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Observational Study
. 2023 Aug 25:14:1225025.
doi: 10.3389/fimmu.2023.1225025. eCollection 2023.

Natural killer cells and BNT162b2 mRNA vaccine reactogenicity and durability

Elizabeth K Graydon  1   2 , Tonia L Conner  1 , Kim Dunham  3 , Cara Olsen  4 , Emilie Goguet  1   2 , Si'Ana A Coggins  1   2 , Marana Rekedal  1   2 , Emily Samuels  1   2 , Belinda Jackson-Thompson  1   2 , Matthew Moser  1   2 , Alyssa Lindrose  1   2 , Monique Hollis-Perry  5 , Gregory Wang  5   6 , Santina Maiolatesi  2   5 , Yolanda Alcorta  5   6 , Anatalio Reyes  5   6 , Mimi Wong  5   6 , Kathy Ramsey  5   6 , Julian Davies  2   7 , Edward Parmelee  2   7 , Orlando Ortega  2   7 , Mimi Sanchez  2   7 , Sydney Moller  3 , Jon Inglefield  3 , David Tribble  7 , Timothy Burgess  7 , Robert O'Connell  7 , Allison M W Malloy  8 , Simon Pollett  2   7 , Christopher C Broder  1 , Eric D Laing  1 , Stephen K Anderson  3 , Edward Mitre  1
Affiliations
Observational Study

Natural killer cells and BNT162b2 mRNA vaccine reactogenicity and durability

Elizabeth K Graydon et al. Front Immunol. .

Abstract

Introduction: Natural killer (NK) cells can both amplify and regulate immune responses to vaccination. Studies in humans and animals have observed NK cell activation within days after mRNA vaccination. In this study, we sought to determine if baseline NK cell frequencies, phenotype, or function correlate with antibody responses or inflammatory side effects induced by the Pfizer-BioNTech COVID-19 vaccine (BNT162b2).

Methods: We analyzed serum and peripheral blood mononuclear cells (PBMCs) from 188 participants in the Prospective Assessment of SARS-CoV-2 Seroconversion study, an observational study evaluating immune responses in healthcare workers. Baseline serum samples and PBMCs were collected from all participants prior to any SARS-CoV-2 infection or vaccination. Spike-specific IgG antibodies were quantified at one and six months post-vaccination by microsphere-based multiplex immunoassay. NK cell frequencies and phenotypes were assessed on pre-vaccination PBMCs from all participants by multi-color flow cytometry, and on a subset of participants at time points after the 1st and 2nd doses of BNT162b2. Inflammatory side effects were assessed by structured symptom questionnaires, and baseline NK cell functionality was quantified by an in vitro killing assay on participants that reported high or low post-vaccination symptom scores.

Results: Key observations include: 1) circulating NK cells exhibit evidence of activation in the week following vaccination, 2) individuals with high symptom scores after 1st vaccination had higher pre-vaccination NK cytotoxicity indices, 3) high pre-vaccination NK cell numbers were associated with lower spike-specific IgG levels six months after two BNT162b2 doses, and 4) expression of the inhibitory marker NKG2A on immature NK cells was associated with higher antibody responses 1 and 6 months post-vaccination.

Discussion: These results suggest that NK cell activation by BNT162b2 vaccination may contribute to vaccine-induced inflammatory symptoms and reduce durability of vaccine-induced antibody responses.

Keywords: COVID; NK cells; SARS-CoV-2 vaccine; antibody durability; mRNA vaccine; reactogenicity; vaccine side effects.

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Conflict of interest statement

SP, TB, and DT report that the Uniformed Services University USU Infectious Disease Clinical Research Program IDCRP, a US Department of Defense institution, and the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. HJF were funded under a Cooperative Research and Development Agreement to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial sponsored by AstraZeneca. The HJF, in support of the USU IDCRP, was funded by the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense to augment the conduct of an unrelated phase III vaccine trial sponsored by AstraZeneca. Both trials were part of the US Government COVID-19 response. Neither is related to the work presented here. The remaining 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
Strobe chart. Of the 271 individuals enrolled in the PASS study by March 30th, 2021, 15 were excluded due to evidence of SARS-CoV-2 exposure prior to vaccination. 188 of the remaining participants received 2 doses of the BNT162b2 mRNA COVID-19 vaccine by March 30th, 2021, completed symptom questionnaires following both vaccinations, and had serum samples obtained at time points between 20-50 and 150-200 days post-2nd vaccination and comprised the final cohort used in this analysis.
Figure 2
Figure 2
NK cell frequencies and functionality in relation to sex. (A) Percentage of NK cells from “total cells” gate, and (B) absolute number of NK cells/µl of blood in female (n=127) and male (n=61) participants at baseline (before vaccination). (C) AUC of percent killing of target cells by NK cells at effector to target (E:T) ratios 10:1, 5:1, 2.5:1, and 1.25:1 in female (n=25) and male (n=27) participants at baseline. (D) AUC of NK cytotoxicity index in female (n=25) and male (n=27) participants at baseline. Mann Whitney U test was performed for all comparisons between males and females.
Figure 3
Figure 3
NK cell frequencies and functionality in relation to age. (A) Percentage and (B) absolute number of NK cells versus age (n=188). (C) AUC of percent killing of target cells by NK cells versus age (n=52). (D) AUC of NK cytotoxicity index versus age (n=52). Spearman’s correlation was performed to evaluate relationships of NK cells percentages, numbers, or killing with age.
Figure 4
Figure 4
Longitudinal frequencies of NK cells. (A) Total NK cells (CD3- CD14- CD19- CD56+) as a percentage of all PBMCs, (B) absolute NK cell numbers as NK cells/µl of blood, and NK cell subsets as a percentage of total NK cells: (C) immature NK cells (CD56bright CD16-) (D) CD16+ mature NK cells (CD56+ CD16+), and (E) CD16- mature NK cells (CD56dim CD16-) at baseline (n=18), 1-7 days post-vaccine 1 (n=18) and less than 30 days post-vaccine 2 (n=17). Analyses between baseline and vaccination time points were conducted using one-way repeated measures ANOVA followed by Dunnett’s multiple comparisons test (*p<0.05).
Figure 5
Figure 5
Symptom scores after vaccination in relation to NK cell frequencies and functionality measured at baseline (pre-vaccination). Absolute NK cells at baseline versus symptom scores following vaccination 1 (A) and vaccination 2 (B) (n=188). AUC for (C) percent killing of target cells by NK cells, and (D) NK cell cytotoxicity index in individuals with low (n=25) and high (n=27) symptom scores after vaccination 1. (E) Percent killing of target cells by NK cells, and (F) NK cell cytotoxicity index in individuals with low (n=31) and high (n=21) symptom scores after vaccination 2. Spearman’s correlation was performed to evaluate the relationship of NK cell percentages with symptom scores and unpaired t-test was performed for comparisons between low and high symptom score groups. *p < 0.05.
Figure 6
Figure 6
IgG levels at 1 month and 6 months post-2nd vaccination in relation to NK cell frequencies and functionality. Absolute number of NK cells/µl of blood at baseline versus spike-specific IgG levels 1 month (A) and 6 months (B) post-2nd vaccination (n=188). AUC of percent killing at baseline vs. spike-specific IgG at 1 month (C) and 6 months (D) post-2nd vaccination (n=52). AUC of NK cytotoxicity index at baseline vs. spike-specific IgG at 1 month (E) and 6 months (F) post-2nd vaccination (n=52). Spearman’s correlation was performed to evaluate the relationship of absolute number, or functionality of NK cells with spike-specific IgG levels at 1 or 6 months.
Figure 7
Figure 7
Heat map of correlations between baseline NK cell receptor expression and post-vaccination symptom scores, and IgG levels at 1 and 6 months post-vaccination. Spearman correlations were examined between expression of 2 activating NK cell receptors (NKG2C, NKG2D), and 4 inhibitory receptors (NKG2A, KIR2DL1, KIR2DL2/L3, KIR3DL1) on all NK cells, or expression on the immature or mature subsets on pre-vaccination samples. Spearman correlation rho values are given between expression of these receptors and post-vaccination symptoms scores and IgG at 1 and 6 months post-vaccination. *p<0.05, ***p<.001.
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