Humoral and cellular immune memory to four COVID-19 vaccines.

Multiple COVID-19 vaccines, representing diverse vaccine platforms, successfully protect against symptomatic COVID-19 cases and deaths. Head-to-head comparisons of T cell, B cell, and antibody responses to diverse vaccines in humans are likely to be informative for understanding protective immunity against COVID-19, with particular interest in immune memory. Here, SARS-CoV-2-spike-specific immune responses to Moderna mRNA-1273, Pfizer/BioNTech BNT162b2, Janssen Ad26.COV2.S, and Novavax NVX-CoV2373 were examined longitudinally for 6 months 100% of individuals made memory CD4+ T cells, with cTfh and CD4-CTL highly represented after mRNA or NVX-CoV2373 vaccination. mRNA vaccines and Ad26.COV2.S induced comparable CD8+ T cell frequencies, though only detectable in 60-67% of subjects at 6 months. A differentiating feature of Ad26.COV2.S immunization was a high frequency of CXCR3+ memory B cells. mRNA vaccinees had substantial declines in antibodies, while memory T and B cells were comparatively stable. These results may also be relevant for insights against other pathogens.

Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals.

Understanding adaptive immunity to SARS-CoV-2 is important for vaccine development, interpreting coronavirus disease 2019 (COVID-19) pathogenesis, and calibration of pandemic control measures. Using HLA class I and II predicted peptide "megapools," circulating SARS-CoV-2-specific CD8+ and CD4+ T cells were identified in ∼70% and 100% of COVID-19 convalescent patients, respectively. CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers. The M, spike, and N proteins each accounted for 11%-27% of the total CD4+ response, with additional responses commonly targeting nsp3, nsp4, ORF3a, and ORF8, among others. For CD8+ T cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted. Importantly, we detected SARS-CoV-2-reactive CD4+ T cells in ∼40%-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating "common cold" coronaviruses and SARS-CoV-2.

Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity.

Limited knowledge is available on the relationship between antigen-specific immune responses and COVID-19 disease severity. We completed a combined examination of all three branches of adaptive immunity at the level of SARS-CoV-2-specific CD4+ and CD8+ T cell and neutralizing antibody responses in acute and convalescent subjects. SARS-CoV-2-specific CD4+ and CD8+ T cells were each associated with milder disease. Coordinated SARS-CoV-2-specific adaptive immune responses were associated with milder disease, suggesting roles for both CD4+ and CD8+ T cells in protective immunity in COVID-19. Notably, coordination of SARS-CoV-2 antigen-specific responses was disrupted in individuals ≥ 65 years old. Scarcity of naive T cells was also associated with aging and poor disease outcomes. A parsimonious explanation is that coordinated CD4+ T cell, CD8+ T cell, and antibody responses are protective, but uncoordinated responses frequently fail to control disease, with a connection between aging and impaired adaptive immune responses to SARS-CoV-2.

Stimulating Antitumoral Immunity by Percutaneous Cryoablation and Combination Immunoadjuvant Therapy in a Murine Model of Hepatocellular Carcinoma.

PURPOSE: To test the hypothesis that antitumoral immunity can be induced after cryoablation (cryo) of hepatocellular carcinoma (HCC) through coadministration of the immunostimulant CpG and an immune checkpoint (programmed cell death 1 [PD-1]) inhibitor. MATERIALS AND METHODS: Sixty-three immunocompetent C57BL/6J mice were generated with 2 orthotopic HCC tumor foci: 1 for treatment and 1 to observe for antitumoral immunity. Tumors were treated with incomplete cryo alone or intratumoral CpG and/or a PD-1 inhibitor. The primary endpoint was death or when the following criteria for sacrifice were met: tumor > 1 cm (determined using ultrasound) or moribund state. Antitumoral immunity was assessed using flow cytometry and histology (tumor and liver) as well as enzyme-linked immunosorbent assay (serum). Analysis of variance was used for statistical comparisons. RESULTS: At 1 week, the nonablated satellite tumor growth was reduced by 1.9-fold (P = .047) in the cryo + CpG group and by 2.8-fold (P = .007) in the cryo + CpG + PD-1 group compared with that in the cryo group. Compared with cryo alone, the time to tumor progression to endpoints was also prolonged for cryo + CpG + PD-1 and cryo + CpG mice, with log-rank hazard ratios of 0.42 (P = .031) and 0.27 (P < .001), respectively. Flow cytometry and histology showed increased cytotoxic T-cell infiltration (P = .002) and serum levels of the proinflammatory cytokine interferon-γ (P = .015) in tumors and serum of cryo + CpG mice compared with those in tumors and serum of mice treated with cryo alone. High serum levels of the anti-inflammatory cytokine tumor growth factor-ß and the proangiogenesis chemokine C-X-C motif chemokine ligand 1 were correlated with a shorter time to endpoints and faster tumor growth. CONCLUSIONS: Cryo combined with the immunostimulant CpG promoted cytotoxic T-cell infiltration into tumors, slowed tumor growth, and prolonged the time to progression to endpoints in an aggressive murine HCC model.

NVX-CoV2373 vaccination induces functional SARS-CoV-2-specific CD4+ and CD8+ T cell responses.

NVX-CoV2373 is an adjuvanted recombinant full-length SARS-CoV-2 spike trimer protein vaccine demonstrated to be protective against COVID-19 in efficacy trials. Here we demonstrate that vaccinated individuals made CD4+ T cell responses after 1 and 2 doses of NVX-CoV2373, and a subset of individuals made CD8+ T cell responses. Characterization of the vaccine-elicited CD8+ T cells demonstrated IFN-γ production. Characterization of the vaccine-elicited CD4+ T cells revealed both circulating T follicular helper (cTfh) cells and Th1 cells (IFN-γ+, TNF-α+, and IL-2+) were detectable within 7 days of the primary immunization. Spike-specific CD4+ T cells were correlated with the magnitude of the later SARS-CoV-2-neutralizing antibody titers, indicating that robust generation of CD4+ T cells, capable of supporting humoral immune responses, may be a key characteristic of NVX-CoV2373 that utilizes Matrix-M adjuvant.

Humoral and cellular immune memory to four COVID-19 vaccines.

Multiple COVID-19 vaccines, representing diverse vaccine platforms, successfully protect against symptomatic COVID-19 cases and deaths. Head-to-head comparisons of T cell, B cell, and antibody responses to diverse vaccines in humans are likely to be informative for understanding protective immunity against COVID-19, with particular interest in immune memory. Here, SARS-CoV-2-spike-specific immune responses to Moderna mRNA-1273, Pfizer/BioNTech BNT162b2, Janssen Ad26.COV2.S and Novavax NVX-CoV2373 were examined longitudinally for 6 months. 100% of individuals made memory CD4 + T cells, with cTfh and CD4-CTL highly represented after mRNA or NVX-CoV2373 vaccination. mRNA vaccines and Ad26.COV2.S induced comparable CD8 + T cell frequencies, though memory CD8 + T cells were only detectable in 60-67% of subjects at 6 months. Ad26.COV2.S was not the strongest immunogen by any measurement, though the Ad26.COV2.S T cell, B cell, and antibody responses were relatively stable over 6 months. A differentiating feature of Ad26.COV2.S immunization was a high frequency of CXCR3 + memory B cells. mRNA vaccinees had substantial declines in neutralizing antibodies, while memory T cells and B cells were comparatively stable over 6 months. These results of these detailed immunological evaluations may also be relevant for vaccine design insights against other pathogens.

Low-dose mRNA-1273 COVID-19 vaccine generates durable memory enhanced by cross-reactive T cells.

Vaccine-specific CD4+ T cell, CD8+ T cell, binding antibody, and neutralizing antibody responses to the 25-µg Moderna messenger RNA (mRNA)­1273 vaccine were examined over the course of 7 months after immunization, including in multiple age groups, with a particular interest in assessing whether preexisting cross-reactive T cell memory affects vaccine-generated immunity. Vaccine-generated spike-specific memory CD4+ T cells 6 months after the second dose of the vaccine were comparable in quantity and quality to COVID-19 cases, including the presence of T follicular helper cells and interferon-γ­expressing cells. Spike-specific CD8+ T cells were generated in 88% of subjects, with equivalent memory at 6 months post-boost compared with COVID-19 cases. Lastly, subjects with preexisting cross-reactive CD4+ T cell memory exhibited stronger CD4+ T cell and antibody responses to the vaccine, demonstrating the biological relevance of severe acute respiratory syndrome coronavirus 2­cross-reactive CD4+ T cells.