First Human Trial of AAV as a Delivery Vehicle for HIV Neutralizing Antibodies Gets Underway

Over the past few years there has been growing interest in the use of adeno-associated virus (AAV) as a vehicle for generating anti-HIV neutralizing antibodies in humans. The approach is different from traditional vaccination, in that AAV is used essentially as a gene therapy: the AAV vector is designed to take up residence in cells and then act as a factory for churning out broadly neutralizing antibodies against HIV (genes that encode these antibodies are inserted into the vector). This novel idea may be able to circumvent the challenging problem of inducing the production of broadly neutralizing antibodies with traditional vaccines, and could potentially offer significant protection against HIV acquisition. 

As covered previously on the blog, there are two main research groups working on AAV-based HIV prevention. The laboratory of David Baltimore has named their approach vectored immunoprophylaxis (VIP) and last Sunday they published a study in Nature Medicine demonstrating protection against vaginal HIV transmission in a humanized mouse model (the study was supported by the National Institute of Allergy and Infectious Diseases, who issued a press release drawing attention to the findings). Meanwhile Philip Johnson and colleagues at the Children’s Hospital of Philadelphia are collaborating with the International AIDS Vaccine Initiative (IAVI) on a phase I clinical trial of an AAV vector encoding the HIV neutralizing antibody PG9, and, according to clinicaltrials.gov, the trial started recruiting participants last month. This is a major milestone for the research, as there were many challenges associated with obtaining regulatory approval for a human trial and Johnson and IAVI have been working toward this goal for many years. The estimated date for completion of the study is January 2016. 

Nature Medicine (2014) doi:10.1038/nm.3471

Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission

Alejandro B Balazs, Yong Ouyang, Christin M Hong, Joyce Chen, Steven M Nguyen, Dinesh S Rao, Dong Sung An & David Baltimore

Received 03 October 2013 Accepted 07 January 2014 Published online 09 February 2014

The vast majority of new HIV infections result from relatively inefficient transmission of the virus across mucosal surfaces during sexual intercourse. A consequence of this inefficiency is that small numbers of transmitted founder viruses initiate most heterosexual infections. This natural bottleneck to transmission has stimulated efforts to develop interventions that are aimed at blocking this step of the infection process. Despite the promise of this strategy, clinical trials of preexposure prophylaxis have had limited degrees of success in humans, in part because of lack of adherence to the recommended preexposure treatment regimens. In contrast, a number of existing vaccines elicit systemic immunity that protects against mucosal infections, such as the vaccines for influenza and human papilloma virus. We recently demonstrated the ability of vectored immunoprophylaxis (VIP) to prevent intravenous transmission of HIV in humanized mice using broadly neutralizing antibodies. Here we demonstrate that VIP is capable of protecting humanized mice from intravenous as well as vaginal challenge with diverse HIV strains despite repeated exposures. Moreover, animals receiving VIP that expresses a modified VRC07 antibody were completely resistant to repetitive intravaginal challenge by a heterosexually transmitted founder HIV strain, suggesting that VIP may be effective in preventing vaginal transmission of HIV between humans.

Comments

[Gary Smith]

Hello Sir,

We haven't heard on hiv AAV pg9 trial supposed to complete Jan 2016.
Is there any update please?

Thanks,
Gary

[Richard Jefferys]

Hi Gary, it took a long time to hear news from the trial - I just learned this evening that unfortunately none of the nine participants showed detectable levels of the PG9 antibody. The problem appears to relate to the development of antibodies against the PG9 antibody (these were seen in 7 of 9 participants), a problem that has also been seen in animal model studies.

A number of researchers are working to try and solve this problem, particularly the group of Ron Desrosiers, there's a video of a recent presentation by him where he discusses some of the work: https://www.youtube.com/watch?v=JY0MIAPkgmw