Immunogenicity in the context of COVID-19

By Samrah Siddiqi

The COVID-19 (or SARS-Cov-2) pandemic has accelerated drug and vaccine development worldwide, with scientists working diligently to produce effective and, most importantly, safe therapeutics that can be made available for urgent use across the globe. Vaccine safety and efficacy is evaluated using randomised clinical trials prior to approval by a regulatory body. For example, the U.S Food and Drug Administration (FDA) requires three successful phase trials to be conducted before approving treatments for clinical use (National Institute on Aging, 2020). For COVID-19 in particular, these trials enable scientists to gather valuable data regarding the duration of protection, efficacy, safety, and immunogenicity of the vaccine against the SARS-CoV-2 virus in a wide range of individuals (Pfizer, 2020). This information facilitates a better understanding of the how the foreign virus elicits a humoral and/or cellular immune response both when administered to patients artificially and also when the virus is naturally borne. 

The gravity of the disease differs between each infected individual, providing an extra measure of difficulty when attempting to measure clinical endpoints. For COVID-19, introduction of the vaccine aims to target specific clinical endpoints including reduction in asymptomatic and symptomatic infections as well as hospitalisations and deaths. Clinical trials involve comparing a group of vaccinated individuals to a group of individuals who receive a placebo. A statistically significant reduction in the clinical endpoints mentioned previously in the vaccinated group compared to the placebo group would indicate that the vaccine possesses efficacy. 

Vaccines must possess efficacy; they must be able to effectively protect against disease. 

To do so, the vaccine must be immunogenic i.e., it must be able to provoke a humoral and/or cellular immune response in an individual (BC Centre for Disease Control, 2009). The immunogenicity of a vaccine is key to its efficacy. The vaccinated individual receives an attenuated part of or an inactivated form of a pathogen which triggers the body’s innate immune response to recognise the foreign pathogen and recruit the adaptive immune cells to develop a memory. Upon re-infection with the same invader, this memory will be activated to help the immune system react more quickly and effectively than otherwise. 

Immunogenicity is affected by a variety of factors including the route of administration of the vaccine (e.g., intradermal, subcutaneous, intramuscular etc.), drug-drug interactions and the age of the vaccinated patient (Science Direct). Research has shown that the immunogenicity of vaccines deteriorates with age due to immunosenescence – the gradual age-related decline in immune system function (Ramasamy et al., 2020; Science Direct). This immune dysfunction reduces the ability of the elderly to respond to and fight infections as well as their ability to sustain a long-term memory acquired by infection or vaccination (Science Direct). Consequently, the eligibility of the COVID-19 vaccines has prioritised older adults (age ≥70 years) as they are at increased risk of severe disease and death after contracting the virus (Ramasamy et al., 2020). 

Scientists objectives are two-fold when measuring immunogenicity. They observe antibody and T-cell production to determine the types and longevity of vaccine-induced immune responses (Astra Zeneca, 2020). Antibodies are Y-shaped proteins produced when naïve or memory B cells are activated by a specific antigen on the surface of the invading pathogen (Alberts et al., 2002). An effective adaptive immune response relies on two types of antibodies: binding and neutralising antibodies. It is the latter that can bind to and neutralise the spike protein on the SARS-CoV-2 virus. This inhibits the virus’ ability to dock to the angiotensin-converting enzyme 2 receptor, preventing the fusion of viral and cellular membranes and its subsequent disastrous effects. A study found that neutralising antibodies against the SARS-CoV-2 spike protein remained for at least 5 months post-viral infection (Wajnberg et al., 2020).

A binding antibody is able to perform the function of a neutralising antibody in addition to stimulating the production of compliment proteins to mark the pathogens for destruction by immune cells (opsonisation). Vaccinated individuals are said to be sero-positive as they have higher levels of antibodies that are able to bind to the virus than sero-negative individuals who have had no previous exposure to the pathogen. Scientists are able to measure the immunogenic capacity of vaccines via the expected increase in antibody levels post-infection/vaccination using techniques such as enzyme-linked immunosorbent serum assay (ELISA) and neutralising assays (e.g., plaque reduction neutralisation assay and microneutralisation assay) (Astra Zeneca, 2020). T-cells are also involved in the adaptive immune response and can be sub-divided into two types: helper T-cells and cytotoxic T-cells. Helper T cells recognise the foreign antigen presented on the major histocompatibility complex class II on the surface of a phagocytosed pathogen and releasing cytokines to activate cytotoxic T-cells. Cytotoxic T-cells consequently release cytotoxic factors to kill infected and abnormal cells and prevent survival of the pathogen (Astra Zeneca, 2020; Laing, n.d.) Measuring T-cell responses is often more complex than measuring antibody levels, however immunospot assays can be performed to determine the number of T-cells secreting specific cytokines in response to vaccine-administered SARS-CoV-2 antigens (Hodgson et al., 2020). 

Measuring immunogenicity provides important insights into how effective a vaccine is as well as how it should be administered (i.e., dosage and scheduling) (Astra Zeneca, 2020).  However, there are challenges associated with measuring such a complex process, especially with a novel virus like SARS-CoV-2. Firstly, the level, or titre, of antibodies and T-cells needed for sufficient protection against the virus has not yet been identified as scientists are still in the process of understanding what defines an effective natural immune response (Astra Zeneca, 2020). Additionally, the longevity of protection is still very much unknown but can start to be investigated once the vaccinations have been rolled out to the public. Secondly, scientists face challenges relating to the lack of global standardisation when measuring immunogenicity. Different methodologies have been carried out when performing assays to measure the immune response in various laboratories across the globe, making it difficult to compare vaccines based on their immunogenicity data (Hodgson et al., 2020). Standardised methods of measuring immunogenicity will further our scientific knowledge and understanding of the immune response to the SARS-CoV-2 virus which is vital to therapeutic intervention for this deadly disease. 

References:

Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K. & Walter, P. (2002) Molecular Biology of the Cell. 4th Edition. New York, Garland Science. Available from: https://www.ncbi.nlm.nih.gov/books/NBK26884/ [Accessed 3rd February 2021]

Astra Zeneca. (2020) What does immunogenicity mean in the context of COVID-19 vaccines? Available from: https://www.astrazeneca.com/what-science-can-do/topics/disease-understanding/what-does-immunogenicity-mean-in-the-context-of-covid-19-vaccines.html# [Accessed 3rd February 2021].

BC Centre for Disease Control. (2009) Vaccine Immunogenicity, Efficacy and Effectiveness. Available from: http://www.bccdc.ca/resource-gallery/Documents/Guidelines%20and%20Forms/Guidelines%20and%20Manuals/Epid/CD%20Manual/Chapter%202%20-%20Imms/VaccineImmunogenicity.pdf [Accessed 3rd February 2021]

Hodgson, S. H., Mansatta, K., Mallett, G., Harris, V., Emary, K. R. W. & Pollard, A. J. (2021) What defines an efficacious COVID-19 vaccine? A review of the challenges assessing the clinical efficacy of vaccines against SARS-CoV02. The Lancet Infectious Diseases. 21(2), 26-35. Available at https://pubmed.ncbi.nlm.nih.gov/33125914/ [Accessed: 3rd February 2021].

Laing, K. (n.d.) Immune responses to viruses. Available from: https://www.immunology.org/public-information/bitesized-immunology/pathogens-and-disease/immune-responses-viruses [Accessed 3rd February 2021]

National Institute on Aging. (2020) What are clinical trials and studies? Available from: https://www.nia.nih.gov/health/what-are-clinical-trials-and-studies [Accessed 3rd February 2021]

Pfizer. (2020) PFIZER AND BIONTECH ANNOUNCE PUBLICATION OF RESULTS FROM LANDMARK PHASE 3 TRIAL OF BNT162B2 COVID-19 VACCINE CANDIDATE IN THE NEW ENGLAND JOURNAL OF MEDICINE. Available from: https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-publication-results-landmark [Accessed 3rd February 2021]

Ramasamy, N. M., Minassian, A. M., Ewer, K. J., Flaxman, A. L., Folegatti, P. M., Owens, D. R., Voysey, M., Aley, P. K., Angus, B., Babbage, G., Belij-Rammerstorfer, S., Berry, L., Bibi, S., Bittaye, M., Cathie, K., Chappell, H., Charlton, S., Cicconi, P., Clutterbuck, E. A., Colin-Jones, R., Dold, C., Emary, K. R. W., Fedosyuk, S., Fuskova, M., Gbesemete, D., Green, C., Hallis, B., Hou, M. M., Jenkin, D., Joe, C. C. D., Kelly, E. J., Kerridge, S., Lawrie, A. M., Lelliott, A., Lwin, M. N., Makinson, R., Marchevsky, N. G., Mujadidi, Y., Munro, A. P. S., Pacurar, M., Plested, E., Rand, J., Rawlinson, T., Rhead, S., Robinson, H., Ritchie, A. J., Ross-Russell, A. L., Saich, S., Singh, N., Smith, C. C., Snape, M. D., Song, R., Tarrant, R., Themistocleous, Y., Thomas, K. M., Villafana, T. L., Warren, S. C., Watson, M. E. E., Douglas, A. D., Hill, A. V. S., Lambe, T., Gilbert, S. C., Faust, S. N., Pollard, A. J. & Oxford COVID Vaccine Trial Group. (2020) Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. The Lancet. 396(10267), 1979-1993. Available from: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32466-1/fulltext [Accessed 3rd February 2021]

Science Direct. (2004) Immunosenescence. Available from: https://www.sciencedirect.com/topics/medicine-and-dentistry/immunosenescence [Accessed 3rd February 2021]

Science Direct. (n.d.) Vaccine Immunogenicity. Available from: https://www.sciencedirect.com/topics/medicine-and-dentistry/vaccine-immunogenicity [Accessed 3rd February 2021]

Wajnberg, A., Amanat, F., Firpo, A., Altman, D. R., Bailey, M. J., Mansour, M., McMahon, M., Meade, P., Mendu, D. R., Muellers, K., Stadlbauer, D., Stone, K., Strohmeier, S., Simon, V., Aberg, J., Reich, D. L., Krammer, F. & Cordon-Cardo, C. (2020) Robust neutralizing antibodies to SARS-CoV-2 infection persist for months. Science. 370(6521), 1227-1230. Available from: doi:10.1126/science.abd7728.

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