On the eve of the 25th World AIDS Day (December 2014), President Barack Obama expressed hope to our nation, proclaiming that an “AIDS-free generation is within our reach.” During his speech, Obama expressed how our nation has made significant strides toward strengthening scientific investments, building effective HIV/AIDS education and prevention programs and bringing together public and private stakeholders.
About the same time, members of the National Institutes of Health claimed 2015 could be the mark of a HIV/AIDS-free future.
While no safe and effective cures exist, scientists are working hard to find a cure, and remain hopeful. That is, despite the daunting totals of about 34.2 million people living with the HIV virus around the world and 2.3 million new HIV-1 infections annually. And while drug development and candidate microbicides are in the works, vaccines may be the most promising aspect to an AIDS-free nation.
HIV research has been on the map for about 30 years, and there have been several attempts and several clinical trials that have tested immunogens for vaccines and have ultimately failed to show any type of protection or efficacy. HIV vaccines are hard to develop due to the genetic variability of the virus, the masking in self-antigens and the lack of targets.
However, in October of 2003, the first HIV vaccine efficacy clinical trial in history was conducted on a vaccine candidate called RV 144, also known as the Thai trial. The trial tested the “prime-boost” combination of two vaccines: ALVAC HIV vaccine (the prime) and AIDSVAX B/E vaccine (the boost), based on HIV strains that circulated in Thailand. Testing for HIV amongst the 16,402 participants until July 2006.
Results of the trial were released in September 2009 by the U.S. Army, where the trial demonstrated the vaccine regiment was safe and modestly effective in preventing HIV infection, showing that the prime-boost combination lowered the rate of HIV infection by 31.2%, compared to placebo based on the modified intent-to treat population. This study overall showed that a preventive HIV vaccine is possible, and is providing scientific direction to help guide future vaccine development and testing.
After the released results, researchers performed multiple studies to figure out how the vaccine gave some measure of protection against HIV-1. They studied about 30 or 40 different types of immunological parameters, and in April, 2012, the New England Journal of Medicine published a paper that detailed clues as to why the vaccine tested in the RV144 trial protected some participants. The study focused on those who became infected compared to those who didn’t. One finding was that immunoglobulin G antibodies that bind to the V1/V2 region of HIV’s envelope protein correlated with lower infection rates among those who were vaccinate.
The result, according to Dr. Noah Sather, PhD, principal scientist, Seattle Biomedical Institute, was quite unexpected. Overall the finding shows that people infected by HIV in the study were infected because the virus was able to get around that V1/V2 response. “Moving forward, it became important to understand the types of antibodies elicited in pre-clinical vaccine studies in light of the correlates of protection that came out of this study, and, in particular, which vaccines can recapitulate the same types of V1/V2 antibodies,” says Sather.
What this study has also led to is trying to design envelope immunogens that express similar pieces of conserved epitopes that would be present on every HIV virus. And that is where Sather’s latest research comes into play. Sather and his research group have identified that a human subject had developed antibodies to the CD4 binding site epitope, and they decided to use the immunogens to see if they could target an antibody response there as the epitope is present on every virus, no matter where it comes from or who it comes from.
“The direction of my laboratory is actually two-fold. We work on the design and testing, pre-clinical testing, of HIV Envelope immunogens, but we also study natural antibody responses to the Envelope protein in HIV-1 infected subjects,” says Sather. “And the idea is that we don’t know quite yet what a protective antibody response looks like, and so we are studying humans that developed broadly neutralizing antibodies to HIV-1. This information, together with the tremendous effort of other research groups in identifying broadly neutralizing antibodies to HIV, is used to guide the design of Envelope immunogens that can be used as vaccines. And hopefully these vaccines can re-elicit similar antibodies in a person who is not infected, which then will fight off infection if they are exposed to HIV-1.”
The research team, in late January, identified two HIV-1 envelope immunogens that elicit broadly neutralizing antibodies when introduced into a vaccine. The research was published in PLOS ONE. The HIV-1 envelope protein immunogens were derived from an elite neutralizer, an individual with an unusually potent antibody response effective against the majority of HIV subtypes. Through animal models involving rabbits, the researchers identified two envelope immunogens that elicited cross-reactive binding antibodies to the variable regions 1 and 2 (V1/V2) region of the envelope protein and induced antibodies capable of neutralizing an array of HIV from different subtypes.
“We believe, that in the field moving forward, broadly neutralizing antibodies are likely going to have to be one of the critical components of any HIV vaccine,” says Sather. “And based on the RV144 findings, we believe that these V1/V2 antibodies could be very advantageous in helping with protection.”
The laboratory’s future plans are to use each pre-clinical trial as an iterative process to learn what the team can better do to create immunogens. One of the things that the team learned with the recent two envelope immunogens is that they need to work on increasing the potency and broadly neutralizing activity.
“The V1/V2 activity is great and there is some broadly neutralizing activity,” says Sather. “But we could do better.”
What the team has done is re-designed the immunogens and modified them in specific ways based on what it known in the literature about antibody binding and responses in humans in other trials. And what they are trying to do now is work on the broadly neutralizing antibody side to increase that. “These studies will be going on shortly,” says Sather.
The team has re-designed and produced these immunogens as soluble vaccines and they now are entering a new round of pre-clinical trials.