A major step in HIV vaccine research, but much more to do

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Louis Picker, MD, associate director of the Oregon Health & Science University’s Vaccine and Gene Therapy Institute.

In commemoration of HIV Vaccine Awareness Day (May 18), Science Speaks conducted the following interview with Louis Picker, MD, associate director of the Oregon Health & Science University’s Vaccine and Gene Therapy Institute (VGTI). Dr. Picker led a team of researchers from VGTI, the National Cancer Institute – Frederick, and the International AIDS Vaccine Initiative that reported a promising HIV vaccine approach in the advance online edition of the journal Nature last week.

Investigators gave 24 healthy rhesus macaque monkeys a vaccine for simian immunodeficiency virus (SIV), the monkey equivalent of HIV, containing a genetically modified form of the Rhesus cytomegalovirus, which is used as a “vector,” or a carrier that transfers an infective agent from one host to another. Thirteen of the monkeys responded to the vaccine, with 12 of the monkeys showing no signs of SIV infection 12 months later.  Authors say this will significantly contribute to the development of an effective HIV vaccine for humans.

Meanwhile, a paper in The Lancet Infectious Diseases reports a vaccine trial in South Africa (HVTN 503- Phambili Study) involving 801 patients was halted due to lack of proof of efficacy. Despite set-backs, many remain optimistic that the scientific community will succeed in developing an effective HIV vaccine.

Dr. Picker discusses key elements of his SIV vaccine study and its implications for developing an effective HIV vaccine, including projecting how long until a human trial will begin, below.

How different are SIV and HIV, apart from the obvious?
Apart from that one infects humans and one infects monkeys? Both HIV and SIV came from SIV in African, non-human primates or simians. HIV actually came about through a type of SIV found in chimpanzees.

SIV is quite similar to HIV in terms of virologic characteristics, immunity, and pathogenesis (including onset of AIDS), but SIV tends to be more pathogenic.  The SIV strain used in our study manifests 50 to 100 times more viral replication than typical HIV in humans, and the onset of AIDS in monkeys infected with this SIV is approximately 10 times more rapid than in humans.

Otherwise they are very similar.

Explain to me, in layperson’s terms, what this study found. Why is this considered a “fresh” approach to an HIV vaccine?
First, we need a little more background. These viruses, both in the Lentivirus group, are different from other types of viruses in that once the infection gets established, it is no longer controlled by the immune system. So, with infrequent exceptions, persons infected with HIV that are not treated with antiretrovival drugs will eventually progress to AIDS. The problem with this pathogen is that there is really no good natural immunity that you can mimic with a vaccine. So, we’re in a situation where we’re trying to do better than nature as we create a vaccine.

Our hypothesis was that the virus would be much more vulnerable to immune response early on, right at infection. We know that infection is started by one or two viruses only and that the infection takes a while to establish itself – so we want to intercept the virus at that early stage. Most vaccines developed so far have been unable to do that.

Our goal is to develop a vaccine that will generate a T-cell response (think armed troops in place at the borders) early in the first few days after infection. This is the difference between this vaccine and previous T-cell vaccines. This approach takes advantage of our understanding of how T-cells work – if you want armed T-cells at the beaches, you need a vaccine that’s persistent and keeps its arms up throughout. Ordinarily, T-cells go back to “base” – they fight off an infection and then go back to their dormant, resting phase. This vaccine is designed to keep the armed troops at the border (viral entry site) and ready to go, always. We call these effector memory T-cells.

To achieve this, we took pieces of a persistent cytomegalovirus (CMV) and we put bits of SIV into that CMV. The CMV is able to persist, meaning the T-cells are kept constantly at arms, and we found that it maintains these effector memory T-cells at the entry sites basically for life.

What is cytomegalovirus?
CMV is a herpes family virus – it’s different from herpes simplex but a member of that family. It’s ubiquitous and by that I mean the majority of humans on this earth are infected. Virtually everyone in the developing world is infected and about 50 percent of people in the developed world are infected.

Infecting people with a form of CMV would basically be giving them a version of something they already have. The vast majority of people don’t even notice when they’re infected. So we co-opted this virus to make the vaccine vector, so we wouldn’t be infecting people with anything new.

The press release says that the vast majority of the animals have maintained “control over the virus” for more than a year… does that mean they are still infected?
This statement is in reference to the SIV in CMV vector-vaccinated animals that were protected.   SIV was not detectable by conventional test, but special highly sensitive tests revealed traces of viral nucleic acid.  So even though we could not find replication competent virus, we can’t say outright the infection was cleared.  So, either the virus is controlled at an unprecedentedly low level or its was cleared.

Thirteen of the 24 primates that received the vector were able to control the “SIV challenge” and take it to undetectable levels almost immediately. Twelve of them, or 50 percent, were long-term controllers. This is unprecedented. You don’t see this with many other vaccine candidates.

In the first 30 weeks, there was the occasional blip of viremia, but then that would go away. It was clearly a very strong control even in the first 30 weeks, and any evidence that these monkeys had been infected at all started disappearing after 30 weeks.

After a year or so, we had to develop super sensitive tests to look for infection in the tissue of the animals. We even tried several ways of getting the virus to pop back out, such as CD8 depletion, and those were unsuccessful. It was really quite remarkable.

Is this the best result we have had to date in a vaccine tested in primates?
This is the most promising nonhuman primates (NHP) result for a T-cell targeted AIDS vaccine for sure.

What’s next? Human trials?
There are actually some important steps before we get to that point.

As I said, CMV is ubiquitous and however many billion people are infected, about as many go through life without any signs of infection.  However, CMV can cause disease in certain instances. It can be an opportunistic infection at late-stage AIDS, but that’s not really relevant here. It can be a problem in transplant patients. But if you inadvertently gave a “wild-type” CMV vector (or CMV with bits of HIV in it, as we used in the study) to a pregnant woman or someone with an immune deficiency, you could potentially have a problem. In a pregnant woman, CMV can potentially cause fetal damage. While  fetal CMV is rare overall, its still an important cause of fetal infections. To avoid this, we have to develop a CMV vector that is safe even in those circumstances so there is little or no chance of causing disease. To do that, we are going to retain the good part – the immunogenicity – but take away CMV’s ability to cause disease.

Preliminary data available suggest that this is possible, but it will take about three years to develop and engineer a safe vector.

Four years from now, if all goes well, we hope to move forward with human clinical trials. I liken it to climbing Half Dome. If making an AIDS vaccine is like a cliff like Half Dome that you want to climb, at the bottom it looks overwhelming and impossible. This study shows there is actually a path to the top. But even with the path, you still have to do the climbing.

Why do we still need a vaccine?
If everyone could be treated with antiretrovirals (ARVs) then you would definitely have an impact on the epidemic, but that seems to be a long way off, especially in resource-limited countries. The HPTN 052 study results announced last week that show that if an HIV-infected person takes ARVs it suppresses their virus and the chance of infecting an HIV-negative partner much less… that finding is not a surprise in itself, but what is surprising is that the reduction in transmissibility is so great. It’s a positive thing – now you have a way to go forward with discordant partnerships.

But right now a lot of infections aren’t recognized and many that are recognized are not treatable, whether because there is not enough money or not enough drugs to go around. A vaccine that could prevent full infection would be preferable and really the only way to stop this epidemic. That’s not to say other approaches to preventing HIV infection aren’t important, and they will help, but it is not likely they are going to get us all the way there.

There are other suggestions that you treat those who are uninfected but at high risk, but that’s even harder to do on a worldwide scale at this point. When you can’t even treat everyone that has the virus, how are you going to treat those that don’t prophylactically? I think we still need a vaccine.

One thought on “A major step in HIV vaccine research, but much more to do

  1. Nkuza

    I think these are great news keep on doing the good work.More importantly I think all goverments should put more money to these research institute.So how long can we wait.


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