Third and fourth vaccine doses broaden and prolong immunity to SARS-CoV-2 in immunocompromised adult patients (preprint)

Background. Previous studies have reported impaired humoral responses after SARS-CoV-2 mRNA vaccination in immunocompromised patients with immune-mediated inflammatory diseases (IMID), particularly those treated with anti-tumor necrosis factor (TNF) biologics. We previously reported that IMID patients exhibited greater waning of antibody and T cell responses compared to healthy controls after dose 2. Fewer data are available on the effects of third and fourth doses. Methods. This observational cohort study collected plasma and peripheral blood mononuclear cells from healthy controls and untreated or treated IMID patients, pre-vaccination and after one to four doses of SARS-CoV-2 mRNA vaccine (BNT162b2 or mRNA-1273). SARS-CoV-2- specific antibody levels, neutralization, and T cell cytokine responses were measured against Wildtype (WT) and BA.1 and BA.5 variants of concern (VOCs). Results. Third vaccine doses substantially restored and prolonged antibody and T cell responses in IMID patients and broadened responses against VOCs. Fourth dose effects were subtle but also prolonged antibody responses. However, IMID patients treated with anti-TNF, especially inflammatory bowel disease (IBD) patients, exhibited lower antibody responses even after the fourth dose. Although T cell IFN{gamma} responses were maximal after one dose, IL-2 and IL-4 production increased with successive doses, and early production of these cytokines was predictive of neutralization responses at 3-4 months post-vaccination. Conclusion. Our study demonstrates that third and fourth doses of the SARS-CoV-2 vaccine sustain and broaden immune responses to SARS-CoV-2, supporting the recommendation for three- and four-dose vaccination regimens in IMID patients. Funding. COVID-19 Immunity Task Force and Speck family donation

Antibody and T cell responses to SARS-CoV-2 mRNA vaccines during maintenance therapy for immune-mediated inflammatory diseases (preprint)

Background Limited information is available on the impact of immunosuppressants on COVID-19 vaccination in patients with immune-mediated inflammatory diseases (IMID). This study investigated antibody and T cell responses to SARS-CoV-2 mRNA vaccines in IMID patients undergoing immunomodulatory maintenance therapy. Methods This observational cohort study examined the immunogenicity of SARS-CoV-2 mRNA vaccines in adult patients with inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis or psoriatic disease, with or without maintenance immunosuppressive therapies. T cell and antibody responses to SARS-COV-2, including neutralization against SARS-CoV-2 variants were determined pre-vaccination and after 1 and 2 vaccine doses. Findings We prospectively followed 150 subjects, 26 healthy controls, 9 IMID patients on no treatment, 44 on anti-TNF, 16 on anti-TNF with methotrexate/azathioprine (MTX/AZA), 10 on anti-IL-23, 28 on anti-IL-12/23, 9 on anti-IL-17, and 8 on MTX/AZA. Most patients showed increased antibody responses from dose 1 to dose 2, with decreases apparent by 3 months post dose 2, albeit with considerable variability within groups. Overall, T cell responses were not consistently different between groups; however, antibody levels and neutralization efficacy in the anti-TNF treated group was lower than controls and waned substantially by 3 months post-dose 2. Implications These findings support the need for a third dose of mRNA vaccine and for continued monitoring of immunity over time.

Immunity to SARS-CoV-2 persists 9 months post-symptoms with an altered T cell phenotype compared to influenza A virus-specific memory (preprint)

SARS-CoV-2 induces T cell, B cell and antibody responses that are detected for several months in recovered individuals. Whether this response resembles a typical respiratory viral infection is a matter of debate. Here we followed T cell and antibody responses in 24 mainly non-hospitalized SARS-CoV-2 recovered subjects at two time points (median of 45- and 145-days post-symptom onset). Antibody responses were detected in 95% of subjects, with a strong correlation between plasma and salivary anti-S and anti-RBD IgG, as well as a correlation between circulating T follicular helper cells and the SARS-CoV-2-specific IgG response. Based on intracellular cytokine production or proliferation, CD4+ T cell responses to SARS-CoV-2 were detected in all subjects, decaying with a half-life of 5-6 months for S-specific IL-2-producing cells. CD4+ responses were largely of the T helper 1 phenotype, but with a lower ratio of IFN-{gamma} : IL-2 producing cells and a lower frequency of CD8+: CD4+ T cells compared to influenza A virus-(IAV)-specific memory responses within the same subjects. Analysis of secreted molecules also revealed a lower ratio of IFN-{gamma}: IL-2 and IFN-{gamma}: IL-6 and an altered cytotoxic profile for S- and N-specific compared to IAV-specific responses. These data suggest that the memory T-cell phenotype after a single infection with SARS-CoV-2 persists over time, with an altered cytokine and cytotoxic profile compared to long term memory to IAV within the same subjects.

Systematic examination of T cell responses to SARS-CoV-2 versus influenza virus reveals distinct inflammatory profile (preprint)

There is a pressing need for an in-depth understanding of immunity to SARS-CoV-2. Here we investigated T cell recall responses to fully glycosylated Spike trimer, recombinant N protein as well as to S, N, M and E peptide pools in the early convalescent phase. All subjects showed SARS-CoV-2-specific T cell responses to at least one antigen. SARS-CoV-2-specific CD4+ T cells were primarily of the central memory phenotype and exhibited a lower IFN-[gamma] to TNF-[alpha] ratio compared to influenza-specific responses of the same donors, independent of disease severity. SARS-CoV-2-specific T cells were less multifunctional than influenza-specific T cells, particularly in severe cases, potentially suggesting exhaustion. High IL-10 production was noted in response to N protein, possibly contributing to immunosuppression, with potential implications for vaccine design. We observed granzyme B+/IFN-[gamma] CD4+ and CD8+ proliferative responses to peptide pools in most individuals, with CD4+ responses predominating over CD8+ responses. Peripheral T follicular helper responses to S or N strongly correlated with serum neutralization assays as well as RBD-specific IgA. Overall, T cell responses to SARS-CoV-2 are robust, however, CD4+ Th1 responses predominate over CD8+ responses and are more inflammatory with a weaker Tfh response than influenza-specific CD4+ responses, potentially contributing to COVID-19 disease.