The AIDS vaccine trials in India are one step closer to fruition. Sandhya Srinivasan examines the ethical problems posed by such trials, particularly in developing countries

On April 16, 2002, the National AIDS Control Organisation (NACO), the International AIDS Vaccine Initiative (IAVI) and the Indian Council of Medical Research (ICMR) announced that a year-old collaborative project to develop an AIDS vaccine for use in India had advanced one step closer to fruition.

Speakers at a meeting for the press indicated that vaccine development was proceeding according to schedule; phase I clinical trials were expected to start in 2003, and an advisory board set up to address ethical issues concerning the AIDS vaccine trials had just held its first meeting.

The project kicked off in March 2001 when the ICMR, IAVI and the US biotechnology firm Therion Biologics signed an agreement to develop an AIDS vaccine suitable for India. IAVI would fully fund Therion's development of an AIDS vaccine specific to the HIV (subtype C) common to India, and would 'accelerate' the process of getting this vaccine into clinical trials. Therion would produce the vaccine in quantities sufficient for phase I clinical trials, after which it would transfer the technology to an Indian vaccine manufacturer which would produce lots for further trials. If the vaccine cleared all trials, it would be made available in India at a 'reasonable' cost.

The genetic material to develop the vaccine was collected by researchers at the National AIDS Research Institute (NARI) in Pune, cloned and sequenced and then taken to Therion for vaccine construction.

What exactly is the HIV vaccine? The preventive vaccine under development is described as a 'modified vaccinia Ankara (MVA) vaccine'. Genetic material from six HIV genes (env, pol, gag, rev, nef and tat) from an Indian isolate of subtype C (accounting for 80 % of infections in India) is inserted in an MVA viral 'vector' -- or transport mechanism for the HIV DNA. Scientists say that vaccinia Ankara is a harmless version of a pox virus; it was also the basis for smallpox vaccines. The vaccine is constructed from pieces of HIV DNA, which cannot form a whole virus, and so there is no risk that recipients of the vaccines could become infected with HIV. The idea is that when the immune system recognises the HIV genetic material contained in the vaccine, it will stimulate the production of cytotoxic T lymphocytes, specific immune cells that kill other cells infected with HIV. Thus the preventive vaccine would prepare the immune system to react fast if the person becomes infected with HIV, and control the virus before it is able to take hold. This approach is based partly on research to understand how it is that some people don't get infected with HIV despite repeated exposure to the virus; it was found that they had naturally high levels of these HIV-specific 'killer cells', which presumably enable them to resist infection. Trials of HIV vaccines are being carried out world-wide, though it will be many years before a vaccine will reach the market. IAVI-sponsored research has produced two candidate vaccines currently under trial in Africa. Glaxo Smith Kline has a protein-based vaccine poised to enter trials. The Phase III trial by the Bangkok Vaccine Evaluation Group of VaxGen's gp120 vaccine, in a cohort of 2545 intravenous drug users, is ongoing. Some activist groups have given a cautious welcome to the announcement of an HIV vaccine for India. They raise three basic questions: 1) Will all efficacy be maximised and risks minimised? 2) Will the programme move carefully to ensure that vulnerable groups are not exploited, and that human studies are appropriate, done with fully informed and voluntary consent of participants, and do not harm them physically or socially? 3) How will vaccine research and development proceed effectively when preventive programmes are in chaos, and drug treatment is a luxury for the very, very rich?

Partners of commercial sex workers and intravenous drug users - people at high risk of getting infected with HIV -- have been identified for the vaccine trials in Maharashtra, Tamil Nadu and the North-East.

IAVI is a non-profit organisation founded in 1996 to help develop preventive HIV vaccines for use throughout the world. According to its website (www.iavi.org), its work is concentrated in four areas: "creating global demand for AIDS vaccines through advocacy and education; accelerating scientific progress; encouraging industrial involvement in AIDS vaccine development; and assuring global access". IAVI's funders include USAID, the World Bank, UNAIDS and various private foundations.

Boston, USA-based Therion Biologics Corporation is essentially in the development of therapeutic vaccines for cancer, according to Mark Chataway of IAVI. According to Therion's website, it is also developing preventive AIDS vaccines in a programme supported entirely by the United States National Institutes of Health. It has four such candidate vaccines in development, one of which is in Phase I clinical trials.

IAVI and the Indian government have committed themselves to ensuring that AIDS vaccine clinical trials in India will be conduced with community participation and adequate infrastructure, and after addressing the ethical issues concerning clinical trials. The government says the process will be transparent and it will ensure that participants' consent is voluntary and informed. It says that meetings planned with the various stakeholders are meant to solicit their support to expedite vaccine research.

The April 16 announcement raises a number of issues that merit informed public discussion. A few of them are mentioned below:

AIDS vaccine trials pose a number of ethical problems, particularly in countries like India where a higher estimated incidence of HIV (than for example in the US) permits smaller sample sizes and faster results. They are conducted on groups whose vulnerability is the very reason they are at higher risk of HIV.

These trials depend on healthy participants getting exposed to the virus due to their behaviour; a significantly higher incidence of HIV in the control group is needed to prove the vaccine's efficacy. Researchers experience a conflict of interests: between this technical requirement and their obligation to provide preventive advice on safer sex and injecting practices, as well as condoms and clean needles or bleach.

Researchers will also have to ensure that participants truly understand that the experimental vaccine is not proven effective, and they should presume that it offers no protection. Further, participants will not know if they have received the experimental vaccine or a placebo which offers no protection at all.

What will the standard of care be for participants who become sero-positive during the AIDS vaccine trial? The Helsinki Declaration requires that participants in a trial be provided the best known prophylactic and therapeutic care. Will the government commit to providing the highest possible standard of treatment - life-long triple anti-retroviral therapy -- as available to research participants in the developed world?

None of the vaccines under development are expected to have 100 per cent efficacy. In fact, a vaccine of just 50 per cent efficacy may be considered acceptable for a country with a high prevalence of HIV, because of the number of infections it could reduce. Before trials begin, we will need to know more about the estimated efficacy of the vaccine currently poised for trials in India. Second, given the controversies on HIV figures in India, we will need to know by what calculation it was considered acceptable. Finally, how will the programme ensure that vaccinated people truly understand the limits of protection?

Ensuring availability: The NACO-ICMR-IAVI venture envisages that once a vaccine is developed and clears Phase I clinical trials, Therion would transfer the technology to an Indian pharmaceutical for further production and trials. The licensed vaccine would be sold in this region at 'manufacturing cost (excluding all development costs) plus a small margin'. This may still be unaffordable to the majority of people at risk of HIV. The programme needs to tell us exactly how it will make any AIDS vaccine available to the poorest of the poor, who would need it the most.

Drug trials in India: Informed consent is not taken There is no comprehensive information on drug trials - or medical research of any kind - in India. It is believed that most drug trials are done in public hospitals, and on poor patients. Over-stretched researchers in government hospitals are effectively bribed with the offer of equipment like computers, and some stipends to pay for extra staff, notes Dr Yash Lokhandwala, cardiologist at Hinduja Hospital, Mumbai. Ethics committees are usually controlled by the hospital dean, says Dr Sunil Pandya, neurosurgeon at Jaslok Hospital, Mumbai, so when a project bringing in a lot of money is presented to the ethics committee, it will get cleared. Informed consent is not taken; most doctors believe - incorrectly -- it's just not possible to take informed consent of the illiterate. It has been established that patients in public hospitals when approached to participate in research believe that if they refused, they would be denied the care for which they came. Government authorities such as the Indian Council for Medical Research can control only the research that they fund. So when a US 'entrepreneur' got to test out a vaccine for the Bovine Immunodeficiency Virus (BIV) on people with HIV in Mumbai, through a local support group, it was only when the family of a patient who died -- after receiving the vaccine -- filed a criminal case that the police took action. (According to a report in the BMJ, the lawyers of Dr I S Gilada, who was arrested in this connection, said that he had disassociated himself from the vaccine trials before any patients received injections, and also that the death of the vaccine recipient was a consequence of the HIV infection and not the vaccine.) At the same time, some ICMR institutions don't have functioning ethics committees. Unfortunately, even those with functioning ethics committees cannot guarantee that the committee has screened the proposal properly, let alone monitored the research once it starts.

InfoChange News & Features, May 2002