Search

Background: 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., Competing Interests: Peter B Gilbert received funds from NIAID/NIH, consulting fees from Curevo Vaccine Company and MinervaX Vaccine Company, served unpaid on a Moderna Advisory Board for Zika vaccines, AstraZeneca Vaccine SAB, Sanofi SAB, and Vaccine Company SAB. Lawrence Corey, Fatima Laher, Sharlaa Badal-Faesen, Sinead Delany-Moretlwe, Mina C Hosseinipour, Craig A Magaret, Erica Andersen-Nissen, Yunda Huang, M. Juliana McElrath, Cissy Kityo, Grace Mboya, and Jessica Andriesen received funding from NIAID/NIH paid to their institutions. Sufia Dadabhai and Noel Kayange report salary support from Johns Hopkins University. M. Juliana McElrath reports NIAID and Bill & Melinda Gate's Foundation payments to institution, payment from Stanford, CROI, NIH VRC, Ragon Institute. Richard Lessells is a current member of University of KwaZulu- Natal Biomedical Research Ethics Committee, one of the committees that reviewed and approved the CoVPN 3008 study, however he recused himself from decision making because of the conflict of interest. All other authors have nothing to declare., (© 2025 The Authors.)

Background: Deeper insight is needed on how monoclonal antibodies (mAbs) affect vaccine-mediated immune responses when targeting the same protein. We describe the first prospective randomised trial designed to understand mAb-mediated alterations in vaccine-induced immune responses to SARS-CoV-2 spike protein epitopes., Methods: This randomised, open-label, parallel-group study assessed the potential interaction of a mAb combination, casirivimab and imdevimab, with a vaccine, Moderna's mRNA-1273, in healthy SARS-CoV-2 immunologically naive, seronegative adults at six centres in the USA. Participants were randomly assigned (per prespecified randomisation ratios within enrolment waves) according to a computer-generated randomisation scheme, stratified by age (<65 years and ≥65 years), to various intravenous or subcutaneous doses of casirivimab and imdevimab before, after, or at the same time as mRNA-1273 or to mRNA-1273 only. The doses of casirivimab and imdevimab were chosen to mimic various time intervals between receipt of 1200 mg of the mAb and the first dose of a primary series with mRNA-1273. The primary endpoint was vaccine-induced 50% inhibitory dilution neutralising antibody titres to SARS-CoV-2 spike protein, 56 days after the first vaccination. Secondary endpoints included vaccine-induced total antibodies to SARS-CoV-2 antigens and incidence of treatment-emergent adverse events. Exploratory endpoints included blood-derived T-cell and B-cell responses. The per-protocol set was used for the analysis of the primary endpoint and included all randomly assigned participants who received both doses of the vaccine and completed the injection or infusion of casirivimab and imdevimab per protocol, had no evidence of SARS-CoV-2 infection in the past or in the 56 days after the first dose of vaccine, and did not receive any intervention outside of the study that could alter the immune response. Safety was assessed in the safety analysis set, which included all randomly assigned participants who had received one or more doses of mRNA-1273 or any study drug, and analysed based on treatment received. The study is registered with ClinicalTrials.gov, NCT04852978, and is complete., Findings: Between April 29, 2021, and Nov 21, 2022, 807 participants were assessed for eligibility and 295 were randomly assigned. 293 participants were included in the safety analysis set and 260 were included in the per-protocol set. All vaccinated participants developed neutralising antibodies to SARS-CoV-2, with median titres above the published protective threshold (100 IU/mL) against the SARS-CoV-2 D614G variant (considered a reference strain at the time the initial COVID-19 vaccines were developed). Titres were decreased up to 4-fold (median titres 280-450 IU/mL for casirivimab and imdevimab vs 1160 IU/mL for vaccine only on day 56) when casirivimab and imdevimab was given 85 days or less before vaccination (150-1200 mg intravenously) or co-administered subcutaneously (600 mg or 1200 mg) with vaccination. Minimal reduction in neutralisation titres was observed in the 48 mg and 12 mg intravenous groups, corresponding to receipt of casirivimab and imdevimab 113 days and 169 days, respectively, before vaccination, and when administering the vaccine 6 days before the mAb. Across all groups, mAbs had a minimal effect on vaccine-induced total antibodies and T-cell responses to the spike protein. Casirivimab and imdevimab plus mRNA-1273 was generally well tolerated; a slight increase in treatment-emergent adverse events was observed in the casirivimab and imdevimab plus vaccine groups versus the vaccine-only group., Interpretation: Casirivimab and imdevimab administration before or at the time of COVID-19 vaccination reduced the elicitation of SARS-CoV-2 neutralising antibodies, but minimal effect was observed when vaccination occurred before mAb administration. Although the clinical significance of this decrease in neutralisation is unclear, this evidence suggests that further investigation of potential interactions could be warranted before concurrent clinical use of mAbs and vaccines targeting the same viral proteins as their main modes of action for the prevention or treatment of infectious diseases., Funding: Regeneron Pharmaceuticals and F Hoffmann-La Roche., Competing Interests: Declaration of interests FI and JDH are employees and stockholders of Regeneron Pharmaceuticals, and report having patents pending, which have been licensed and receiving royalties, with Regeneron Pharmaceuticals. AMGO, BAO, TB, SG, LF, SCI, MT, GPG, and BM are employees and stockholders of Regeneron Pharmaceuticals. JM is an employee of Regeneron Pharmaceuticals. EF-N is a former employee and current stockholder of Regeneron Pharmaceuticals, and reports patents pending, which have been licensed and receiving royalties, with Regeneron Pharmaceuticals. IH is an employee and stockholder of Regeneron Pharmaceuticals, and a stockholder of Merck & Co. ATH is an employee and stockholder of Regeneron Pharmaceuticals, is a stockholder of Pfizer, and reports a patent pending, which has been licensed and receiving royalties, with Regeneron Pharmaceuticals. AB, CAK, and GDY are employees and stockholders of Regeneron Pharmaceuticals and report having issued patents (US patent numbers 10 787 501, 10 954 289, and 10 975 139) and pending patents, which have been licensed and receiving royalties, with Regeneron Pharmaceuticals. CDP is an employee and stockholder of Regeneron Pharmaceuticals and reports a patent pending with Regeneron Pharmaceuticals. MJM reports funding from Regeneron Pharmaceuticals, paid to her institution, and grants from the US National Institute of Allergy and Infectious Diseases, the Biomedical Advanced Research and Development Authority, Moderna, Sanofi Pasteur, and Janssen, paid to her institution. SCDR reports grants from the National Institutes of Health and the Bill & Melinda Gates Foundation awarded to his institution, and contracts from Regeneron Pharmaceuticals, The Henry M Jackson Foundation, Johnson & Johnson Innovative Medicine (formerly Janssen Pharmaceuticals), Gates Medical Research Institute, Paul G Allen Family Foundation, and Battelle, awarded to his institution. KWC reports funding from Regeneron Pharmaceuticals, paid to her institution, and is an employee and stockholder of Moderna. LDW CAH, AJO, AHP, and GDT report funding and provision of study materials from Regeneron Pharmaceuticals, paid to their institution. GAH is an employee and stockholder of Regeneron Pharmaceuticals and reports having a patent pending, which has been licensed and receiving royalties, with Regeneron Pharmaceuticals, as well as a pending patent application. MM, JH, LP, and FAF declare no competing interests., (Copyright © 2024. Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)