A Critical Role of Non-Dysbiotic Oral Microbiota in Mrna Covid-19 Vaccine Effectiveness in Immunocompromised Individuals

Abstract

Background: Research on the microbiome's role in vaccine responsiveness has primarily focused on the general population and gut microbiome.

Methods: In this study, we investigated the mRNA COVID-19 vaccine and the role of oral microbiome in immunocompromised patients prone to vaccination failure. Paired saliva and blood samples from healthy individuals or immunocompromised due to hematopoietic cell transplantation, chronic lymphocytic leukemia, or primary immunodeficiency (total N=221), were stratified based on their antibody responses in a six-month follow-up of BNT162b2 COVID-19 mRNA vaccination. Metagenomic comparative analysis of oral microbiome prior to vaccination was conducted using whole-genome sequencing.

Findings: While the microbiome variation was influenced by disease conditions, the vaccine responsiveness was characterized by distinct microbial features. High vaccine responders within each disease group generally exhibited an oral microbiome enriched of commensals and notably few virulence features. This stands in stark contrast to the significant overexpression of virulence factors assigned to toxin-antitoxin modules, antimicrobial resistance, and type III, IV, and VI secretion systems in low responders across all participant groups. Moreover, low vaccine responsiveness was not linked to oral mucositis or mucosal corticosteroid use following hematopoietic stem cell transplantation and was associated with use of systemic antibiotics and immunosuppressants prior to vaccination.

Conclusion: Our findings suggest that a dysbiotic oral microbiome with increased virulence load is linked to mRNA vaccine failure, especially in immunocompromised individuals, potentially increasing their risk of COVID-19-related complications and opportunistic infections.

Note:
Funding Information: This research was funded by Knut and Alice Wallenberg Foundation, Swedish Research Council, Swedish Cancer Association, Center for Innovative Medicine, Radiumhemments forskningsfonder.

Declaration of Interests: SM received honoraria via his institution from Celgene/BMS, Novartis, Gilead/Kite, DNA Prime for lectures and educational events and as a member and/or head of data safety monitoring boards from Miltenyi and Immunicum outside the submitted work. PL reports grants from Pfizer, grants from MSD, grants and personal fees from Takeda, personal fees from AiCuris, personal fees from OctaPharma, Enanta pharmaceuticals and BMS, outside the submitted work. HGL has served on the UK-CIC Oversight Committee, led the Karolinska Institutet COVID-19 vaccine group, and is on the scientific advisory group for the International Vaccine Institute. He has obtained grants from Knut and Alice Wallenberg Foundation, Swedish Research Council, and Nordstjernan AB for studies on COVID-19 and COVID-19 vaccines. SA has received honoraria for lectures and educational events, not related to this work, from Gilead, AbbVie, MSD, Biogen and Netdoktor, and reports grants from Knut and Alice Wallenberg Foundation for this study. MSC has received honoraria from Gilead, reports grants from CIMED, Radiumhemmets fonder, Swedish Cancer Association for this study and is co-founder of SVF AB.

Ethics Approval Statement: Ethical approval for the COVAXID clinical trial was granted by the Swedish Medical Product Agency (ID 5.1-2021-5881) and the Swedish Ethical Review Authority (IDs 2021-00451 and 2020-06381). Written informed consent was obtained from all participants prior to inclusion.

Trial Registration: COVAXID Clinical Trial (NCT04780659)

Keywords: Oral microbial metagenome, Saliva, mRNA vaccination, COVID-19, Haematopoietic stem cell transplantation, Chronic lymphocytic leukemia, Primary immunodeficiency disease