July 14, 2015
A paper published earlier this month in Science augurs a major new effort to advance a prime-boost HIV vaccine strategy into human efficacy trials. The vaccine components are manufactured by Crucell Holland B.V, which is now one of the Janssen Pharmaceutical Companies of Johnson & Johnson, and -- in a very welcome development for the HIV vaccine field -- Janssen has recently outlined a comprehensive development plan that they hope will lead to a licensable HIV vaccine. Frank Tomaka, MD, Clinical Leader, HIV Vaccines, presented details on an AVAC webinar held May 18th (slides and audio are available online). Since the failure of Merck's candidate in 2007, there has been a dearth of major pharmaceutical company involvement in HIV vaccine research, and planning for further efficacy trials was limited to one collaborative endeavor known as the Pox-Protein Public-Private Partnership (P5) (the work of P5 is also described on the AVAC webinar by Glenda Gray). The promising macaque results described in the new Science paper offer some insight into why Janssen has now entered the fray.
The experiments involved a priming immunization with an adenovirus serotype 26 (Ad26) vector encoding SIV Env/Gag/Pol antigens followed by boost with either an SIV envelope trimer protein or an Ad35 vector also expressing Env/Gag/Pol. Twelve macaques received each of the vaccine regimens and eight served as controls. Six of the 12 recipients of the Ad26/Env trimer combination remained uninfected after six sequential challenges with the highly pathogenic SIVmac251, compared to two in the Ad26/Ad35 group. Two of the infected animals in the Ad26/Env trimer group controlled viral load to undetectable levels whereas the 10 infected recipients of Ad26/Ad35 displayed detectable viral loads typical of progressive disease. As expected, high viral loads were seen in all unimmunized controls.
The researchers (led by Dan Barouch from Beth Israel Deaconess Medical Center) conducted several experiments to confirm that the apparently protected macaques were truly uninfected, including transfer of 60 million peripheral blood and lymph node mononuclear cells into naïve animals. While cells from the two macaques controlling viral load efficiently transferred SIV infection, this was not the case for any of the protected macaques. The results are impressive because the challenge virus SIVmac251 has historically been very difficult to protect against. The authors also note that in a separate experiment with a different challenge virus (the HIV/SIV hybrid SHIV162P3), protection was also observed in recipients of the Ad26/Env trimer regimen albeit at a slightly lower rate (8 of 20 animals or 40%).
In both sets of experiments, protection correlated with the presence of antibodies capable of exerting multiple Fc effector functions (referred to as polyfunctional antibody responses). Fc effector functions include induction of immunological mechanisms such as antibody-dependent cellular phagocytosis, which can mediate clearance of infected cells. Notably, the Env trimer protein boost was found to be essential for inducing a more polyfunctional antibody response.
Several human clinical trials are now evaluating the safety and immunogenicity of different components of the vaccine regimen. This ongoing work was highlighted in a press release about the macaque study issued by Johnson & Johnson. If all goes according to plan, efficacy trials may begin in 2017.
Richard Jefferys is the coordinator of the Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog at the Treatment Action Group (TAG). The original blog post may be viewed here.
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