New HIV vaccine enters human trials

Almost exactly 40 years ago, Parisian researchers Luc Montagnier and Francoise Barre-Sinoussi, announced that they had isolated the virus responsible for causing AIDS; they called it HIV - human immunodeficiency virus. In the wake of the discovery, which earned the pair a Nobel Prize, a bullish medical community predicted a vaccine within a few years. Yet 4 decades on, we're still waiting.

The evidence that it should be possible to make a vaccine is that if we look at people who have been infected with HIV for a year or so, often they make very powerful antibodies capable of stopping HIV - in all its different forms - in its tracks. By then, of course, for them it's too late, because the infection has already taken hold throughout the body. But if those antibodies could be produced by a vaccine before a person was infected, then they should be well protected.

The problem has been engineering a vaccine capable of making the immune system respond in the right way to do this. You need to show the body the right part of the virus in the right way to make the immune helper T cells cooperate with the antibody-producing B cells to generate high levels of antibodies. The virus has naturally evolved to thwart this process, and keeps the parts of its outer coat, or envelope, hidden from the immune system to reduce the chances of this happening. And that's why vaccines have been hard to make.

But now, Julie McElrath, at the Fred Hutchinson Cancer Centre in Washington, has developed a new way to do it: she's got what can best be described as a “molecular meatball” comprising a particle that has sticking out from its surface multiple copies of the linchpin part of the viral coat that she wants the immune system to react against. Because this effectively force feeds the immune system with the region of the virus that HIV normally strives to keep hidden, it provokes a strong response, which she's recently been able to test in human clinical trials…

Julie - So the vaccine is a particle and that particle is displaying a part of the HIV envelope, but in multiple copies, up to 60 different copies of it. By having all those copies and the fact that they're displayed in a way that it's going to ignite that really early process is key. So we're showing it the right thing. And then also the molecule that allows that to be held together as particle is also being seen. And so that also stimulates the T cell response as well. All of those factors help to get a really strong T cell response that can be pretty broad, and that way we can nurture the B cells in the way that they need to be nurtured in order to eventually mature into the response that we need.

Chris - So how have you tested this so far and what gives you confidence that you're on the right track?

Julie - So we've given the vaccine to healthy adults in two doses, two months apart, and blood is drawn before they get any vaccine and then it's drawn after they get each dose of the vaccine. And so we're looking for what is new, what has been induced by the vaccination. And so we can look at the B cells, we can look at the T cells, and we look at the antibody responses. And it's from looking at all three of those things that we can understand how the vaccine is working in particular for the T cells, we're looking to see what they're recognising and they're recognising the parts of the vaccine. The B cells are being activated by parts of the vaccine to make these antibodies that can recognise and important targets to neutralise an incoming virus.

Chris - Can you take samples of those antibodies from those human recipients and demonstrate that they're capable of neutralising the virus for real? Can you do tests like that to then prove those antibodies are capable of knocking the virus on the head where an incoming infection in those people?

Julie - We can do that. That's part of what is done in these studies. So you basically look to see, well, how does it do it? Can it block infection? So those are the types of experiments that have been done to determine what the response is in these vaccine studies.

Chris - HIV is notoriously slippery as a target. It's a shapeshifter, it continues to evolve and change its appearance. So what makes you think that the antibodies that you are making here to this vaccine will continue to protect against strains of the virus that are continuing to evolve in a population?

Julie - Yeah, with this vaccine, we're going after just one part of the envelope that we know is a target for neutralisation, but there are others, seven or eight of them. So it's very likely that we'll need to look at additional targets other than this one. But this is a start. Starting with one, which we think is a really important target. And then we'll be looking at other places on the envelope in a sort of similar way to try to attack that. Ultimately the vaccine that we come up with will likely have to target more than one site.

Chris - Wouldn't it be nice if this year, 40 years after Françoise Barré-Sinoussi, from the Institut Pasteur in Paris said, we know what the virus is that's causing this and we'll have a vaccine in no time. And that was 40 years ago. Wouldn't it be nice if on the 40th anniversary you do get this to work? Are you now going to move this in a phase two trial where you're actually going to see if vaccinating a susceptible group of people does lead to protection?

Julie - So the things that are in process now is to test this in the form of an mRNA, similar to that platform that's been used in COVID. And so we're looking at that because as you know, the mRNA technology allows us to move fast. They can be made quickly. And so that's happening. And then the other thing that is happening is we have to boost this response. So it's going to be a sequential vaccine approach. And so we're now looking at the second step, the booster.