J Virol
. 2025 Jan 31:e0168524.
doi: 10.1128/jvi.01685-24. Online ahead of print. mRNA vaccine-induced SARS-CoV-2 spike-specific IFN-γ and IL-2 T-cell responses are predictive of serological neutralization and are transiently enhanced by pre-existing cross-reactive immunity
Philip Samaan 1 , Chapin S Korosec 2 3 , Patrick Budylowski 4 5 , Serena L L Chau 5 , Adrian Pasculescu 6 , Freda Qi 6 , Melanie Delgado-Brand 6 , Tulunay R Tursun 6 , Geneviève Mailhot 6 , Roya Monica Dayam 6 , Corey R Arnold 7 , Marc-André Langlois 7 , Justin Mendoza 5 , Thomas Morningstar 5 , Ryan Law 5 , Erik Mihelic 5 , Salma Sheikh-Mohamed 8 , Eric Yixiao Cao 8 , Nimitha Paul 9 , Anjali Patel 9 , Keelia Quinn de Launay 9 , Jamie M Boyd 9 , Alyson Takaoka 9 , Karen Colwill 6 , Vitaliy Matveev 5 , Feng Yun Yue 5 , Allison McGeer 1 6 , Sharon Straus 9 , Anne-Claude Gingras 6 10 , Jane M Heffernen 2 3 , Mario Ostrowski 1 4 5 8 9 11
Affiliations
The contributions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells to vaccine efficacy and durability are unclear. We investigated relationships between mRNA vaccine-induced spike-specific interferon- gamma (IFN-γ) and interleukin-2 (IL-2) T-cell responses and neutralizing antibody development in long-term care home staff doubly vaccinated with BNT162b2 or mRNA-1273. The impacts of pre-existing cross-reactive T-cell immunity on cellular and humoral responses to vaccination were additionally assessed. Mathematical modeling of the kinetics of spike-specific IFN-γ and IL-2 T-cell responses over 6 months post-second dose was bifurcated into recipients who exhibited gradual increases with doubling times of 155 and 167 days or decreases with half-lives of 165 and 132 days, respectively. Differences in kinetics did not correlate with clinical phenotypes. Serological anti-spike IgG, anti-receptor binding domain (RBD) IgG, anti-spike IgA, and anti-RBD IgA antibody levels otherwise decayed in all participants with half-lives of 63, 57, 79, and 46 days, respectively, alongside waning neutralizing capacity (t1/2 = 408 days). Spike-specific T-cell responses induced at 2-6 weeks positively correlated with live viral neutralization at 6 months post-second dose, especially in hybrid immune individuals. Participants with pre-existing cross-reactive T-cell immunity to SARS-CoV-2 exhibited greater spike-specific T-cell responses, reduced anti-RBD IgA antibody levels, and a trending increase in neutralization at 2-6 weeks post-second dose. Non-spike-specific T-cells predominantly targeted SARS-CoV-2 non-structural protein at 6 months post-second dose in cross-reactive participants. mRNA vaccination was lastly shown to induce off-target T-cell responses against unrelated antigens. In summary, vaccine-induced spike-specific T-cell immunity appeared to influence serological neutralizing capacity, with only a modest effect induced by pre-existing cross-reactivity.
Importance: Our findings provide valuable insights into the potential contributions of mRNA vaccine-induced spike-specific T-cell responses to the durability of neutralizing antibody levels in both uninfected and hybrid immune recipients. Our study additionally sheds light on the precise impacts of pre-existing cross-reactive T-cell immunity to severe acute respiratory syndrome coronavirus 2 on the magnitude and kinetics of cellular and humoral responses to vaccination. Accordingly, our data will help optimize the development of next-generation T cell-based coronavirus vaccines and vaccine regimens to maximize efficacy and durability.
Keywords: SARS-CoV-2; T-cell immunity; cross-reactivity; humoral immunity; hybrid immunity; mRNA vaccines.
. 2025 Jan 31:e0168524.
doi: 10.1128/jvi.01685-24. Online ahead of print. mRNA vaccine-induced SARS-CoV-2 spike-specific IFN-γ and IL-2 T-cell responses are predictive of serological neutralization and are transiently enhanced by pre-existing cross-reactive immunity
Philip Samaan 1 , Chapin S Korosec 2 3 , Patrick Budylowski 4 5 , Serena L L Chau 5 , Adrian Pasculescu 6 , Freda Qi 6 , Melanie Delgado-Brand 6 , Tulunay R Tursun 6 , Geneviève Mailhot 6 , Roya Monica Dayam 6 , Corey R Arnold 7 , Marc-André Langlois 7 , Justin Mendoza 5 , Thomas Morningstar 5 , Ryan Law 5 , Erik Mihelic 5 , Salma Sheikh-Mohamed 8 , Eric Yixiao Cao 8 , Nimitha Paul 9 , Anjali Patel 9 , Keelia Quinn de Launay 9 , Jamie M Boyd 9 , Alyson Takaoka 9 , Karen Colwill 6 , Vitaliy Matveev 5 , Feng Yun Yue 5 , Allison McGeer 1 6 , Sharon Straus 9 , Anne-Claude Gingras 6 10 , Jane M Heffernen 2 3 , Mario Ostrowski 1 4 5 8 9 11
Affiliations
- PMID: 39887249
- DOI: 10.1128/jvi.01685-24
The contributions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells to vaccine efficacy and durability are unclear. We investigated relationships between mRNA vaccine-induced spike-specific interferon- gamma (IFN-γ) and interleukin-2 (IL-2) T-cell responses and neutralizing antibody development in long-term care home staff doubly vaccinated with BNT162b2 or mRNA-1273. The impacts of pre-existing cross-reactive T-cell immunity on cellular and humoral responses to vaccination were additionally assessed. Mathematical modeling of the kinetics of spike-specific IFN-γ and IL-2 T-cell responses over 6 months post-second dose was bifurcated into recipients who exhibited gradual increases with doubling times of 155 and 167 days or decreases with half-lives of 165 and 132 days, respectively. Differences in kinetics did not correlate with clinical phenotypes. Serological anti-spike IgG, anti-receptor binding domain (RBD) IgG, anti-spike IgA, and anti-RBD IgA antibody levels otherwise decayed in all participants with half-lives of 63, 57, 79, and 46 days, respectively, alongside waning neutralizing capacity (t1/2 = 408 days). Spike-specific T-cell responses induced at 2-6 weeks positively correlated with live viral neutralization at 6 months post-second dose, especially in hybrid immune individuals. Participants with pre-existing cross-reactive T-cell immunity to SARS-CoV-2 exhibited greater spike-specific T-cell responses, reduced anti-RBD IgA antibody levels, and a trending increase in neutralization at 2-6 weeks post-second dose. Non-spike-specific T-cells predominantly targeted SARS-CoV-2 non-structural protein at 6 months post-second dose in cross-reactive participants. mRNA vaccination was lastly shown to induce off-target T-cell responses against unrelated antigens. In summary, vaccine-induced spike-specific T-cell immunity appeared to influence serological neutralizing capacity, with only a modest effect induced by pre-existing cross-reactivity.
Importance: Our findings provide valuable insights into the potential contributions of mRNA vaccine-induced spike-specific T-cell responses to the durability of neutralizing antibody levels in both uninfected and hybrid immune recipients. Our study additionally sheds light on the precise impacts of pre-existing cross-reactive T-cell immunity to severe acute respiratory syndrome coronavirus 2 on the magnitude and kinetics of cellular and humoral responses to vaccination. Accordingly, our data will help optimize the development of next-generation T cell-based coronavirus vaccines and vaccine regimens to maximize efficacy and durability.
Keywords: SARS-CoV-2; T-cell immunity; cross-reactivity; humoral immunity; hybrid immunity; mRNA vaccines.