All Not Well With Global AIDS Vaccine Trials in India

[Guest guest]

All Not Well With Global AIDS Vaccine Trials

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 , 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)

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