Potent induction of humoral and cellular immunity after bivalent BA.4/5 mRNA vaccination in dialysis patients with and without history of SARS-CoV-2 infection (preprint)

Knowledge on immunogenicity of the bivalent Omicron BA.4/5 vaccine in dialysis patients and the effect of a previous infection is limited. Therefore, vaccine-induced humoral and cellular immunity was analyzed in dialysis patients and immunocompetent controls with and without prior infection. In an observational study, 33 dialysis patients and 58 controls matched for age, sex and prior infection status were recruited. Specific IgG, neutralizing antibody activity and cellular immunity towards the spike-antigen from parental SARS-CoV-2 and Omicron subvariants BA.1, BA.2 and BA.4/5 were analyzed before and 13-18 days after vaccination. The bivalent vaccine led to a significant induction of IgG, neutralizing titers, and specific CD4 and CD8 T-cell levels. Neutralizing activity towards the parental strain was highest, whereas specific T-cell levels towards parental spike and Omicron subvariants did not differ indicating substantial cross-reactivity. Dialysis patients with prior infection had significantly higher spike-specific CD4 T-cell levels with lower CTLA-4 expression compared to infection-naive patients. When compared to controls, no differences were observed between individuals without prior infection. Among infected individuals, CD4 T-cell levels were higher in dialysis patients and neutralizing antibodies were higher in controls. Vaccination was overall well tolerated in both dialysis patients and controls with significantly less adverse events among dialysis patients. In conclusion, our study did not provide any evidence for impaired immunogenicity of the bivalent Omicron BA.4/5 vaccine in dialysis patients. Unlike in controls, previous infection of patients was even associated with higher levels of spike-specific CD4 T cells, which may reflect prolonged encounter with antigen during infection.

Head-to-head analysis of immunogenicity and reactogenicity of heterologous ChAdOx1 nCoV-19-priming and BNT162b2 or mRNA-1273-boosting with homologous COVID-19 vaccine regimens (preprint)

Head-to-head analyses of immunogenicity and reactogenicity between the authorized homologous vaccine-regimens and heterologous combinations thereof are currently limited. Using a convenience cohort of 331 healthy individuals, we show that humoral and cellular immunity after vaccination with ChAdOx1-nCoV-19 followed by either BNT162b2 (n=66) or mRNA-1273 (n=101) is equivalent or superior to homologous mRNA-regimens (n=43 BNT162b2, n=59 mRNA-1273), and more pronounced than after homologous ChAdOx1-nCoV-19 vaccination (n=62). Levels of spike-specific CD8 T cells were highest in both heterologous regimens, and significantly higher than all three homologous combinations. Among mRNA-containing combinations, spike-specific CD4 T-cell levels in regimens including mRNA-1273 were higher than respective combinations with BNT162b2. Polyfunctional T-cell levels were highest in regimens based on ChAdOx1-nCoV-19-priming. All five regimens were well tolerated with most pronounced reactogenicity upon ChAdOx1-nCoV-19-priming and mRNA-1273-boosting. In conclusion, immunogenicity after heterologous vector/mRNA-boosting and homologous mRNA-regimens is superior to homologous vector-regimens with notable differences between mRNA vaccines.

Immunogenicity and reactogenicity of a heterologous COVID-19 prime-boost vaccination compared with homologous vaccine regimens (preprint)

Heterologous priming with the ChAdOx1-nCoV-19 vector-vaccine followed by boosting with an mRNA-vaccine is currently recommended in Germany, although data on immunogenicity and reactogenicity are not available. Here we show that the heterologous regimen induced spike-specific IgG, neutralizing antibodies, and spike-specific CD4 T-cells, which were significantly more pronounced than after homologous vector boost, and higher or comparable in magnitude to the homologous mRNA regimens. Moreover, spike-specific CD8 T-cell levels after heterologous vaccination were significantly higher than after both homologous regimens. Cytokine expression profiling showed a predominance of polyfunctional T-cells expressing IFN{gamma}, TNF and IL-2 with subtle differences between regimens. Both recipients of the homologous vector-regimen and the heterologous vector/mRNA-combination were most affected by the priming vector-vaccination, whereas heterologous boosting was well tolerated and comparable to homologous mRNA-boosting. Taken together, heterologous vector-mRNA boosting induces strong humoral and cellular immune responses with acceptable reactogenicity profile. This knowledge will have implications for future vaccine strategies.

Cellular immunity predominates over humoral immunity after the first dose of COVID-19 vaccines in solid organ transplant recipients (preprint)

Knowledge on the vaccine-induced cellular and humoral immunity and on immunogenicity of vector-based and mRNA vaccines in solid organ transplant recipients is limited. Therefore, SARS-CoV-2 specific T-cells and antibodies were analyzed in 40 transplant recipients and 70 age-matched controls after the first dose of vector-based or mRNA vaccines. Plasmablasts and SARS-CoV-2 specific CD4 and CD8 T-cells were quantified using flow-cytometry. Specific antibodies were analyzed by ELISA and neutralization assay. SARS-CoV-2 specific antibodies and T-cells were induced in both groups with significantly lower levels in patients. While antibodies were detected in 80% of controls and 5.3% of patients, specific CD4 and/or CD8 T-cells were more frequently found in both controls (84.3%) and patients (23.7%). The two vaccine types showed notable differences, as IgG and neutralizing activity were more pronounced after mRNA vaccination (p<0.0001 each), whereas CD4 and CD8 T-cell levels were higher after vector vaccination (p=0.009; p<0.0001). Plasmablast numbers were significantly higher in controls and correlated with SARS-CoV-2 specific IgG- and CD4 T-cell levels. In conclusion, assessment of antibodies is not sufficient to identify COVID-19-vaccine responders. Together with differences in immunogenicity among vaccines, this necessitates combined analysis of humoral and cellular immunity to reliably assess responders among immunocompetent and immunocompromised individuals.

High levels of SARS-CoV-2 specific T-cells with restricted functionality in patients with severe course of COVID-19 (preprint)

Patients infected with SARS-CoV-2 differ in the severity of disease. In this study, SARS-CoV-2 specific T-cells and antibodies were characterized in patients with different COVID-19 related disease severity. Despite severe lymphopenia affecting all major lymphocyte subpopulations, patients with severe disease mounted significantly higher levels of SARS-CoV-2 specific T-cells as compared to convalescent individuals. SARS-CoV-2 specific CD4 T-cells dominated over CD8 T-cells and closely correlated with the number of plasmablasts and SARS-CoV-2 specific IgA- and IgG-levels. Unlike in convalescents, SARS-CoV-2 specific T-cells in patients with severe disease showed marked alterations in phenotypical and functional properties, which also extended to CD4 and CD8 T-cells in general. Given the strong induction of specific immunity to control viral replication in patients with severe disease, the functionally altered phenotype may result from the need for contraction of specific and general immunity to counteract excessive immunopathology in the lung.