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. 2023 May 30;15(6):1276.
doi: 10.3390/v15061276.

Integration of Cellular and Humoral Immune Responses as an Immunomonitoring Tool for SARS-CoV-2 Vaccination in Healthy and Fragile Subjects

Giulia Brisotto  1 , Marcella Montico  2 , Matteo Turetta  1 , Stefania Zanussi  1 , Maria Rita Cozzi  1 , Roberto Vettori  1 , Romina Boschian Boschin  1 , Lorenzo Vinante  3 , Fabio Matrone  3 , Alberto Revelant  3 , Elisa Palazzari  3 , Roberto Innocente  3 , Giuseppe Fanetti  3 , Lorenzo Gerratana  4 , Mattia Garutti  4 , Camilla Lisanti  4 , Silvia Bolzonello  4 , Milena Sabrina Nicoloso  5 , Agostino Steffan  1 , Elena Muraro  1
Affiliations

Integration of Cellular and Humoral Immune Responses as an Immunomonitoring Tool for SARS-CoV-2 Vaccination in Healthy and Fragile Subjects

Giulia Brisotto et al. Viruses. .

Abstract

Cellular and humoral immunity are both required for SARS-CoV-2 infection recovery and vaccine efficacy. The factors affecting mRNA vaccination-induced immune responses, in healthy and fragile subjects, are still under investigation. Thus, we monitored the vaccine-induced cellular and humoral immunity in healthy subjects and cancer patients after vaccination to define whether a different antibody titer reflected similar rates of cellular immune responses and if cancer has an impact on vaccination efficacy. We found that higher titers of antibodies were associated with a higher probability of positive cellular immunity and that this greater immune response was correlated with an increased number of vaccination side effects. Moreover, active T-cell immunity after vaccination was associated with reduced antibody decay. The vaccine-induced cellular immunity appeared more likely in healthy subjects rather than in cancer patients. Lastly, after boosting, we observed a cellular immune conversion in 20% of subjects, and a strong correlation between pre- and post-boosting IFN-γ levels, while antibody levels did not display a similar association. Finally, our data suggested that integrating humoral and cellular immune responses could allow the identification of SARS-CoV-2 vaccine responders and that T-cell responses seem more stable over time compared to antibodies, especially in cancer patients.

Keywords: IFN-γ; SARS-CoV-2; antibody; cancer patients; cellular immune response; humoral immune response; mRNA vaccine; vaccination boost.

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Conflict of interest statement

M.T. owns shares of a start-up company with the exclusive license of the patent number ITRM20130700A1, 19 December 2013. Patent family ID 50073355 (published as CN105849559A; CN105849559B; EP3084434A1; EP3084434B1; ES2673597T3; WO2015092726A1; ITRM20130700A1; JP2017502312A; JP6437009B2; US2017003306A1; US9958463B2). M.G. reports advisory board funding from Novartis, Eli Lilly, Pierre Fabre, and Roche and travel fees from Daichii Sankyo, all outside the submitted work. All the other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Dynamics of anti-SARS-CoV-2 IgG levels in paired HCW samples after the second vaccination dose. Correlation between anti-SARS-CoV-2 IgG levels evaluated at 30 (IgG_T1) and 120 days (IgG_T2) after the second dose of vaccination. Each symbol represents an individual subject whose antibody titer was available for both time-points (n = 146); empty circles refer to infection-naïve HCWs (n = 126), grey diamonds to individuals with a previous history of SARS-CoV-2 infection (n = 20); the solid line represents the linear trend; Spearman’s rho 0.69, p < 0.001. AU, arbitrary units.
Figure 2
Figure 2
Frequency of the magnitude of HCWs’ vaccination side effects based on anti-SARS-CoV-2 IgG levels detected at least 120 days after the second vaccination dose (IgG_T2). By considering IgG_T2 distribution in tertiles, HCWs were divided into those with a low level of IgG (i.e., within the I tertile; IgG_T2 I tertile) and those with a higher amount of antibodies (i.e., within the II and III tertiles; IgG_T2 II-III tertile) and then grouped by the number of self-reported vaccination side effects (no side effects (0), dark grey; at least one side effect (1), light grey; ≥2 side effects (2+), grey); p for trend = 0.017 (McNemar’s test).
Figure 3
Figure 3
SARS-CoV-2-specific cellular immune response between HCWs and cancer patients. Comparison of the IFN-γ (A,B) and TNF-α (C,D) levels after Ag1 (A,C) and Ag2 (B,D) stimulation in HCWs and cancer patients, as detected at least 120 days after receiving 2 doses of vaccination. HCWs, healthcare workers; IU, international units. * p < 0.05.
Figure 4
Figure 4
Dynamic of the anti-SARS-CoV-2 antibody levels with respect to SARS-CoV-2-specific cellular immunity status in HCWs. Comparison of the SARS-CoV-2 IgG decay, reported as the fold change of the IgG level at 120 (IgG_T2) and 30 days (IgG_T1) after the second vaccination dose, between HCWs resulting negative (QF_T2 neg) or positive (QF_T2 pos) for the presence of SARS-CoV-2-specific cellular immunity at least 120 days after the second vaccination dose.* p < 0.05.
Figure 5
Figure 5
SARS-CoV-2-specific immunity before and after vaccination boost in HCW cohort. Correlation between IFN-γ levels evaluated at 120 days after the second (QF_T2) and the booster (QF_T3) vaccination dose after Ag1 (A) and Ag2 (B) stimulation. Correlation between specific SARS-CoV-2 IgG levels detected at 120 days after the second (IgG_T2) and the booster (IgG_T3) vaccination dose in HCWs stratified for their QF_T2 and QF_T3 global result status (C) (HCWs negative for QF_T2 and positive for QF_T3 were indicated as full black circles, HCWs negative for both identified as empty diamonds, HCWs positive for both QF_T2 and QF_T3 shown as full grey squares; the solid line represents the linear trend; Spearman’s rho 0.258, p = 0.070).
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