Advancement in science has reached up to the level where infectious diseases such as malaria and typhoid can be effectively treated with the standard drug regimen. However, death due to malaria is still happening in India as the vulnerable population has no access to the best available healthcare systems. An ineffective treatment regimen could give rise to a generation of antimicrobial resistant varieties, which further contribute to the complex healthcare challenges that India is facing as of today.

The current healthcare systems including disease surveillance in India are still in their dark ages. India has hugely advanced economically and in certain sectors of research such as space exploration. However, according to WHO malaria report 2017, the Indian malaria disease surveillance system can detect only 8% of cases as compared to Nigeria, which detects 16% of the cases (1). Hence, the Indian government is not capable of estimating the real burden of disease and subsequent resource allocation. However, like any other nation, India also needs a healthy population for sustainable development.

India is the biggest manufacturer of vaccines. The national immunisation programme of the Indian government, including the recently launched Indradhanush Programme has been a robust system that successfully achieved polio elimination despite the lower sanitation and health care, higher temperature, larger heterogeneous population and diverse geography. Furthermore, the Indian government is also launching various research programs to strengthen the immunisation coverage such as Immunization Data: Innovating for Action, IDIA.

Basic research in India has advanced to the stage where it could perform under the challenge of development for a solution as per societal needs. Academic research has resulted in the development of at least three malaria vaccine candidates, whereas a newly WHO prequalified typhoid vaccine has been developed by an Indian company Bharat Biotech (2–4). However, surprisingly the protective efficacy data for this WHO prequalified typhoid vaccine has been generated at the University of Oxford using Controlled Human Infection Models (CHIM), which might be due to the fragile and complicated clinical trials ecosystem in India (5).

The conventional clinical trial ecosystem of India is very complicated. Since 2005, the International Committee of Medical Journal Editors requires prospective registration of clinical trial (i.e., registration before the first enrollment) to preclude reporting biases however the Clinical Trial Registry of India still accepts retrospective registration.  The HPV vaccine clinical trial created a huge uproar leading to the seventy-second report from the parliament standing committee, an investigation by the expert committee, media buzz and most importantly, loss of public trust. The failure of clinical research systems to detect severe adverse events has been noticed by the expert committee examining the HPV trials in India (6).

The use of vaccines could lower the disease burden which in turn reduces the drug use, and thus vaccination could reduce the rise of antibiotic resistance. Given a better immunization programme, vaccine manufacturing facilities and basic vaccine research existing in India, how could the vaccine development in India be accelerated to fulfil the societal needs? Should we expose the larger population to a candidate vaccine when we do not have sufficient data on its protective efficacy? Or will it be prudent to evaluate the vaccine protective efficacy in highly controlled settings and then proceed for larger population trials?

CHIM (for malaria, Controlled Human Malaria Infection, CHMI) provides a platform to reasonably evaluate the protective efficacy of a vaccine candidate without going out for larger trials. The term “Controlled” in CHMI reflects the requirement of highly controlled settings such as well-characterised parasite strains, effective drug(s) for infection elimination and highly efficient diagnostic system for stringent monitoring. The term “infection” reflects that the experimental protocol intends to induce controlled infection and not cause disease. The term “Human” reflects that the subject will be human, as with any clinical vaccine research evaluating protective efficacy.

The capacity to perform CHIM studies has been developed in many countries such as USA, UK, Germany, Tanzania and Kenya. In the USA, more than 1000 volunteers have participated in CHMI trial since the last 25 years without any CHMI-related adverse events (7). Although for infectious disease, we mostly imported solutions in the form of drugs/vaccines from outside world, the situation is rapidly changing, e.g., development of rotavirus vaccine in India.

It is always easier to import rather than develop an indigenous solution. However, if polio vaccine would have been developed in India, we could be free of polio by a generation. Developing a CHIM study in India will require an arduous effort. In the current situation, it could be for diseases such as malaria and typhoid and not for Zika, dengue and even tuberculosis. It is also better not to perform the CHIM studies if the highest standards could not be maintained.

The most important obstacle in CHIM is of public perception. The perception could only be addressed if we could develop the scientific, ethical and regulatory framework for conducting CHIM studies involving the best of expertise in basic research, clinical research, ethics, regulation, law and social science, which should define the highest standards while conducting CHIM studies. The media should be allowed for their valuable criticism and wider transparent dissemination of proceedings.

The primary effort should be by a government organisation to prevent public suspicion of the involvement of commercial benefits by pharmaceutical companies as a motive force. One or two academic institutions of excellence should be chosen and the capacity to conduct CHIM studies could be developed. As infectious diseases are a moving target, the rigorous effort to discuss CHIM studies in India is urgently needed.

 

References:

1. WHO. World Malaria Report. World Malar Rep. 2017;
2. WHO | WHO prequalifies breakthrough vaccine for typhoid. WHO [Internet]. 2018 [cited 2018 Jan 17]; Available from: http://www.who.int/medicines/news/2017/WHOprequalifies-breakthrough-typhoid-vaccine/en/
3. Malaria Vaccines Development efforts in India through DBT Support | Department of Biotechnology [Internet]. [cited 2018 Jan 17]. Available from: http://www.dbtindia.nic.in/malaria-vaccines-dev-efforts-dbt/
4. Bhardwaj R, Shakri AR, Hans D, Gupta P, Fernandez-Becerra C, del Portillo HA, et al. Production of recombinant PvDBPII, receptor binding domain of Plasmodium vivax Duffy binding protein, and evaluation of immunogenicity to identify an adjuvant formulation for vaccine development. Protein Expr Purif [Internet]. 2017 Aug [cited 2018 Jan 17];136:52–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26578115
5. Feasey NA, Levine MM. Typhoid vaccine development with a human challenge model. Lancet (London, England) [Internet]. 2017 Dec 2 [cited 2018 Jan 17];390(10111):2419–21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28965714
6. Final report HPV vaccine [Internet]. 2501 [cited 2018 Jan 17]. Available from: http://www.icmr.nic.in/final/HPV PATH final report.pdf
7. Spring M, Polhemus M, Ockenhouse C. Controlled Human Malaria Infection. J Infect Dis [Internet]. 2014 Jun 15 [cited 2018 Jan 16];209(suppl 2):S40–5. Available from: https://academic.oup.com/jid/article-lookup/doi/10.1093/infdis/jiu063

 

Manish Manish is a SERB young scientist working at ICMR-National Institute of Malaria Research, New Delhi. Smriti Mishra is an ICMR-Research associate working at Jawaharlal Nehru University, New Delhi. Manish Manish is supported by SERB young scientist scheme YSS/2015/0031 and work at ICMR-NIMR. The opinions in the article are of the authors and do not reflect the opinion of either SERB or ICMR.