Was the start of Phase II AAV AIDS vaccine trials in Africa in 2005 justified?

Published in The Hindu on December 20, 2007

During the beginning of this year, many questions were raised on why the AIDS vaccine trial in Pune was started on February 7, 2005, two weeks before the preliminary results of an ongoing trial conducted in Germany and Belgium were announced.

The central issue then was the failure of the International AIDS Vaccine Initiative (IAVI) to be transparent and not share the results of the Europe trial before starting the trial at the National AIDS Research Institute (NARI), Pune.

If starting the vaccine trial using an adeno-associated virus (AAV) vector in India days before the preliminary results were available has been criticised, conducting a Phase II trial of the same vaccine at five sites in Africa is shocking.

Phase II trials were started at three sites in South Africa in November 2005 and one site each in Uganda (February 2006) and Zambia (April 2006).

Starting Phase II trials

According to the Centers for Disease Control and Prevention (CDC), Atlanta, “advancement from one phase of a clinical trial to the next depends on the successful completion of the preceding phase.” It also notes that “if the vaccine produces the desired immune response and is well tolerated, a phase II trial is conducted.”

Alas, the start of the Phase II trials in Africa meets neither of the above mentioned criteria. The final results of the Phase I trials in Europe and India were announced only in February this year at a conference in Seattle.

The immune response from Phase I trials has been found to be about 20 per cent, much below the desired immune response required.

“I think we should not go for a Phase II trial till we get the data of Phase I trial analysed,” said Dr. Sekar Chakraborty, Deputy Director of the National Institute of Cholera and Enteric Diseases, Kolkata.

Dr. Chakraborty was responsible for producing the construct of the second AIDS vaccine (MVA) currently undergoing Phase I trial in Chennai.

So why did the trials ever start in Africa?

“Candidate vaccines that are proven to be safe in Phase I trials move on to Phase II trials, allowing investigators to test the immune response and acquire more data on safety,” noted an IAVI press release announcing the start of the Phase II trial in South Africa.

So if safety data from Phase I trial was the sole criterion to begin a Phase II trial, is it difficult to imagine the basis on which the Indian trial was started? Since the safety of the vaccine is assessed continuously, it will not be incorrect to assume that IAVI cared little about the preliminary immune response results before starting the trial at NARI, more so, as it was considered a part of one trial. This is considering that IAVI and the Indian authorities did not know the preliminary results before the start of the Pune trial.

That is not all. The dose of the vaccine used in Phase II cannot be more than the highest dose used in Phase I trial as the safety of such a higher dose has not been studied in the Phase I trial.

Dosage issues

However, that was not the case with the Phase II trials in Africa; the highest dose used was 3×10¹²  compared with the highest dose of 3×10¹¹ used in the Phase I trials. A booster dose (3×10¹²) was also used in Africa.

Extended Phase I trial

“It cannot be a Phase II trial. It can be called as an extended Phase I trial,” noted Dr. P.M. Bhargava, former Director of the Centre for Cellular and Molecular Biology, Hyderabad. Dr. Jacob John, Former Head of Clinical Virology, CMC, Vellore, said: “It is a mix of Phase I and II as the safety of the higher dose is not known.”

“I think they should not have used a higher dose than what was used in a Phase I trial,” said another scientist, who wished to remain anonymous.

It is difficult to imagine such a Phase II trial ever being conducted in a developed country.

Now coming back to the question of starting the trial in India, was it right to go ahead with the trial despite the fact that in 2005 there were no promising subtype C candidate vaccines worth pursuing?

The preliminary data from the two sites in Europe showed that the AAV vaccine was safe and well tolerated. But the immune response was only about 20 per cent.

Phase I trial looks for safety and levels of immune response. The immune response of nearly 20 per cent is well below the 60 per cent required by IAVI before moving forward to testing the vaccine for efficacy.

“The Phase I trial at NARI … was part of one joint international protocol in Belgium, Germany and India. … As this was part of one trial, the European data was not considered as a go/no go for the Indian portion of the trial,” explained Dr. Patricia Fast, Executive Director, Medical Affairs, IAVI in an email communication to this correspondent.

According to IAVI, the entire premise of the trial was to evaluate if there were any differences in the responses between the two populations.

Experts in the field of vaccine trial are refusing to buy this explanation.

“Not considering the Indian trial as a go/no go is not correct,” said Dr. Bhargava. While the safety of the vaccine seen at the two sites in Europe justifies trying it out in India, the immune response that has been below par does not.

Only marginal changes

“Marginal changes in immune response can be expected with injectable vaccines [when tried out in a different population] but not marked changes. There has been no recorded case of such marked changes,” Dr. Bhargava stressed. Dr. Chakraborty, agrees with Dr. Bhargava.

Even a booster dose given to the volunteers in the two European sites did little to improve the immune responses. The immune response seen in Pune was 20 per cent, the same as what was recorded in Belgium and Germany.

“All in all, I don’t think there was a case for conducting the trial in India,” Dr. Bhargava remarked.