mRNA NEOANTIGEN VACCINES AND THE CD8 T CELL RESPONSE TO INFECTIONS

 Lomoio S, Giordano D. mRNA neoantigen vaccines and the CD8 T cell response to infections. International Journal of Infection. 2025;9(3):67-69.

S. Lomoio ^1* and D. Giordano²

¹ Department of Neuroscience, Tufts University, Boston, USA;
² Faculty of Medicine, Sant’Andrea University Hospital, Rome, Italy.

*Correspondence to:
Dr. Selene Lomoio,
Department of Neuroscience,
Tufts University,
Boston, USA.
e-mail: Selene.lomoio@tufts.edu

Received: 01 September, 2025 Accepted: 04 October, 2025

ISSN 1972-6945 [online] Copyright 2025 © by Biolife-publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: all authors report no conflicts of interest relevant to this article.

ABSTRACT

Neoantigens are novel proteins usually generated by tumor mutations, that are recognized by the immune system as non-self. Infections can also lead to the generation of neoantigens, resulting in a strong response from CD8⁺ cytotoxic cells. CD8⁺ immune cells are specialized in recognizing intracellular foreign antigens (as occurs in viral infections) and eliminating infected cells. In addition to having a lytic function, CD8⁺ cells and their cellular subpopulations also maintain immune homeostasis. During infection, almost all microbial antigens are neoantigens that are generated through specific genetic mutations recognized as foreign by the immune system. RNA neoantigen vaccines were developed following the creation of mRNA vaccines. Neoantigens are identified through genome sequencing, and the mRNA vaccine is designed by synthesizing an mRNA encoding the neoantigen. Neoantigen vaccines elicit an immune response that protects the body from these new proteins.

KEYWORDS: mRNA, neoantigen, vaccine, CD-8 T, tumor, infection, immune response

INTRODUCTION

Neoantigens are altered proteins that appear as a result of genetic mutations in tumor cells or cells infected by microorganisms. These novel antigens are recognized as non-self by the immune system (1). Neoantigens derive from mutated or abnormal proteins produced only by diseased cells, not by healthy cells. The immune system selectively attacks cells that express neoantigens.

These concepts can also be applied to viral, bacterial, and/or parasitic infections, where a strong CD8+ T cell response is required. CD8⁺ lymphocytes are very important in infections because many viral and bacterial pathogens (such as Mycobacterium tuberculosis), replicate within the host cell (2). In these cases, the antibodies (Abs) produced by B cells are insufficient to fight the infection, and therefore, cytotoxic CD8+ cells are needed to kill the infected cells.

Cytotoxic CD8+ cells are immune cells specialized in recognizing and destroying cells infected by viruses or intracellular bacteria (3). In addition to their cell-lysis function, CD8+ cells also participate in immune homeostasis (4). They are a family of cells that includes several subtypes: T central memory cells (Tcm), which are COR7⁺ and CD62L⁺ and reside in lymph nodes and multiply rapidly; effector memory (Tem) or tissue memory T cells such as CCR7^– and CD62L^– present in peripheral tissues; and tissue resident memory cells (Trm) CD69⁺ and CE103⁺ which do not circulate but are stable in tissues (5). Another subpopulation of CD8⁺ cells is exhausted T cells (Tex) present in chronic infections and tumors (6). They express PD-1+, TNM-3+, and LAG-3+, and their function is mildly cytotoxic. The cytotoxic regulatory T (Treg) subtypes that express CD8+ are less well known than CD4+ Tregs which express CD25+, FoxP3+, and CTL-A4+ (7). Tregs function to suppress excessive immune responses, as occurs in autoimmunity. Virtual memory (VM) CD8+ T cells possess immune memory without exposure to antigen (8). They are generated by cytochemical signals such as IL-5 and IL-4, while stem cell-like memory (SCM) CD8+ T cells are subtypes with a very long memory capable of self-renewal and a phenotype similar to naive T cells.

DISCUSSION

By inducing the intracellular expression of antigens, mRNA vaccines are well-suited to stimulating major histocompatibility complex (MHC)-I and therefore CD8+ cells (9). Neoantigens are newly formed antigens that are not self-antigens and can arise from mutations, infectious agents, or recognition. In infectious states, almost all microbial antigens are neoantigens that form following specific genetic mutations, particularly in tumor cells (10).  These mutations can be recognized as foreign by the body and thus activate an immune response.

RNA neoantigen vaccines are derived from mRNA vaccines and are tailored to induce an immune response against tumor neoantigens (tumor-specific mutations are not present in healthy tissue) (11).  Neoantigen identification is done by sequencing the tumor genome and comparing it with the patient’s healthy DNA. Neoantigens are selected based on their immunogenicity and ability to bind to the patient’s MHC-I and II molecules (1).

The mRNA vaccine is designed by synthesizing an mRNA encoding the selected neoantigens. The mRNA is optimized and enclosed in lipid nanoparticles (LNPs)to protect it and facilitate cell entry. Once ready, the vaccine is administered to the patient, where the LNPs fuse with the cell membrane, releasing the mRNA into the host cell’s cytoplasm (12). The mRNA is then translated into antigenic peptides by antigen-presenting cells (APCs) such as macrophages and dendritic cells. Peptides enter the endoplasmic reticulum, loaded onto MHC-I, and are presented to cytotoxic CD8+ T lymphocytes, with some neoantigens binding to MHC-II and activating CD4+ helper T cells. CD8+ T lymphocytes then recognize and destroy tumor cells expressing the neoantigen (13).

Using mRNA neoantigen vaccines presents a lower risk of autoimmunity than other antigens (14).  RNA neoantigen vaccines result in effective immune stimulation and tumor cell recognition, resulting in a strong CD8+ T cell response. Activated CD4+ cells release cytokines that enhance the CD8+ response and stimulate B lymphocytes (15). Neoantigens can induce immunological memory against tumor neoantigens.

CD8+ immune cells play an important role in recognizing and eliminating infected cells or tumor cells. They recognize antigens present on target cells via MHC-I (16). The mechanisms of destruction of cells expressing neoantigens form the basis of immunotherapy against tumor cells. Neoantigens play an important role in infections where viruses and intracellular bacteria induce new proteins in the host cell (17). These proteins are detected by the immune system, which recognizes them as foreign neoantigens and initiates a specific immune response. In particular, bacterial infections, which cause genetic mutations or alterations in the host cell, can potentially generate neoantigens that stimulate the immune system (17). Although there are some differences, the basic mechanism of an immune response is similar in both tumors and microbial infections, as these reactions tend to eliminate the pathogen, which in the case of tumors, is the tumor cell (18). In infections, the immune system acts to eliminate the microorganism with a rapid and strong response, while in tumors, neoantigens are generated through pathological cellular evolution that makes their elimination difficult, as tumor cells can evade the immune system (19).

CONCLUSIONS

Neoantigens can be formed either through tumor mutations or through intracellular infection. CD8+ cells and their subtypes work by eliminating cells infected by intracellular microorganisms. Vaccines against neoantigens help protect the body from these new protein formations.

Conflict of interest

The authors declare that they have no conflict of interest.

REFERENCES

1. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69-74. doi:https://doi.org/10.1126/science.aaa4971
2. Jhunjhunwala S, Hammer C, Delamarre L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. Nature Reviews Cancer. 2021;21(5):298-312. doi:https://doi.org/10.1038/s41568-021-00339-z
3. Anne-Gaëlle Goubet, Mathieu Rouanne, Derosa L, Kroemer G, Zitvogel L. From mucosal infection to successful cancer immunotherapy. Nature Reviews Urology. 2023;20(11):682-700. doi:https://doi.org/10.1038/s41585-023-00784-5
4. Reading JL, Gálvez-Cancino F, Swanton C, Lladser A, Peggs KS, Quezada SA. The function and dysfunction of memory CD8+T cells in tumor immunity. Immunological Reviews. 2018;283(1):194-212. doi:https://doi.org/10.1111/imr.12657
5. Savas P, Virassamy B, Ye C, et al. Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nature Medicine. 2018;24(7):986-993. doi:https://doi.org/10.1038/s41591-018-0078-7
6. Laura Codarri Deak, Nicolini V, Hashimoto M, et al. PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells. Nature. 2022;610(7930):161-172. doi:https://doi.org/10.1038/s41586-022-05192-0
7. Zhang C, Shen H, Yang T, et al. A single-cell analysis reveals tumor heterogeneity and immune environment of acral melanoma. Nature Communications. 2022;13(1). doi:https://doi.org/10.1038/s41467-022-34877-3
8. Gay-Mimbrera J, Lozano-Ojalvo D, Gómez-Arias PJ, et al. Comprehensive single-cell chromatin and transcriptomic profiling of peripheral immune cells in nonsegmental vitiligo. Br J Dermatol. 2025;193(1):115-124. doi:10.1093/bjd/ljaf041
9. Cho S, Kwak W, Yoon H, et al. Rapid‐Turnaround Co‐Administration of mRNA‐Based MHC‐I and MHC‐II‐Restricted Neoantigens Enhances Immune Responses of Antigen‐Specific CD8 ⁺ T Cells and Anti‐Cancer Efficacy in Colorectal Cancer. Advanced Science. 2025;12(39):e06426-e06426. doi:https://doi.org/10.1002/advs.202506426
10. Redenti A, Im J, Redenti B, et al. Probiotic neoantigen delivery vectors for precision cancer immunotherapy. Nature. 2024;635(8038):453-461. doi:https://doi.org/10.1038/s41586-024-08033-4
11. Rojas LA, Sethna Z, Soares KC, et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature. 2023;618(7963):1-7. doi:https://doi.org/10.1038/s41586-023-06063-y
12. Kon E, Ad-El N, Hazan-Halevy I, Stotsky-Oterin L, Peer D. Targeting cancer with mRNA–lipid nanoparticles: key considerations and future prospects. Nature Reviews Clinical Oncology. 2023;20(11):739-754. doi:https://doi.org/10.1038/s41571-023-00811-9
13. Lhuillier C, Nils Rudqvist, Yamazaki T, et al. Radiotherapy-exposed CD8+ and CD4+ neoantigens enhance tumor control. The Journal of clinical investigation. 2021;131(5). doi:https://doi.org/10.1172/jci138740
14. Zhai Y, Chen L, Zhao Q, et al. Cysteine carboxyethylation generates neoantigens to induce HLA-restricted autoimmunity. Science. 2023;379(6637). doi:https://doi.org/10.1126/science.abg2482
15. Klarquist J, Cross EW, Thompson SB, et al. B cells promote CD8 T cell primary and memory responses to subunit vaccines. Cell Reports. 2021;36(8). doi:https://doi.org/10.1016/j.celrep.2021.109591
16. Jurtz V, Paul S, Andreatta M, Marcatili P, Peters B, Nielsen M. NetMHCpan-4.0: Improved Peptide–MHC Class I Interaction Predictions Integrating Eluted Ligand and Peptide Binding Affinity Data. The Journal of Immunology. 2017;199(9):3360-3368. doi:https://doi.org/10.4049/jimmunol.1700893
17. Gao Q, Zhu H, Dong L, et al. Integrated Proteogenomic Characterization of HBV-Related Hepatocellular Carcinoma. Cell. 2019;179(2):561-577.e22. doi:https://doi.org/10.1016/j.cell.2019.08.052
18. Leemans CR, Snijders PJF, Brakenhoff RH. The molecular landscape of head and neck cancer. Nature Reviews Cancer. 2018;18(5):269-282. doi:https://doi.org/10.1038/nrc.2018.11
19. Wolf NK, Kissiov DU, Raulet DH. Roles of natural killer cells in immunity to cancer, and applications to immunotherapy. Nature Reviews Immunology. 2022;23. doi:https://doi.org/10.1038/s41577-022-00732-1