A recent study published to the bioRxiv* preprint server identified the gut microbial and immune variables linked to heterogeneous messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccine responses between individuals.
Most people develop a significant protective adaptive immunity against COVID-19 following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccinations, such as Pfizer BNT162b2, encoding the spike (S). Nonetheless, the magnitude of vaccine-elicited T-cell and antibody responses varies greatly. Although numerous factors, including COVID-19 history, gender, age, and ethnicity, are linked to inter-individual heterogeneity in BNT162b2-induced adaptive immunity, the root cause for this variance is still not completely understood.
Certain immune cell groups and transcripts have been recognized as determinants of antibody or T-cell responses generated by vaccination against hepatitis B virus, influenza virus, and malaria through thorough studies of immunological conditions of blood cells at the initial point and early vaccine reactions. Additionally, several investigations showed a connection between gut microbiota and vaccine-triggered adaptive immunity. Importantly, these variables may serve as predictors of vaccine responses and therapeutic targets to enhance vaccine responses.
Yet, the variation in immunological conditions and gut microbial populations linked to responses to the SARS-CoV-2 mRNA vaccinations is still uncertain.
About the Study
In the current work, the researchers analyzed the association of the BNT162b2 vaccine-induced adaptive immune responses with specific gut microbial and immune parameters in humans using a systems biology method consisting of multi-omics investigations of human stool and blood samples. They aimed to determine immune cell transcripts, populations, commensal microbial taxa, and activities associated with vaccine-induced T-cell and antibody responses.
The authors recruited 96 healthy Japanese volunteers from Okinawa, Japan, including 53 women and 42 men with an average age of 52.4 ± 14.9 years, ranging from 20 to 81 years, from May to August 2021. All subjects submitted written informed consent before enrolling.
The team collected blood samples from the participants at five timestamps (T1 to T5) pre- and post-BNT162b2 vaccination. Further, they extracted plasma and peripheral blood mononuclear cells (PBMCs) and kept them at -20℃ and in liquid nitrogen till use, respectively.
The scientists assessed the SARS-CoV-2 S-selective antibody reaction in plasma and the T-cell reaction in PBMCs to estimate the degree of vaccine-elicited adaptive immunity. Additionally, they leveraged PBMCs to establish profiles of immune cell types utilizing cytometry by time of flight (CyTOF) assessment and bulk ribonucleic acid sequence (RNA-seq) examination to determine the mRNA expression. Furthermore, the researchers took a stool sample from each participant once during the study period to examine the gut microbiome.
Results & Discussions
The scientists discovered a rise in SARS-CoV-2 S-specific antibody and T cell responses in all individuals on Day 41±3 following the second BNT162b2 vaccine dose. Yet, there were notable inter-individual variations in reaction intensity.
The study results illustrated a positive correlation between activator protein 1 (AP-1) genes and antibody responses elicited by the BNT162b2 vaccine. In addition, it offers novel information regarding the function of AP-1 genes in vaccine-triggered T-cell responses.
The authors found that ex vivo BNT162b2 stimulation rapidly reduced AP-1 expression throughout PBMCs. The initial expression of AP-1 transcription factors, such as activating transcription factor 3 (ATF3) and FOS, was negatively linked with the induction of T-cell responses by the BNT162b2 mRNA vaccination.
The researchers discovered that transcription modules connected to the basal function of CD14+ monocytes andwere linked positively with FOS expression, which was correlated inversely with vaccine-evoked T-cell responses. Moreover, initial FOS expression was associated negatively with T cell activation-related transcription modules following ex vivo BNT162b2 stimulation. These data imply that FOS-reliant regulation of basal immune cell function or baseline FOS and other AP-1 component expressions across T cells might hinder T-cell activation induced by mRNA vaccines.
Besides, the study data point to a novel functional connection between the human immune system and the gut microbial rhamnose/fucose degradation pathway. According to the results, rhamnose/fucose breakdown may lead to a rise in short-chain fatty acids (SCFAs), promoting the development of regulatory T cells (Tregs). These responses subsequently inhibit vaccine-triggered T-cell reactions.
Further, the team stated that SCFAs increase prostaglandin E2 (PGE2) generation via upregulating cyclooxygenase 2 (COX2) expression. Interestingly, the elevated COX2 expression boosts FOS expression across PBMCs. Remarkably, the BNT162b2-triggered T-cell reactions were inversely connected with the gut microbial rhamnose/fucose degradation pathway and positively associated with the ATF3 and FOS expression.
In the present study, the investigators used a systems biology approach and discovered different human immune cell types, transcripts, gut bacterial taxa, and functional mechanisms connected to BNT162b2-induced immune reactions.
Notably, BNT162b2-induced antibody responses were positively, and T-cell responses negatively correlated with the baseline transcription module connected to the AP-1 transcription factor circuit. Congruent with this, the T cell reaction was linked negatively with the initial expression of the AP-1 genes (FOSB, FOS, and ATF3). Furthermore, there was an inverse correlation between T-cell responses and the gut microbial rhamnose/fucose pathway. These findings contribute to the growing understanding of how immunological and microbial variables influence inter-individual differences in vaccine-triggered adaptive immunity.
Taken together, the study findings showed that the baseline AP-1 gene expression, linked to the gut microbial rhamnose /fucose degradation pathway, was a vital negative predictor of T-cell responses elicited by BNT162b2. The authors noted that future studies should examine the viability of these variables as basal predictors of vaccine outcome and as therapeutic targets to augment vaccine responses.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.