Booster Vaccination Against SARS-CoV-2 Induces Potent Immune Responses in People With Human Immunodeficiency Virus

Abstract

Background: People with human immunodeficiency virus (HIV) on antiretroviral therapy (ART) with good CD4 T-cell counts make effective immune responses following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are few data on longer term responses and the impact of a booster dose.

Methods: Adults with HIV were enrolled into a single arm open label study. Two doses of ChAdOx1 nCoV-19 were followed 12 months later by a third heterologous vaccine dose. Participants had undetectable viraemia on ART and CD4 counts >350 cells/µL. Immune responses to the ancestral strain and variants of concern were measured by anti-spike immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA), MesoScale Discovery (MSD) anti-spike platform, ACE-2 inhibition, activation induced marker (AIM) assay, and T-cell proliferation.

Findings: In total, 54 participants received 2 doses of ChAdOx1 nCoV-19. 43 received a third dose (42 with BNT162b2; 1 with mRNA-1273) 1 year after the first dose. After the third dose, total anti-SARS-CoV-2 spike IgG titers (MSD), ACE-2 inhibition, and IgG ELISA results were significantly higher compared to Day 182 titers (P < .0001 for all 3). SARS-CoV-2 specific CD4+ T-cell responses measured by AIM against SARS-CoV-2 S1 and S2 peptide pools were significantly increased after a third vaccine compared to 6 months after a first dose, with significant increases in proliferative CD4+ and CD8+ T-cell responses to SARS-CoV-2 S1 and S2 after boosting. Responses to Alpha, Beta, Gamma, and Delta variants were boosted, although to a lesser extent for Omicron.

Conclusions: In PWH receiving a third vaccine dose, there were significant increases in B- and T-cell immunity, including to known variants of concern (VOCs).

Keywords: SARS-CoV-2; T-cell responses; antibody responses; people with HIV; vaccination.

Figure 1.

Anti-SARS-CoV-2 antibody responses are boosted following third dose of COVID-19 vaccines in PWH. A, Vaccination schedule for all participants showing timepoints where samples were used for this study in black. PWH received either BNT162b2, mRNA1273, or ChAdOx1 nCoV-19 vaccines. The third dose was given as close to 1 y after the first vaccine dose as possible. The “Day 365” visit sample was the “post-third dose” sample”. B, Anti-SARS-CoV-2 spike IgG antibody titers before priming vaccine dose at day 0 and post-prime doses at day 182 and 365 (after third dose). C, Anti-SARS-CoV-2 spike IgG antibody titers in HIV positive participants with pre- and post-third dose timepoints. D, In-house ELISA showing anti-spike IgG responses at baseline, day 182 and after third dose (E) ACE-2 inhibition assay on day 0, 182, and after third dose in all participants. F and G, ACE-2 inhibition assay in participants with pre- and post-third dose timepoints expressed as F, AU/mL or G, % inhibition. Comparison of 2 timepoints within the same group was done by Wilcoxon matched pair sign ranked test. Where indicated * = P <.05, ** = P <.01, *** = P < .001 and **** = <.000. “Pre-B” and “Post-B” refer to pre-third dose and post-third dose. Dotted lines indicate cutoff points determined for each SARS-CoV-2 spike antigen based on pre-pandemic sera + 3 × SD. N = 27–33 for HIV positive volunteers in MSD assay. Error bars represent median and interquartile range. Abbreviations: COVID-19, coronavirus disease 2019; ELISA, enzyme-linked immunosorbent assay; HIV, human immunodeficiency virus; IgG, immunoglobulin G; MSD, MesoScale Discovery; PWH, people with HIV; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 2.

T-cell response to SARS-CoV-2 following third dose of COVID-19 vaccines in PWH. T-cell responses measured by AIM assay showing magnitude of CD4+ T-cell responses to (A) SARS-CoV-2 S1 and (B) SARS-CoV-2 S2 and magnitude of CD8+ T-cell responses to (C) SARS-CoV-2 S1 and (D) SARS-CoV-2 S2 on days 182 and after third dose (D365). Proliferative T-cell responses assessing kinetics of the T-cell response longitudinally for CD4+ T cells to (E) SARS-CoV-2 S1 and (F) SARS-CoV-2 S2 and CD8+ T cells to (G) SARS-CoV-2 S1 and (H) SARS-CoV-2 S2. Statistical test in (A–D) was done by Mann-Whitney t test. Statistical test in (E–H) was done by Wilcoxon matched pair sign ranked test. Where indicated * = P <.05, ** = P <.01, *** = P < .001 and **** = P <.000. Dotted lines indicate cutoff points determined based on DMSO controls + 3 × SD. n = 24–40 for AIM assay and 41–52 for proliferation assay. Error bars represent median and interquartile range. Abbreviations: AIM, activation induced marker; DMSO, dimethyl sulfoxide; PWH, people with HIV; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SD, standard deviation.

Figure 3.

Phenotype of AIM+ antigen specific responses following third COVID-19 vaccine dose in PWH. Comparative analysis of the magnitude of antigen-specific T cells to SARS-CoV-2 S1, SARS-CoV-2 S2, and CMVpp65 in (A) CD4+ and (B) CD8+ T cells. Phenotype of antigen specific T cells 6 m after the priming ChAdOx1 nCoV-19 dose and after third heterologous dose showing (C) CXCR3+ CCR6-Th1, (D) CXCR3− CCR6-Th2, (E) CXCR3− CCR6+ Th17, and (F) CXCR5+ circulating Tfh CD4+ T cells. Statistical tests for (A) and (B) were done by Kruskal-Wallis with Dunn's multiple comparison. Statistical tests in (C–F) were done by Mann-Whitney t test. Where indicated * = P <.05, ** = P <.01, *** = P < .001, and **** = <.000. n = 20–40. Error bars represent median and interquartile range. Abbreviations: AIM, activation induced marker; COVID-19, coronavirus disease 2019; PWH, people with HIV; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 4.

Immune response to SARS-CoV-2 VOC following third dose of COVID-19 vaccines in PWH. A, Total anti-spike IgG antibody responses (B) ACE-2 inhibition assay to circulating VOC. Proliferation assay comparing magnitudes of proliferative T-cell response to SARS-CoV-2 parental strain to a panel of VOC for CD4+ (C) SARS-CoV-2 S1, (D) SARS-CoV-2 S2 and CD8+, (E) SARS-CoV-2 S1, (F) SARS-CoV-2 S2. Statistical tests were done by Wilcoxon matched pair sign ranked test. Where indicated * = P <.05, ** = P <.01, *** = P < .001 and **** = P <.000. Dotted lines indicate cutoff points determined for each SARS-CoV-2 spike antigen based on pre-pandemic sera + 3 × SD for antibody responses and cutoff points determined based on DMSO controls + 3 × SD for proliferative responses. n = 37–40 for antibody analysis and n = 41 or proliferation assay. Error bars represent median and interquartile range. Abbreviations: DMSO, dimethyl sulfoxide; IgG, immunoglobulin G; PWH, people with HIV; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SD, standard deviation; VOC, variants of concern.