Adverse effects following anti–COVID-19 vaccination with mRNA-based BNT162b2 are alleviated by altering the route of administration and correlate with baseline enrichment of T and NK cell genes
Ayesa Syenina, Esther S. Gan , Justin Z. N. Toh, Ruklanthi de Alwis, Lowell Z. Lin, Christine Y. L. Tham, JiaXin Yee, Yan Shan Leong, Huizhen Sam, Charlene Cheong, Yii Ean Teh, Ian L. E. Wee, Dorothy H. L. Ng, Eng Eong Ooi
Abstract
Ensuring high vaccination and even booster vaccination coverage is critical in preventing severe Coronavirus Disease 2019 (COVID-19). Among the various COVID-19 vaccines currently in use, the mRNA vaccines have shown remarkable effectiveness. However, systemic adverse events (AEs), such as postvaccination fatigue, are prevalent following mRNA vaccination, and the underpinnings of which are not understood. Herein, we found that higher baseline expression of genes related to T and NK cell exhaustion and suppression were positively correlated with the development of moderately severe fatigue after Pfizer-BioNTech BNT162b2 vaccination; increased expression of genes associated with T and NK cell exhaustion and suppression reacted to vaccination were associated with greater levels of innate immune activation at 1 day postvaccination. We further found, in a mouse model, that altering the route of vaccination from intramuscular (i.m.) to subcutaneous (s.c.) could lessen the pro-inflammatory response and correspondingly the extent of systemic AEs; the humoral immune response to BNT162b2 vaccination was not compromised. Instead, it is possible that the s.c. route could improve cytotoxic CD8 T-cell responses to BNT162b2 vaccination. Our findings thus provide a glimpse of the molecular basis of postvaccination fatigue from mRNA vaccination and suggest a readily translatable solution to minimize systemic AEs.
Introduction
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused 100s of millions cases of Coronavirus Disease 2019 (COVID-19) globally. Through airborne and droplet transmission, SARS-CoV-2 has spread rapidly to cause a pandemic [1,2] and genetic variants of SARS-CoV-2, such as Delta and Omicron, have and will continue to emerge to worsen and prolong the pandemic. Fortunately, timely development and deployment of COVID-19 vaccines have begun to reduce the impact of COVID-19 on global health and economies. Among these vaccines, the most efficacious ones have been the mRNA-based vaccines, namely BNT162b2 and mRNA-1273 developed by Pfizer-BioNTech and Moderna, respectively. However, while these vaccines are remarkably efficacious against COVID-19, they are reactogenic [3,4]. Over 50% of people who have received either of these vaccines have reported systemic adverse events (AEs) [5]. These symptoms, especially fatigue, are self-limiting, although they can be debilitating [3,5–8]. Such systemic AEs are thought to contribute, at least to some extent, to the hesitancy to be vaccinated or to be boosted after completion of the primary 2-dose vaccination series [9–12].
Materials and methods
Clinical trial design
This study was approved by the SingHealth Centralized Institutional Review Board (CIRB/F 2021/2014). Healthcare workers from the Singapore Health Services institutions who were eligible for COVID-19 vaccination were invited to participate in this study, and written informed consent was obtained. Whole blood samples were collected for microarray profiling at D0 (predose1), D1, D20 (predose 2), and D21 and for T-cell response analysis at D0 (prevaccination), D7, D10, and D20 after vaccination with the Pfizer-BioNTech BNT162b2 vaccine.
Results
Characteristics of participants and AEs
An overview of the study is shown in Fig 1. A total of 175 healthcare workers who received the Pfizer-BioNTech (BNT162b2) COVID-19 vaccine were enrolled to our study. Demographics of participants included in this study are shown in S1 Table. Participants were monitored for onset of AEs within the first 7 days of receiving dose 1 and dose 2 of the vaccine. Participants who reported AEs were followed up until resolution of AEs. We classified AEs by system organ class according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Local AEs (Fig 2A) included the development of pain or tenderness, rash, swelling, and redness at the site of injection, while systemic AEs (Fig 2B) included fever, chills, and fatigue. AEs were also subcategorized into gastrointestinal (abdominal pain, diarrhea, and nausea), musculoskeletal (arthralgia and myalgia), central nervous system (headache and dizziness), and respiratory (cough, sore throat, and runny nose) (Fig 2C). Other reported AEs included palpitations, cervical lymphadenopathy, exacerbated hay fever symptoms, heightened sense of smell, malaise, and swelling of lymph nodes (Fig 2C).
Discussion
Despite the remarkable efficacy of mRNA vaccines in protecting against COVID-19, there remains some level of concern about the reactogenicity of this vaccine that has contributed to vaccine hesitancy [9–12]. This has not only limited uptake of this 2-dose vaccine in some countries, but it could also limit the uptake of the third or booster dose, which has started for specific at-risk populations. Understanding the molecular underpinnings of AEs following immunization with mRNA vaccines would thus be important, not only for public health authorities to assuage safety concerns, but also to enable a less reactogenic approach to mRNA vaccination.
Acknowledgments
We thank Dr LiminWijaya of the Singapore General Hospital for allowing us to collect the residual vaccines that would otherwise be discarded for our study. We also thank Professor SubhashVasudevan for facilitating the animal protocols.
Conclusions
In conclusion, our findings suggest that elevated baseline levels of transcripts associated T and NK cell activity and function are susceptibility factors for postmRNA vaccination fatigue. Furthermore, s.c. inoculation of mRNA vaccines could be a pragmatic approach to reducing the rate and severity of systemic AEs without compromising vaccine efficacy.
Citation: Syenina A, Gan ES, Toh JZN, de Alwis R, Lin LZ, Tham CYL, et al. (2022) Adverse effects following anti–COVID-19 vaccination with mRNA-based BNT162b2 are alleviated by altering the route of administration and correlate with baseline enrichment of T and NK cell genes. PLoSBiol 20(5): e3001643. https://doi.org/10.1371/journal.pbio.3001643
Academic Editor: XupingXie, The University of Texas Medical Branch at Galveston, UNITED STATES
Received: March 1, 2022; Accepted: April 22, 2022; Published: May 31, 2022
Copyright: © 2022 Syenina et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting information files. The microarray profiling raw dataset has been deposited in the ArrayExpress database at EMBL-EBI (www.ebi.ac.uk/arrayexpress) under accession number E-MTAB-11656.
Funding: This study was supported by the National Medical Research Council (NMRC) Open Fund-Large Collaborative Grant (OFLCG19May-0034) and Senior Clinician-Scientist Award (MOH-000135-00) to E.E.O, and the Open Fund-Young Investigator Research Grant (MOH-OFIRG18nov-0004) to R.D.A. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared no competing interests exists.
Abbreviations: AE, adverse event; AUC, area under the curve; BTM, blood transcription module; CFS, chronic fatigue syndrome; COVID-19, Coronavirus Disease 2019; CTCAE, Common Terminology Criteria for Adverse Events; FC, fold change; GSEA, gene set enrichment analysis; i.m., intramuscular; IFN, interferon; IFNγ, interferon gamma; IL, interleukin; ITIM, immunoreceptor tyrosine-based inhibitory motif; K18-hACE2, K18 human angiotensin converting enzyme 2; KLRF1, killer cell lectin-like receptor F1; LEG, leading edge gene; NTD, N-terminal domain; PCA, principal component analysis; PMBC, peripheral blood mononuclear cell; RBD, receptor binding domain; s.c., subcutaneous; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; sVNT, surrogate virus neutralization test; TIGIT, T-cell immunoglobulin and ITIM domain; TLR, Toll-like receptor; TNFα, tumor necrosis factor alpha
https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001643#sec009
