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

Abstract

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.

Keywords: COVID-19; Hybrid immunity; People living with HIV; SARS-CoV-2; Vaccine immunity; mRNA-1273.

Fig. 1

CONSORT diagram. Analysis populations. Enrolled participants were assigned to study groups based on HIV status and anti-spike SARS-CoV-2 point-of-care serology (POC anti-S) status. Participants were assigned to receive two doses of mRNA-1273 if their baseline POC anti-S was negative (vaccine immunity) and assigned to receive one dose of mRNA-1273 if their baseline POC anti-S was positive (hybrid immunity). The Full Analysis Set (FAS) consisted of participants who were enrolled and received at least one dose of mRNA-1273. The Safety Subset consisted of a simple random sample of the FAS within each of the four study groups. Six analysis groups (AGs), including the hybrid and vaccine immunity groups, were defined based on study group assignment and the overall SARS-CoV-2 status at baseline. The overall SARS-CoV-2 status was considered positive unless baseline nasal swab NAAT, POC anti-S, and central lab anti-nucleoprotein serology (anti-NP) were all negative. AGs are annotated in terms of HIV status, overall SARS-CoV-2 status, and the number of vaccine doses assigned. Specifically, AG1 represents people living with HIV (PLWH), overall SARS-CoV-2 status negative, and assigned 2 doses (PLWH, vaccine immunity). AG2-1 represents PLWH, overall SARS-CoV-2 status positive (POC anti-S positive), and assigned 1 dose (PLWH, hybrid immunity). AG2-2 represents PLWH, overall SARS-CoV-2 status positive (POC anti-S negative but anti-NP or NAAT positive) and assigned 2 doses. AG3 represents HIV-negative, SARS-CoV-2 status negative, and assigned 2 doses (HIV-negative, vaccine immunity). AG4-1 represents people living without HIV (PLWoH), overall SARS-CoV-2 status positive (POC anti-S positive), and assigned 1 dose (PLWoH, hybrid immunity). AG4-2 represents PLWoH, overall SARS-CoV-2 status positive (POC anti-S negative but anti-NP or NAAT positive) and assigned 2 doses. The Per-Protocol (PP) cohort consisted of participants in the FAS who received the intended number of pre-month 6 vaccination doses: two doses (for POC anti-S negative participants) or one dose (for POC anti-S positive participants), with no major protocol deviations. The data cut-off for the described safety and efficacy analyses occurred on March 31, 2023, 14 days after the last month 6 vaccination visit in Part A of the study. All COVID-19 and severe COVID-19 endpoints were based on data by this date, except one COVID-19 endpoint with symptom data collected through April 10, 2023. SARS2, SARS-CoV-2. ∗Participant anti-Spike SARS-CoV-2 value was negative in the site source data but was entered in the Case Report Form as positive. ∗∗Out of visit-window vaccination was not considered a major deviation.

Fig. 2

Association of hybrid versus vaccine immunity against COVID-19 in PLWH, PLWoH, and all participants. Shown is the cumulative incidence of COVID-19 events based on the CDC case definition among PLWH in the Full Analysis Set (FAS) (Panel A), among PLWH in the Per-Protocol (PP) cohort (Panel B), among PLWoH in FAS (Panel C), among PLWoH in PP cohort (Panel D), among all PLWH and PLWoH in FAS (Panel E), and among all PLWH and PLWoH in PP cohort (Panel F) for the vaccine immunity group (orange) and the hybrid immunity group (blue), counting events starting 1 day after the first vaccination in FAS, and 14 days after the last vaccination in the PP cohort. The number of COVID-19 events shown in this figure contains a subset of the total number of 358 events based on the CDC case definition because only the hybrid immunity and vaccine immunity groups are included, and two more analysis groups AG2-2 and AG4-2 are excluded. Comparisons including other subgroups are in the Supplementary Material. To ensure stability of estimated standard error, pointwise, and simultaneous intervals are reported starting 14 days after the first vaccination in FAS, and 27 days after the last vaccination in the PP cohort. The vaccine immunity group represents participants who were overall SARS-CoV-2 negative and received 2 doses of mRNA-1273 at enrolment and month 1, and the hybrid immunity group represents participants who were overall SARS-CoV-2 positive and received 1 dose of mRNA-1273 at enrolment. Arrows along the x-axis in Panels A, C, and E indicate enrolment and month 1 vaccination visits, and the tick marks in the curves in Panels A–F indicate censored data. Forest-plot shows hazard ratios of COVID-19 (Panel G) and of severe COVID-19 (Panel H) for the comparison of hybrid immunity versus vaccine immunity in PLWH, PLWoH (only for COVID-19 events), and in all participants in FAS and PP cohort groups. SARS2, SARS-CoV-2. 1d, one vaccine dose. 2d, two vaccine doses.

Fig. 3

Association of hybrid versus vaccine immunity against COVID-19 in people living with HIV, within strata defined by HIV immunocompetence and HIV viraemia. Shown is the cumulative incidence of COVID-19 events based on the CDC case definition among people living with HIV (PLWH) in the Full Analysis Set (FAS) with CD4 count ≥350 cells/μl (Panel A), with CD4 count <350 cells/μl (Panel B), with HIV viral load <50 copies/mL (Panel C), and with HIV viral load ≥50 copies/mL (Panel D) for the vaccine immunity group (orange) and the hybrid immunity group (blue), counting events starting 1 day after the first vaccination. To ensure stability of estimated standard error, pointwise and simultaneous intervals are reported starting 14 days after the first vaccination. The vaccine immunity group represents participants who were overall SARS-CoV-2 negative and received 2 doses of mRNA-1273 at enrolment and month 1, and the hybrid immunity group represents participants who were overall SARS-CoV-2 positive and received 1 dose of mRNA-1273 at enrolment. Arrows along the x-axis in Panels A–D indicate enrolment and month 1 vaccination visits. Forest-plot shows hazard ratios of CDC case definition COVID-19 for the comparison of hybrid versus vaccine immunity in PLWH in the FAS within each CD4 count and viral load stratum (Panel E). SARS2, SARS-CoV-2. 1d, one vaccine dose. 2d, two vaccine doses.

Fig. 4

Lineages and persistence of SARS-CoV-2 infections. Panel A shows the lineages of SARS-CoV-2 associated with the diagnosis of COVID-19 endpoints based on the CDC endpoint definition over calendar time in the two primary comparison groups: People living with HIV (PLWH) vaccine immunity group (HIV+, SARS2−, 2d) and PLWH hybrid immunity group (HIV+, SARS2+, 1d). Panel B shows the lineages of SARS-CoV-2 associated with the first occurrence of all COVID-19 infections (positive NAAT tests) regardless of symptoms obtained at either baseline or post-baseline visits based on all sequences available at the time of the analysis. The viral lineage is illustrated by the colour and plot character. Lineage typing was performed with both PANGOLIN and NextClade, and the call with the highest confidence was selected (see Methods). Due to insufficient viral material, many sequences were either (i) unable to be obtained (indicated by “Lineage Unknown”); (ii) exhibited such a degree of missingness that they were incapable of being lineage typed (also indicated by “Lineage Unknown”); or (iii) obtained a lineage from at least one platform, but failed QC on both platforms. These latter sequences are regarded as having low-confidence lineage calls and are indicated in this figure by having their plot character inlaid with grey. Most sequences were lineage-typed within omicron, so these sequences are grouped in the figure by the basal omicron lineage (B.1.1.529), the five major omicron sub-lineages (BA.1 through BA.5; e.g., BE.7 is classified as “BA.5.∗”) or recombinant status (e.g., XBB). Non-omicron lineages, almost exclusively occurring among the low-confidence lineage calls, are classified as “Other”. Q, three-month quarter: Q1 (January–March), Q2 (April–June), Q3 (July–September), and Q4 (October–December). NAAT, nucleic acid amplification test. SARS2, SARS-CoV-2. 1d, one vaccine dose. 2d, two vaccine doses.

Fig. 5

Persistent SARS-CoV-2 infections. Panel A shows the 22 participants who experienced persistent NAAT positivity for ≥50 days. Panel B shows the number and frequencies of persistent NAAT positivity (≥50 days) and total number of NAAT positive results by analysis group. NAAT, nucleic acid amplification test. SARS2, SARS-CoV-2. 1d, one vaccine dose. 2d, two vaccine doses.