb10.1016/j.eclinm.2024.103054https://pubs.cidrz.org/handle/123456789/10358BACKGROUND: With limited access to mRNA COVID-19 vaccines in lower income countries, and people living with HIV (PLWH) largely excluded from clinical trials, Part A of the multicentre CoVPN 3008 (Ubuntu) study aimed to assess the safety of mRNA-1273, the relative effectiveness of hybrid versus vaccine immunity, and SARS-CoV-2 viral persistence among PLWH in East and Southern Africa during the omicron outbreak. METHODS: Previously unvaccinated adults with HIV and/or other comorbidities associated with severe COVID-19 received either one (hybrid immunity) or two (vaccine immunity) 100-mcg doses of ancestral strain mRNA-1273 in the first month, depending on baseline evidence of prior SARS-CoV-2 infection. In a prospective cohort study design, we used covariate-adjusted Cox regression and counterfactual cumulative incidence methods to determine the hazard ratio and relative risk of COVID-19 and severe COVID-19 with hybrid versus vaccine immunity within six months. The ongoing Ubuntu study is registered on ClinicalTrials.gov (NCT05168813) and this work was conducted from December 2021 to March 2023. FINDINGS: Between December 2021 and September 2022, 14,237 participants enrolled, and 14,002 (83% PLWH, 69% SARS-CoV-2 seropositive) were included in the analyses. Vaccinations were safe and well tolerated. Common adverse events were pain or tenderness at the injection site (26.7%), headache (20.4%), and malaise (20.3%). Severe adverse events were rare (0.8% of participants after the first and 1.1% after the second vaccination), and none were life-threatening or fatal. Among PLWH, the median CD4 count was 635 cells/μl and 18.5% had HIV viraemia. The six-month cumulative incidences in the hybrid immunity and vaccine immunity groups were 2.02% (95% confidence interval [CI] 1.61-2.44) and 3.40% (95% CI 2.30-4.49) for COVID-19, and 0.048% (95% CI 0.00-0.10) and 0.32% (95% CI 0.59-0.63) for severe COVID-19. Among all PLWH the hybrid immunity group had a 42% lower hazard rate of COVID-19 (hazard ratio [HR] 0.58; 95% CI 0.44-0.77; p < 0.001) and a 73% lower hazard rate of severe COVID-19 (HR 0.27; 95% CI 0.07-1.04; p = 0.056) than the vaccine immunity group, but this effect was not seen among PLWH with CD4 counts <350 cells/μl or HIV viraemia. Twenty PLWH had persistent SARS-CoV-2 virus at least 50 days. INTERPRETATION: Hybrid immunity was associated with superior protection from COVID-19 compared to vaccine immunity with the ancestral mRNA-1273 vaccine. Persistent infections among immunocompromised PLWH may provide reservoirs for emerging variants. FUNDING: National Institute of Allergy and Infectious Diseases.