Scientists achieve the first proof of concept for an HIV broadly neutralising antibody vaccine in monkeys

In a step forward in the search for an HIV vaccine, Professor Denis Burton and colleagues from the Scripps Institute in La Jolla, California have manufactured an HIV vaccine that, with just one shot, induced six out of 12 monkeys to make antibodies that significantly delayed infection or (in two cases) even prevented it. The findings are published in the 15 January issue of Immunity.

Why we need a broadly neutralising antibody vaccine

We have had proof that an HIV vaccine can work ever since the RV144 trial in 2009. Currently two phase III trials – Uhambo and Imbokodo – are underway in Africa.

While it is hoped that these vaccines will have considerable efficacy, they are also a long way from the kind of one-shot, easily manufactured, very efficacious vaccine that would be needed for a global HIV vaccination drive. So research is ongoing into vaccines that could be cheaper and more potent.

The Uhambo vaccine requires five shots spaced over a year and the Imbokodo vaccine four. While there are reasons to hope that they will have greater efficacy than the 31% protection against HIV offered by RV144 – maybe as much as the 67% seen in monkeys in the predecessor to Imbokodo – it’s unclear how long this protection will last. As a result, people may need to repeat the vaccine every few years to maintain protection.

This would also make them expensive, and while one component of these vaccines – the “boost” of purified HIV gp120 envelope protein – is reasonably cheap to make – the “prime” is a vector vaccine, which involves encapsulating HIV gene fragments inside the shell of an inactive virus and is altogether trickier and more expensive to make.

Technical and financial barriers also pose challenges for vaccines further down the pipeline. There had been great excitement about the CMV replicating-vector vaccine that had resulted in an apparent reversal of infection in monkey trials several years ago. But this was extremely complex to engineer and making a safe version for humans has apparently proved impossible.

Broadly neutralising antibodies have been successfully used as so-called ‘passive immunisation’, which is really just using them like drugs; the HIV Research for Prevention (HIVR4P) conference recently heard about the AMP trial, which is using them as experimental PrEP (pre-exposure prophylaxis). Monkeys have even been cured of HIV by using gene therapies that induce their cells to make broadly neutralising antibodies.

How this new vaccine works

Importantly, though, this is the first time that effective broadly neutralising antibodies (bNAbs) to any infection have been generated in monkeys (indeed, in any mammals other than cows) by vaccinating them.

The vaccines already under study in Uhambo and Imbokodo produce normal anti-HIV antibodies that do have a significant effect. But a vaccine that induced the body to make bNAbs – which are normally only seen in some people after years of infection – would make a strong, and complete response to HIV much more likely in the event of exposure to it. This would be true ‘sterilising immunity’ that would repel, rather than just contain, infection.

Importantly, the vaccine was active against so-called ‘tier 2’ viruses. These are potent viruses that resemble those that cause ongoing infection and progression to AIDS in humans. Researchers often try out vaccines against ‘tier 1’ viruses at first; these are more susceptible to neutralisation by antibodies but are less pathogenic or easily transmitted.

The vaccine in this new trial is called the SOSIP BG505 env trimer vaccine. It is also based on the gp120 envelope vaccine like the boost vaccines in Uhambo and Imbokodo.The problem is that this protein does not generate an immune response by itself. This is because when detached from its viral ‘placeholder’ gp120 is unstable and does not remain in the shape it needs to in order to generate an effective and long-lasting immune response.

This shape is a trimer: a trio of identical protein subunits that looks a little like a fidget spinner. The gp120 protein needs to adopt this shape in order to infect cells. The trimer conformation also exposes parts of the protein that are highly ‘conserved’; the virus finds it difficult to change these without losing function, and so can’t mutate away from any immune responses generated to it.

The vaccine in this study is stabilised by ‘bracing’ the gp120 trimer with rigid molecules that feature two sulphur atoms (SOSIP stands for sulphur-oxygen-sulphur induced potency). This generates soluble, stable gp120 trimers than can, it is hoped, be relatively easier to make in bulk and be used for a variety of experimental vaccines.

The Scripps researchers already presented a study at HIVR4P where it was shown that the BG505 env trimer could elicit a significant immune response against HIV in the lab dish and that the responses it generated, while not as strong, were more broad-spectrum than responses generated by actual viral infection.

The Scripps vaccine study

The Scripps researchers’ study was designed as a proof of concept study rather than an efficacy or dose-finding study. Its aim was to show that protective levels of broadly neutralising antibodies could be achieved with a single HIV vaccine inoculation, and to find out what level of antibody response would confer protection against HIV.

The researchers vaccinated 78 monkeys. Because of their aims, they then picked the monkeys with the six highest antibody responses and then matched them with six of the low-responders, matched for gender, age and weight. They also compared these responses with six control monkeys who were not vaccinated but were challenged with a monkey-adapted form of HIV (simian HIV, or SHIV) – as were the vaccinated animals.

The viral challenge consisted of six weekly rectal doses of the pathogenic SHIV BG505 virus, which was the one whose envelope protein was used as the basis for the vaccine. Again, because this is a proof-of-concept study, the researchers wanted vaccine and virus to be the best ‘fit’ possible. In later studies, one would want to use other viruses to demonstrate that the antibodies generated by the vaccine had the broadest efficacy possible. The virus dose given should, it was calculated, infect at least 75% of monkeys after one challenge.

The SHIV BG505 challenge was introduced four weeks after the vaccine inoculation. In the high-titre monkeys, because only two out of six were infected after six challenges, the researchers waited for five weeks and then gave six more weekly challenges.

Antibody response is measured by titre. This means the degree to which blood plasma or other antibody-containing fluid has to be diluted before the antibodies become undetectable in an assay. This is an easier and more reliable test than directly quantifying the amount of antibody proteins.

The six highest responders had an average antibody titre of 1:3750, meaning that antibodies in their blood plasma remained detectable up to a solution of one part blood plasma in 3750 parts of saline. The average titre of the lower responders was 1:103, or a 36-fold lower response.

Interestingly this was a lot higher than the antibody response seen in control animals when they were infected, which ranged from 1:102 in the highest responders to less than 1:10 in the lowest responders.

Levels of efficacy

Five of the control animals were infected after the first dose and one after the second, which roughly corresponds to the 75% transmission efficiency predicted.

The vaccine was slightly effective in the low-titre monkeys. Two of these were infected after the first challenge and the other four after the second. Although this was not statistically different from the infection rate in the non-immunised monkeys, they did develop a lower viral load. The average peak viral load in the control animals was 5.5 million copies/ml but 150,000 copies/ml in the low-titre immunised monkeys. One animal had two periods with a viral load below 50 copies/ml in the 20 weeks after infection.

In contrast only one of the high titre monkeys was infected after the first set of viral challenges and so a second set was started at week eleven after the first challenge. One other monkey developed a viral load between the two sets of challenges, and two more were infected at the tenth and twelfth challenges. However, two monkeys remained uninfected. Average peak viral load in the four infected monkeys was 32,000 copies/ml. The average number of challenges before the high-titre animals were infected was eleven, corresponding to a short-term efficacy of the vaccine of roughly 90%.

Antibodies to SHIV BG 505 developed eight to 12 weeks after infection, not too dissimilar to the length of time taken for a full antibody response to develop in human infections. The immunised animals that were infected already had antibody responses to SHIV due to the vaccine; after infection, they developed stronger ones, and these developed only one to two weeks after infection.

The researchers were able to calculate that an antibody titre of just under 1:500 corresponded to 90% protection against SHIV. None of the low-titre monkeys developed this level of antibodies prior to being infected but all of the high-titre animals did. Antibody titres did fall in the four high-titre monkeys that were infected over the course of the first eight to 12 weeks and they were infected when their antibody titre fell on average below 1:200. In contrast the antibody titre of the two uninfected animals fell to 1:700 by 15 weeks after immunisation but after that plateaued at that level.

The only immune parameter associated with protection from infection was the antibody titre – the general levels of antibody proteins in the blood. Other measures of immune activation such as anti-HIV CD4 cell response were not predictive of protection.

This vaccine study is very much a first, and because of its design we don’t even know how many monkeys in general would be protected by such a vaccine. But it does enable scientists to predict whether similar vaccines designed to produce broadly neutralising antibodies will be effective without having to mount viral challenges, which should shorten the process of research. And above all it marks the first time scientists have ever induced a mammal, other than cows, to make these rare, exotic and potent antibodies in response to a vaccine.