2025.09.13
Immunogenicity refers to the ability of a substance (such as a vaccine or biotherapeutic drug) to induce an immune response in the body. This property plays a dual role in disease prevention and treatment: on one hand, it is crucial in vaccine development as it can stimulate protective immunity; on the other hand, unnecessary immunogenicity may lead to reduced efficacy or safety risks. In recent years, related research has continued to deepen, providing solid support for drug and vaccine innovation. Based on authoritative literature, this article explores the core progress and application value of immunogenicity.
In the field of vaccines, immunogenicity is a key indicator for evaluating effectiveness. For example, studies on COVID-19 vaccines have shown that CoronaVac, as an inactivated vaccine, exhibits good safety and immunogenicity in healthy adults, and its potential to stimulate immune responses has been confirmed through large-scale clinical trials, providing a reliable tool for epidemic prevention and control [1]. Similarly, mRNA vaccine technology enhances immunogenicity and protective efficacy by increasing antigen expression, laying the foundation for the development of vaccines against infectious diseases such as malaria, tuberculosis, and HIV [2]. Researchers have also explored fusion protein strategies, combining multiple viral antigens or unrelated proteins to enhance immunogenicity, which has been proven to increase the intensity and persistence of the vaccine's immune response [3]. In the evaluation process, the Tick-Borne Encephalitis (TBE) vaccine has shown sufficient immunogenicity, safety, and interchangeability in adult and pediatric populations, indicating that well-designed vaccines can meet the needs of different age groups [4].
However, immunogenicity is not always beneficial. A common challenge in biotherapy is the generation of anti-drug antibodies (ADA). For instance, biotherapeutic proteins (such as antibody drugs) may induce ADA, which can reduce drug bioavailability, alter pharmacokinetics, and even lead to decreased efficacy or immune-related adverse events [5][6]. For approved biologic protein drugs, clinical management often faces the problem of high ADA incidence, with influencing factors including molecular structure, patient population differences, and treatment environment, highlighting the importance of immunogenicity risk assessment and mitigation strategies [7][8]. In some extreme cases, immunogenicity may lead to drug development failure or limited patient benefits, especially in disease areas where standard treatment is ineffective, and immunogenicity risks may prompt drug discontinuation [9].
Innovative strategies for reducing immunogenicity have become a research hotspot. Bioinspired drug delivery systems (such as biomembrane-mimicking nanoplatforms) can significantly improve biocompatibility and reduce unnecessary immunogenicity by simulating natural components, thereby targeting disease mechanisms more precisely [10][10]. Specific cases include the regulation of lipid nanoparticles; researchers are exploring how to optimize their surface properties to inhibit the activation of the innate immune system, thereby reducing adverse effects and immunogenicity-related risks [11]. Breakthroughs have also been made in addressing the immunogenicity of cell-based biomaterials in tissue engineering; genetic modification technology is used to express immunoregulatory genes, effectively reducing immune rejection and opening new paths for regenerative medicine [12]. In addition, the assessment of the immunogenicity of extracellular vesicles (EVs) indicates that understanding their clearance mechanisms can lead to the development of mitigation strategies to avoid unnecessary immune recognition [13].
Immunogenicity assessment methods involve multidimensional testing and clinical translation. International symposiums (such as the EIP Symposium) emphasize comprehensive discussions on immunogenicity testing, clinical relevance, risk assessment, and regulatory frameworks, providing guidance for standardized processes [14]. In experiments, researchers collect immunogenicity data, use statistical analysis (such as analysis of variance) to detect patterns, and calculate standardized immunogenicity rates to reveal differences across samples [15]. In practical applications, the use of research-grade preparations (such as research-grade trastuzumab and bevacizumab) for risk assessment has been proven feasible because they can effectively simulate the immunogenicity characteristics of clinical drugs [16]. Despite challenges—such as the difficulty in establishing clinically relevant detection methods and uncertainties in in vivo performance evaluation [17][6]—based on existing models, researchers are continuously optimizing preclinical immunogenicity testing methods to identify risks as early as possible [18][19].
In conclusion, immunogenicity research is a key bridge connecting basic science and clinical applications. It reveals the precise regulatory mechanisms of the immune system and points out the pain points in drug development. Existing work shows that continuous promotion of research in this field will better balance the benefit-risk relationship [20][20] and pave the way for new therapies.
1. Bueno, Susan M et al. “Safety and Immunogenicity of an Inactivated Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine in a Subgroup of Healthy Adults in Chile.” Clinical infectious diseases : an official publication of the Infectious Diseases Society of America vol. 75,1 (2022): e792-e804. doi:10.1093/cid/ciab823
2. Matarazzo, Laura, and Paulo J G Bettencourt. “mRNA vaccines: a new opportunity for malaria, tuberculosis and HIV.” Frontiers in immunology vol. 14 1172691. 24 Apr. 2023, doi:10.3389/fimmu.2023.1172691
3. Gattinger, Pia et al. “Fusion protein-based COVID-19 vaccines exemplified by a chimeric vaccine based on a single fusion protein (W-PreS-O).” Frontiers in immunology vol. 16 1452814. 28 Jan. 2025, doi:10.3389/fimmu.2025.1452814
4. Rampa, John Ethan et al. “Immunogenicity and safety of the tick-borne encephalitis vaccination (2009-2019): A systematic review.” Travel medicine and infectious disease vol. 37 (2020): 101876. doi:10.1016/j.tmaid.2020.101876
5. Siegel, Michel et al. “Development and characterization of dendritic cell internalization and activation assays contributing to the immunogenicity risk evaluation of biotherapeutics.” Frontiers in immunology vol. 15 1406804. 20 Aug. 2024, doi:10.3389/fimmu.2024.1406804
6. Lagassé, H A Daniel et al. “Secondary failure: immune responses to approved protein therapeutics.” Trends in molecular medicine vol. 27,11 (2021): 1074-1083. doi:10.1016/j.molmed.2021.08.003
7. Tsakok, T et al. “Immunogenicity of biologic therapies in psoriasis: Myths, facts and a suggested approach.” Journal of the European Academy of Dermatology and Venereology : JEADV vol. 35,2 (2021): 329-337. doi:10.1111/jdv.16980
8. Carter, Paul J, and Valerie Quarmby. “Immunogenicity risk assessment and mitigation for engineered antibody and protein therapeutics.” Nature reviews. Drug discovery vol. 23,12 (2024): 898-913. doi:10.1038/s41573-024-01051-x
9. Sauna, Zuben E et al. “Understanding preclinical and clinical immunogenicity risks in novel biotherapeutics development.” Frontiers in immunology vol. 14 1151888. 12 May. 2023, doi:10.3389/fimmu.2023.1151888
10. Zhang, Limei et al. “Bioinspired and biomimetic strategies for inflammatory bowel disease therapy.” Journal of materials chemistry. B vol. 12,15 3614-3635. 17 Apr. 2024, doi:10.1039/d3tb02995f
11. Lee, Yeji et al. “Immunogenicity of lipid nanoparticles and its impact on the efficacy of mRNA vaccines and therapeutics.” Experimental & molecular medicine vol. 55,10 (2023): 2085-2096. doi:10.1038/s12276-023-01086-x
12. Jiang, Zhiwei et al. “Genetically modified immunomodulatory cell-based biomaterials in tissue regeneration and engineering.” Cytokine & growth factor reviews vol. 66 (2022): 53-73. doi:10.1016/j.cytogfr.2022.05.003
13. Xia, Yutian et al. “Immunogenicity of Extracellular Vesicles.” Advanced materials (Deerfield Beach, Fla.) vol. 36,33 (2024): e2403199. doi:10.1002/adma.202403199
14. Tourdot, Sophie et al. “Proceedings of the 15th European immunogenicity platform open symposium on immunogenicity of biopharmaceuticals.” mAbs vol. 17,1 (2025): 2487604. doi:10.1080/19420862.2025.2487604
15. Borrega, Rodrigo et al. “Systematic Review and Principal Components Analysis of the Immunogenicity of Adalimumab.” BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy vol. 35,1 (2021): 35-45. doi:10.1007/s40259-020-00458-3
16. Tsai, Wen-Ting K et al. “Nonclinical immunogenicity risk assessment for knobs-into-holes bispecific IgG1 antibodies.” mAbs vol. 16,1 (2024): 2362789. doi:10.1080/19420862.2024.2362789
17. Lamparelli, Erwin Pavel et al. “Optimizing mRNA delivery: A microfluidic exploration of DOTMA vs. DOTAP lipid nanoparticles for GFP expression on human PBMCs and THP-1 cell line.” International journal of pharmaceutics vol. 672 (2025): 125324. doi:10.1016/j.ijpharm.2025.125324
18. Maliqi, Liridona et al. “Assessing immunogenicity barriers of the HIV-1 envelope trimer.” NPJ vaccines vol. 8,1 148. 30 Sep. 2023, doi:10.1038/s41541-023-00746-3
19. Zhang, Xuanxuan et al. “Research progress on substitution of in vivo method(s) by in vitro method(s) for human vaccine potency assays.” Expert review of vaccines vol. 22,1 (2023): 270-277. doi:10.1080/14760584.2023.2178421
20. Grudzinska-Goebel, Joanna et al. “Immunogenicity risk assessment for tailored mitigation and monitoring of biotherapeutics during development: recommendations from the European Immunogenicity Platform.” Frontiers in immunology vol. 16 1581153. 22 May. 2025, doi:10.3389/fimmu.2025.1581153
