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bioRxiv2024

mRNA Vaccine-Induced SARS-CoV-2 Spike-Specific IFN-γ and IL-2 T-cell Responses are Predictive of Serological Neutralization and are Transiently Enhanced by Pre-Existing Cross-Reactive Immunity

The contributions of SARS-CoV-2-specific T-cells to vaccine efficacy and durability are unclear. We investigated the relationships between mRNA vaccine-induced spike-specific IFN-{gamma} and IL-2 T-cell responses, anti-spike/RBD IgG/IgA antibodies, and live virus neutralizing capacity in long-term-care-home staff doubly vaccinated with BNT162b2 or mRNA-1273. The impacts of pre-existing cross-reactive T-cell immunity to SARS-CoV-2 on cellular and humoral responses to vaccination were additionally assessed. Mathematical modelling of the kinetics of spike-specific IFN-{gamma} and IL-2 T-cell responses over 6-months post-second dose was bifurcated into recipients who exhibited gradual increases (54% and 42%, respectively) with doubling times of 173 days, or decreases (46% and 58%, respectively) with half-lives of 115 days. Differences in kinetics did not correlate with any clinical phenotypes, although increases were proposed to be due to subclinical viral exposures. Serological anti-spike/RBD IgG/IgA antibody levels had otherwise decayed in all participants with half-lives of 55, 53, 76, and 59 days, respectively. Spike-specific T-cell responses induced at 2-6 weeks correlated with live viral neutralization at 6-months post-second dose, especially in hybrid immune individuals. Participants with pre-existing cross-reactive T-cell immunity to SARS-CoV-2 exhibited greater spike-specific T-cell responses, reduced anti-RBD IgA antibody levels, and a trending increase in neutralization at 2-6 weeks post-second dose. Non-spike-specific T-cells predominantly targeted SARS-CoV-2 non-structural protein at 6-months post-second dose in cross-reactive participants. mRNA vaccination was lastly shown to induce off-target T-cell responses against unrelated antigens. In summary, vaccine-induced spike-specific T-cell immunity appeared to influence serological neutralizing capacity, with only a modest effect induced by pre-existing cross-reactivity. IMPORTANCEOur findings provide important insights on the potential contributions of mRNA vaccine-induced spike-specific T-cell responses to the durability of neutralizing antibody levels in both uninfected and hybrid immune recipients. Our study additionally sheds light on the precise impacts of pre-existing cross-reactive T-cell immunity to SARS-CoV-2 on the magnitude and kinetics of cellular and humoral responses to vaccination. This study should ultimately inform the development of novel pan-coronavirus vaccines and vaccine regimens that can maximize the durability and breadth of protection against both current and future human coronaviruses of concern.

immunology↗

bioRxiv2023

Immunogenicity of COVID-19 vaccines and their effect on the HIV reservoir in older people with HIV

Older individuals and people with HIV (PWH) were prioritized for COVID-19 vaccination, yet comprehensive studies of the immunogenicity of these vaccines and their effects on HIV reservoirs are not available. We followed 68 PWH aged 55 and older and 23 age-matched HIV-negative individuals for 48 weeks from the first vaccine dose, after the total of three doses. All PWH were on antiretroviral therapy (cART) and had different immune status, including immune responders (IR), immune non-responders (INR), and PWH with low-level viremia (LLV). We measured total and neutralizing Ab responses to SARS-CoV-2 spike and RBD in sera, total anti-spike Abs in saliva, frequency of anti-RBD/NTD B cells, changes in frequency of anti-spike, HIV gag/nef-specific T cells, and HIV reservoirs in peripheral CD4+ T cells. The resulting datasets were used to create a mathematical model for within-host immunization. Various regimens of BNT162b2, mRNA-1273, and ChAdOx1 vaccines elicited equally strong anti-spike IgG responses in PWH and HIV- participants in serum and saliva at all timepoints. These responses had similar kinetics in both cohorts and peaked at 4 weeks post-booster (third dose), while half-lives of plasma IgG also dramatically increased post-booster in both groups. Salivary spike IgA responses were low, especially in INRs. PWH had diminished live virus neutralizing titers after two vaccine doses which were rescued after a booster. Anti-spike T cell immunity was enhanced in IRs even in comparison to HIV- participants, suggesting Th1 imprinting from HIV, while in INRs it was the lowest. Increased frequency of viral blips in PWH were seen post-vaccination, but vaccines did not affect the size of the intact HIV reservoir in CD4+ T cells in most PWH, except in LLVs. Thus, older PWH require three doses of COVID-19 vaccine to maximize neutralizing responses against SARS-CoV-2, although vaccines may increase HIV reservoirs in PWH with persistent viremia.

immunology↗