In Canada, we are inundated with immunizations from the minute we enter the world – measles, mumps, tetanus, chickenpox and meningitis C, to name just a few. It can be easy to forget that creating a successful vaccine is an arduous process that hinges on many factors and requires vast resources. With its high incidence and mortality rate, HIV-1 has long been a priority target for vaccine development, affording researchers the benefit of substantial funding, top intellectual talent and institutionalized international support. However, despite decades of research, not a single vaccine candidate has demonstrated comprehensive protection against HIV-1 infection in clinical trials. The following article provides some insight into the herculean effort required to develop an effective HIV vaccine and discusses how the existing challenges are being addressed.

Multitudinous Diversions
Most currently available vaccines function by using attenuated virus or viral components to induce the production of neutralizing antibodies by the host immune system. These antibodies are able to control infection by binding viral particles in the bloodstream or by targeting infected cells for deletion. While this method has been successfully employed against myriad viral pathogens, HIV presents a unique challenge. Similar to HPV, HIV triggers poor natural immune responses. This, combined with the virus’ capacity for rapid mutation, has traditionally discouraged the use of attenuated HIV virions for vaccine development due to the high risk of reactivation and the low chance of evoking a protective antibody response. Additionally, HIV has multiple subtypes with few conserved epitopes on its envelope surface, and those that do exist are typically obscured by non-native or hypervariable epitopes that are immunodominant. As a result, even with potent combinations of recombinant HIV proteins, viral DNA and strong adjuvants, vaccine candidates to date have only been able to generate type-specific or non-neutralizing antibodies, not the broadly neutralizing antibodies (bNAbs) required to target hidden conserved epitopes.

The decline of cellular immunity that occurs in acute HIV infection further complicates the task by severely restricting the window during which the body can effectively prevent chronic infection; once the virus has integrated into the host cell genome, it establishes a latent reservoir that has so far been impossible to eliminate. Fortunately, with improved detection of bNAbs from HIV patients and better tools for genetic manipulation, researchers have begun fine-tuning HIV vaccines using reverse-engineered immunogens that can induce potent, protective antibody responses. Additionally, several recent HIV vaccine designs have revisited the use of attenuated virus, and just last year, the first killed,  whole-virus HIV-1 vaccine, designed by the research team of Dr. Chil-Yong Kang at the University of Western Ontario, successfully completed phase I safety trials.

Trial and Error
While creating an HIV vaccine that performs well in non-human primates and humanized mice is itself no small feat, designing a clinical trial to test the functionality of the vaccine in humans presents challenges as well. Without clear examples of effective immune responses to HIV in humans, it can be difficult to determine which measures of immune function best reflect the quality and mechanism of any protective effects that are observed. Given the resilience of the viral reservoir and the immune dysfunction that stems from the resulting chronic inflammation, viral load is often used as the primary correlate of immune protection. However, of the three HIV vaccines that progressed to clinical trials in recent years (ALVAC-HIV, AIDSVAX, and RV-144), only RV-144 generated significant (though minimal) protection against HIV and this manifested as a decreased rate of HIV infection in the vaccinated cohort rather than a decreased viral load in vaccinees who ultimately became infected. Further examination of the data revealed an inverse correlation between disease occurrence and levels of IgG specific for the V1V2 region of the HIV envelope protein, suggesting that titres of bNAbs could serve as an alternate – and important – measure of vaccine effectiveness. Retrospective analyses of immune protection metrics are thus a critical component of any clinical trial, as the emergent correlations may drive the design and focus of future studies.

Cure, Interrupted
Another obstacle to arranging large-scale clinical trials is the drastic improvement in post-infection therapeutic options. In recent years, increased uptake of anti-retroviral therapy in middle and low-income countries has effectively decreased the annual mortality from AIDS-related causes by one million, and the life expectancy of individuals living with HIV is now nearly akin to that of the general population. Pre-exposure prophylactic (PrEP) administration of anti-retroviral drugs to individuals at high risk of contracting HIV-1, such as health care workers or partners in serodiscordant relationships, has also been introduced as a key addition to existing preventive measures like male circumcision and vaginal microbicides. In light of these positive developments, recruitment of volunteers for clinical trials of untested HIV vaccines becomes much more difficult, and even ethically questionable in cases where assessment of clinical correlates of protection requires interruption of existing treatment regimens.

Even with its advances, anti-retroviral therapy remains a poor substitute for a preventative vaccine. To be effective, the lifelong regimen requires reliable access to medication and strict compliance on the part of the individual. Furthermore, despite several hopeful cases of long-term viral suppression following removal from anti-retroviral therapy, neither early nor prolonged therapy has been sufficient to eliminate the HIV reservoir altogether or to restore immune function even in the absence of full viral clearance. While researchers, clinicians and communities worldwide continue to work towards a solution to the HIV epidemic, many scientific and ethical issues regarding HIV treatment remain unresolved and it will be years yet before a vaccine becomes available.

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Kieran Manion

Design Director
Kieran Manion is a senior PhD student studying the breakdown of B cell tolerance in systemic lupus erythematosus in the Department of Immunology at the University of Toronto. In her spare time, she practises using digital platforms for general artwork and graphic design.
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