Groundbreaking HIV vaccine's effects were real – and could be made to work better

Findings from further studies using a reformulation of the only HIV vaccine that has ever worked in a large efficacy trial were presented at the recent HIV Research for Prevention conference (HIVR4P). They showed evidence of stronger antibody responses, and in-depth analysis of these responses shows that by further developing a similar vaccine it may be possible to push the immune system into generating an antibody response to HIV that is sufficiently strong to prevent most infections.

The RV144 vaccine had such a slight beneficial effect that when its results were first announced, some people wondered if they were not just a statistical fluke. In its original trial in Thailand, it did prevent four out of ten HIV infections that would otherwise have happened, but the results observed were only just statistically significant. This was largely because the vaccine’s efficacy appeared to wane with time – if the trial had been stopped a year after the first injection, its efficacy would have been 60%. It also seemed to have little effect in people at higher risk of HIV such as people who inject drugs and gay men.

At last year’s AIDS Vaccine conference in Barcelona, however, several studies were presented that showed the RV144 vaccine’s effects were real and depended on a very specific kind of antibody response to HIV that developed in some, but not all, vaccine recipients.

Vaccine produces better results in South Africa than Thailand

Glenda Gray, head of the South African Medical Research Council, presented the results from a small study, HVTN097, which gave a version of the RV144 vaccine protocol to 100 volunteers (51 men and 49 women).

The vaccine actually contains two components. One is a vaccine called ALVAC. This is a vector vaccine, consisting of HIV proteins encased in the shell of another virus. This 'fake infection' is intended to stimulate the cellular immune response: this is the part of the immune system that stimulates CD8 cells to attack other, infected cells. It was given in four components: zero, one, three and six months from the start of the study.

The other component is called AIDSVAX. This consists of HIV envelope (surface) proteins intended to stimulate the humoral immune response: this is the part of the immune system that generates the soluble proteins called antibodies that directly attack viruses. It was given at month three and month six.

Why has it taken so long to re-try a vaccine that produced positive results five years ago? The main problem is that expectations of the original study were so low that Vaxgen, the company making AIDSVAX, used all its stock and did not make more; the vaccine has had to be re-manufactured from scratch.  

As was observed in the original study, the South African vaccine did not stimulate the cellular immune response to a useful degree. Some degree of immune response to HIV was stimulated in volunteers’ CD4 cells, and was more common and stronger in the South African trial: 69% of South African volunteers’ CD4 cells became sensitive to HIV as opposed to 50% of original vaccine recipients’ cells. However, there was little evidence of the desired CD8 response – only 5% of South African and 0.6% of the original Thai recipients had CD8 responses.

In contrast, and as seen in the original study, there was a strong and universal antibody response generated to the gp120 component of HIV. This protein forms the ‘knobs’ on the surface of HIV that attach to cells and is one of the components of AIDSVAX. There was also a near-universal (98.6%) response to a specific part of gp120 called the V1-V2 loop, a section of the protein chain that first attaches to cells. More analysis of the immune responses is underway and it looks as if the antibodies generated in the vaccine recipients in South Africa have a stronger effect against lab-engineered HIV viruses, being able, for instance, to neutralise (disable from reproducing) 25% more clade B viruses than Thai-recipient antibodies.

In January 2015 a new study, HVTN100, will give trial volunteers a vaccine based on RV144 but reformulated to contain proteins from the HIV subtype (clade) most common in south Africa, namely clade C instead of the Thai clade A/E. Depending on efficacy, this could then lead to a much bigger efficacy trial.

Thai vaccine boost regenerates immune response

In the original RV144 study, it had been found that an effective immune response to HIV depended on being on the right side of an antibody balance. Two different kinds of antibody response were generated, a dominant one of the antibody types called immunoglobulin A (IgA), and a less dominant one called IgG. The higher the ratio of IgG to IgA the more effective the immune response; indeed a high ratio of IgA to IgG actually enhanced vulnerability to HIV infection.

In a Thai study, RV305, volunteers for the original RV144 study were recalled and – eight years after they first received the vaccine – were given it again. Analysis showed that this boost produced a similar antibody response to the original vaccine; 70% of volunteers who received both vaccine components produced IgG antibodies to HIV and 56% of those who just received AIDSVAX, while 10% and 14% respectively had antibodies specific to the V1/V2 loop.

The IgA response was roughly ten times as strong as the IgG response but, significantly, no IgA specific to the HIV gp120 protein was found in rectal secretions. This suggests the vaccine could be ‘fine turned’ to produce more specific responses.

This immune response, however, is only active against varieties of HIV that are relatively easy to disable, so-called ‘tier 1’ viruses. The reason HIV vaccines are not more effective is that during infection, HIV and the immune system are locked into an arms race that HIV generally wins, staying one step ahead of the body’s response to it. While the body develops ever more elaborate antibodies, and about 35% of people eventually develop the so-called ‘broadly neutralising’ antibodies that can disable most transmitted viruses, the virus gets there first, always having mutations in hand of higher-tier viruses that are antibody-resistant.

Passive-immunity studies, in which volunteers are given injections of broadly neutralising antibodies, confirms that if we could get a vaccine to generate these antibodies from the start, they would be effective in repelling the vast majority of viral invaders. The problem is that cells capable of doing this are initially extremely rare and it is only the continued provocation of the presence of HIV that drives the production of broadly neutralising antibodies. An ideal vaccine would be one that would, so to speak, fool the immune system into thinking that it had already been dealing with a chronic HIV infection for ten years or more.

Could repeated vaccine boosts push the body into an effective anti-HIV response?

How far along this road are we? Michael Moody of Duke University told the conference that a truly effective antibody response against HIV would need to have four characteristics.

It would need to generate significant numbers of antibodies to the V1/V2 loop of the HIV gp120 molecule. It would needed to be able to 'deglycosylate' gp120, which means it would have to penetrate a sticky coating of sugars that gp120 coats itself in as a defence against antibodies. It would need to have a specific affinity for two amino acids in the V1/V2 loops.

And it would need to have an unusual characteristic that only the rarest, most broadly neutralising antibodies have; this is an extended 'prong' in the part of the antibody called the third heavy-chain complementarity determining region (H-CDR3), which is able to penetrate parts of the gp120 protein that are highly specific to HIV’s ability to infect, and therefore not mutable – they are “conserved” – but which are only exposed for a fraction of a second during the infection process. (Essentially, antibodies with long H-CDR3s almost literally throw a ‘spanner in the works’ of HIV infection.)

Moody said that the vaccine boost in the RV305 study more than doubled the proportion of antibodies, from 2.56% to 5.52%, that had mutations indicative of a shift towards being able to broadly neutralise HIV. A much higher proportion (11.6% versus 1.35%) had H-CDR3 loops more than 21 amino acids long, which indicates that they may possibly have broadly neutralising ability. In addition, 2.4% of the antibodies produced had mutations specifically adapting them to particular glucose molecules and enabling them to bind very strongly to gp120. However, these were not the same antibodies as the ones with long H-CDR3s, in the main, and when these antibodies were isolated and used against a panel of viruses, it was still only the ‘tier 1’ viruses they could neutralise.

However, one specific antibody called Ab8850, which represented 2.5% of the total antibodies produced, was molecularly near-identical to an already-studied broadly neutralising antibody called CH04 – its H-CDR3 loop was just three antibodies shorter, and this made all the difference.

Moody said that so far we had not seen, in the RV144 research programme, production of an antibody with all four characteristics needed for it to fully neutralise HIV, but had progressed from producing antibodies with two of these characteristics to ones with three.

He speculated that repeated boosts of AIDSVAX or a similar vaccine could have the effect of ‘pushing’ the immune system into developing broadly neutralising antibodies that might eventually fully protect an individual against HIV – the obvious problem being that, with the vaccines we have at present, this might take several years’ worth of inoculations at considerable expense.

It might also depend on individuals’ genetic make-up too much to be widely applicable, but the principal that it is even possible to do this has now been established.