‘If there are more correlates, we can develop better vaccines’

Dr Ramesh Paranjape

The National AIDS Research Institute (NARI), set up by Indian Council of Medical Research (ICMR) in 1992, has come a long way from setting up a virus bank in the same year, to undertaking development of Modified Vaccinia Ankara (MVA) vaccine candidate in 2001. Presently, NARI is deeply engaged in developing a suitable vaccine candidate for the Indian population. It is also conducting phase II/III trials for vaginal microbicide Pranim, an alternative mode of HIV infection prevention. Senior deputy director and officer-in-charge Dr Ramesh Paranjape speaks to Soumya Viswanathan on NARI’s role in finding the right vaccine for India.

What is NARI’s role in the memorandum of understanding that ICMR has signed with the International Aids Vaccine Initiative?
NARI, along with National Institute for cholera and enteric diseases is working towards development and phase I trial of HIV vaccine. Our role is to identify and study virus strains and HIV-1 genes for inclusion in the candidate vaccines. We would also conduct Phase I trials to study the immunogenicity and safety of the vaccine. We are also likely to conduct Phase III trials depending on the results of Phase I and II. After phase III, ICMR and NACO will take a decision on how to use the trial results and NARI will not have a major role.

Since when has NARI been working on this particular vaccine candidate?
Though vaccine-oriented approach began only two years back, we have been working on making a virus repository, undertaking studies to understand the characteristics of the virus and studying the epidemiology of HIV infection. After we identified the genes that could go into MVA, the work on vaccine development started.

Which are the candidates NARI is working on and how far has the development progressed?
We are actively working on the MVA candidate vaccine where the vector is the modified vaccinia (smallpox vaccine strain) virus. The development of the vaccine started with the identification of the virus sequence, isolation of the virus and identificatin of the genes that have gone into it. Six genes from HIV subtype C (from Pune) have been inserted in a single constrict of MVA. The advantages of MVA are high level of gene expression, and the inability of the virus to multiply in the vaccinated volunteer.

Another candidate that NARI is considering is a multi-epitope based vaccine (where small portions of the virus protein called epitopes are used). In this case, we shall identify epitopes from virus strains and use them for vaccine development instead of using the whole gene or virus. This way, we can have broader immune response which may be able prevent divergent HIV strains from infecting. Though this may be a better concept, it is still at the experimental stage. The third candidate is a DNA vaccine for which we have put up a proposal. Its approval by ICMR will take things forward.

How did you zero in on MVA?
The decision was taken by national agencies, NACO and ICMR after considering various factors. MVA is safe. This is established through some of the animal experiments, which have been successful. IAVI was also willing to transfer MVA technology under MOU. It is also possible to insert many genes into MVA. More genes means more antigens which means more response. The vaccine is based on genes from HIV subtype C (which is predominant in our country).

Based on the sequences of various virus strains we have derived a common sequence closest to all Indian subtype C virus strains. The gene sequences closest to this sequence are used for vaccine development. We hope this candidate will give a broader response.

What are the challenges that scientists in the lab face in identifying the best concept?
There are several challenges. First and foremost, there are no suitable animal models for HIV infection. Secondly, there are no known correlates of protection. Antibodies produced in response to the vaccine do not indicate protection because of the nature of virus. Presently, cytotoxic T lymphocyte response is considered the closest correlate of protection based on scientific evidence. If correlates of protection are understood, we may be able to develop better candidates. Other challenges are genetic variations in HIV -- arising due to mutation of HIV, which help escape from immune apparatus and no sufficient scientific data on mucosal immunity. Mucosal immunity may be crucial as the portal of entry for the virus is mucosal surfaces of genital organs as most infections in the country are acquired through sex.

Will the route of administration affect the reponse of vaccine if mucosal immunity is different from peripheral immunity?
We have no reason to believe that immune responses are grossly different through different routes, though one of the key scientific dilemmas is to induce mucosal protection. At present, we are looking at assessing the response in peripheral circulation. We would test whether the vaccine can induce cytotoxic T lymphocyte (CTL) response. We want to see whether the person who is administered the vaccine develops good CTL response.

Are there only a few vaccine candidates in the global pipeline?
No. Nearly 100 different vaccine candidates based on more than half a dozen concepts are being investigated. They differ in the type of immunity generated, vector used, genes inserted, etc. To get into Phase I involves lot of preparation. There are many candidates in phase one, few in Phase II and only 2 in phase III. But it may take nearly 8 to 10 years from the scientific concept to reach and complete Phase III.

Can you tell us about the development on the vaginal microbicide Pranim?
The scientific community is looking at the vaginal microbicide as a preventive measure. Issues related to it are safety, efficacy and acceptance. National Institute for Research in Reproductive Health, Mumbai and Post Graduate Institute of Medical Education and Research, Chandigarh have done Phase I. We are interested in doing Phase II/ III trials. After two years, we will be in a position to establish the safety and efficacy. We will have two groups of low risk and high risk women, 20 women in each. The end point will be to see how many developed STDs.