Modulation of innate immune response to mRNA vaccination after SARS-CoV-2 infection or sequential vaccination in humans
Fredrika Hellgren, Anja Rosdahl, Rodrigo Arcoverde Cerveira, Klara Lenart, Sebastian Ols, Yong-Dae Gwon, Seta Kurt, Anna Maria Delis, Gustav Joas, Magnus Evander, Johan Normark, Clas Ahlm, Mattias N.E. Forsell, Sara Cajander, Karin Loré
Fredrika Hellgren, Anja Rosdahl, Rodrigo Arcoverde Cerveira, Klara Lenart, Sebastian Ols, Yong-Dae Gwon, Seta Kurt, Anna Maria Delis, Gustav Joas, Magnus Evander, Johan Normark, Clas Ahlm, Mattias N.E. Forsell, Sara Cajander, Karin Loré
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Research Article Immunology Vaccines

Modulation of innate immune response to mRNA vaccination after SARS-CoV-2 infection or sequential vaccination in humans

Abstract

mRNA vaccines are likely to become widely used for the prevention of infectious diseases in the future. Nevertheless, a notable gap exists in mechanistic data, particularly concerning the potential effects of sequential mRNA immunization or preexisting immunity on the early innate immune response triggered by vaccination. In this study, healthy adults, with or without documented prior SARS-CoV-2 infection, were vaccinated with the BNT162b2/Comirnaty mRNA vaccine. Prior infection conferred significantly stronger induction of proinflammatory and type I IFN–related gene signatures, serum cytokines, and monocyte expansion after the prime vaccination. The response to the second vaccination further increased the magnitude of the early innate response in both study groups. The third vaccination did not further increase vaccine-induced inflammation. In vitro stimulation of PBMCs with TLR ligands showed no difference in cytokine responses between groups, or before or after prime vaccination, indicating absence of a trained immunity effect. We observed that levels of preexisting antigen-specific CD4 T cells, antibody, and memory B cells correlated with elements of the early innate response to the first vaccination. Our data thereby indicate that preexisting memory formed by infection may augment the innate immune activation induced by mRNA vaccines.

Authors

Fredrika Hellgren, Anja Rosdahl, Rodrigo Arcoverde Cerveira, Klara Lenart, Sebastian Ols, Yong-Dae Gwon, Seta Kurt, Anna Maria Delis, Gustav Joas, Magnus Evander, Johan Normark, Clas Ahlm, Mattias N.E. Forsell, Sara Cajander, Karin Loré

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Figure 1

Three doses of vaccine required to attain similar levels of humoral immunity in SARS-CoV-2 infection naive as infection-experienced individuals.

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Three doses of vaccine required to attain similar levels of humoral immu...
(A) Schematic of group division and sampling schedule. (B and C) Spike-binding (B) and RBD-binding (C) IgG plasma titers, quantified by binding ELISA. Data reported as IU/mL based on the WHO First International Standard. Data are shown as geometric mean ± geometric SD. (D) Plasma live virus neutralizing titers (Wu-Hu-1 equivalent strain, Swedish isolate). Data are shown as geometric mean ± geometric SD. (E) Antibody potency index, calculated as ratio of virus neutralizing titer (IC50) to spike binding titer (IU/mL). Line indicates geometric mean. (F) Spike IgG antibody avidity measured by chaotropic wash ELISA, reported as avidity index (% of antibody binding remaining after chaotropic wash). Data are shown as mean ± SEM. (G) Fraction of RBD-binding plasma IgG out of total spike binding measured by competition ELISA using recombinant RBD in solution. Dotted line indicates binding ratio of 1.0. Data are shown as mean ± SEM. (H) Fractions of total spike-specific and spike/RBD-specific IgG+ B cells over time, shown as percentage of total B cells. Representative gating of total spike and spike/RBD-specific B cells shown in Supplemental Figure 14. Data are shown as mean ± SEM. (I) Spike-specific CD4 T cells producing IFN-γ and/or IL-2 in response to SARS-CoV-2 spike overlapping peptide stimulation. Data shown as percentage of CD4 memory T cells. Data are shown as mean ± SEM. (J) Spike-specific CD8 T cells producing IFN-γ in response to SARS-CoV-2 spike overlapping peptide stimulation. Data are shown as percentage of CD8 memory T cells. Data are shown as mean ± SEM. Groups were compared by multiple Mann-Whitney U test with comparison between groups at each time point and P value adjustment using the Holm-Šidák method (α threshold 0.05). Number of participants analyzed: Week 0 = 30; Week 4 = 30 (A–G), 28 (H–J); Week 6 = 29; Week 18 = 29; Week 30 = 23; Week 30 + 14d = 24; Week 51 = 28 (B–G, I, and J), 27 (H). The x axis indicates time point.