Neutralizing Activity and T-Cell Responses Against Wild Type SARS-CoV-2 Virus and Omicron BA.5 Variant After Ancestral SARS-CoV-2 Vaccine Booster Dose in PLWH Receiving ART Based on CD4 T-Cell Count

Abstract

Background: We evaluated severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-specific humoral and cellular responses for up to 6 months after the 3rd dose of ancestral coronavirus disease 2019 (COVID-19) vaccination in people living with HIV (PLWH) and healthy controls (HCs) who were not infected with COVID-19.

Methods: Anti-spike receptor-binding domain IgG (anti-RBD IgG) concentrations using chemiluminescence immunoassay and neutralizing antibodies using focus reduction neutralization test (FRNT) were assessed at 1 week after each dose of vaccination, and 3 and 6 months after the 3rd dose in 62 PLWH and 25 HCs. T-cell responses using intracellular cytokine stain were evaluated at 1 week before, and 1 week and 6 months after the 3rd dose.

Results: At 1 week after the 3rd dose, adequate anti-RBD IgG (> 300 binding antibody unit /mL) was elicited in all PLWH except for one patient with 36 CD4 T-cell count/mm³. The geometric mean titers of 50% FRNT against wild type (WT) and omicron BA.5 strains of SARS-CoV-2 in PLWH with CD4 T-cell count ≥ 500 cells/mm³ (high CD4 recovery, HCDR) were comparable to HC, but they were significantly decreased in PLWH with CD4 T-cell count < 500/mm³ (low CD4 recovery, LCDR). After adjusting for age, gender, viral suppression, and number of preexisting comorbidities, CD4 T-cell counts < 500/mm³ significantly predicted a poor magnitude of neutralizing antibodies against WT, omicron BA.5, and XBB 1.5 strains among PLWH. Multivariable linear regression adjusting for age and gender revealed that LCDR was associated with reduced neutralizing activity (P = 0.017) and interferon-γ-producing T-cell responses (P = 0.049 for CD T-cell; P = 0.014 for CD8 T-cell) against WT, and strongly associated with more decreased cross-neutralization against omicron BA.5 strains (P < 0.001).

Conclusion: HCDR demonstrated robust humoral and cell-mediated immune responses after a booster dose of ancestral SARS-CoV-2 vaccine, whereas LCDR showed diminished immune responses against WT virus and more impaired cross-neutralization against omicron BA.5 strain.

Keywords: COVID-19 Vaccines; Cellular Immunity; HIV; Neutralizing Antibodies.

Fig. 1. Longitudinal analysis of anti-SARS-CoV-2 RBD IgG responses in people living with HIV and HCs. (A) Schematic of the study design and sampling points’ details. (B) SARS-CoV-2 anti-RBD IgG levels against the ancestral wild type. Black solid circle represents for HC, red open square represents for LCDR, and blue solid square represents for HCDR. Statistical analysis was performed using the two-sided Kruskal-Wallis test with Dunns’ multiple comparisons test.

HC = healthy control, PLWH = people living with human immunodeficiency virus, FRNT50 = 50% focus reduction neutralization test, Ag = antigen, LCDR = low CD4 recovery (CD4 T-cell count < 500 cells/mm³), HCDR = high CD4 recovery (CD4 T-cell count ≥ 500 cells/mm³), RBD = receptor-binding domain, Ig = immunoglobulin, BAU = binding antibody unit, SARS-CoV-2 = severe acute respiratory syndrome-coronavirus-2, HIV = human immunodeficiency virus, ns = not significant. ^**P < 0.01.

Fig. 2. Longitudinal Analysis of neutralizing activity against live wild-type (A), omicron BA.5 (B), and XBB.1.5 (C) variant virus in PLWH and HC. Neutralizing activity between PLWH and HC was compared at indicated time points. Black solid circle represents for HC, red open square represents for LCDR, and blue solid square represents for HCDR. Statistical analysis was performed using the two-sided Kruskal-Wallis test with Dunns’ multiple comparisons test.

FRNT50 = 50% focus reduction neutralizing titer, HC = healthy control, HCDR = high CD4 recovery (CD4 T-cell count ≥ 500 cells/mm³), LCDR = low CD4 recovery (CD4 T-cell count < 500 cells/mm³), PLWH = people living with human immunodeficiency virus, ns = not significant. ^*P < 0.05; ^**P < 0.01; ^***P < 0.001; ^****P < 0.0001.

Fig. 3. T-cell responses induced by the booster vaccination in PLWH and HC. Frequency of IFNγ-producing CD4+ and CD8+T cells was compared at indicated time point. (A) Flow cytometry gating strategy. (B) The frequency of IFN-γ-producing CD4+ (left) and CD8+T cells (right). Two-way ANOVA corrected for multiple comparisons in (B).

DMSO = dimethylsulfoxide, HC = healthy control, HCDR = high CD4 recovery (CD4 T-cell count ≥ 500 cells/mm³), IFN-γ = interferon-gamma, LCDR = low CD4 recovery (CD4 T-cell count < 500 cells/mm³), PLWH = people living with human immunodeficiency virus, ns = not significant. ^*P < 0.05, ^***P < 0.001.