Low quantity and quality of anti-spike humoral response is linked to CD4 T-cell apoptosis in COVID-19 patients

Abstract

In addition to an inflammatory reaction, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)-infected patients present lymphopenia, which we recently reported as being related to abnormal programmed cell death. As an efficient humoral response requires CD4 T-cell help, we hypothesized that the propensity of CD4 T cells to die may impact the quantity and quality of the humoral response in acutely infected individuals. In addition to specific immunoglobulins (Ig)A, IgM, and IgG against SARS-CoV-2 nucleocapsid (N), membrane (M), and spike (S1) proteins, we assessed the quality of IgG response by measuring the avidity index. Because the S protein represents the main target for neutralization and antibody-dependent cellular cytotoxicity responses, we also analyzed anti-S-specific IgG using S-transfected cells (S-Flow). Our results demonstrated that most COVID-19 patients have a predominant IgA anti-N humoral response during the early phase of infection. This specific humoral response preceded the anti-S1 in time and magnitude. The avidity index of anti-S1 IgG was low in acutely infected individuals compared to convalescent patients. We showed that the percentage of apoptotic CD4 T cells is inversely correlated with the levels of specific IgG antibodies. These lower levels were also correlated positively with plasma levels of CXCL10, a marker of disease severity, and soluble Fas ligand that contributes to T-cell death. Finally, we found lower S-Flow responses in patients with higher CD4 T-cell apoptosis. Altogether, these results demonstrate that individuals with high levels of CD4 T-cell apoptosis and CXCL10 have a poor ability to build an efficient anti-S response. Consequently, preventing CD4 T-cell death might be a strategy for improving humoral response during the acute phase, thereby reducing COVID-19 pathogenicity.

Repetitive mRNA vaccination is required to improve the quality of broad-spectrum anti–SARS-CoV-2 antibodies in the absence of CXCL13

“…Having observed differences in the IgG response between vaccinated individuals and those previously infected with SARS-CoV-2, we then compared their IgA responses. We and others have shown that humoral response against the S protein also includes IgA ( 21 , 43 – 45 ). Furthermore, IgA were reported to dominate the early antibody response to SARS-CoV-2 ( 21 , 29 ).…”

“…We assessed in the S-Flow assay ( 21 ) the impact of such conformational changes using a mAb that recognizes the NTD domain. This mAb recognized cells expressing the Wuhan-Hu strain (fig.…”

“…We and others have shown that humoral response against the S protein also includes IgA (21,(43)(44)(45). Furthermore, IgA were reported to dominate the early antibody response to SARS-CoV-2 (21,29). The presence of IgA, boosted by the mRNA vaccine, could be of importance, since IgA is the most abundant antibody isotype in the mucosa, where these antibodies provide the first line of immune defense against pulmonary viral infections (46).…”

“…Beyond neutralizing antibody, it has been shown that Fc effector mechanisms including antibody-dependent complement deposition, antibody-dependent neutrophil phagocytosis, and antibodydependent cellular cytotoxicity responses may contribute in the control of viral dissemination by clearing viral-infected cells and limiting disease severity (19,20). We recently demonstrated that the amount of IgG capable to recognize the Wuhan-Hu S-protein on cell surface of transfected cells are lower in patients with severe coronavirus 2019 (COVID- 19), and this was associated with frequent CD4 T cell apoptosis (21,22). Furthermore, it has been suggested that antibody cellular effector functions induced by mRNA vaccine are preserved despite the loss of Omicron neutralization, indicating a disconnection between the requirements for quantity and quality of antibodies for the two functions (23).…”

T cell immunity following COVID-19 vaccination in adult patients with primary antibody deficiency – a 22-month follow-up

“…In healthy immunocompetent adults, COVID-19 vaccinations induce humoral and cell-mediated responses (3, 4), of which neutralizing antibodies are associated with protective immunity (5). In addition, both CD4+ and CD8+ T cells are needed to generate a robust humoral response (6)(7)(8)(9) and antigen-specific T cells are shown to limit the disease severity (10). Previous studies on immunocompromised patients have demonstrated weak or absent antibody responses but robust cellmediated responses after two doses of the COVID-19 vaccine (11,12).…”