An antigen refers to a molecule that is able to bind to the cells of the immune system. If an antigen can also stimulate an immune response, it is termed an immunogen. Immunogenicity is a measure of this ability to activate the immune response: that is, the B and T cells underlying humoral and cellā€mediated immunity. Understanding the concept of immunogenicity is therefore vital in understanding the field of immunology as a whole. The determinants of immunogenicity are complex, but much research has been conducted in this area in the context of vaccination and protein therapeutics, where understanding immunogenicity is of key clinical significance. While obtaining accurate measures of immunogenicity is difficult, a range of techniques to both predict the immunogenicity of a substance and to measure immunogenicity based on B and T cell activation have been developed.

Key Concepts

  • Immunogenicity is defined as the ability of a substance to elicit an adaptive immune response.
  • The immunogenicity of a substance depends on multiple factors relating to the properties of the substance itself, the biological system, and how the substance is delivered to the biological system.
  • Immunogenicity is necessary for our body to respond to and destroy pathogens, as well as to remove tumourogenic and dying cells.
  • Understanding immunogenicity is important for pharmaceutical development, where it is sometimes necessary to either increase (vaccination) or decrease (protein therapeutics) the immunogenicity of a product.
  • Experimental model systems, and more recently, computational tools, are being developed to predict immunogenicity.
  • Immunogenicity can be measured empirically by assessing the numbers of activated T or B cells, or antibody levels during a response to the substance.

Keywords: immunology; immunoregulation ; adaptive immunity; T cells; B cells; antigen; vaccination; protein therapeutics

Figure 1. The adaptive immune response. After an immunogenic substance enters a biological system, multiple pathways are activated to produce an adaptive immune response. The antigen is endocytosed by antigen‐presenting cells (including B cells), and presented on their surface in an antigen–MHC II complex. Cognate CD4 T cells interact with the antigen–MHC II complex to become activated. Further T cell activation occurs through interaction of the CD80/CD28 co‐stimulatory surface receptors. The first step of B cell activation occurs by direct binding of their B cell receptor (BCR) to the antigen. The second step of B cell activation then occurs either via activation of nonspecific surface receptors (TI‐1), extensive cross‐linking of the BCR (TI‐2), or by interaction with a CD4 T cell interacting with the antigen‐MHC complex on the B cell with the co‐receptors CD40/CD40L (TD). Once activated, the B cell proliferates, and differentiates into plasma cells, which produce antibody and memory cells to mediate long‐lasting protection. Interacting with the antigen–MHC I complex on infected cells activates CD8 T cells. Activated CD4 and CD8 T cells also differentiate to produce memory cells. Dotted red boxes indicate the initial effector cells of the adaptive immune response that can be measured to quantify immunogenicity.
Figure 2. Factors affecting immunogenicity. Immunogenicity of a substance is influenced by multiple properties of the antigenic substance, the biological host and features of delivery of the substance into the host. The figure details some of the main factors known to affect immunogenicity.


Altman J, Moss P, Goulder P, et al. (1996) Phenotypic analysis of antigen‐specific T lymphocytes. Science 274 (5284): 94–96.

Ariza A, Collado D, Vida Y, et al. (2014) Study of protein haptenation by amoxicillin through the use of a biotinylated antibiotic. PLoS One 9 (3): e90891.

Bailon P, Palleroni A, Schaffer CA, et al. (2001) Rational design of a potent, long‐lasting form of interferon: a 40 kDa branched polyethylene glycol‐conjugated interferon alpha‐2a for the treatment of hepatitis C. Bioconjugate Chemistry 12 (2): 195–202.

Beeson PB (1994) Age and sex associations of 40 autoimmune diseases. The American Journal of Medicine 96 (5): 457–462.

Blankenstein T, Coulie PG, Gilboa E, et al. (2012) The determinants of tumour immunogenicity. Nature Reviews. Cancer, Nature Publishing Group 12 (4): 307–313.

Costa AR, Rodrigues ME, Henriques M, et al. (2014) Glycosylation: impact, control and improvement during therapeutic protein production. Critical Reviews in Biotechnology 34 (4): 281–299.

De Groot AS and Berzofsky JA (2004) From genome to vaccine‐‐new immunoinformatics tools for vaccine design. Methods (San Diego, Calif.) 34 (4): 425–428.

De Groot AS and Scott DW (2007) Immunogenicity of protein therapeutics. Trends in Immunology 28 (11): 482–490.

Friedman A and Weiner HL (1994) Induction of anergy or active suppression following oral tolerance is determined by antigen dosage. Proceedings of the National Academy of Sciences of the United States of America 91 (14): 6688–6692.

Galson JD, Pollard AJ, Trück J, et al. (2014) Studying the antibody repertoire after vaccination: practical applications. Trends in Immunology 35 (7): 319–331.

Giersing B, Miura K, Shimp R, et al. (2005) Posttranslational modification of recombinant Plasmodium falciparum apical membrane antigen 1: impact on functional immune responses to a malaria vaccine candidate. Infection and Immunity 73 (7): 3963–3970.

Green DR, Ferguson T, Zitvogel L, et al. (2009) Immunogenic and tolerogenic cell death. Nature Reviews. Immunology 9 (5): 353–363.

Guy B (2007) The perfect mix: recent progress in adjuvant research. Nature Reviews. Microbiology 5 (7): 505–517.

Hurford A and Day T (2013) Immune evasion and the evolution of molecular mimicry in parasites. Evolution; International Journal of Organic Evolution 67 (10): 2889–2904.

Jaber A and Baker M (2007) Assessment of the immunogenicity of different interferon beta‐1a formulations using ex vivo T‐cell assays. Journal of Pharmaceutical and Biomedical Analysis 43 (4): 1256–1261.

Janeway CA Jr, Travers P, Walport M, et al. (2008) Immunobiology. New York: Garland Science.

Kamatani Y, Wattanapokayakit S, Ochi H, et al. (2009) A genome‐wide association study identifies variants in the HLA‐DP locus associated with chronic hepatitis B in Asians. Nature Genetics 41 (5): 591–595.

Kau AL, Ahern PP, Griffin NW, et al. (2011) Human nutrition, the gut microbiome and the immune system. Nature 474 (7351): 327–336.

Koch CA and Platt JL (2003) Natural mechanisms for evading graft rejection: the fetus as an allograft. Springer Seminars in Immunopathology 25 (2): 95–117.

Kovarik J and Siegrist CA (1998) Immunity in early life. Immunology Today 19 (4): 150–152.

La Cava A and Matarese G (2004) The weight of leptin in immunity. Nature Reviews. Immunology 4 (5): 371–379.

Lamason R, Zhao P, Rawat R, et al. (2006) Sexual dimorphism in immune response genes as a function of puberty. BMC Immunology 7: 2.

Leader B, Baca Q and Golan D (2008) Protein therapeutics: a summary and pharmacological classification. Nature Reviews. Drug Discovery 7 (1): 21–39.

Lord GM, Matarese G, Howard JK, et al. (1998) Leptin modulates the T‐cell immune response and reverses starvation‐induced immunosuppression. Nature 394 (August): 897–901.

Mongey A‐B and Hess EV (2008) Drug insight: autoimmune effects of medications‐what's new? Nature Clinical Practice. Rheumatology 4 (3): 136–144.

Myers LK, Myllyharju J, Nokelainen M, et al. (2004) Relevance of posttranslational modifications for the arthritogenicity of type ii collagen. The Journal of Immunology, American Association of Immunologists 172 (5): 2970–2975.

O'Connor D and Pollard AJ (2013) Characterizing vaccine responses using host genomic and transcriptomic analysis. Clinical Infectious Diseases 57 (6): 860–869.

Park J, Kim M, Kang SG, et al. (2015) Short‐chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR‐S6K pathway. Mucosal Immunology, Society for Mucosal Immunology 8 (1): 80–93.

Parker D (1993) T cell‐dependent B cell activation. Annual Review of Immunology 11: 331–360.

Png E, Thalamuthu A, Ong RTH, et al. (2011) A genome‐wide association study of hepatitis B vaccine response in an Indonesian population reveals multiple independent risk variants in the HLA region. Human Molecular Genetics 20 (19): 3893–3898.

Pollard AJ, Perrett KP and Beverley PC (2009) Maintaining protection against invasive bacteria with protein‐polysaccharide conjugate vaccines. Nature Reviews. Immunology 9 (3): 213–220.

Pradeu T and Carosella ED (2006) On the definition of a criterion of immunogenicity. Proceedings of the National Academy of Sciences of the United States of America 103 (47): 17858–17861.

Ratanji KD, Derrick JP, Dearman RJ, et al. (2014) Immunogenicity of therapeutic proteins: influence of aggregation. Journal of Immunotoxicology 11 (2): 99–109.

Rhodes DG and Laue TM (2009) Determination of protein purity. Methods in Enzymology 463: 677–689.

Richmond P, Kaczmarski E, Borrow R, et al. (2000) Meningococcal C polysaccharide vaccine induces immunologic hyporesponsiveness in adults that is overcome by meningococcal C conjugate vaccine. The Journal of Infectious Diseases 181 (2): 761–764.

Schernthaner G (1993) Immunogenicity and allergenic potential of animal and human insulins. Diabetes Care 16 (3): 155–165.

Shaw FE, Guess HA, Roets JM, et al. (1989) Effect of anatomic injection site, age and smoking on the immune response to hepatitis B vaccination. Vaccine 7 (5): 425–430.

Steere AC, Klitz W, Drouin EE, et al. (2006) Antibiotic‐refractory Lyme arthritis is associated with HLA‐DR molecules that bind a Borrelia burgdorferi peptide. The Journal of Experimental Medicine 203 (4): 961–971.

Taneja V and David C (1998) HLA transgenic mice as humanized mouse models of disease and immunity. Journal of Clinical Investigation 101 (5): 921–926.

Tobery TW, Dubey SA, Anderson K, et al. (2006) A comparison of standard immunogenicity assays for monitoring HIV type 1 gag‐specific T cell responses in Ad5 HIV Type 1 gag vaccinated human subjects. AIDS Research and Human Retroviruses 22 (11): 1081–1090.

Van Schouwenburg PA, Rispens T and Wolbink GJ (2013) Immunogenicity of anti‐TNF biologic therapies for rheumatoid arthritis. Nature reviews. Rheumatology 9 (3): 164–172.

Wierda D, Smith HW and Zwickl CM (2001) Immunogenicity of biopharmaceuticals in laboratory animals. Toxicology 158 (1‐2): 71–74.

Further Reading

Baker MP, Reynolds HM, Lumicisi B, et al. (2010) Immunogenicity of protein therapeutics: the key causes, consequences and challenges. Self/Nonself 1 (4): 314–322.

Cai XY, Thomas J, Cullen C, et al. (2012) Challenges of developing and validating immunogenicity assays to support comparability studies for biosimilar drug development. Bioanalysis 4 (17): 2169–2177.

Jiang H and Chess L (2009) How the immune system achieves self‐nonself discrimination during adaptive immunity. Advances in Immunology 102: 95–133.

Slifka MK and Amanna I (2014) How advances in immunology provide insight into improving vaccine efficacy. Vaccine, Elsevier Ltd 32 (25): 2948–2957.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Galson, Jacob D, and O'Connor, Daniel(Jul 2015) Immunogenicity. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000937]