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Highest immune response yet in TB vaccine trial

15 May 2008, 14:25

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by Robert Walgate

A vaccine in Phase 1 trials in South Africa has shown the highest CD8 responses – which are important for TB protection – of any TB vaccine candidate so far. The trial was small, but preliminary data from animal studies suggest the vaccine does protect against childhood TB.

With its growing drug resistance, and clever manipulation of the immune system, the slow-growing, air-‘breathing’ tuberculosis mycobacterium is a challenge to medical science, and particularly to researchers working to produce a vaccine. So recent news that one of the several vaccine candidates – the AERAS-402/Crucell Ad35 vaccine is producing a strong, positive immune response is very welcome. RealHealthNews interviewed the President of Aeras, Jerald Sadoff, about the result.

>RHN: Can you tell us exactly what this vaccine is?

Jerry Sadoff: It’s a non-replicating virus, an adenovirus Ad35 viral vector that makes TB antigens when it gets inside cells. We’ve tested it in the United States, in a Phase 1 trial, in people that had not been primed with BCG… [BCG, a weakened cattle TB strain, has been very widely used, since its introduction in 1921, as a childhood vaccine to provide limited protection against human TB] …and then we went into South Africa and we tested it, in the Phase 1 trial, in people that had had BCG at or near birth. And we started at low doses and then we went up to higher doses.

READ ON: The Aeras Global TB Vaccine Foundation

At the highest dose, we gave one group one vaccination and in the second group two. In both those groups, those that responded – and it’s about a 50-70% response – we found CD4 responses which were quite good, and we got some of the highest CD8 responses that we’ve seen for a TB vaccine, or for most vaccines that have been tested in humans to give CD8 responses… [CD8 cells, part of the immune system that helps kill TB bacilli, form an important arm of the body’s protection against TB.] …We saw this primarily in this group in South Africa where they had been given BCG before. We didn’t see quite such high responses in our studies in the United States.

Now, I have to emphasise these are very preliminary results.

>RHN: Well, sure. It’s a Phase 1 safety and immunogenicity trial.

JS: And the numbers are small. At the higher doses of three times ten to the tenth viral particles it was really only 20 volunteers, of which a couple from each group are placebos. The trial’s still blinded so it’s really in about 16 volunteers that we saw the responses at the high dose.

>RHN: Right, so it is pretty early.

“This gives more of a balanced response than we’ve seen before in other vaccines, and that’s why we thought it was important”

JERALD SADOFF

JS: Pretty early, but we were excited about it, because at least in the field of TB, most vaccines that have been tested so far in humans do not induce CD8 responses and it’s been recently shown that CD8 responses, at least in primates, are quite important in protection. So this gives more of a balanced response than we’ve seen before in other vaccines, and that’s why we thought it was important.

Now like I said, it’s preliminary and we have to repeat it with larger numbers of subjects. And, in fact, the study is going on right now in St Louis in the United States, where we’re actually giving people BCG and then waiting different lengths of time and then boosting them. So we’ll be able to see it in a much clearer way and in greater numbers.

>RHN: Do you have any understanding of why it has this effect in the BCG-vaccinated people?

READ ON: Crucell

JS: Well, it turns out, we designed the Ad35 vector, that we made with [the Dutch vaccine company] Crucell, to contain antigens [molecules that trigger the immune system] that are also in BCG. So BCG makes some of the same antigens that are in our vaccines. So it’s part of what we call a ‘prime-boost regimen’ where you prime with BCG and boost with something else.

Our ultimate goal is to make a recombinant of BCG that actually makes more of the same antigens that are going to be in the boost, and we’ve got those made and they should be going into humans this year as well. In our animal studies in non-human primates, we show even better responses when we prime with the recombinant BCG and boost with the BCG. But what we have now in humans is just BCG followed by the adenovirus vaccine.

>RHN: Yes, but the BCG is a childhood BCG in this case – so the ‘prime’ was a long time ago in adult patients.

“That’s what amazing – how long that prime effect lasts, it’s simply remarkable”

JERALD SADOFF

JS: That’s what amazing – how long that prime effect lasts, it’s simply remarkable. All along the way people could be exposed during their lifetime to organisms that may have something like these antigens in the environment, so we can’t prove that… But it is pretty remarkable, like you say that with BCG given at birth, you do see this very long priming up.

BCG you know, and our recombinant BCGs when we vaccinate, probably stay around in the body for a month or so. It is very unusual for vaccine to persist so long. Maybe that’s why it is such a good priming agent for later coming back with boosting.

>RHN: How good is BCG alone at protecting?

JS: BCG itself has been tested in lots of Phase 3 trials in the last 60-70 years. Early on and up to the 1950s, it looked like it was working, at least in the Northern countries, But in the most recent study, which is in the 1970s in India, a very large study which had over 200 000 volunteers didn’t show any efficacy at all.

However, the reason we use BCG even though it doesn’t work well, is that it probably saves between 40-70 000 lives [each year] because it does protect against disseminated disease [rampant TB, normally a disease of the lungs, that has spread to other organs of the body].

So we know BCG works to prevent, to a fairly large extent – 70 to 80% – against TB in places like the brain and in the bone. And so that’s why WHO continues to recommend its use worldwide to save at least those children’s lives. That’s why we can’t abandon it, we have to either improve on it or substitute for it with something that’s as good.

>RHN: So if it was only effective against disseminated TB, why use the BCG antigens again?

JS: Why do we use it at all?

>RHN: Yes.

“I don’t think that BCG ‘presents’ the antigens to the body in a way that necessarily makes it protective, that’s the problem”

JERALD SADOFF

JS: BCG makes a lot of the same antigens that TB makes… and when you look at people that have got TB and have controlled it, they have made good responses against these particular antigens. That’s how they were chosen. But I don’t think that BCG ‘presents’ the antigens to the body in a way that necessarily makes it protective, that’s the problem.

>RHN: Is it not possible that you’re getting this response to your vaccine simply because you are so to speak, detecting the BCG vaccination that’s already taken place? It still may not have any effect on the TB infection.

JS: Yes, and that’s an excellent question. Along those lines there are two things. We’re looking at BCG, or recombinant BCG boosted with this vaccine in non-human primates where we can actually challenge them [with TB itself, to see if the vaccine protects]. And our preliminary data from in the Netherlands shows that the recombinant BCG boosted with this vaccine, does give protection against childhood TB. But that’s also preliminary data and has to be repeated, and we’re doing much larger studies now.

READ ON: Press release on the AERAS-402/Crucell Ad35 vaccine

And the second thing we’re going to do to prove this, is we’re going to have to go into infants, which we could go into in South Africa, where we’re doing our trials, because they have a very high rate of [natural] infection there, and we can actually test a relatively small number – somewhere between 7-800 – and compare it to BCG and see if it gives better protection. So we’ll actually look in infants.

I agree with you, your question is the question we have in the field – will these better responses actually give better protection. The only way to answer that question is by actually doing protection studies in non-human primates and in small-scale test-of-concept studies. And we’re doing them.


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