By Sandhya Srinivasan
MUMBAI, Apr 13 (IPS) – Why were phase-1 safety trials for an HIV vaccine started in India days before the release of the results of the same trial in Belgium and Germany? And why were phase-2 trials of the same vaccine conducted in Africa?
These are some of the questions that scientists and ethicists knowledgeable about the HIV/AIDS vaccine trials in India are asking about phase-1 trials here of tgAAC09, a recombinant adeno-associated viral vector-based candidate vaccine against HIV infection.
But such questions have been met with a deafening silence from the India office of the International AIDS Vaccine Initiative (IAVI) which has coordinated research and development of the vaccine. Sweta Das, director programme operations, IAVI-India, acknowledged a list of questions sent to her office on Apr. 2 but did not reply to them.
Some of these questions are asked in an editorial in the Indian Journal of Medical Ethics entitled ‘AIDS vaccine trials in India: ethical benchmarks and unanswered questions.’ The editorial’s authors are Amar Jesani, advisory board member of IAVI, and Lester Coutinho, former consultant with IAVI.
IAVI-India and the National AIDS Research Institute in Pune collaborated to test this vaccine candidate in India. The vaccine was developed, with IAVI funding, by the United States-based Targeted Genetics Corporation (TGC).
IAVI, a nonprofit organisation founded in 1996, states that its mission is to ensure the development of safe, effective, accessible, preventive HIV vaccines for use throughout the world. With offices in New York city and Washington, D.C., and representation in Europe and Africa IAVI benefited in 2001 from a US 100 million dollar challenge grant from the Bill and Melinda Gates Foundation.
Phase-1 trials for safety and immune response of tgAAC09 were started at NARI on Feb. 7, 2005. A total of 30 healthy human volunteers were eventually injected with the vaccine.
But the results of phase-1 trials on 50 volunteers in Belgium and Germany, started in December 2003, were already known unofficially, says C.M. Gulhati, editor of the Monthly Index of Medical Specialities, India and an expert on clinical trials.
“Preliminary results indicated that tgAAC09 was not working well at all,” said Gulhati. “The trial had virtually collapsed. Why permit the same phase-1 trials in India?”
The India trials may have been done in the hope that the population here would have a better immune response to the vaccine, says a senior virologist familiar with HIV vaccine research in India, who does not wish to be named. “But at the very least, they should have waited two weeks till the Europe trial results were out.”
On Feb. 22, barely two weeks after the India trial started, TGC announced the Europe trial results: “a single administration of the vaccine at the doses evaluated in this initial study did not elicit significant immune responses,” though “no safety concerns were identified” either.
The insignificant immune responses were in contrast to expectations when the Europe trial started: “Results to date demonstrate safety and suggest the ability to elicit robust immune responses after a single injection,” said Philip Johnson, president of Columbus Children’s Research Institute and, with Targeted Genetics, the developer of tgAAC09 and the rAAV technology underlying it, in a press release when the trial was launched in Belgium in 2003.
Did IAVI and Targeted Genetics share the preliminary findings of the Europe trial, ask Jesani and Coutinho in their editorial. Did the Indian collaborators ask to examine the foreign data before starting the India trial?
“This apparent lack of communication raises questions on the nature of the partnership between the Indian and overseas partners,” they write.
The Pune site was originally being prepared for TBC-M4 (Modified Vaccinia Ankara HIV-1 multigenic subtype C) to be tested at NARI. The senior virologist suggests that stability problems with the MVA vaccine led to its replacement by the tgAAC09 vaccine. “The NARI site was ready, another vaccine came along and the opportunity was utilised.” The MVA trial started two years later in Chennai.
If experts were surprised by the hasty beginning of the NARI trial, they were even more shocked to find that in November 2005, phase-2 trials (for immunogenicity) of the vaccine were started — not in Belgium, Germany or India but in Zambia, Uganda and South Africa.
Critics speculate that the Africa sites were chosen because of the lower costs, because there is a large pool of treatment naïve and high risk volunteers — and because these countries would accept phase-1 data from other countries. “They are taking advantage of lax regulations in Africa,” Pune-based health activist Anant Phadke told IPS.
“They may also have been driven to test this vaccine in another genetically distinct area — distinct for virus strain as well as human population,” says the virologist, conceding that the Africa trial might have some rationale. “Only a dose-escalation phase-2 will actually tell whether the vaccine raises the right types of immunity, and genetic diversity would have a major impact on vaccine-elicited immune responses.”
However, “it is not good practice to use safety data from one population to drive phase-2 trials in another population,” notes the virologist.
Gulhati opined that ‘’no one would have permitted phase-2 trials in Germany or Belgium on the basis of the unsatisfactory phase-1 results.”
Doubts have been raised about the vaccine itself. “This is a weak vaccine and should not be pursued in a phase-2,” says the virologist. “A vaccine with any hope for even partial success should aim to achieve more than a ’20 percent modest immune response’. Also consider that this vaccine construct has only one HIV gene (gag). It is clear from literature that the breadth of immune response is important, i.e. a response to multiple HIV proteins.”
Targeted Genetics’ own press release reports a “modest” immune response against gag, the principal HIV protein encoded by tgAAC09. Though animal trials elicited both T- and B-cell responses, only HIV-specific T-cell responses were observed in the human trials, and that too in barely one in five participants receiving the highest dose of tgAAC09 tested; antibody responses were not observed.
Preparations for the HIV vaccine trial involved extensive consultations and negotiations, establishing ethical benchmarks for all clinical trials in India, acknowledge Jesani and Coutinho in their editorial.
“The informed consent and participant information documents disclosed all known risks and clearly stated the right to withdraw from the trial at any stage. Guidelines for recruitment prevented coercion and exploitation of the poor and uneducated. Participants who became HIV positive during the trial would receive free access to care, support and treatment, including anti-retroviral therapy, for five years, and, all participants were insured for care, treatment and compensation for trial-related injuries.”
Few argue with the desperate need for an HIV vaccine in India which sees hundreds of thousands of new HIV infections each year. Jesani and Coutinho also ask why there is no systematic effort to develop a therapeutic vaccine to reduce the viral load in those already infected with the virus. It would pose fewer ethical challenges, they write, and it would also be cheaper to vaccinate infected people alone.
They conclude with food for thought on the driving forces behind vaccine research today: “The field of vaccine development today is shaped as much by philanthropy as by competitive market interests, global institutional arrangements of intellectual property rights, patents, scientific capacities (or the lack thereof), and the interests of investors and shareholders.”
(*Sandhya Srinivasan is executive editor of the Indian Journal of Medical Ethics published from Mumbai) (END/2007)