Hybrid Versus Vaccine Immunity of MRNA-1273 Among People Living with HIV in East and Southern Africa: a Prospective Cohort Analysis from the Multicentre CoVPN 3008 (Ubuntu) Study

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.

References

Blencowe H, Cousens S, Bianchi Jassir F, Say L, Chou D, Mathers C . National, regional, and worldwide estimates of stillbirth rates in 2015, with trends from 2000: a systematic analysis. Lancet Glob Health. 2016; 4(2):e98-e108. DOI: 10.1016/S2214-109X(15)00275-2. View

Hoft M, Burgers W, Riou C . The immune response to SARS-CoV-2 in people with HIV. Cell Mol Immunol. 2023; 21(2):184-196. PMC: 10806256. DOI: 10.1038/s41423-023-01087-w. View

Bertagnolio S, Thwin S, Silva R, Nagarajan S, Jassat W, Fowler R . Clinical features of, and risk factors for, severe or fatal COVID-19 among people living with HIV admitted to hospital: analysis of data from the WHO Global Clinical Platform of COVID-19. Lancet HIV. 2022; 9(7):e486-e495. PMC: 9090268. DOI: 10.1016/S2352-3018(22)00097-2. View

Cele S, Karim F, Lustig G, San J, Hermanus T, Tegally H . SARS-CoV-2 prolonged infection during advanced HIV disease evolves extensive immune escape. Cell Host Microbe. 2022; 30(2):154-162.e5. PMC: 8758318. DOI: 10.1016/j.chom.2022.01.005. View

Tukei V, Hoffman H, Greenberg L, Thabelo R, Nchephe M, Motsoane T . Adverse Pregnancy Outcomes Among HIV-positive Women in the Era of Universal Antiretroviral Therapy Remain Elevated Compared With HIV-negative Women. Pediatr Infect Dis J. 2021; 40(9):821-826. PMC: 8357042. DOI: 10.1097/INF.0000000000003174. View

Weigang S, Fuchs J, Zimmer G, Schnepf D, Kern L, Beer J . Within-host evolution of SARS-CoV-2 in an immunosuppressed COVID-19 patient as a source of immune escape variants. Nat Commun. 2021; 12(1):6405. PMC: 8568958. DOI: 10.1038/s41467-021-26602-3. View

Meiring S, Tempia S, Bhiman J, Buys A, Kleynhans J, Makhasi M . Prolonged Shedding of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at High Viral Loads Among Hospitalized Immunocompromised Persons Living With Human Immunodeficiency Virus (HIV), South Africa. Clin Infect Dis. 2022; 75(1):e144-e156. PMC: 8903337. DOI: 10.1093/cid/ciac077. View

van der Laan M, Polley E, Hubbard A . Super learner. Stat Appl Genet Mol Biol. 2007; 6:Article25. DOI: 10.2202/1544-6115.1309. View

Baden L, El Sahly H, Essink B, Kotloff K, Frey S, Novak R . Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2020; 384(5):403-416. PMC: 7787219. DOI: 10.1056/NEJMoa2035389. View

10.

Rice B, Annapragada A, Baker R, Bruijning M, Dotse-Gborgbortsi W, Mensah K . Variation in SARS-CoV-2 outbreaks across sub-Saharan Africa. Nat Med. 2021; 27(3):447-453. PMC: 8590469. DOI: 10.1038/s41591-021-01234-8. View

11.

Nyberg T, Ferguson N, Nash S, Webster H, Flaxman S, Andrews N . Comparative analysis of the risks of hospitalisation and death associated with SARS-CoV-2 omicron (B.1.1.529) and delta (B.1.617.2) variants in England: a cohort study. Lancet. 2022; 399(10332):1303-1312. PMC: 8926413. DOI: 10.1016/S0140-6736(22)00462-7. View

12.

Pratama N, Wafa I, Budi D, Putra M, Wardhana M, Kencono Wungu C . mRNA Covid-19 vaccines in pregnancy: A systematic review. PLoS One. 2022; 17(2):e0261350. PMC: 8809595. DOI: 10.1371/journal.pone.0261350. View

13.

Madhi S, Kwatra G, Myers J, Jassat W, Dhar N, Mukendi C . Population Immunity and Covid-19 Severity with Omicron Variant in South Africa. N Engl J Med. 2022; 386(14):1314-1326. PMC: 8908853. DOI: 10.1056/NEJMoa2119658. View

14.

Motsoeneng B, Bhiman J, Richardson S, Moore P . SARS-CoV-2 humoral immunity in people living with HIV-1. Trends Immunol. 2024; 45(7):511-522. DOI: 10.1016/j.it.2024.05.005. View

15.

Polack F, Thomas S, Kitchin N, Absalon J, Gurtman A, Lockhart S . Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020; 383(27):2603-2615. PMC: 7745181. DOI: 10.1056/NEJMoa2034577. View

16.

Westling T, Luedtke A, B Gilbert P, Carone M . Inference for treatment-specific survival curves using machine learning. J Am Stat Assoc. 2024; 119(546):1541-1553. PMC: 11339859. DOI: 10.1080/01621459.2023.2205060. View

17.

Hunter D, Abdool Karim S, Baden L, Farrar J, Hamel M, Longo D . Addressing Vaccine Inequity - Covid-19 Vaccines as a Global Public Good. N Engl J Med. 2022; 386(12):1176-1179. DOI: 10.1056/NEJMe2202547. View

18.

Bobrovitz N, Ware H, Ma X, Li Z, Hosseini R, Cao C . Protective effectiveness of previous SARS-CoV-2 infection and hybrid immunity against the omicron variant and severe disease: a systematic review and meta-regression. Lancet Infect Dis. 2023; 23(5):556-567. PMC: 10014083. DOI: 10.1016/S1473-3099(22)00801-5. View

19.

Aydillo T, Gonzalez-Reiche A, Aslam S, van de Guchte A, Khan Z, Obla A . Shedding of Viable SARS-CoV-2 after Immunosuppressive Therapy for Cancer. N Engl J Med. 2020; 383(26):2586-2588. PMC: 7722690. DOI: 10.1056/NEJMc2031670. View

20.

Carazo S, Skowronski D, Brisson M, Barkati S, Sauvageau C, Brousseau N . Protection against omicron (B.1.1.529) BA.2 reinfection conferred by primary omicron BA.1 or pre-omicron SARS-CoV-2 infection among health-care workers with and without mRNA vaccination: a test-negative case-control study. Lancet Infect Dis. 2022; 23(1):45-55. PMC: 9491856. DOI: 10.1016/S1473-3099(22)00578-3. View