Early T cell and binding antibody responses are associated with COVID-19 RNA vaccine efficacy onset

Abstract

Background: RNA vaccines against coronavirus disease 2019 (COVID-19) have demonstrated ∼95% efficacy in phase III clinical trials. Although complete vaccination consisted of 2 doses, the onset of protection for both licensed RNA vaccines was observed as early as 12 days after a single dose. The adaptive immune response that coincides with this onset of protection could represent the necessary elements of immunity against COVID-19.

Methods: Serological and T cell analysis was performed in a cohort of 20 healthcare workers after receiving the first dose of the Pfizer/BioNTech BNT162b2 vaccine. The primary endpoint was the adaptive immune responses detectable at days 7 and 10 after dosing.

Findings: Spike-specific T cells and binding antibodies were detectable 10 days after the first dose of the vaccine, in contrast to receptor-blocking and severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) neutralizing antibodies, which were mostly undetectable at this early time point.

Conclusions: Our findings suggest that early T cell and binding antibody responses, rather than either receptor-blocking or virus neutralizing activity, induced early protection against COVID-19.

Funding: The study was funded by a generous donation from The Hour Glass to support COVID-19 research.

Keywords: COVID-19; RNA vaccine; T cells; binding antibodies; neutralizing antibodies; vaccine efficacy.

Graphical abstract

Figure 1

Early humoral responses following 1^st dose of vaccine (A–C) Antibody responses in serum following dose 1 of vaccine were characterized in study participants at pre-dose, and at days (D) 7, 10, and 21 post-vaccination. SARS-CoV-2 S-specific IgM (A), IgA (B), and IgG (C) were measured using a bead-based immunoassay and binding data reported as median fluorescence intensity (MFI). Data were fitted with a locally weighted scatterplot smoothing (LOESS) regression analysis (blue, purple, and red lines for IgM, IgA, and IgG, respectively). IgM, IgA, and IgG data for the study population at each of the time points is presented as geometric mean MFI (GMFI). Percentage of response in the study healthcare population was calculated using a positive threshold of a ≥4-fold increase in GMFI over pre-dose. (D) Inhibition of RBD binding to hACE2 receptor was tested using the commercial cPASS kit at 1:20 serum dilution, with a positive antibody response defined as RBD-hACE2 binding inhibition >20%. Pie charts show the percentage of study participants with positive RBD-hACE2 antibody response at each study time point.

Figure 2

Induction of SARS-CoV-2 spike-specific T cell responses following 1^st dose of vaccine (A) The frequency of antigen-specific stimulation measured by activation-induced markers (AIM⁺) CD69⁺4-1BB⁺ expression in CD8 T cells (left) and OX40⁺4-1BB⁺ expression in CD4 T cells (right). Summarized graph represents the percentage of activation after the background subtraction of cells without SARS-CoV-2 spike (S) stimulation. (B) The amount of IFN-γ secreted upon whole-blood stimulation with the SARS-CoV-2 S-peptide pool after deduction with the respective DMSO control. (C) The frequency of IFN-γ SFU reactive to the SARS-CoV-2 S-peptide pool after subtraction against the negative control. The black line indicates the median responses at different time points in (A)–(C), and n = 20 unless indicated on the figure. Whole-blood IFN-γ assay and other T cell assays were only performed in 18 and 19 individuals, respectively, on D21 due to the lack of samples. The pie graph below the axis in (A–(C) represents the summarized number of positive responses (red) defined as having a T cell response compared to D1. Statistical comparisons were performed using nonparametric ANOVA, Friedman test. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001, and N.S. indicates not significant. See also Figure S2.