Researchers Unveil Plans for Follow-up Trials to RV144
Less than a year after the RV144 trial in Thailand provided the first evidence of protection against HIV infection through vaccination, researchers are preparing to launch two new trials and are planning other future trials that may show whether tweaks to the prime-boost regimen tested in RV144 could increase the efficacy of this approach. Jerome Kim, deputy director of science at the US Military HIV Research Program (MHRP), a key collaborator in RV144, spoke about future plans to build on the modest efficacy results from RV144 at a recent HIV vaccine symposium at The New York Academy of Sciences in New York City on May 19.
More than 130 individuals attended the event, held the day after World AIDS Vaccine Day, which marks the day in 1997 that then-US President Bill Clinton delivered a speech calling for a renewed commitment to the development of an AIDS vaccine. The Global HIV Vaccine Enterprise and the Academy jointly sponsored the event.
The RV144 prime-boost regimen consisted of a canarypox vector-based candidate, ALVAC-HIV (vCP1521), and AIDSVAX B/E, a genetically engineered version of HIV’s gp120 surface protein (see Figure 1 below for dosing schedule).
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In a post-hoc analysis performed after the trial was unblinded, Kim said it appeared that the vaccine efficacy among vaccinated volunteers six months after the last injection may have been as high as 60%. Unfortunately, it is difficult to draw any conclusions from this observation because the study was not designed to measure whether a certain number of injections were effective or if the protective responses waned over time. “If you had a 60% efficacy at two years, it might be a reasonable vaccine to consider for licensure in places where the epidemic is substantial,” said Kim.
But at the conclusion of the six-year RV144 study, the overall efficacy of the prime-boost regimen declined to 31.2%. “The question is, if we take the same regimen and the same population, but use a boost at 12 months, could we see a 60% efficacy at 24 months [post-vaccination]?” asked Kim. An initial series of trials are planned to examine what happens immunologically after boosting.
One trial, known as RV305, will measure the effect of administering two additional protein booster shots to 108 of the 16,000 vaccinated participants from RV144. The planned RV305 study will have three arms, each including 36 vaccinated volunteers from RV144, 30 of whom will receive the additional booster shots and six who will receive placebo. The first group will receive an ALVAC/AIDSVAX boost, the second will receive just ALVAC, and the third group will receive just AIDSVAX. The booster shots will be given at 48 and 60 months post follow-up of RV144. Kim said MHRP intends to seek regulatory approval from the US Food and Drug Administration soon and hopes to launch this trial by 2011.
Another follow-up trial, known as RV306, which is expected to begin in mid- to late-2011, will involve collection of more samples from vaccinated volunteers so that researchers can gather more information regarding the immunogenicity of the ALVAC/AIDSVAX prime-boost combination.
Plans for this trial aren’t finalized but Kim said it may enroll about 500 HIV-uninfected individuals and include four study arms. Each arm would include 125 volunteers, 10 of whom will receive placebo. All four groups will receive the standard ALVAC/AIDSVAX regimen administered in RV144, but 48 weeks following the initial vaccination, one group of volunteers will receive another dose of ALVAC and AIDSVAX, a second group will receive just an AIDSVAX boost, a third group will receive only an ALVAC boost, and the fourth group will not receive any boost. Trial investigators are hoping to obtain regulatory approval early next year for this trial.
With the volunteer’s consent, researchers will perform leukapheresis in a small number of subjects, a lengthy process that spins out white blood cells by first pumping a person’s blood through a centrifuge. The procedure takes several hours per volunteer, but ultimately enables investigators to better characterize immune responses following vaccination. Mucosal specimens, including gut tissue, will also be sampled. “Ultimately, we want to see whether there are changes induced by the late vaccination, which will help us determine which combinations are the ones we should use as a booster,” said Kim.
Kim said another trial comparing a prime-boost regimen containing NYVAC—a poxvirus-based vector similar to ALVAC that was also developed by Sanofi Pasteur—to one containing ALVAC, is also being contemplated. This trial would have the same dosing schedule as RV144, but would also include an additional protein boost at 12 months. The collaborators are interested in exploring NYVAC because it may improve immune responses. The study population size for this trial hasn’t yet been determined.
MHRP is also considering conducting larger efficacy trials of the ALVAC/AIDSVAX prime-boost regimen with an additional boost at 12 months. Researchers are considering a trial in 2,500 men who have sex with men in Thailand who are specifically at high risk of HIV infection. They have also discussed a larger trial in Thailand that would involve 27,500 volunteers at community risk, a population similar to that enrolled in RV144. But as opposed to the three and a half year follow-up of volunteers that occurred in RV144, investigators would plan to analyze the data from this trial after two years. However, Kim acknowledged that the field is divided about whether to commit to another “gigantic trial” at this time. A major barrier to moving forward with another large efficacy trial is funding. “We can’t pay for all of it,” said Kim, adding that MHRP would have to rely on industrial or governmental partners to be able to conduct a 27,500 person study. —Regina McEnery
US Government Singles Out Eight Countries for Pilot Program on Global Health Initiative
A year after unveiling a US$63 billion six-year Global Health Initiative (GHI), a more integrated strategy for tackling preventable diseases and improving maternal and child health and nutrition in more than 80 countries, the US government singled out eight countries that are slated to receive $200 million in additional funding to quickly implement this new approach.
The eight countries—collectively referred to as GHI Plus countries—are Bangladesh, Ethiopia, Guatemala, Kenya, Malawi, Mali, Nepal, and Rwanda. The US Agency for International Development (USAID), one of several US agencies involved in the implementation of the GHI, said the US government intends to add additional countries to the GHI Plus list in the future. What is learned from the GHI Plus pilot program will be used to improve service delivery in all countries that have GHI-related programs and inform decision making of the US government and its partners.
The GHI, which encompasses all existing global public health initiatives funded by the US government, seeks to build on nine target areas: HIV/AIDS, malaria, tuberculosis, maternal health, child health, nutrition, family planning and reproductive health, neglected tropical diseases, and health systems strengthening. The US President’s Emergency Plan for AIDS Relief (PEPFAR) accounts for $51 billion of the GHI funding over six years. PEPFAR began under former President George W. Bush and was reauthorized in 2008 for five years to fight HIV, tuberculosis, and malaria in 31 countries.
Mark Harrington, executive director of the AIDS advocacy organization Treatment Action Group, says the GHI is a “great and timely idea,” but he believes the initiative is not adequately funded, and therefore its impact will suffer. US President Barack Obama’s administration has requested $9.6 billion in funding for GHI programs in 2011. Spending for GHI programs was $8.4 billion in 2009 and $8.8 in 2010.
For more information on the Global Health Initiative, click here. —Regina McEnery