Date Published: September 12, 2017
Publisher: BioMed Central
Author(s): Robin Shattock.
HIV vaccine development is one of the greatest biological challenges of our generation. Overcoming viral diversity is a major issue, but many additional challenges will need to be addressed before an effective vaccine can be successfully formulated to achieve the necessary levels of protection required. For example, broadly neutralizing anti-HIV antibodies (bNAbs) that arise during natural HIV-1 infections often take several years to develop and tend to have unusual features which are likely to pose challenges for elicitation through vaccination. These include high levels of somatic mutation, autoreactivity with self-proteins, and long complementarity determining regions . For antibody induction, it is critical that the field better understands the structure of the native Env trimer and the role of the glycan shield in antibody interactions [2–4]. While the induction of bNAbs remains a key goal of HIV research, increasing emphasis is being placed on additional antibody functions beyond classical neutralization including Antibody Dependent Cytotoxicity (ADCC) and phagocytosis (ADCP). While there is much debate over the protective utility of these functions in the absence of neutralization, it is clear they have potential to augment neutralizing activity. Exploiting such mechanisms may enhance the potential efficacy of vaccine candidates. Indeed, two vaccine strategies in late stage efficacy trials are solely dependent on the elicitation of antibodies that only function through FcR mediated mechanisms and display little appreciable neutralization . These studies will prove key in testing whether such functions by themselves are capable of mediating effective protection in individuals at high risk of HIV infection. While development of a prophylactic vaccine remains the primary goal of vaccine research, a renewed interest has been placed on the role of vaccines in effecting long-term remission (effective “cure”) for HIV infected individuals, reducing the need for life-long medication . A desirable long-term goal is to merge parallel B cell and T-cell focused vaccine strategies into an immunological “one-two punch”. This combined approach would incorporate vaccine elements that enable elicitation of antibodies that effectively block infection, coupled with elements that elicit favorable T-cell responses to provide immune-mediated control of breakthrough infections. Without question, the development of a successful HIV vaccine is a sophisticated task and needs collective global effort.
In the last several decades, Canadian researchers have made significant contribution to HIV vaccine development. Several Canadian researchers have developed their own unique anti-HIV vaccines. For instance, Dr. Yong Kang from UWO, recently tested his whole-killed HIV vaccine (SAV001), in a phase 1 human clinical trial. The vaccine preparation was genetically modified by deleting the nef and vpu genes and fully inactivated by aldrithiol-2 and γ-irradiation  while his collaborator, Dr. Yong Gao (UWO) has developed a polyvalent anti-HIV vaccine by utilizing multiple different HIV-1 subtype strains . The Gao lab has found that sequential vaccination strategy could generate broad humoral immune responses (able to neutralize HIV-1 subtype A, B, C and D strains) in a human CD4 B cell transgenic model. Continuing on the theme of invoking a strong humoral response, Drs. Trina Racine, Gary P. Kobinger (UL), and Eric J Arts (UWO) are now working with International AIDS Vaccine Initiative (IAVI) in developing a VSV-based HIV vaccine  that will combine unique Canadian research on the HIV-1 Env glycoprotein and on the VSV vaccine vector with the goal of developing a vaccine with a robust and potent anti-HIV immune response with an emphasis on generating quality antibodies to protect against HIV challenge. Again success of any humoral-based vaccine, is dependent of neutralizing antibody production as well as Abs that elicit ADCC. Dr. Andres Finzi (UOM) has been studying how the structural properties of HIV-1 Env might have contributed to the modest efficacy of the RV144 trial and has recently used this knowledge to develop new strategies aimed at sensitizing HIV-1-infected cells to ADCC by easy to elicit non-neutralizing Abs .
Canadian Federal Government funding towards the development of an HIV vaccine through CHVI (Canadian HIV Vaccine Initiative) has helped to cultivate a Canadian HIV vaccine community with internationally recognized strengths capable of making major contributions. The keen interest shown by IAVI and EAVI to involve Canadian researchers is clear evidence of their ability to make unique contributions. No one country can create a successful vaccine due to prohibitive costs of translational vaccine studies for country-specific funding organizations and the need for centralized facilities, such as transgenic animal models, humanized mouse models, non-human primates, certified good manufacturing practices (GMP), and other expensive infrastructure and resources. Fortunately, these facilities and resources key to vaccine development and testing are available to these multination collaborations largely funded by the Gates Foundation, the US and European funding bodies. It is also critical to maintain a two-pronged approach directing strategic funding towards specific areas where translational progress was most likely, while maintaining support for innovative projects that address unresolved basic and social research issues.