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Optimism is not without merit, but the science remains incredibly fragile

By Richard Jefferys

We’re pretty optimistic in this 15-year period
we will get those two new tools.

—Bill Gates, World Economic Forum, January 23, 2015

Earlier this year, Bill Gates caused a ripple in the media by expressing optimism that a vaccine and a cure for HIV will become a reality within the next 15 years. Gates didn’t exactly offer a prediction, but the resulting headlines inevitably steamrollered over the subtleties: “Bill Gates Just Predicted We’ll Basically Have a Cure for AIDS in the Next 15 Years” trumpeted Business Insider; the Guardian chimed in with “Bill Gates Predicts HIV Vaccine by 2030.”

From TAG’s perspective, Gates’s buoyancy does have some scientific basis—there have been encouraging signs of progress on both the vaccine and cure fronts in recent years—but the challenges that lie ahead must not be underestimated.

The first compelling hint that vaccination may be able to prevent HIV infection in humans arrived in 2009 with the results of a large randomized clinical trial in Thailand, RV144. A prime-boost combination of an ALVAC canarypox vector and AIDSVAX B/E (a combination of gp120 proteins from clades B and CRF01_AE) reduced the risk of acquiring HIV by 31.2%—a slim but statistically significant degree of protection. After a disconcertingly long lag due to the need to produce new gp120 protein components— an example of the type of problem that can undermine predicted timelines—studies are now getting under way in South Africa that will begin to assess whether the RV144 results can be reproduced, and possibly improved, in other populations at higher risk of HIV infection.

A preliminary trial has shown that the original RV144 regimen induces immune responses that are at least comparable, and in some cases of greater frequency, in South African individuals. February 2015 saw the launch of HVTN 100, a clinical trial that will evaluate the safety and immunogenicity of modified versions of the vaccines based on HIV-1 clade C, the prevalent virus in South Africa, and also include an additional boost after 12 months (analysis of RV144 after the first year suggests protection may have been around 60% at that early period, providing a rationale for the extra immunization). Should HVTN 100 prove successful, a 5,400-person follow-up efficacy trial will be conducted (HVTN 702) with the potential to lead to licensing of the regimen if a sufficiently significant degree of protection can be achieved. The Bill & Melinda Gates Foundation is a member of the Pox Protein Public Private Partnership (P5) that is sponsoring this research. The work of the P5 may represent the best hope for the development of a licensable vaccine within the time frame Gates cited in Davos, but there is no guarantee that efficacy will be demonstrated.

There are other burgeoning areas of HIV vaccine development that hold promise, but are at an earlier stage. New technologies have contributed to the identification of many broadly neutralizing antibodies (bNAbs) capable of potently inhibiting multiple HIV isolates from all clades. There is now an intense focus on creating strategies capable of coaxing B cells into generating bNAbs using sequential immunizations with HIV antigens specifically designed for this purpose. Researchers have also made progress in constructing HIV envelope proteins that more closely mimic the natural form—the three-pronged trimer structure is unstable, making it difficult to preserve for creating vaccine antigens—and preliminary results in animal models suggest that this approach may induce antibodies with improved neutralization capacity.

A potential shortcut to providing bNAbs to individuals at risk for HIV infection is passive immunization using a gene transfer approach. A phase I human trial began last year in the United Kingdom testing an adeno-associated virus (AAV) vector as a delivery vehicle for a gene encoding a bNAb. The AAV takes up residence in muscle cells where it acts as a factory for manufacturing the antibody; however, it remains to be seen if protective levels of bNAbs can be obtained. The technology also needs to be proven safe in healthy HIV-negative individuals.

An alternative means of protection involves rapidly eliminating infected cells before they can ignite a systemic infection. Evidence suggests that this type of mechanism may have been involved in the outcome of RV144, since the vaccine regimen did not induce neutralizing antibodies. Rather, researchers believe that antibody-mediated cellular cytotoxicity, in which non-neutralizing antibodies flag infected cells for destruction, played an important role. Work is under way to develop methods to maximize this activity with future vaccine candidates. Macaque studies involving a replicating CMV vector have shown that effector T-cell responses could have the potential to clear HIV infections, and several vaccine candidates based on other replicating vectors are under evaluation in early clinical trials (with the CMV
vector possibly entering human testing in the not-too-distant future).

While no particular HIV vaccine strategy in the pipeline is certain to bear fruit in the next 15 years, the field clearly is far from fallow, and there is at least reason to hope that Bill Gates’s optimism will turn out to be justified.

A larger question mark may hang over the near-term prospects for a broadly effective HIV cure. Timothy Brown is still the only individual considered cured; he has not shown any signs of a viral return since receiving two stem cell transplants from a donor lacking the CCR5 co-receptor (part of a daunting and risky series of treatments he required for a life-threatening cancer eight years ago). The doctor responsible for Brown’s transplants, Gero Hütter, recently published a letter describing six other HIV-positive individuals with cancers who received stem cell transplants from CCR5-negative donors; sadly, none survived more than a year, due to either cancer recurrence or complications from the transplantation.

For a brief period in 2013, it was thought that three additional cases of HIV cures had been identified: the “Mississippi Baby” who acquired infection perinatally, received ART almost immediately and showed no return of virus after a treatment interruption, and two adult men in Boston who received stem cell transplants for cancers (from CCR5-positive donors) and subsequently stopped ART without an immediate viral load rebound. But HIV eventually returned: after 27 months in the child in Mississippi and around three and eight months in the two individuals in Boston.

In all three of these cases, the HIV reservoir had been diminished to levels that were too low for any current technology to detect. It is estimated that the Boston patients experienced reductions in the size of their HIV reservoir of at least 3 logs (1,000-fold), but this was insufficient to lead to a cure. This has potentially sobering implications for current research because in clinical trials of interventions that aim to deplete the HIV reservoir, there has been little or no evidence of even small reductions. Additionally, mathematical modeling indicates that reservoir reductions of 5 logs (100,000-fold) or greater would be needed to achieve long-term remission from HIV replication in the absence of ART in a majority of individuals.

All is not lost, however. Studies of two-pronged strategies designed to awaken the latent HIV reservoir and then target the infected cells for destruction are only just beginning. Examples are clinical trials combining HDAC inhibitors and therapeutic vaccines or bNAbs. There are other approaches that may not necessarily require reservoir reductions, such as gene therapies that aim to protect vulnerable CD4 T cells from HIV and thus promote more effective immune responses against the virus.

While not considered cured, a group of 20 individuals in France—known as the VISCONTI cohort—is displaying prolonged control of HIV replication after being treated with ART soon after becoming infected, then interrupting therapy several years later. Some members of the cohort have now been off ART for a decade and have maintained viral load levels below 50 copies/mm3. It’s not yet known if this control of HIV may come at a cost, such as elevated levels of inflammation, but the cohort does at least offer some reason to believe that—in the absence of a complete cure—long-term suppression of HIV replication without ART may be an attainable goal (and this may have been the type of outcome—sometimes referred to as a “functional cure”—that Bill Gates was thinking of when he made his comments in Davos).

While the cure field is at a relatively early stage, and has not produced any candidates that are likely to start on a path toward licensing in the near future, there is always the potential for surprises. A widely publicized study published recently in the journal Nature is an example. A research team led by Michael Farzan at Scripps described a newly created HIV inhibitor named eCD4-Ig that has unprecedented potency against a very diverse array of HIV (and SIV) isolates. When delivered to macaques by an AAV vector (the same approach being studied as a possible means of bNAb delivery), robust protection against infection was documented. The intent is to now evaluate eCD4-Ig for both prevention and treatment.

Bill Gates hopeful reading of the scientific tea leaves is understandable, and likely partly derived from the involvement of his foundation in supporting research in both arenas. But hope does not equate to inevitability and must not lead to complacency. Advances in the vaccine field are underpinned by significant increases in funding over the years; in the mid-1990s, the writer Mark Schoofs penned a piece for the Village Voice pointing out that annual HIV vaccine research spending was less than the budget of the flop movie Waterworld. Cure research would similarly benefit from increased investment, but the world’s leading supporter of scientific research, the National Institutes of Health, has seen funding fail to keep pace with inflation in recent years. This flatlining of funding also creates a grim outlook for young scientists—often the source of new ideas and potential breakthroughs—seeking to pursue a career in HIV.

Beyond funding, the regulatory pathway that candidate HIV vaccines and cures would follow to approval is not entirely clear yet, particularly in the case of partially successful interventions—exactly how good would be good enough for licensing? What criteria would be needed to consider someone cured, and how many years of follow-up would be required?

And, ultimately, an approved vaccine or curative therapy will be useless if the people who need it the most cannot get it, a problem faced already in the case of ART and now being grimly recapitulated with highly efficacious but immorally overpriced hepatitis C cures. All of these issues and uncertainties will require ongoing vigilance and advocacy to ensure their resolution and turn hopes for a vaccine and cure into a reality.•


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