Understanding Advances in Therapeutic Vaccine Research
What recent developments are fueling research into using vaccines to treat or even cure HIV?
By Mary Rushton
The word vaccine is generally used to describe any substance administered to confer immunity and therefore prevent disease. However, HIV researchers, as well as researchers in fields such as cancer, are pursuing another type of vaccine that is intended as therapy. These so-called therapeutic vaccines are administered to individuals that already are infected with the virus or have the disease, and are intended to boost the immune responses against the pathogen. Or in the case of HIV, induce better immune responses than what the body makes naturally (see VAX March 2013 Primer on Understanding Therapeutic Vaccination). One of the reasons HIV is so hard to control and to clear—to date, only one individual is considered cured of HIV (see VAX July 2013 Spotlight article, The WHO Casts A Wider Net)—is that the immune responses the body naturally mounts against the virus are, in all but rare cases, insufficient to effectively control HIV. Therefore, for a therapeutic vaccine to work, it will need to induce immune responses that are different than those induced in natural infection.
Interest in therapeutic HIV vaccines started off strong, but following the introduction of highly successful antiretroviral therapy in the 1990s, and mostly disappointing results from clinical trials of therapeutic vaccine candidates, the field languished for some time. None of the early candidates were found to improve the overall health of the HIV-infected volunteers in the trials or slow their rate of disease progression. Now, the relatively young and promising field of HIV cure research has rejuvenated interest in therapeutic vaccination.
While there are still many missing pieces to the HIV cure puzzle, a therapeutic vaccine is considered a key component to achieving a cure. Therapeutic HIV vaccine research is also benefitting from recent advances in preventive vaccine research. Now more than ever, the fields of therapeutic and preventive vaccine research, treatment, and cure research are overlapping (see Spotlight, this issue).
The biggest obstacle
Once a person is HIV infected, the virus stakes out hiding spots in the body. Some virus hides out in cells that are inactive (not replicating) and therefore is impervious to the effects of antiretroviral therapy. However, if therapy is interrupted, this sleeping or so-called latent virus can come roaring back and begin actively replicating. The pool of latent virus, known collectively as the viral reservoir, is one of the main obstacles to an HIV cure. Take for example the recent case of an infant who began antiretroviral treatment within hours after birth (see VAX July 2014 Spotlightarticle, Melbourne’s Rallying Cry: Step Up The Pace). Even in this infant, whose HIV infection was treated almost immediately, HIV began replicating to detectable levels once antiretroviral treatment was interrupted.
To counter this problem, scientists are testing various compounds designed to root HIV out of its hid
ing spots. Once exposed, therapeutic vaccination is one method researchers are exploring to enable the immune system to clear these HIV-infected cells, thereby reducing or even eliminating the viral reservoir.
Scientists in Denmark, for instance, just began a Phase I study involving HIV-infected volunteers to evaluate a therapeutic vaccine candidate called Vacc-4x, along with a cancer drug that in a previous study was able to wake up latent HIV in inactive (or resting) T cells. This combination approach, sometimes referred to as “kick and kill,” is relying on the therapeutic vaccine candidate to generate a strong enough immune response to kill the virus that is reawakened in the body.
Antibodies for prevention and therapy
The same antibodies that are the focus of preventive vaccine research these days may also have a role in therapeutic vaccination. An ongoing study at the US National Institute of Allergy and Infectious Diseases that began last year is testing what is called passive transfer of antibodies in both HIV-infected and uninfected volunteers. In passive transfer studies, broadly neutralizing antibodies (those capable of inactivating a wide variety of HIV strains) are injected directly into the body to see if they can either prevent HIV infection or induce prolonged suppression of the virus in HIV-infected volunteers (see VAX March 2014 Primer on Understanding the Expanding Role for Broadly Neutralizing Antibodies). Another strategy is using gene therapy to deliver just the genes for the broadly neutralizing antibodies, which are taken up by cells that then produce the antibodies, rather than injecting the antibodies directly.
Similar to the preventive vaccine field, therapeutic vaccine researchers are also testing combination strategies to try to induce broader immune responses to HIV. However, there are still significant gaps in understanding how to design and assess such candidates in HIV-infected individuals. Designing clinical trials to evaluate therapeutic vaccines is more difficult because there isn’t an accurate way, currently, to measure the size of the viral reservoir or therefore the impact a vaccine candidate has on reducing it. And, interrupting antiretroviral treatment in HIV-infected individuals can be fraught.
While animal models are one of the best ways to evaluate the safety and efficacy of new medicines and vaccine candidates, the lack of a perfect animal model for HIV—one that mimics this uniquely human disease—has been problematic in defining how well a candidate will perform in people. To address this issue, some researchers are suggesting using a step-wise series of small clinical research trials be carried out in HIV-infected volunteers to find the most useful targets for therapeutic immunization.
Mary Rushton is a freelance writer based in Cambridge, Massachusetts.