RBD- specific Th1 responses are associated with vaccine-induced protection against SARS-CoV-2 infection in patients with hematological malignancies.

The SARS-CoV-2 pandemic still represents a threat for immunosuppressed and hematological malignancy (HM) bearing patients, causing increased morbidity and mortality. Given the low anti-SARSCoV-2 IgG titers post-vaccination, the COVID-19 threat prompted the prophylactic use of engineered anti-SARS-CoV-2 monoclonal antibodies. In addition, potential clinical significance of T cell responses has been overlooked during the first waves of the pandemic, calling for additional in-depth studies. We reported that the polarity and the repertoire of T cell immune responses govern the susceptibility to SARS-CoV-2 infection in health care workers and solid cancer patients. Here, we longitudinally analyzed humoral and cellular immune responses at each BNT162b2 mRNA vaccine injection in 47 HM patients under therapy. Only one-third of HM, mostly multiple myeloma (MM) bearing patients, could mount S1-RBD-specific IgG responses following BNT162b2 mRNA vaccines. This vaccine elicited a S1-RBD-specific Th1 immune response in about 20% patients, mostly in MM and Hodgkin lymphoma, while exacerbating Th2 responses in the 10% cases that presented this recognition pattern at baseline (mostly rituximab-treated patients). Performing a third booster barely improved the percentage of patients developing an S1-RBD-specific Th1 immunity and failed to seroconvert additional HM patients. Finally, 16 patients were infected with SARS-CoV-2, of whom 6 developed a severe infection. Only S1-RBD-specific Th1 responses were associated with protection against SARS-CoV2 infection, while Th2 responses or anti-S1-RBD IgG titers failed to correlate with protection. These findings herald the paramount relevance of vaccine-induced Th1 immune responses in hematological malignancies.

The Polarity and Specificity of Antiviral T Lymphocyte Responses Determine Susceptibility to SARS-CoV-2 Infection in Patients with Cancer and Healthy Individuals.

Vaccination against coronavirus disease 2019 (COVID-19) relies on the in-depth understanding of protective immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We characterized the polarity and specificity of memory T cells directed against SARS-CoV-2 viral lysates and peptides to determine correlates with spontaneous, virus-elicited, or vaccine-induced protection against COVID-19 in disease-free and cancer-bearing individuals. A disbalance between type 1 and 2 cytokine release was associated with high susceptibility to COVID-19. Individuals susceptible to infection exhibited a specific deficit in the T helper 1/T cytotoxic 1 (Th1/Tc1) peptide repertoire affecting the receptor binding domain of the spike protein (S1-RBD), a hotspot of viral mutations. Current vaccines triggered Th1/Tc1 responses in only a fraction of all subject categories, more effectively against the original sequence of S1-RBD than that from viral variants. We speculate that the next generation of vaccines should elicit Th1/Tc1 T-cell responses against the S1-RBD domain of emerging viral variants. SIGNIFICANCE: This study prospectively analyzed virus-specific T-cell correlates of protection against COVID-19 in healthy and cancer-bearing individuals. A disbalance between Th1/Th2 recall responses conferred susceptibility to COVID-19 in both populations, coinciding with selective defects in Th1 recognition of the receptor binding domain of spike. See related commentary by McGary and Vardhana, p. 892. This article is highlighted in the In This Issue feature, p. 873.

Mortality in COVID-19 disease patients: Correlating the association of major histocompatibility complex (MHC) with severe acute respiratory syndrome 2 (SARS-CoV-2) variants.

Genetic factors such as the HLA type of patients may play a role in regard to disease severity and clinical outcome of patients with COVID-19. Taking the data deposited in the GISAID database, we made predictions using the IEDB analysis resource (TepiTool) to gauge how variants in the SARS-CoV-2 genome may change peptide binding to the most frequent MHC-class I and -II alleles in Africa, Asia and Europe. We caracterized how a single mutation in the wildtype sequence of of SARS-CoV-2 could influence the peptide binding of SARS-CoV-2 variants to MHC class II, but not to MHC class I alleles. Assuming the ORF8 (L84S) mutation is biologically significant, selective pressure from MHC class II alleles may select for viral varients and subsequently shape the quality and quantity of cellular immune responses aginast SARS-CoV-2. MHC 4-digit typing along with viral sequence analysis should be considered in studies examining clinical outcomes in patients with COVID-19.