Developing a vaccine is not a straightforward science. There are different processes and issues needed to be taken into consideration for its development, preparation, and administration. Hence, despite the availability of several vaccines for various infectious diseases, in addition to the advancements in science and medicine, developing one against a specific pathogenic agent remains challenging. This has been demonstrated by the absence of a vaccine for known diseases such as the human immunodeficiency virus, the single-celled microorganisms called Plasmodium group responsible for malaria, the dengue virus, and specific strains of the influenza virus, among others.
Why is it Difficult to Develop a Vaccine: Factors, Considerations, Challenges, and Issues
Biological Considerations in Inducing Immunity
For starters, to understand the difficulty or challenges in vaccine development, it is important to understand first that a vaccine is a substance containing an agent that includes a weakened form of a particular disease-causing pathogen, an engineered resemble such as an mRNA vaccine, the toxins in produce, or its surface proteins. It works by triggering an immune response required for the body to develop a defense against the involved pathogen.
More specifically, the substance should effectively stimulate the immune system to recognize the agent contained therein as a threat, thus allowing the body to mount an attack while also equipping it with the capability to recognize a microorganism associated with that agent to confer active acquired immunity in the future. Developing this substance requires different biological considerations.
Stefan H. E. Kaufmann et al. noted in their review study that one of the factors affecting the successful development of a vaccine centers on the need to ensure that it triggers the production of native antigens and induces adequate, strong, and long-lasting immune response for efficacious and effective protection.
Another review by Stanley A. Plotkin explained that its development must take into consideration the variability of different pathogens, short effector memory, evoking functional responses, and the identification of antigens that generate protective responses.
There are also different types of vaccines: inactivated, attenuated, toxoid, subunit, conjugate, experimental, valence, and heterotypic. These types represent different strategies for inducing immunity. However, they also demonstrate the fact that there is no one-size-fits-all strategy for prompting an immune response to different kinds of pathogens.
Factors and Issues in the Preparation of Vaccines
Preparing a vaccine for a particular pathogen requires the identification of a medium for its propagation. The influenza virus can easily propagate in fertilized hen eggs. However, not all viruses and bacteria can propagate the same way. Some grow in bovine kidney cells or dog kidney cells, while others require using monkey cell lines or monkey cell lines.
These mediums based on culture tissue cell lines can be time-consuming, expensive, and difficult to prepare. Furthermore, there are also several considerations researchers must factor in to ensure adherence to safety standards, general scientific protocols, and ethical principles.
Of course, the identification of medium only touches pathogen propagation. Researchers also need to find a host that will react immunologically to the particular virus or bacteria without getting substantially sick. This host will provide a stable supply of blood serum needed for potency titration and dose dilution calculations.
The challenge in prompting an immunological response actually revolves around the selection of a suitable host and the actual agent that will constitute the vaccine. In the case of the latter, it is difficult to identify which region of the pathogen, its protein, or toxin will generate an immune response. Remember that there is no single strategy for vaccine development.
Success in the first two phases of vaccine preparation is also negligible if the final product lacks efficacy or raises safety concerns. Vaccines such as MRKAd5 gag for HIV-1, MVA85A for tuberculosis, and CYD tetravalent for dengue demonstrated partial efficiency and safety during the late stage of their respective clinical trials.
Pathogen Variability and Pathogen-Specific Problems
Another reason why it is difficult to develop a vaccine is due to the variability of pathogens. Different viruses or bacteria have different characteristics. Remember that in preparation, it is important to determine how a pathogen derivative will trigger an immune response.
Mutation is also a problem. One of the challenges in eradicating HIV/AIDS centers on the fact that HIV-1 readily mutates to escape the immune system. The rapid adaptability of this virus comes from the fact that it replicates rapidly and randomly by replicating the genome from several RNA bases of other HIVs
The influenza virus is another notable example of pathogen variability. It has hundreds of strains, each with its own molecular configurations. Also, its surface protein called hemagglutinin readily mutates. A new strain of influenza emerges every year with a mutated surface protein. Manufacturers of the influenza vaccine must come up with a new formula every year.
Problems specific to the pathogens also render the entire concept of vaccination useless. For example, an infection from the herpesvirus group often produces so-called non-neutralizing antibodies that do not result in defensive and adaptive immune response. These viruses end up hiding in immune cells or nerve tissues.
The same issue was observed in a new candidate vaccine for tuberculosis based on bacille Calmette-Guérin. Despite the addition of genes from Mycobacterium tuberculosis, viral vectors carrying those genes, and even attenuated M. tuberculosis strains, clinical trials showed that it failed to induce an immune response, thereby indicating uncertain correlates of protection.
Cost of Production and Commercial Viability
Another factor affecting vaccine development is the underlying economics of drug research, development, production, and marketing. The process of developing a vaccine should also take into consideration the factors of production, the factors affecting demand, demand shifter, barriers to market entry, as well as supply shifters. For starters, there are six stages, including three to four phases of clinical trials involving vaccine development. These stages and phases are costly. Pharmaceutical and biotechnological companies need to have an incentive to pursue the research and development of a vaccine against a particular disease.
Some situations do not provide sizable revenue potential. Diseases such as malaria, tuberculosis, dengue, and HIV/AIDS occur primarily in impoverished countries. Furthermore, there are infectious diseases that are relatively rare and affect a small portion of the population. These examples do no provide companies with an incentive to invest their resources in developing a treatment option due to the absence of a revenue-generating market.
A study by Dimitrios Gouglas et al. revealed that a single cost of developing a single epidemic infectious disease vaccine from preclinical trials through to end of phase 2a is between USD 31 and 68 million. The cost can swell to USD 319 to 469 million when covering development from preclinical trial to end of phase 2. Safety and efficacy factors determine the feasibility of a candidate vaccine. Investing millions of dollars alone does not guarantee returns.
Findings from another study by Esther S. Pronker et al. that involved analyzing all vaccine projects in development from 1998 to 2009 showed that vaccine development from discovery to licensure could cost billions of dollars. The entire process can also take ten years to complete. From the analyzed projects, there was an average 94 percent chance of failure.
The World Health Organization also explained the logistical requirements needed for the sufficient production and distribution of vaccines. In less developed countries, the most significant barriers to vaccine development are substantial financial infrastructure and workforce expertise requirements needed for market entry. Reproducing an existing vaccine formulation from a new facility would require undergoing complete clinical testing.
Takeaway: The Factors of Vaccine Development
The success of vaccines remains one of the hallmarks of medical science. Despite some criticisms from anti-vaccination groups, there is overwhelming evidence and, thus, scientific consensus endorsing their effectiveness and necessity.
Remember that a particular vaccine works by showing the immune system what to look for and destroy, thereby inducing a form of active adaptive immunity. From this mechanism, immunization through vaccination has been recommended as one of the viable options for addressing an outbreak, epidemic, or pandemic caused by a transmissible disease.
Nevertheless, for a specific vaccine to become accepted for mass administration, it needs to satisfy the following criteria: must be inexpensive, provoke immunity to the particular disease, generate long-lasting immunity, and provide little to no side effects.
FURTHER READINGS AND REFERENCES
- Cohen, J. 2017. “Why Flu Vaccines So Often Fail. Science. DOI: 1126/science.aaq0105
- Gouglas, D., Thanh Le, T., Henderson, K., Kaloudis, A., Danielsen, T., Hammersland, N. C., … Røttingen, J.-A. (2018). Estimating the Cost of vaccine Develoment Against Epidemic Infectious Diseases: A Cost Minimisation Study. The Lancet Global Health. 6(12): e1386–e1396. DOI: 1016/s2214-109x(18)30346-2
- Gray, G. E., Allen, M., Moodie, Z., Churchyard, G., Bekker, L.-G., Nchabeleng, M., Mlisana, K., Metch, B., de Bruyn, G., Latka, M. H., Roux, S., Mathebula, M., Naicker, N., Ducar, C., Carter, D. K., Puren, A., Eaton, N., McElrath, M. J., Robertson, M., … Kublin, J. G. 2011. “Safety and Efficacy of the HVTN 503/Phambili Study of a Clade-B-Based HIV-1 Vaccine in South Africa: a Double-blind, Randomised, Placebo-controlled Test-of-Concept Phase 2b Study.” The Lancet Infectious Diseases.11(7): 507–515. DOI: 1016/s1473-3099(11)70098-6
- Kaufmann, S. H., Juliana McElrath, M., Lewis, D. J., and Del Giudice, G. 2014. “Challenges and Responses in Human Vaccine Development.” Current Opinion in Immunology. 28: 18-26. DOI: 1016/j.coi.2014.01.009
- Mascola, J. R. and Montefiori, D. C. 2003. “HIV-1: Nature’s Master of Disguise.” Nature Medicine. 9:393-394. DOI: 1038/nm0403-393
- Plotkin, S. A. 2015. “Increasing Complexity of Vaccine Development.” Journal of Infectious Diseases. 212(S1): S12-S16. DOI: 1093/infdis/jiu568
- Pronker, E. S., Weenen, T. C., Commandeur, H., Claassen, E. H. J. H. M., and Osterhaus, A. D. M. E. (2013). Risk in Vaccine Research and Development Quantified. PLoS ONE. 8(3): e57755. DOI: 1371/journal.pone.0057755
- Sabchareon, A., Wallace, D., Sirivichayakul, C., Limkittikul, K., Chanthavanich, P., Suvannadabba, S., Jiwariyavej, V., Dulyachai, W., Pengsaa, K., Wartel, T. A., Moureau, A., Saville, M., Bouckenooghe, A., Viviani, S., Tornieporth, N. G., & Lang, J. 2012. “Protective Efficacy of the Recombinant, Live-attenuated, CYD Tetravalent Dengue Vaccine in Thai Schoolchildren: A Randomised, Controlled Phase 2b Trial.” The Lancet. 380(9853): 1559-1567. DOI: 1016/s0140-6736(12)61428-7
- Tameris, M. D., Hatherill, M., Landry, B. S., Scriba, T. J., Snowden, M. A., Lockhart, S., Shea, J. E., McClain, J. B., Hussey, G. D., Hanekom, W. A., Mahomed, H., and McShane, H. 2013. “Safety and Efficacy of MVA85A, A New Tuberculosis Vaccine, In Infants Previously Vaccinated with BCG: A Randomized, Placebo-Controlled Phase 2b Trial.” The Lance. 381(9871): 1021-1028. 1016/s0140-6736(13)60177-4
- World Health Organization. (2011). Increasing Access to Vaccines Through Technology Transfer and Local Production. World Health Organization. ISBN: 978-924-150236 8