The Merck ad5 candidate AIDS vaccine, which appears to have increased the HIV infection risk of some trial participants (see this report), may have done so because it specifically increased the vulnerability of uncircumcised men to infection through insertive anal sex, the Fifteenth Conference on Retrovirues and Opportunistic Infections was told today in Boston.
This implies that the vaccine may have abrogated an immune response that was protective to uncircumcised men. This may (or may not) have been related to pre-existing immunity to the ad5 adenovirus, which was the vaccine’s ‘delivery vehicle’.
To summarise briefly: the Merck V520 ad5 vaccine consisted of three stretches of HIV genome taken from HIV’s gag, pol and nef genes enclosed within a shell derived from adenovirus type 5, a common virus that in its natural state causes common cold symptoms.
This viral shell was made replication-incompetent so that while it could initially infect cells and therefore stimulate a cellular immune response, it could not produce further generations of virus.
The STEP trial
In the STEP Trial, 1,500 volunteers at high risk of HIV in the Americas and Australia were originally recruited, starting in December 2004. They were largely gay men and female sex workers. Sixty-two per cent were male and the average age was 29. They were at high risk of infection, with 25% of men and 50% of women having had at least 20 sex partners in the previous six months.
Originally, people with high levels of pre-existing immunity to the Ad5 adenovirus had been excluded from the STEP trial, but a decision to double the trial’s size had been taken in August 2005 when reasonable immune responses were observed in this group. The trial had reached its target of 3,000 volunteers by March 2007.
The trial was stopped in September 2007 when its data and safety monitoring board realised that the vaccine conferred neither a protective effect against HIV infection nor any effect on the subsequent course of infection.
However analyses of the trial data revealed a more alarming fact: there were more infections in the vaccine recipients than the placebo recipients – 49 versus 33, to be exact.
There was only one infection in a female volunteer, which is probably due to there being rather low levels of prevalent HIV infection in heterosexual men in the trial countries: an African STEP trial might have produced more infections in women. All the following analyses are therefore for male volunteers only.
Over the whole trial group, the difference in infection rates between vaccine and placebo recipients was only marginally statistically significant, with a probability of 0.044 if the effect observed was caused by the vaccine alone (so-called ‘one-tailed’ probability), and 0.077 if the effect was caused by some combination of a direct vaccine effect and some kind of protective characteristic of the placebo group that was removed (‘two-tailed’ probability).
In the group that had high levels of adenovirus immunity, however, there were 21 infections in vaccine recipients and only nine in placebo recipients, and this was statistically significant (p = 0.02 one-tailed, 0.029 two-tailed).
Adenovirus immunity increased infection risk in vaccine group
This suggested that the vaccine may either have generated an immune activation response that, perhaps by stimulating HIV-receptor cells, made people more vulnerable to HIV, or it removed an immune defence against HIV that was somehow conferred by pre-existing ad5 immunity.
Merck’s Mark Robertson, presenting preliminary data on immune responses in the trial, showed that volunteers with high ad5 immunity levels had higher levels of generalised CD4 cell activation. This difference was even more marked in HIV seroconverters than those who remained uninfected, so some kind of inflammatory interaction with the vaccine vector may be to blame.
But presenter Susan Buchbinder of UCSF said that the latter possibility appeared stronger. The incidence of HIV infection, at about 4-5% a year, was the same in vaccine recipients regardless of their ad5 immunity level. However the incidence of infection was lower in placebo recipients who had higher levels of ad5 immunity, ranging from 4% a year in those with the lowest level to 1.2% a year in those with the highest level. The vaccine may therefore somehow have removed a protective effect of ad5 immunity.
Both in a univariate model and in a multivariate model that progressively eliminated other possible confounding factors, high ad5 immunity conferred a threefold higher risk of infection in vaccine recipients than in placebo recipients, compared to no increased risk in people with low ad5 immunity when compared to the placebo group.
However, Buchbinder added, the real reason for the additional risk in vaccine recipients may have had little to do with ad5 immunity, or it may only have had an accessory role.
Uncircumcised men at greater risk
There was one more important risk factor for HIV acquisition in vaccine recipients when compared to the placeo group: circumcision, or rather, the lack of it.
Uncircumcised vaccine recipients were, in univariate and multivariate analyses, four times more likely to become infected with HIV if they received vaccine than if they received placebo. In contrast there was no difference at all in infection rates between circumcised vaccine versus placebo recipients.
In questions after the presentation, Buchbinder commented that the risk to uncircumcised men was greater than the risk to men with high ad5 immunity, and that the latter may be a passive marker for the former. This was because the men with high ad5 immunity, who were largely recruited in the second wave, also tended to come from countries and communities with lower rates of circumcision; they were younger and more likely to come from Latin America, for instance.
She also commented that preliminary data hinted that the enhancement of infection risk was specifically seen in uncircumcised gay men who largely or exclusively had insertive anal sex. This would imply that the vaccine was abrogating some immune mechanism that normally protected uncircumcised ‘tops’ from infection through the mucosa of the foreskin.
However, this would not explain in itself why placebo recipients were less likely to get HIV if they had high ad5 immunity, so the two effects may be synergistic.
There are still many questions left unanswered by the STEP trial. Buchbinder said that the trial participants would be followed to find out if the apparent extra vulnerability to HIV conferred by the vaccine was long-lasting, and Mark
Robertson outlined a whole range of other factors that would be analysed, including other immune activation markers and CD4 subsets, markers of genetic vulnerability to infection such as HLA genotypes, herpes (HSV-2) status, seminal immune-cell subsets and seminal HIV viral load in seroconverters, and so on.
Are we wasting our time with current vaccine research?
The STEP vaccine trial may, like another ‘failed’ trial, the SMART trial, generate a considerable amount of knowledge about HIV infection and vulnerability.
But it failed in its primary aim. After the STEP presentations, Ron Desrosiers of the New England Primate Research Centre at Harvard University and Neal Nathanson of the University of Pennsylvania mounted an elegant two-handed demolition of the entire current philosophy of HIV vaccine research, both saying that vaccine research had to go back to basic science and change its philosophy of generating similar ‘pipeline products’ to be tested in wasteful and expensive human trials.
Desrosiers said that the enormous genetic diversity of HIV, its ability “to replicate unrelentingly despite everything the immune system can throw at it”, the fact that the immune system cannot protect against superinfection, and the fact that we do not currently know what constitutes an immune response to HIV, all persuaded him that at the current time an effective HIV vaccine “is not feasible”.
We should not be surprised the Merck vaccine failed, he said, because strictly-designed monkey studies had already shown it was not protective; it also contained only one single genetic sequence of each of its three HIV antigens, compared with the thousands of variants HIV could throw up. For similar reasons, he believed that none of the products in the current vaccine pipeline stood any reasonable chance of showing efficacy.
He said that repeated trial failures might have serious ramifications both in terms of ‘donor fatigue’ – which could reduce funding for basic science as well as efficacy trials – and ‘volunteer fatigue’ in affected communities.
He accused the US National Institutes of Health, the largest single funder of HIV prevention technologies, of “losing its way” in its vaccine research strategy. And he said that advocates who bemoaned the lack of pharmaceutical company interest in vaccines were misled.
“The discoveries that are going to lead to a successful vaccine have not been made yet,” he said. “The drug companies know this, which is why, with the exception of Merck, they have not got involved. Once an HIV vaccine does become possible, pharma will jump on development and research.”
He urged a return to basic discovery research, and instanced work being done with artificial viral vectors that actually generate broadly neutralising antibodies against HIV (beginning to be recognised as essential in a vaccine) themselves, instead of trying to stimulate the body to make them.
Neal Nathanson, though less robustly, broadly agreed. He said that he and other researchers had long ago defined HIV as a virus “that defies vaccination”. He too urged a return to basic science such as the devising of genetic assays to search for broadly neutralising antibodies, and said that the marginal effects seen so far in lowering HIV viral load in human volunteers did not justify further large human studies such as the imminent PAVE study.
He ended on a note of optimism, saying that HIV could be controlled even in the absence of a vaccine, and citing Botswana as a country that was not only becoming able to treat all its citizens who needed antiretrovirals, but was also beginning to achieve reductions in HIV incidence.
Robertson M, Buchbinder S et al. Efficacy results from the STEP Study (Merck V520 protocol 023/HVTN 502): a phase II test-of-concept trial of the MRKad5 HIV-1 gag/pol/nef trivalent vaccine. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 88LB, 2008.
Robertson M et al. Immunological characterization of subjects from the STEP Study: a phase IIB test-of-concept trial of the MRKad5 HIV-1 gag/pol/nef trivalent vaccine. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 89LB, 2008.
Desrosiers R. Scientific obstacles to an effective HIV vaccine. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston. Plenary presentation 91, 2008.
Nathanson N. AIDS vaccine at the crossroads. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, plenary presentation 92, 2008.