Vaccine research in India

THE most important conceptual problem that confronts research into the development of a vaccine to counter the Human Immunodeficiency Virus (HIV) is the lack of information on potential immunological correlates of protection, that is, what kind of immune response suffices to confer long-term immunity.

Dr. Jose Esparza, Director of Research, United Nations Programme on HIV/AIDS (UNAIDS), says: "The problem is that the bodies of most people infected with HIV mount a broad range of immune responses but these fail to control viral replication or avoid progression to disease. Of course, one possibility, and a hope, is that innate immune responses induced by prophylactic vaccines could be sufficient to prevent infections, or at least to modify the course of infection and/or the disease."

Another serious problem is that HIV exhibits considerable genetic variability. Esparza says: "At the present we do not know what could be the significance of HIV genetic subtypes for vaccine development." This is because the classification of HIV in different subtypes is according to the Env genes, the code for the envelope glycoproteins gp120 and gp41, which elicit only neutralising antibody responses. For example, the VaxGen vaccine, which is due for Phase-III trials - the only vaccine to reach this stage of trials in 17 years - is a sub-unit vaccine based on gp120. It is known that vaccines must also elicit the Cytotoxic T-cell Lymphocyte (CTL) response, the cellular arm of the immune system, to confer protection; therefore, some experts think that this vaccine may not really work.

Epidemiologically, all important subtypes of the virus belong to the M-group of HIV. There are 10 subtypes referred to by the letters A to J. These HIV genetic subtypes have a very distinct geographical distribution. Subtype B is the subtype prevalent in North America and Western Europe. In South Africa, the prevalent subtype is C, while in equatorial and Central Africa it is A. In South-East Asia (particularly in Thailand), the prevalent strain is B while subtype E also has been found. In the Indian subcontinent, the subtype C has been found to be the most dominant. However, strains belonging to B (mainly in northeastern India) and A have also been reported. The complexity is further increased by reports of inter-subtype recombinant strains in Africa.

Even within a subtype there is tremendous genetic variation, and the frequency of mutation is very high. In India, the circulating strain is predominantly the variant C3. It is not uncommon to find many quasi-species in the same individual, and researchers at the All India Institute of Medical Sciences (AIIMS), New Delhi, have found C2 and C3 to be present together in some cases. Director-General of the Indian Council of Medical Research Dr. N.K. Ganguly says that the generation of such quasi-species will also pose a problem in identifying the most appropriate vaccine candidate.

ANOTHER serious hurdle before researchers is that there is no animal model to test HIV vaccines for humans. The only way is to conduct clinical trials in HIV-negative human volunteers (which would raise ethical and legal issues). However, different experimental vaccines have shown different degrees of success in preventing infection or disease in animal models. Also, results from primate protection experiments have been at times contradictory and even paradoxical, thus preventing an understanding of their relevance to humans.

Subtype C accounts for the largest number of infections (48 per cent) in the world. Subtype B accounts for 25 per cent, A for 16 per cent, D and E 4 per cent each and the remaining subtypes 3 per cent. Most of the current research in vaccine development is targeted at subtype B, the one prevalent in North America and Western Europe. Very little is being done to develop vaccines against other subtypes, most notably the C subtype afflicting the Indian population.

If the projections are correct, India will soon have the largest number of HIV-infected persons and the importance of a prophylactic vaccine for India cannot be underestimated. But the questions are: can India use a vaccine developed elsewhere in the light of the fact that the dominant subtype is different? If not, what should be the strategy for vaccine development in the country, and what subtype should the vaccine be for?

It is true that vaccines developed in the West have undergone Phase-I trials in many developing countries, including China, Brazil, Thailand and Cuba (trials will start soon in Uganda). Thailand is about to conduct even a Phase-III trial on a B subtype vaccine. A bivalent B and E type vaccine is also due for trial. It is also true that genetic subtypes do not uniquely correspond to different potential immunotypes. That is, people infected by one subtype may develop antibodies capable of neutralising other subtypes, although neutralisation patterns have been difficult to interpret and immunotypes have not been clearly identified. On the other hand, people infected with HIV, or vaccinated with certain candidate vaccines, have been found to exhibit CTL responses broadly cross-reactive across subtypes, except for the subtype E which appears to be immunologically more distant. One could, therefore, argue that vaccines developed elsewhere could be tested here. But the Government of India's policy is to develop a vaccine indigenously. Besides this is the apprehension that the country's population may be used as guinea pigs for vaccines meant for the West.

The ownership of a vaccine developed in India will be a crucial factor in having an affordable vaccine for public health use. The Department of Biotechnology (DBT) has been given the mandate for the development of a vaccine.

To evolve a suitable strategy, the National AIDS Control Organisation (NACO) of the Ministry of Health organised a brain-storming session on November 9. Indian and foreign experts (who had attended the International Congress on Immunology (ICI), most notably Dr. Anthony S. Fauci of the National Institutes of Health (NIH), United States participated in the meeting. There is already some significant vaccine- and virology-related research going on in the AIIMS and the National Institute of Immunology (NII), New Delhi, the Indian Institute of Science (IISc), Bangalore, the National AIDS Research Institute (NARI) and the National Institute of Virology (NIV), Pune, and the National Institute of Cholera and Enteric Diseases (NICED), Calcutta. However, the work has been sub-optimal and not well focussed.

Significantly, a complete molecular characterisation and sequencing of the Indian isolates is yet to be done. Similarly, the infectivity and transmissivity patterns of the C subtype have not been fully studied. Dr. Shahid Jameel of the International Centre of Genetic Engineering and Biotechnology (ICGEB), New Delhi, said: "Money is not so much a problem as the lack of good ideas in HIV research in India. We have just begun to talk. Development of a vaccine is a very long way off."

The experts recommended a mission-oriented approach towards developing a C subtype-based vaccine. They also recommended research into potential candidate vaccines - the DNA-vaccine approach at the AIIMS and the IISc and the work based on the vaccinia virus at NICED - be consolidated instead of initiating new candidates. The formation of a core group has been proposed, which will coordinate R&D efforts, testing in animal models, clinical trials, product development and manufacture. It will have adequate powers in the identification of scientists and laboratories and in exploring funding. The NACO will fund and coordinate the mission with the DBT as the nodal agency.

The meeting also recommended collaborative research programmes with U.S. scientists under the ongoing Vaccine Action Programme (VAP), in terms of understanding techniques, exchanging plasmids and vectors for the development of vaccines, and so on. Institutions such as the NIH, the Centres for Disease Control (CDC), U.S., and the International Vaccine Initiative and the UNAIDS programme are expected to collaborate with Indian researchers in various ways.

The World Bank funded the $84-million Phase-I trial in 1992 and funding for the $200-230 million Phase-II trial has been approved in principle.

The NACO has to come up with a plan before April 1999. Its Project Director, J.V.R. Prasada Rao, said that the Phase-I trial did not have any HIV-related research component but the proposed HIV vaccine mission would be partly funded - up to about 10 per cent - out of the $200 million. By the standards of funding in other fields of biomedical research, $20 million is not a small amount; and significant results should come out of the project. Dr. Pradeep Seth of the AIIMS estimates that the cost of research to develop a vaccine in India will be about $1 million.

Hopefully, the body of research findings in all the failed vaccines will enable Indian researchers to zero in on a correct vaccine design strategy at a much lower cost. But, in the absence of a therapy or a vaccine emerging in the short term, health care and support to the infected and diseased in hospitals require far greater attention from the health authorities than what is evident. And by the turn of the century the problem may overwhelm the already strained health care infrastructure in the country. A mission-oriented approach in that direction is perhaps more urgent than the development of a vaccine.