The World Health Organization estimates that vaccines save an average of 2.5 million lives every year. With the increasing use of vaccines, even doctors rarely see some diseases such as diphtheria and tetanus. Yet! despite the fact that vaccines are recognized as cost-effective interventions that have proven value in public health, there is not enough investment in the development of new vaccines.
There are many reasons why new vaccine development is infrequent and slow. Potential vaccine candidates are frequently identified based on disease biology in academic laboratories, but progressing beyond the identification of a candidate is challenging.
Usually once a vaccine candidate (may be a whole bacteria or virus) either live or filled or a part of the candidate is identified, its ability to protect from disease needs to be tested in a model of that disease. Sometimes such models are available in animals and mimic all or some aspects of human models but do not predict protection from human disease. If an animal model does not predict whether a vaccine candidate can protect from disease, then choosing which candidate should be developed further becomes challenging because there is no basis for making a decision. Hence, vaccines are not developed.
Very recently, there has been an increasing interest is moving away from the long, slow and unpredictable path that vaccine development have taken previously, to think about more physiologically relevant models of disease in humans. This is being called ‘controlled human infection models’ or ‘experimental human infection models.’ Previously they were known as volunteer studies.
There are many examples of when scientists have deliberately infected themselves and others with infectious agents in order to understand human disease better. Perhaps the most famous case in recent times was of Barry Marshall who in the 1980s deliberately drank a culture of the bacterium now known as Helicobacter pylori to show that it produced stomach ulcers, which had previously been attributed to stress. This work led to the proving of the association of the bacterium with the disease, and ultimately to the Nobel Prize in Physiology or Medicine in 2005.
A number of disease models in humans have been established through volunteer studies. Over 6500 individuals have participated in such studies and about 60 kinds of bacteria, viruses and parasites have been used on volunteers. Some of these studies were done because there was no way of growing the organism except through infecting humans. One prominent example is noroviruses, a very common cause of diarrhoea and vomiting the world over.
Others were established because there were no appropriate models of disease. A typical example is typhoid, where mice can be infected with the bacteria but the illness that is produced in mice is very different from what happens in infected humans. Interestingly, the University of Oxford has established a typhoid challenge model that is being used to evaluate a typhoid vaccine that has been developed by an Indian vaccine manufacturer.
There is no question that using humans to study disease has serious ethical challenges. While naturally infected humans can be studied with their permission, natural infections do not answer some questions related to disease—for example, how many bacteria does a person need to be infected by to get sick? We know that this is about 100 bacteria for Shigella which causes dysentery, but about 1000,000 bacteria for cholera through volunteer studies. But these studies were all done on volunteers in industrialized countries. Is it ethical at all to induce disease in healthy individuals, even with their permission? If it is, what safeguards should be put in place?
In the currently used models in the United Kingdom and the United States of America, the strain to be used is very carefully chosen to be as safe as possible. In a dengue model established at the University of Vermont, the strain used in volunteers only causes a viremia or circulation of the virus in the blood, without high fever or any other forms of severe disease. For bacterial and parasitic infection models such as, for typhoid and malaria, the strains are those that are sensitive to antibiotics or anti-parasitic drugs so that the infection can be stopped before any severe disease occurs.
Volunteers undergo a long process of counselling to ensure that they understand the process and the commitment on their part and that of the scientists. As with all studies, volunteers have the opportunity to withdraw at any time and are very closely followed in case of out-patient studies or are admitted into special research facilities and monitored closely. These studies have been tremendously valuable in understanding how disease develops in humans. The models are now being used not only to study disease but also to evaluate diagnostic tests and vaccines.
The testing of vaccines at least in the early stages in humans if appropriate human infection models are available, offers a tremendous opportunity to quickly and more accurately test potential vaccine candidates.
The candidates that show promise in these disease models can be taken forward for further testing and those that do not work in a small number of human volunteers can be dropped without wasting time and resources.
This allows rapid evaluation of vaccine candidates and decreases the time for development of vaccine. This shift to the left accelerates vaccine research and development.
Of course, these are challenging studies and need caution, commitment and care. So far, such volunteer studies of deliberate infection have not been done in India. We Indians are rightly wary of potentially ethical issues related to medical research in vulnerable populations.
But a question to consider is that just we say that we do not want drugs tested on Indians that will benefit richer populations before they benefit us, is it right, (perhaps taking typhoid as an example), that vaccines for diseases that affect us should be tested in people who will never get the disease in their own countries?