Can you give us some background regarding the trial conducted in Channai?
The trial is the study of a pox virus vector called modified vaccinia Ankara. It is based on the old smallpox vaccine, vaccinia, which is a weaker virus somewhat related to smallpox. There have been a number of groups who have tried to use poxvirus vectors. The most advanced of these is a somewhat related vector called Alvac, which is currently being studied in a large trial in Thailand to see if it protects against HIV infection and AIDS.
The HIV genes of interest are placed into the MVA so it acts as a carrier. The MVA vector delivers the HIV genes - or partial genes - to the right immune cells with the goal of stimulating an immune response. There are a number of studies that are going on in Europe and the U.S. and Africa with such vaccines. IAVI decided to work with the Indian Council of Medical Research, the Indian government's public health organization, to create a vaccine that was tailored for India using the type of HIV found in India. The general group is Clade C and is very prominent in Asia and Africa.
What were the results of the Phase I study, and why were they significant?
The trial evaluated immune responses to the vaccine at two different doses, low and high. After three injections, more than three quarters of people responded to the low dose, and all people responded to the high dose. It is unusual to see such a high proportion of volunteers register immune responses to a candidate vaccine. In most HIV vaccine studies conducted to date, there have been a certain number of people who did not respond, even in vaccines that were considered promising. We must remember, however, that this was a small study, making it hard to generalize too much about the results. But it was certainly promising.
The other thing that was good about these responses was that they seemed to last longer than we have seen with other MVA vaccines. This is important because in an eventual vaccine, we want the responses to last as long as possible because we want people protected for a long time.
The MVA-based vaccine candidate also seemed to have a reasonable level of breadth. There are a lot of immune targets in HIV and what you would like is for an individual to recognize many immune targets, not just a couple. That way if the individual encounters a virus that is different because of a mutation, he or she will still be protected from HIV infection. The more the virus changes, the more difficult it is to get a vaccine that covers a broad range of targets. Broad responses are something we consider good.
On the other hand, the strength of the immune responses was not very great. So we still feel there is some room to improve on the vaccine candidate, and our next step would be to try a preliminary vaccination with a DNA vaccine to try to enhance these responses.
What does the vaccine candidate target on HIV?
The vaccine candidate has six inactive HIV genes in it, including the envelope and several genes from the core of the virus. It also has regulatory genes that control the growth of the virus. Nobody knows which genes should be targeted. That is a big topic of research.
Do the issues raised by the Merck trials cause any concern for these trials?
The Merck vaccine candidate and the MVA-based vaccine candidate tested in this trial are two different vaccines and are designed to work in different ways.
We do not know exactly what caused the vaccinated volunteers in the Merck trial to have a potential greater risk of contracting HIV if exposed to the virus. The risk seemed greatest for individual men who were uncircumcised and had pre-existing antibodies to the Ad-5 vector used in the Merck vaccine candidate itself. The MVA-based vaccine candidate does not use an Ad5 vector, and most people have never encountered a virus like MVA, so we would not expect to see the same issues arise.
That said, results from the Merck trial were completely unexpected. And there is a concern with any vaccine candidate that when you induce an immune response, people could become more likely to get infected should they be exposed to HIV. It is important to note that no vaccine candidate can cause HIV infection.
At this point with the MVA vaccine, we are at an early stage of investigation and the people who are selected for the trial are not at risk of HIV infection. We select people specifically to be low risk. We ask them about any potential risk they might have and then we counsel very carefully to make sure each person understands how one becomes infected with HIV and how to protect themselves. We explain to them that it is not known whether this vaccine will make you more or less susceptible or whether it will make AIDS-related disease progress more quickly.
We are not very concerned in the short term about an effect similar to what happened in the Merck trial, because the first trials are in people at very low risk of exposure to HIV, and they are well-educated about how to protect themselves. In the long term, of course, each step in the progression of any candidate vaccine, will be taken with great caution; that is true for MVA, should this vaccine turn out to be sufficiently promising to go to efficacy trials. I would point out though that the other ongoing large-scale pox trial in Thailand, which is more related to the MVA vaccine, is being monitored by a data monitoring board, and they would have stopped the trial if they observed any harm.
What is the next step?
We have proposed to do two additional clinical trials with this MVA-based candidate and a DNA prime to see whether we can improve upon the immune responses seen in this trial. Given alone, the DNA vaccine candidate is a little bland and does not cause big immune responses. We hope that, given together, both vaccine candidates elicit improved responses immune responses. That has been observed in other cases of DNA followed by MVA. So we are pretty confident that it will happen. We might see bigger responses, we might see longer lasting responses, and we might see broader responses. That is what we are hoping for. We have two trials that are proposed - one in London and one in India. We do not have approval for the one in India so we cannot speak of that much at this point.
(Reporting by Marc Landas)
