Infectious diseases are still the leading global cause of morbidity and mortality. Vaccine-preventable diseases are still responsible for about 25% of the 10 million deaths occurring annually among children under five years of age, and ~25% of adult (15–59 years) deaths are still attributed to infectious diseases.1 Moreover, infectious diseases continue to rise due to an alarming rate of antibiotic resistance among bacteria, and due to the trends of pathogen spreading driven by globalization and enlarged mobility.
Despite the great need to develop novel and more efficient vaccines, the progress has been slow. Current approaches to vaccine antigen discovery are inefficient, costly, and frequently lead to the selection of ineffective targets: only 15% of vaccines that enter clinical trials get market approval.2 It has been estimated that even a 10-percent improvement in predicting failures before embarking on clinical trials could save a pharmaceutical company $100 million in development costs per product.3
Therefore, it is of crucial significance to develop methods, which would predict the efficacy of vaccine candidates in clinical trials with greater certainty.
The reason behind such low success in selecting optimal vaccine candidates lie primarily in the challenges associated with the vaccine antigen selection. Most widely used methods in antigen discovery are:
- reverse vaccinology,
- bioinformatics analysis,
- proteomics, and
- antigenome technology.
Reverse vaccinology as an approach was validated for the first time on a Gram-negative bacteria, Neisseria meningitidis serogroup B (MenB); although it lead to identification of several antigens (the vaccine has successfully completed Phase III clinical trials), the screening process required large resources and several years to complete.4
Other approaches are similarly laborious and frequently biased. Proteomic analysis of cellular fractions or peptides digested from the bacterial surface has the limitations that not all proteins are equally abundant and prone to digestion, and it is difficult to control enzymatic digestion to preserve the integrity of the cell while maximizing the amount of surface digested proteins. Moreover, the proteomic analysis gives no information about the functional significance and protective potential of the identified antigens.
Antigenome approach relies on the use of sera from the patients who overcame infection or healthy individuals expected to contain protective antibodies. However, this approach too is biased towards antigens that are immunogenic but not necessarily protective, and is not suitable for identifying the antigens containing large conformational epitopes or epitopes created by post-transcriptional modifications (due to the use of a non-native antigen expression system which can display only a limited number of amino acids from a native, pathogen-derived antigen).
Besides the challenges encountered during initial antigen screening and selection, a successful vaccine development is further complicated by the biased experimental methods used during pre-clinical validation of antigen efficacy. For example, relying heavily on the animal models and in vitro testing under artificial laboratory culture conditions are not best practices for evaluating protective potential of the vaccines against strictly human pathogens. Such pathogens are highly adapted to the human tissue environment and have developed multiple mechanisms for evading human immune responses (e.g. binding of components of human complement and fibrinogen, escaping or interfering with phagocytosis, binding human immunoglobulins). These immune evasion mechanisms do not operate in other species and therefore, data obtained from such studies cannot be extrapolated to humans. The current requirement by regulatory authorities for extensive data demonstrating the protective efficacy of vaccine candidates in animal models compounds this problem, whereby those engaged in vaccine development continue to utilize animal models that are not relevant for investigating strictly human pathogens.
For each year of delay in vaccine discovery and development, millions human lives are being lost. Overcoming these challenges should be the highest priority of the scientific community and industry: this is the most powerful motivation behind our research efforts at Origimm.
- Adamczyk-Poplawska, M., Markowicz, S. & Jagusztyn-Krynicka, E. K. Proteomics for development of vaccine. Journal of proteomics 8, 1–21 (2011).
- Kola, I. & Landis, J. Can the pharmaceutical industry reduce attrition rates? Nature reviews. Drug discovery 3, 711-5 (2004).
- Innovation or Stagnation. Challenge and Opportunity on the Critical Path to New Medical Products. (Critical white paper). U.S. Department of Health and Human Services. Food and Drug Administration. (2004).
- Kaushik, D.K. & Sehgal, D. Developing antibacterial vaccines in genomics and proteomics era. Scandinavian journal of immunology 67, 544-52 (2008).