Antibody and T-cell responses elicited by coronavirus disease 2019 vaccination in people with HIV-1: the case of late presenters

In this issue of AIDS, Augello et al.[1] report results from a prospective longitudinal study in which they investigated immune responses following two doses of coronavirus disease 2019 (COVID-19) mRNA vaccines in late presenting people with HIV-1 (LP-PWH). The authors show that frequencies of Spike (S)-specific CD4⁺ memory T-cell subsets, circulating follicular CD4⁺ T (cTfh) cells, circulating follicular CD8⁺ T cells (cTfc), poly-functional TH1 type CD4⁺ T cells and the receptor-binding domain (RBD)-specific antibodies increased 6 months postvaccination in LP-PWH; the increases being comparable to those in HIV-negative controls. Additionally, frequencies of S-specific CD8⁺ T cells were also comparable between the two groups. However, they noted higher frequencies of the CCR7-CD45RA+ subset of CD4⁺ T cells as well as of S-specific CD4⁺ TH1 cells in the LP-PWH. Importantly, LP-PWH developed S-specific TH2 CD4⁺ T cells, which were not detected in HIV-negative controls. Surprisingly, titers of RBD-specific, and of RBD-ACE2-binding inhibiting (RABI) antibodies (a surrogate for virus-neutralizing antibodies) were higher 6 months post vaccination in LP-PWH compared with HIV-negative controls; suggesting that vaccine-specific antibodies wane with slower kinetics in LP-PWH. The authors found positive correlation between frequencies of S-specific CD8⁺ T cells and current CD4⁺ T cell counts as well as between RABI antibody titers and both current and nadir CD4⁺ T cell counts. Among CD4⁺ T-cell subsets, only naive CD4⁺ T-cell pool correlated with vaccine-induced immune responses. Furthermore, a previous natural infection with SARS-CoV-2 increased anti-RBD antibodies in both groups at baseline; however, HIV-negative controls but not PWH showed increased cellular responses at baseline, suggesting that the infection reduced the ability of LP-PWH to elicit T-cell responses.

The study highlights dependence of the vaccine-induced immune responses in LP-PWH on their degree of immune recovery. As LP-PWH (a subset of PWH) are less likely to achieve complete immune recovery because of starting combined anti-retroviral therapy (cART) late, they are more likely to elicit suboptimal immune responses to coronavirus disease 2019 (COVID-19), as they do to other viral and nonviral vaccines. Immunogenicity of COVID-19 vaccines in this group of PWH is not well studied. Previous studies [2] investigating immunogenicity of COVID-19 vaccines in PWH lacked power to detect impact of markers of immune recovery such as CD4⁺ T-cell counts, CD4⁺/CD8⁺ T-cell ratios and low-grade inflammation, and so forth. In this respect, Augello et al.[1] investigated COVID-19 vaccine-induced immune responses in LP-PWH; however, caution is warranted to generalize the results as they vaccinated HIV-negative controls with BNT162b2, and PWH with mRNA1273. It is quite possible that LP-PWH may have mounted stronger immune responses compared with HIV-negative controls as the mRNA1273 is known to be more immunogenic than BNT162b2 [3]. For example, slower waning of vaccine-specific antibodies in LP-PWH could be because of the difference in the vaccine used. Nevertheless, some of their results are quite interesting and reminiscent of HIV-induced immune abnormalities in B-cell and T-cell compartments.

Augello et al. [1] show that expansion of the CCR7-CD45RA+ subset of CD4⁺ T cells occurred in LP-PWH but not in HIV-negative controls in response to the vaccination. This CD4⁺ T-cell subset called EMRA comprises terminally differentiated effector cells that produce more IFN-γ and express more cytotoxic molecules than any other CD4⁺ T-cell subset. The authors ascribe this expansion to the vaccine mRNA 1273 used in these individuals because of its higher mRNA content compared with BNT162b2. The expansion is likely more because of a biased skewing of CD4⁺ T-cell differentiation towards this phenotype in HIV-infected individuals [4]. Similarly, increased percentages of TH2 type CD4⁺ T cells detected only in LP-PWH may also be due to HIV-induced skewing of CD4⁺ T-cell differentiation to TH2 phenotype. Another study [5] in LP-PWH (PWH with advanced disease, i.e. with CD4⁺ T cells ≤350/μl) has shown that a third dose of the vaccine significantly improves antibody responses and stabilizes T-cell responses.

HIV-1 induces significant abnormalities in the T-cell and B-cell compartments. Depletion of CD4⁺ T cells, expansion of CD8⁺ T cells and circulating follicular CD8⁺ T (cTfc) cells, decreased CD4⁺/CD8⁺ T-cell ratios, decreased percentages of naive and increased percentages of terminally differentiated and exhausted T cell have been well documented in HIV-infected individuals [6]. Not surprisingly, PWH vaccinated with three doses of mRNA-based vaccines show higher percentages of PD-1+-exhausted T cells. In the case of B-cell compartment, polyclonal B-cell activation and hyper-gammaglobulinemia have been well documented in HIV-infected individuals [7]. The infection skews B-cell maturation towards extrafollicular pathway resulting in reduced germinal center (GC) reactions, somatic hypermutations, and antibody diversification [7]. HIV-infected individuals show increased frequencies of cTfc and decreased frequencies of cTfh, which are in part responsible for the reduced GC reactions. They show increased frequencies of activated and atypical/double-negative (CD21−CD27−) memory B cells (MBC), and decreased frequencies of resting MBC. In these patients, cART suppresses viral replication but does not fully rectify virus-induced abnormalities. In line with these defects, Touizer et al.[8] have shown that decreased antibody responses in PWH vaccinated with COVID-19 vaccine correlate with their global disturbances in the MBC, and not per se with CD4⁺ T-cell counts.

A great concern in COVID-19 vaccination is the emergence of different variants of concern (VOC), especially Omicron and its sub-variants. Augello et al.[1] have not evaluated the ability of their vaccinated individuals against VOC, as they had not emerged at the time when they conceptualized the study. Nevertheless, it would be relevant to mention here that recent studies [9,10] have shown that third and fourth doses of COVID-19 vaccines improve the magnitude and breadth of the virus-neutralizing antibody responses. They substantially increase neutralizing antibody titers against Omicron sub-variant BA.5 and to a lower extent against BQ.1. Despite these additional doses, the titers of Omicron-neutralizing antibodies in PWH remain lower than in HIV-negative controls, and correlate with younger age, CD4⁺ T-cell counts, and absence of comorbidities in the PWH.

In conclusion, the study by Augello et al.[1] has highlighted the case of LP-PWH who respond poorly to COVID-19 vaccines relative to HIV-negative controls because of their enduring HIV-induced defects. In addition to multiple booster doses, novel approaches are required to protect them from newly emerging VOC of the SARS-CoV-2.

Acknowledgements

We thank our colleagues who participated in discussions on COVID-19 vaccinations in late presenting people with HIV-1. We regret that because of space limitation, we could not cite some important works on the subject.

Conflicts of interest

There are no conflicts of interest.