In the history of medicine

In the history of medicine, development of vaccine has been a milestone of success.(Kaufmann, Juliana McElrath, Lewis, & Del Giudice, 2014). In the European history, the “dawn” of vaccine research began with the smallpox vaccine discovered by Edward Jenner in 1796. The golden era of vaccine began with the germ theory introduced by Pasteur, Ramon, Koch and Merieux along with that they came up with now to be known conventional vaccines which was able to protect people against diseases such as diphtheria, tetanus, tuberculosis, pertussis and rabies. (Delany, I., Rappuoli, R., & De Gregorio, E, 2014).

Fig: Historical overview of vaccine development (Delany, I., Rappuoli, R., & De Gregorio, E, 2014).

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The basis of conventional vaccine is the use of inactive or live attenuated pathogens as well as inactivated toxins (toxoids). These vaccines protected against rabies, diphtheria, tetanus, pertussis, and tuberculosis. Conventional vaccines have shown stupendous achievement of eradicating morbidity rate caused by diseases such as polio, small pox and diphtheria.(Anon & Ben-Yedidia, 2003)
However there are major setbacks of conventional vaccine preparation. For example,
1. Difficulty in preparation of vaccines for viruses whose in-vitro cultivation isn’t possible such as in case of parasites or Hepatitis B virus.
2. Live attenuated virus preparations doesn’t give safety assurance as they can revert back to virulence such as in case of HIV causing AIDS.
3. Genetic mutations giving rise to new strains of viruses requires continuous development of vaccines.(Anon & Ben-Yedidia, 2003)

In the light of these limitations, some diseases still remain unpreventable (Delany, I., Rappuoli, R., & De Gregorio, E, 2014). AIDS, Malaria and Tuberculosis and cancer are some global killers against which vaccines are yet to be developed. The breakthrough in vaccinology began in the recent time with systems biology, structure-based antigen design, recombinant technologies and new antigen delivery (Gaurav Gupta, 2011)

New approaches for the design of vaccine associated with their candidate diseases.

1. Recombinant Vaccine- The most recent vaccines produced are against hepatitis B virus and Human papilloma virus by expressing the antigen on infected cells.
2. Live recombinant vaccines by insertion of relevant antigen coding gene genes insides suitable vector. The idea behind this vaccine is use of infectious and immunological properties of the live vector to provide immunity against its own proteins. Bacteria such as Salmonella typhi, and virus (such as vaccinia and adenovirus) are developed as live recombinant vector vaccines.
3. DNA vaccines have been developed for the expression of antigens of different pathogens such as influenza, HIV, leishmaniosis, TB, and malaria.
4. Peptide epitope based vaccine of specific epitope of antigens related to infections or cancer.
5. Synthetic recombinant vaccines will code for relevant epitopes that are inserted into an appropriate vector. Hence, an external epitope will be expressed. For example, the expression of foot and mouth disease virus are expressed using hepatitis B core protein a synthetic recombinant product.
(Arnon & Ben-Yedidia, 2003 and Nascimento & Leite, 2012)

Vaccine development stages
Development of vaccine may take up to 12-15 years to complete:
a) Pre-clinical stage: laboratory testing on animals to assess the safety of antigen safety. So the best candidate vaccine can be selected. This stage includes activities like
-Antigen selection for the use in treatment or prevention of the disease.
-The concept of vaccine is designed.
-Laboratory testing to determine the efficacy of vaccine
– Vaccine is manufactured based on GMP standards to Good Manufacturing Practice standards

b) Clinical development stage: Trial is done on small number of human volunteers and it involves 4 phases:
-Phase I trials are small-scale and involves less than 100 subjects. For the assessment of the safety of the vaccine. Takes 1 year to complete
-Phase II trials carried on more than 100s of volunteer to test the efficacy of the vaccine against artificial infection. Vaccine safety, side-effects and the immune response are also studied. Takes 1-3 years to complete.
-Phase III trials are carried on 1000s of volunteers to assess the efficacy of virus in an original infected population. If the vaccine is safe and effective then it can by applied for obtaining a license. Clinical datas of this stage needs to be submitted to the relevant authorities for approval
-Phase IV stage occurs after licensing of the vaccine also known as post market surveillance stage to determine any adverse effect associated with the vaccine that couldn’t be detected in the previous stages. (Europe, W., ; Book, V. F. (n.d.). 2 Vaccine development and implementation, 52–69)

Fig- Different types of development process for vaccine
(Europe, W., ; Book, V. F. (n.d.). 2 Vaccine development and implementation, 52–69)
Challenges in the development of vaccine
In the research and development (R;D) of vaccine, challenges that are face are- time shortage of discovery of vaccine candidates, assurance of vaccine producing the desired antigen, clinical and production development and whether the immune response induced by vaccine provides the required strength and efficacy for the desired protection. (Kaufmann et al., 2014). However some other challenges are faced such as failure of clinical trials due to lack of detailed information or pre-clinical data, variations in antigen genomics requiring constant upgrade of vaccine, lack of investment on vaccine research. Lastly the access of vaccine to poor and under-developed countries is also seen as a challenge (Oyston ; Robinson, 2012)

Current ongoing vaccine projects
• Bharat Biotech came up with the first Typhoid conjugate vaccine Typbar which got approval from WHO. It can be successfully administered for preventing typhoid fever in adults and children .(World Health Organization, 2018)
• China produced oral polio and hepatitis A vaccine which got prequalification by WHO( Beijing Xinhua,2018)
• Study of aerosol measles vaccine is being conducted under the WHO Measles Aerosol Project. (Maria Henao-Restrepo, Ana ; Greco, Michel ; Laurie, Ximena ; John, Oommen ; Aguado, Teresa. (2010). Measles Aerosol Vaccine Project. Procedia in Vaccinology. 2. 147-15)
• Malaria vaccine RTS, S/AS01 is the most recent advancement in malarial vaccine and is in the phase 3 clinical trial. (Schwartz, Brown, Genton, ; Moorthy, 2012)

Regulatory aspects of vaccine license
To ensure the quality, efficacy and safety of vaccines to be licensed there are extensive regulatory processes where rules and guidelines are set by authorized organizations such as WHO, FDA, EMA and ICH. After the vaccine gets license for marketing, manufacturer must conduct the quality assurance programs to evaluate the manufacturing steps, finally the vaccine is tested for sterility safety, quality and purity to ensure consistency from batch to batch. A final check is done by the national regulatory on the performance of the manufacture, in controlling the production processes based on set guidelines and they might suggest some additional tests done on the final product before it is released in the market for distribution. All these aspects should meet the good manufacturing practiced (GMP) standard. Moreover, regulatory authorities may do industry inspection. Failure on the part of materials, formulations, packaging and incompatibility with GMP standards would call for license suspension, withdrawal or severe consequences of closure of vaccine production plant.(Hardt, Schmidt-Ott, Glismann, Adegbola, ; Meurice, 2013)

Fig: Regulatory affairs of vaccine
(Europe, W., ; Book, V. F. (n.d.). 2 Vaccine development and implementation, 52–69)