T-Cell Responses to COVID-19 Vaccines and Breakthrough Infection in People Living with HIV Receiving Antiretroviral Therapy

Abstract

People living with HIV (PLWH) can exhibit impaired immune responses to vaccines. Accumulating evidence indicates that PLWH, particularly those receiving antiretroviral therapy, mount strong antibody responses to COVID-19 vaccines, but fewer studies have examined cellular immune responses to the vaccinations. Here, we used an activation-induced marker (AIM) assay to quantify SARS-CoV-2 spike-specific CD4+ and CD8+ T cells generated by two and three doses of COVID-19 vaccines in 50 PLWH receiving antiretroviral therapy, compared to 87 control participants without HIV. In a subset of PLWH, T-cell responses were also assessed after post-vaccine breakthrough infections and/or receipt of a fourth vaccine dose. All participants remained SARS-CoV-2 infection-naive until at least one month after their third vaccine dose. SARS-CoV-2 infection was determined by seroconversion to a Nucleocapsid (N) antigen, which occurred in 21 PLWH and 38 control participants after the third vaccine dose. Multivariable regression analyses were used to investigate the relationships between sociodemographic, health- and vaccine-related variables, vaccine-induced T-cell responses, and breakthrough infection risk. We observed that a third vaccine dose boosted spike-specific CD4+ and CD8+ T-cell frequencies significantly above those measured after the second dose (all p < 0.0001). Median T-cell frequencies did not differ between PLWH and controls after the second dose (p > 0.1), but CD8+ T-cell responses were modestly lower in PLWH after the third dose (p = 0.02), an observation that remained significant after adjusting for sociodemographic, health- and vaccine-related variables (p = 0.045). In PLWH who experienced a breakthrough infection, median T-cell frequencies increased even higher than those observed after three vaccine doses (p < 0.03), and CD8+ T-cell responses in this group remained higher even after a fourth vaccine dose (p = 0.03). In multivariable analyses, the only factor associated with an increased breakthrough infection risk was younger age, which is consistent with the rapid increase in SARS-CoV-2 seropositivity that was seen among younger adults in Canada after the initial appearance of the Omicron variant. These results indicate that PLWH receiving antiretroviral therapy mount strong T-cell responses to COVID-19 vaccines that can be enhanced by booster doses or breakthrough infection.

Keywords: COVID-19; HIV; SARS-CoV-2; T cells; antiretroviral therapy; coronavirus; vaccine.

Figure 1

SARS-CoV-2 spike-specific T-cell responses after COVID-19 vaccination. (A) Spike-specific CD4+ T cells were quantified using the AIM assay (defined as OX40+/CD137+ cells) before and after two and three-dose COVID-19 vaccination. People living with HIV (PLWH) are in orange; controls without HIV (CTRL) are in blue. All participants are SARS-CoV-2 infection-naive. Red bars indicate the median and interquartile range. The Mann–Whitney U-test was used for between-group comparisons, and the Wilcoxon matched pairs test was used for longitudinal paired comparisons. p-values are not corrected for multiple comparisons. (B) Same as panel A, but for spike-specific CD8+ T cells quantified using the AIM assay (defined as CD69+/CD137+ cells).

Figure 2

Associations between SARS-CoV-2 spike-specific cellular and humoral immune measures after COVID-19 vaccination. (A) Correlation between spike-specific CD4+ T cells (OX40+/CD137+) and CD8+ T cells (CD69+/CD137+) one month after the second dose (open circles) and one month after the third dose (closed circles) in people living with HIV (PLWH, in orange) and controls without HIV (in blue). (B) Correlation between spike-specific CD4+ T cells and SARS-CoV-2 neutralizing antibodies (reported previously [11,28]), measured one month after the second dose (open circles) and one month after the third dose (closed circles) in people living with HIV (PLWH, in orange) and controls without HIV (in blue). All participants are COVID-19-naive. The assay’s upper limit of quantification (ULOQ) and lower limit of quantification (ULOQ) are indicated.

Figure 3

Longitudinal SARS-CoV-2 spike-specific immune responses in PLWH who remained naive or experienced their first SARS-CoV-2 infection after COVID-19 vaccination. (A) SARS-CoV-2 neutralizing antibody titers (reciprocal dilution) (reported previously [11,28]) in people living with HIV (PLWH) after two, three and four doses of COVID-19 vaccine. Grey lines connect data from the same individual. SARS-CoV-2-naive participants are displayed in orange. SARS-CoV-2 breakthrough participants after the third dose are displayed in green (starting at the point of seroconversion). Note that many antibody titer values overlap, resulting in darker-colored symbols. Asterisks denote naive participants who experienced SARS-CoV-2 breakthrough between six months post-dose third dose and one month post-fourth dose. Red bars indicate the median. The assay’s upper limit of quantification (ULOQ) and lower limit of quantification (LLOQ) are indicated. The Mann–Whitney U-test was used for between-group comparisons, and the Wilcoxon matched pairs test was used for longitudinal paired comparisons. p-values are not corrected for multiple comparisons. (B) Same as panel A, but for spike-specific CD4+ T-cell responses. (C) Same as panels A and B, but for spike-specific CD8+ T-cell responses. The Mann–Whitney U-test was used for between-group comparisons, and the Wilcoxon matched pairs test was used for longitudinal paired comparisons. p-values are not corrected for multiple comparisons.

Figure 4

Analysis of correlates of protection against SARS-CoV-2 breakthrough infection after COVID-19 vaccination. (A) Participant ages are shown at study entry, stratified according to those who remained SARS-CoV-2-naive (n = 78) and those who experienced SARS-CoV-2 breakthrough infection between one and six months after receiving a third vaccine dose (n = 59). PLWH are in orange; controls are in blue. Red bars indicate median and interquartile ranges. (B) Same as panel A, except the frequencies of spike-specific CD4+ T cells one month after three vaccine doses are shown. (C) Same as panels A and B, except the frequencies of CD8+ T cells one month after three vaccine doses are shown. (D) Same as other panels, except SARS-CoV-2 neutralization activities (reported as reciprocal dilution titers) one month after three vaccine doses are shown. For all panels, the Mann–Whitney U-test was used to compare groups, using data from the entire cohort (all; n = 137), from controls only (n = 87), or from PLWH only (n = 50).