Traditional vaccine trials rely on large sample populations and natural infection processes. A quicker, cheaper, but riskier method, called Controlled Human Infection Model studies (CHIMs), has also been in practice for some time. In CHIMs, volunteers are deliberately infected with a pathogen to study its effects or to test the efficacy of a vaccine. In this article, Aditi examines the science behind CHIMs and the ethical implications of legalising this method in India, where such trials are presently banned.
Cholera, a diarrhoeal disease spread through contaminated food and water, is rare in the USA. However, many US citizens who travel to regions where cholera is endemic (parts of Asia, Africa, or the Caribbean) have lost their lives to this disease. In 2016, the US Food and Drug Administration (FDA) approved a vaccine (VaxChora) for this disease based on the results of a quick and cost-effective method called Controlled Human Infection Model studies (CHIMs). As the world now wades through the coronavirus crisis, CHIM studies are again being deliberated upon as a way to fast-track vaccine development. However, insufficient knowledge about the virus and ethical concerns restrict the use of this process.
What are CHIMs?
CHIM studies involve intentionally introducing an infectious agent into the body of a healthy volunteer in a regulated manner to induce infection. This can be used to yield information about the efficacy of novel vaccines, generate knowledge regarding disease progression, and gain insights on host-pathogen interactions. Medical researchers, practitioners, and regulatory authorities of our country are currently deliberating on legitimizing this method since this may help reduce the public health burden of infectious diseases in India.
At first glance, the idea of deliberately introducing an infection may seem dangerous. It can reasonably be asked whether such a risky procedure is needed when similar infection studies have long been conducted on animal models.
The need to conduct CHIM studies arises due to three reasons. First, several diseases cannot be studied in animal models as the pathogens causing them selectively infect humans (For e.g. rabbits and dogs don’t get dengue). Second, host-parasite interactions can differ between humans and animal models. As a result of this, results obtained through infection studies in animals can often fail to replicate in humans, leading to wastage of funds and resources. Third, CHIM studies can speed up vaccine research as ineffective candidates can be eliminated at an early stage by testing them on a small number of individuals (who are given the vaccines, followed by an injection of the infectious agent).
Till date, more than 155CHIM studies have been carried out worldwide involving over 45,000 volunteers, primarily in developed countries like the US, UK, Netherlands etc. Recently, developing nations such as Kenya, Tanzania, and Gabon have also started CHIM trials, but their overall contribution is only 7% of the CHIM study space. CHIM studies, however, are not yet approved in India and currently, vaccines designed in India are sent abroad for CHIM trials.
Of late, the Department of Biotechnology (DBT) along with the Faridabad-based Translational Health Science and Technology Institute (THSTI) have started pushing for policy change to introduce CHIMs in India. The organisations are holding consultations with various stakeholders, including researchers, lawyers, media, and ethicists, to understand the regulatory needs and potential issues associated with such studies in India.
As CHIMs are carried out in many other countries, sceptics argue that one can easily borrow the information and products derived from such studies from other countries where the regulatory norms are already streamlined and medical facilities are better, instead of starting them afresh in India. Researchers in the field, however, caution that due to genetic complexity related to ethnicity, environmental, and nutritional factors, CHIM studies conducted elsewhere may not replicate in India and products tested through such studies elsewhere may not benefit the Indian population.
One evidence for this is the failure of many phase III clinical trials in India, which involve a large number of volunteers. One can argue that if CHIM studies were conducted in their stead, the results about the inefficacy of vaccine would have come at a lesser cost, in lesser time, and by employing a fewer number of volunteers.
“Vaccines that protect against Rotavirus, cholera and polio have shown poor efficacy in India due to varying genetic and environmental conditions in the Indian population. It is, therefore, necessary that we do studies in India on the infections which have huge public health burden in India to ensure that the results are relevant to us,” says Gagandeep Kang, former Executive Director, THSTI.
Further imperative for CHIM studies also comes from growing concern over antimicrobial resistance. With more and more drugs failing against infectious diseases, it is important to invest in studies which accelerate the process of vaccine development.
How safe is the procedure?
Needless to say, CHIM studies carry a certain level of risk. However, the studies generally use well-known microbial strains, appropriate timing, dose, and route of infection, along with continuous monitoring of the volunteer to ensure their safety. Further, volunteers are selected based on their past history of infection as well as other factors which may hinder the study or enhance the associated health risk for the participant.
Due to the infectious nature of the pathogen, the volunteers are usually quarantined and monitored for the duration of the study (although this may vary with the nature of the infection) to ensure that they are out of danger and incapable of spreading the diseases once they step outside the study centre. Since the microbial strains used are not very virulent, the symptoms are mild and they generally don’t lead to full-blown disease. Also, such studies are mostly carried out for diseases where effective treatments are available so that the volunteer can be provided medication and hospital care if they exhibit stronger symptoms than expected.
While the need is established, the deliberate injection of a pathogen in humans raises ethical and regulatory concerns. Although earlier CHIM studies have been successful and no harm to individuals reported so far, risk cannot be ruled out completely, especially in low-income countries where medical facilities are not at par with the developed world.
In this regard, Indian authorities have resolved to do CHIM studies only in a few specialized centres which have the expertise required to carry out such studies. Even though developing countries like India can learn from the experiences and regulatory framework from the developed countries, it has a different set of challenges pertaining to different socio-economic conditions.
Manjulika Vaz, lecturer at St. John’s Research Institute, Bangalore has studied the ethics surrounding CHIM studies in India. According to her, the general public is apprehensive about CHIM studies due to their unfamiliarity and a perception that poor Indians might be used as guinea pigs.
Vaz believes that to ensure that CHIM studies in India do not lead to the exploitation of the poor for money, the volunteers of the study should be healthy, urban, financially sound, educated, health literate, aware of research processes, and altruistic. She adds that this view of ensuring that those who participate truly understand why and what they have agreed to and are not being exploited is also shared by the IVIRC (India Volunteer Infection Research Consortium). It is extremely important to ensure that people who participate in any kind of clinical research truly understand it and that the vulnerable (socially, economically, or culturally) are not exploited.
It is clear that various technical, clinical, ethical and regulatory issues need to be resolved before India joins the CHIM league of countries. The biggest challenge, perhaps, will come from public perception. Amrita Sekhar, Consultant at THSTI, adds that developing guidelines for new types of clinical research like gene editing or controlled human infection is helpful for researchers because they provide standardization and prevent things going awry. However, it is essential to engage the public as well in order to ensure two-way communication, transparency, and trust-building.