Chinese were the first to use smallpox inoculation in 1000 CE but the major success came with the work of Edward Jenner, 1796, using cowpox pustules to provide protection against smallpox; which led to the development of the first successful vaccine. It took nearly 200 years to completely eradicate the disease. Next impact on human disease was brought with the development of rabies vaccine, Louis Pasture in 1885. Mid of 20th century witnessed the development of vaccine research. Recombinant DNA technology and new innovative delivery techniques has led scientists in new directions to develop vaccines for most of the childhood diseases like measles, mumps, rubella, polio etc. and even the most epidemic disease like AIDS, hepatitis etc. Vaccines are prophylactic and therapeutic in nature. Prophylactic vaccines are administered to normal, healthy participants while therapeutic or curative vaccines are given to patients. Many prophylactic vaccines are administered to the paediatric group.
Before these vaccines are made available to general public it is important to conduct clinical trials. Vaccine trials are clinical trials that aim at establishing the safety and efficacy profile of the vaccine, through many years of research, before it is marketed. Research and development process involves experts in many scientific and social disciplines, including public health, immunology, epidemiology & statistics, from the pharmaceutical companies. For comparing the vaccine’s effectiveness a control group is included in the target population forming two groups: A treatment arm and control arm. The control arm can receive any: placebo, an adjuvant- containing vaccine or an already established vaccine (which might be for protection against a different pathogen). Once the vaccine/placebo is administered, data is collected on the antibody production, health outcomes, and side effects. The trial is divided into phases and data are collected in each phase till the post-license phase.
Phase I: This is the first phase where the vaccine is introduced in the low risk human population to study its dose and route of administration along with safety and biological effects (immunogenicity). Apart from these, it also determines the induction of cell mediated immune response, cross reactive antibodies and/or interaction of pre existing antibodies affecting the immune system. Pharmacokinetic study is generally not included.
Phase II: These trials are carried out on the limited target population, like, children, adults, or those who are at risk of exposure to the pathogen to examine the effectiveness (immunogenicity) and dose range. Safety and pharmacokinetic profile is also studied. Early Phase II is called exploratory trial while late Phase II is called pivotal efficacy study.
Phase III: It involves a large no. of volunteers (in thousands), focusing on safety and efficacy assessment along with effectiveness in the prevention of disease. The controlled study determines the level of protection offered by the vaccine providing pivotal data for licensure. Measurement of direct and indirect protection of a non-vaccinated population compared to well-defined vaccinated population determined by vaccine coverage area, and correlation of vaccine strains with circulating strains, are also studied.
Phase IV (Post- Licensure Evaluation): This phase includes the study of rare or unexpected events (that are not observed in smaller Phase II/III studies,) in the entire population or subgroup. Apart from this Phase IV studies also provide information on pharmacodynamic properties such as route of administration, e.g. oral, injection etc. or the presence of novel adjuvants or excipients in the vaccine and the vaccine safety & effectiveness in the larger heterogeneous group of population.
Some ethical concerns also arise with the conduct of vaccine trials. Main concerns are:-
- Many vaccines contain active or live- attenuated micro-organisms which may produce small risk of infection. The participant should be informed beforehand about the same.
- Participants in control group or when subjected to ineffective vaccine develop the possibility of contracting the disease. In such a case, free treatment should be made available and if it requires lifelong treatment it should be brought to the notice of ethics committee.
- Guidelines issued by Department of Biotechnology should be strictly followed since the risks associated with vaccines developed using recombinant DNA technology are not completely known.
- The control group should avail the access to the vaccine even after the trial is over. If it is a paediatric age group vaccine and by the time study is completed, the child might cross the age when the vaccine is supposed to be protective, alternative vaccine should be made available.
- Flexibility and ethical aspects should be examined by EC on case-to-case basis.
- Community from with the trial participants are taken, post trial access to the vaccine should be first provided to them.
- Certificate for the HIV trial participant may be issued so as to avoid any inconvenience for the participant in employment or travel purpose.
- Care should be taken while choosing children with particular age with regard to gender, ethnic background, and health profile while testing the paediatric vaccine, especially if they are from the over-researched /vulnerable community.
- Community should be involved while choosing the comparator in case no effective vaccine is available, in RCT vaccine trials. Comparator can be a placebo.
- In case of paediatric vaccine trials, informed consent should be signed by the parents and all the risks involved should be in detail discussed with them.
The search for safe vaccine for infectious diseases has not been and will not be easy. Nor will it be straightforward or quick, because of the nature of the parasite and its interaction with the humans. But substantial progress has been made over the years in creating safe and effective vaccines.
The design and conduct of vaccine trials too is critical – to accelerate and progress- for creating life saving vaccines for the major life threatening diseases both in children and in adults.