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Understanding the P5 Partnership

How is this research collaboration advancing the development of a safe and effective AIDS vaccine?

By Regina McEnery

A clinical trial in Thailand known as RV144 made history in 2009 by establishing that a vaccine can prevent HIV infection (see VAX Sep. 2009 Spotlight article, First Evidence of Efficacy from Large-Scale HIV Vaccine Trial). Its efficacy was a modest 31% on average—considerably lower than the minimum efficacy of 50% that investigators themselves said was necessary to trigger discussions of possible licensure (see VAX Dec. 2009 Primer on Understanding Vaccine Licensure). Still, scientists and advocates alike welcomed, with some relief, the long-sought proof-of-concept for HIV vaccines.

Since then, a global coalition of researchers has—with some success—been trying to identify the immune responses provoked by the RV144 regimen that provided protection from HIV (see VAX Nov. 2009 Primer on Understanding the Hunt for Immune Correlates of Protection from RV144). The hope, of course, is to use that information to build a better vaccine. Another cadre of researchers has, meanwhile, pushed ahead with a project to test variants of the vaccine regimen evaluated in Thailand in clinical trials. This group, which formed in 2010, is known as the Pox-Protein Public-Private Partnership, or P5, in the jargon of the field.
 
The P5 team includes representatives from six organizations: the US National Institute of Allergy and Infectious Diseases, the Bill and Melinda Gates Foundation; the HIV Vaccine Trials Network; the drug companies, Sanofi-Pasteur and Novartis; and the US Military HIV Research Program, a key collaborator in the RV144 trial. Two efficacy trials are planned, one in men who have sex with men (MSM) in Thailand and another in heterosexual men and women in South Africa, to see if a candidate similar to the one used in RV144 holds up as well, and perhaps improves protection, in a high-risk population.

The vaccine regimen used in the RV144 study of 16,000 at-risk individuals consisted of a canarypox vector-based vaccine candidate ALVAC-HIV (vCP1521) and AIDSVAX B/E, a genetically engineered version of HIV’s gp120 surface protein, also known as the Envelope protein. The two vaccines were paired sequentially in a prime-boost regimen and administered over six months.

That the regimen worked was significant. But researchers were even more encouraged to see that efficacy reached as high as 60% after one year. This intrigued many researchers and suggested that improving the durability of the immune responses induced by this vaccine regimen might dramatically increase the efficacy.

A boost to RV144

So the P5 is trying to do just that with their follow-up trials. In the efficacy trial planned for heterosexual men and women in South Africa, researchers will test a prime-boost candidate that targets the most common subtype of HIV in the region, known as clade C. This differs from the RV144 vaccine regimen, which targeted the recombinant clade A/E strain that is dominant in Thailand. The design of the South African trial also differs from RV144 in two other important ways. It adds a fourth injection at 12 months and employs a different adjuvant—MF59—than the standard alum used in RV144 and most licensed vaccines.

Researchers want to see whether these changes in protocol improve the immune responses in vaccinated volunteers, and whether the improvement is sufficient for the vaccine candidate to be licensed. The P5 is also planning to conduct an efficacy trial among MSM in Thailand that will use the same ALVAC/gp120 B/E candidate as the one used in RV144. Like the upcoming South Africa trial, this study will also include a boost 12 months after the first injection, and use MF59 rather than alum as an adjuvant.

The P5 hopes to launch the South Africa trial in early 2015, and the Thai MSM trial a year after that. But challenges remain in meeting these goals—including uncertainty about the funding and difficulties in finding the right antigens for use in each of the candidate vaccines.

A different viral vector

The P5 is also interested in exploring other promising vectors in hopes of identifying new vaccine candidates and unearthing the so-called correlates of protection—the immune responses that prevent HIV acquisition.

One vector that the P5 is looking at is NYVAC, an altered vaccinia virus that is used in the smallpox vaccine. It is highly attenuated and is not infectious in humans. The P5 selected NYVAC based on previous data that, admittedly, is a bit mixed. In one Phase I study, NYVAC was found to stimulate HIV-specific immune responses, though they were weak. A later Phase I study found that when NYVAC was used in combination with a DNA-based candidate it induced much better immune responses.

Will NYVAC hold up in a larger study? The P5 is hoping to launch a large Phase IIb trial in South Africa of NYVAC alone or in combination with a gp120 candidate. The goal of the study is to see what immune responses are elicited and identify any biomarkers associated with reduction in HIV infection.

The P5 is also involved in two smaller trials. RV305, which began in 2012, is evaluating the impact of an additional boost in volunteers who participated in the RV144 trial. Results from this study are expected in the fall. In the companion study known as RV306, investigators will look at what effect additional boosts of the original RV144 regimen has on 360 volunteers who were not previously enrolled in RV144.

Finally, the HIV Vaccine Trials Network—which is part of the P5—recently began a study, HVTN097, evaluating the safety and immunogenicity of the original RV144 regimen in 100 HIV-uninfected men and women from South Africa. It enrolled its first participant on June 18.

It’s too early to say whether the P5’s multi-pronged approach will bring the world closer to a licensed vaccine. But stay tuned.