Longitudinal humoral and cell-mediated immune responses in a population-based cohort in Zurich, Switzerland between March and June 2022 - evidence for protection against Omicron SARS-CoV-2 infection by neutralizing antibodies and spike-specific T-cell responses

Abstract

Objectives: The correlate(s) of protection against SARS-CoV-2 remain incompletely defined. Additional information regarding the combinations of antibody and T cell-mediated immunity which can protect against (re)infection is needed.

Methods: We conducted a population-based, longitudinal cohort study including 1044 individuals of varying SARS-CoV-2 vaccination and infection statuses. We assessed spike (S)- and nucleocapsid (N)-immunoglobulin(Ig)G and wildtype, Delta, and Omicron-neutralizing antibody (N-Ab) activity. In a subset of 328 individuals, we evaluated S, membrane (M), and N-specific T cells. Three months later, we reassessed Ab (n = 964) and T cell (n = 141) responses and evaluated factors associated with protection from (re)infection.

Results: At the study start, >98% of participants were S-IgG seropositive. N-IgG and M/N-T-cell responses increased over time, indicating viral (re)exposure, despite existing S-IgG. Compared to N-IgG, M/N-T cells were a more sensitive measure of viral exposure. High N-IgG titers, Omicron-N-Ab activity, and S-specific-T-cell responses were all associated with a reduced likelihood of (re)infection over time.

Conclusion: Population-level SARS-CoV-2 immunity is S-IgG-dominated, but heterogeneous. M/N-T-cell responses can distinguish previous infection from vaccination, and monitoring a combination of N-IgG, Omicron-N-Ab, and S-T-cell responses may help estimate protection against SARS-CoV-2 (re)infection.

Keywords: Hybrid immunity; Interferon-gamma release assay; Neutralizing antibodies; SARS-CoV-2; Seroprevalence; T cell responses.

Figure 1

Quantitative antibody and T cell Responses among participants, March 2022. (a) anti-S- and N-IgG geometric mean MFI titer ratios (n = 1044), assay LOD = 6.0. (b) anti-WT, Delta, and Omicron geometric mean neutralizing Ab titers (n = 1044), assay LOD 50.0-2430.0. (c) Geometric mean IFN-gamma production following S or M/N peptide stimulation of whole blood (n = 328). Ab, antibody; IC, inhibitory concentration; IFN, interferon; Ig, immunoglobulin; LOD, limit of detection; MFI, mean fluorescence intensity; M, membrane; N, nucleocapsid; N-Ab, neutralizing antibody; S, spike; TC, T cell; WT, wildtype.

Figure 2

Factors associated with March 2022 S- or N-IgG, N-Ab titers, or S- or M/N-T cell IFN-gamma levels. Multivariable linear regression modeling was used to assess the relationship between gender (female vs male), age group (65+ vs 16-64 years), reporting a previous SARS-CoV-2 infection (positive polymerase chain reaction or antigen test) (yes vs no), and the number of COVID-19 vaccine doses received (1, 2, 3+ vs 0), and S- or N-IgG, N-Ab mean fluorescence intensity ratio titers, or S- or M/N-T cell IFN-gamma levels (natural logarithm-transformed). *P >0.05, ** P >0.01, *** P >0.005. CI, confidence interval; IFN, interferon; Ig, immunoglobulin; M, membrane; N, nucleocapsid; N-Ab, neutralizing antibody; S, spike; TC, T cell; WT, wildtype.

Figure 3

Antibody and T cell responses among participants by infection and vaccination status, March 2022. (a) Quantitative Ab and T cell responses. Log10 anti-S- and N-IgG geometric mean fluorescence intensity titer ratios, anti-WT, Delta, and Omicron geometric mean neutralizing Ab titers, and geometric mean IFN-gamma production following S or M/N peptide stimulation of whole blood. (b) Correlation between Ab and T cell responses. Top left: infected and unvaccinated individuals (n = 53 Ab tested, 14 T cell tested), top right: infected and vaccinated (n = 285 Ab tested, 80 T cell tested), bottom left: uninfected and unvaccinated (n = 15 Ab tested, 3 T cell tested), bottom right: uninfected and vaccinated (n = 686 Ab tested, 229 T cell tested). Values represent Spearman correlation coefficients for indicated Ab and T cell response pairs. Crosses indicate pairs with insufficient data for analysis. Ab, antibody; IFN, interferon; Ig, immunoglobulin; M, membrane; N, nucleocapsid; N-Ab, neutralizing antibody; S, spike; TC, T cell; WT, wildtype.

Figure 4

Quantitative antibody and T cell Responses, June 2022. (a) S- and N-IgG geometric mean MFI ratio titers (n = 964). (b) Geometric mean IFN-gamma production following S or M/N peptide stimulation of whole blood (n = 141). IFN, interferon; Ig, immunoglobulin; M, membrane; MFI, mean fluorescence intensity; N, nucleocapsid; S, spike; TC, T cell; WT, wildtype.

Figure 5

Factors associated with reporting a SARS-CoV-2 infection between March and June 2022. Multivariable logistic regression modeling was used to assess the relationship between gender (female vs male), age group (65+ vs 16-64 years), quantiles of S- or N-IgG, N-Ab Titers, or S- or M/N-T cell IFN-gamma levels in March 2022, and reporting a previous SARS-CoV-2 infection (positive polymerase chain reaction or antigen test) (yes vs no) in June/July 2022. For S- and N-IgG MFI ratio titers, individuals were assigned to one of three expression quantiles (<33%, 33-67%, 67+% of all participants); for N-Ab IC50 values, and S- and M/N-T cell IFN-gamma levels, individuals were assigned to one of four expression quantiles (<25%, 25->50%, 50->75%, 75+% of all participants). Corresponding MFI ratios/IC50 titers/IFN-gamma levels are listed next to each variable. *P >0.05, ***P >0.005. CI, confidence interval; IC, inhibitory concentration; IFN, interferon; Ig, immunoglobulin; M, membrane; MFI, mean fluorescence intensity; N, nucleocapsid; N-Ab, neutralizing antibody; S, spike; TC, T cell; WT, wildtype.