The 2023 Nobel Prize in Physiology or Medicine was awarded to Katalin Karikó and Drew Weissman “for their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19.” Not surprisingly, given the fact that the mRNA vaccine, due to its high programmability, was a powerful tool to protect us against this quickly evolving virus.
The advent of mRNA vaccines has ushered in a new era of disease prevention and treatment, holding immense promise across a wide spectrum of diseases. These vaccines represent a breakthrough technology capable of swiftly adapting to emerging pathogens. Beyond infectious diseases, the potential of mRNA vaccines extends to various other fronts. In the realm of cancer, mRNA vaccines offer the ability to stimulate the immune system to target and eradicate tumor cells, paving the way for personalized cancer immunotherapies. Moreover, mRNA vaccines hold great potential in addressing the treatment of autoimmune disorders, allergies, and rare genetic diseases by targeting specific disease-related proteins. They can also revolutionize the field of regenerative medicine by promoting tissue repair and regeneration. The versatility and adaptability of mRNA technology provide a powerful toolbox for tackling an array of diseases, giving hope for more effective, tailored, and scalable treatments across diverse medical disciplines.
The Role of Single Cell Analysis in mRNA vaccine development
To unleash the full potential of the mRNA vaccine as a precise weapon against infectious agents or degenerate cells like cancer cells, it is indispensable to have accurate information on the abnormal cells that should be targeted. Single cell sequencing has emerged as a powerful technology in the field of molecular biology, enabling researchers to gain unprecedented insights into cellular heterogeneity and gene expression profiles at the single-cell level. In recent years, single cell sequencing has played a pivotal role in advancing our understanding of mRNA vaccine mechanisms and discovering novel approaches to improve human health.
The immune response to viral antigens following infection or vaccination requires effective, lasting, and sufficient production of antibodies and T cells. Traditionally, population-based monitoring has focused solely on antibody titers, neglecting further characterization and quantification of T and B cell responses. That is where single cell sequencing techniques come into play. There are hundreds of publications in the last several years using single cell sequencing to study and develop mRNA vaccines (Figure 1). In this review, we will discuss the applications and findings from recent noteworthy papers that showcase how single cell sequencing has contributed to the development and optimization of mRNA vaccines.
Figure 1: Google Scholar search results using “single cell sequencing” AND “mRNA vaccine” as keywords.
Key Publications Using Single Cell Analysis in mRNA Vaccine Research
Kramer et al. (2022) used a combination of different single cell analysis methods to identify and characterize antigen-specific cells and antibody responses to the RNA vaccine BNT162b2 against SARS-CoV-2 causing COVID-19 disease. Antigen-specific memory CD4+ and CD8+ T cells with characteristics of follicular or peripheral helper cells were identified. Furthermore, B cell receptor sequencing was able to visualize progression from IgM to SARS-CoV-2-specific IgA and IgG memory B cells and plasmablasts.
Taking the investigation of T cell and B cell responses upon mRNA vaccination to the next level, Zhang et al. (2023) used multimodal sequencing technologies to longitudinally analyze circulating human leukocytes obtained prior to and after BNT162b2 vaccination. Distinct subsets of antigen-specific CD8+ T cells expressing characteristic biomarkers were reliably detected 28 days after the initial vaccination.
Of course, mRNA vaccine has a much broader range of applications and can also be designed to protect against infectious diseases other than COVID-19. Xiong et al. (2023) employed Singleron’s single cell sequencing products, among other methods, to study an mRNA-based broad-spectrum vaccine candidate showing cross-protection against heterosubtypic influenza A viruses by activating antigen-specific T cells. Putting more emphasis on B cell responses, de Assis et al. (2023) employed elegantly designed multiomic single-cell analysis to show a coordinated development of plasmablasts and CD71+ activated and resting memory B cells in response to primary SARS-CoV-2 mRNA 1273 vaccination.
The versatile and precise nature of mRNA vaccine also makes it a powerful tool for personalized cancer immunotherapy. In a Phase I study of adjuvant autogene cevumeran (Rojas et al., 2023) that was recently published in Nature, mRNA neoantigen vaccine was synthesized in real time from surgically removed pancreatic ductal adenocarcinoma (PDAC) tumors and administrated to 16 patients together with anti-PD-L1 antibodies. Using T cell sequencing, vaccine-expanded T cells were found to account for up to 10% of all blood T cells and contain long-lived polyfunctional neoantigen-specific effector CD8+ T cells. Single cell sequencing allowed to characterize the molecular signatures of those CD8+ T cells. The responder patients with vaccine-expanded T cells had a longer median recurrence-free survival (not reached at 18-months median follow-up) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003), demonstrating the promise of mRNA vaccine in cancer therapy.
With modern treatments for cancer shifting from a “one drug fits them all” approach to more tailored therapies, combinations of mRNA vaccines together with immunotherapies are currently being tested in clinical trials.
As Sun Tzu wrote in the Art of War, “If you know the enemy and know yourself, you need not fear the result of a hundred battles”. In the battle against human diseases, single cell analysis is the ideal tool for gaining a comprehensive understanding of both pathological conditions and the weapons at our disposal, such as mRNA vaccines. Single cell analysis enables us to unravel the mechanisms of mRNA function and decipher the effectiveness and potential challenges of mRNA vaccines, and thus accelerate their advancements from bench to bedside.
Kramer, K.J., Wilfong, E.M., Voss, K. et al. Single-cell profiling of the antigen-specific response to BNT162b2 SARS-CoV-2 RNA vaccine (2022). Nat Commun 13, 3466. https://doi.org/10.1038/s41467-022-31142-5
Zhang, B., Upadhyay, R., Hao, Y. et al. (2023). Multimodal single-cell datasets characterize antigen-specific CD8+ T cells across SARS-CoV-2 vaccination and infection. Nat Immunol 24, 1725–1734. https://doi.org/10.1038/s41590-023-01608-9
De Assis, F.L., Hoehn, K.B., Zhang, X. et al. (2023). Tracking B cell responses to the SARS-CoV-2 mRNA-1273 vaccine. Cell Rep. 42 (7)
Xiong, F., Zhang, C., Shang, B., et al. (2023). An mRNA-based broad-spectrum vaccine candidate confers cross-protection against heterosubtypic influenza A viruses. Emerg Microbes Infect. 12(2):2256422.
Rojas, L.A., Sethna, Z., Soares, K.C. et al (2023). Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144–150. https://doi.org/10.1038/s41586-023-06063-y
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