HIV Therapeutic Vaccine Advances

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Treatment Horizons

Another Kind of Morning
HIV therapeutic vaccines try to come of age
by Mariel Selbovitz, MPJ, and David Miller
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Despite over three decades of research on therapeutic vaccines for the treatment of HIV, clinical advances have been slow in coming for this important class of drug. While there are a plethora of therapeutic vaccines in development, only a few have reached Phase II clinical trials. Combination HIV antiretrovirals (ARVs) have made daily use of ARVs more manageable and plausible for many HIV patients; however, the long-term effects of ARVs, cost, toxicity, drug resistance and treatment fatigue make the possibility of extended drug holidays, that a therapeutic vaccine could provide, even more alluring than ever before.

Although programs like PEPFAR and The Global Fund continue to provide antiretroviral therapy to HIV-positive people in resource-limited countries, coverage is still limited and the goal of universal access is, in reality, unachievable. An effective therapeutic vaccine would stretch limited funding for ARVs by increasing the pre-ART time period and by redirecting funds during ART-free blocks of time, after the initial initiation of therapy, to others in need.

Therapeutic vaccines are based on the premise of boosting the immune system’s response, enabling it to better fight and destroy HIV, both before and after it infects cells. Different forms of therapeutic vaccines target particular cells like dendritic cells or monocytes and attempt to elicit distinct types of natural anti-HIV immune responses. Diverse vectors or “delivery systems” are also being researched. The therapeutic vaccines currently being studied for HIV act against various sub-types of HIV-1. Some therapeutic vaccines are made for specific strains while others aim to be effective against a wide array of HIV subtypes, enabling them to work in a higher number of people with HIV.

One promising strategy is the use of therapeutic vaccines in conjunction with viral host restrictive factors. We are equipped with a large and diverse set of proteins that inhibit the replication of retroviruses, including HIV. However, HIV has evolved to evade these responses.

OyaGen is developing a Vif dimerization antagonist and an APOBEC3G agonist. This approach is both an antiviral and eradication strategy. These drugs could rid any viremia not killed off by therapeutic vaccines, bringing patients to an undetectable viral load, or eliminating the virus altogether, by allowing cells’ natural defense against HIV to work while the virus is brought under control and CD4 counts restored by a therapeutic vaccine. The study of viral host restrictive factors is, of late, a dominant area in HIV pathogenesis research. Understanding and manipulating these viral host functions might lead to the ability to eradicate HIV infection, enable a durable ART-free remission of viremia and disease or provide new ways to treat HIV.

At CROI 2014 this past March, therapeutic vaccines were discussed as a potential part of a cure strategy. Dr. Romas Geleziunas from Gilead presented on the utility of therapeutic vaccines in combination with drugs that purge the HIV latent reservoirs such as HDAC inhibitors or romidepsin, an improved HIV-purging drug being studied by Gilead, to patrol the body and pick off the remaining HIV-infected cells that are activated. He discussed preclinical results, presented at the 2013 AIDS Vaccine Conference last year in Barcelona, regarding a CMV-based therapeutic vaccine given to monkeys that appeared to produce a functional cure in fifty percent of the monkeys and generated an immune response of a depth and breadth never before seen. These results were the most talked about at the AIDS Vaccine 2013 conference.

The second-most talked about study results were about an HIV vaccine called HIV Conserv, which while initially tested as a preventative vaccine, could possibly be a therapeutic vaccine as well, being used in the same way as the CMV vaccine would be in helping to suppress the last remnants of HIV in cells after the majority of the HIV-infected cells had been purged by immune-stimulating drugs.

Also presented at the 2013 AIDS Vaccine conference were preliminary results of a Phase I/II study of a therapeutic vaccine, THV01, in development by Theravectys, a Paris-based biotechnology company. THV01 is a lentiviral vector-based therapeutic vaccine currently being studied in people with HIV. As a therapeutic vaccine, the goal of THV01 is to stimulate the immune system by delivering DNA into dendritic cells, instructing them to kill HIV-infected T cells, generating a strong immune response. THV01 is based on research conducted at Institut Pasteur in Paris.

THV01 uses a lentiviral vector to carry an immunogen to dendritic cells. A lentivirus is a group of viruses from the Retroviridae family and includes HIV. Lentiviruses usually have long incubation periods and can deliver viral RNA into the cell’s DNA inside the nucleus. They can infect non-dividing cells, making them a great vector for the delivery of HIV antigens. The vaccine is delivered by intramuscular injection.

Lentiviral vaccines have been used to treat other diseases such as cancer. Dr. Carl June of the Perelman School of Medicine made headlines for curing adults and children with end-stage leukemia with the use of an HIV-based lentiviral vector as part of a generation of Chimeric Antigen Receptors (CAR). Dr. June removed T cells from his patients and reengineered them to attack the cancer cells, effectively killing the leukemia. T cells are transduced by lentiviral vectors that will express components of a receptor that will then allow the redirection of transduced T cells against tumor cells. Several patients who participated in clinical trials utilizing this approach achieved remission and continue to be cleared of leukemia.

THV01 is currently being studied in a Phase I/II double-blind, placebo-controlled clinical trial in HIV-positive adults, conducted at twelve sites throughout France and Belgium. The goal of the study is to measure the safety and tolerability of the vaccine as well as its immunogenicity. Furthermore, vaccine efficiency is being evaluated by the interruption of the HAART treatment in all patients, including placebo. Thirty-six participants have enrolled in the thirty-six-week study.

Study participants will be randomized into three arms where they will be given various doses of the vaccine or placebo. They will receive intramuscular injections of the vaccine or placebo at weeks 0 and 8. During this time antiretroviral treatment will be alleviated starting at weeks 7 or 2 before the first injection, depending on the half life of the ARVs used by the patients, and fully restored at week 9. ARVs will be interrupted at week 24 and continued based on viral load and CD4 count. The reason for alleviating ARVs during the vaccination phase is to allow for the vaccine to be effectively introduced into the cells’ nucleus. The second ARV discontinuation will monitor how the immune system responds to THV01. This trial is ongoing and preliminary results are expected in June.

As HIV remission-based research begins to secure a higher level of priority and attention, so does support of therapeutic vaccine research as one of many strategies towards a functional “cure” for HIV, where HIV patients will be able to take structured therapeutic interruptions. The number of people with HIV in need of life-long antiretrovirals will continue to grow despite the lack of new PEPFAR and Global Fund donors. Treatment methods don’t include ongoing daily ARVs and the funding to develop these to commercialization are vitally needed to ensure those in need of treatment are able to access care and effectively control viral replication, and thus reduce inflammation, in the absence of ARVs.

The U.S. Military HIV Research Program (MHRP) is a critical research initiative for the study of therapeutic vaccines, as the main focus of the program is on vaccine research. One of the elite fighters in the war against AIDS, the MHRP conducted the landmark RV144 study which demonstrated thirty-three percent efficacy of a preventative vaccine, ALVAX and AIDSVAX, the only clinical trial to date of a vaccine to demonstrate any efficacy. Another critical program to advance therapeutic vaccine research is the Delaney AIDS Research Enterprise (DARE), an NIH initiative dedicated to cure research.

A successful HIV therapeutic vaccine capable of eliciting strong HIV responses could be the coup de grace needed to end HIV in one or more of several ways. Together with host restrictive factors, gene therapy, or other new and novel therapies, therapeutic vaccines may hold potential in accomplishing the ultimate goal of eradicating HIV from the body. Alternatively, therapeutic vaccines may facilitate immune control allowing for a reduction in the use of ARVs that, in turn, would allow for ARV access for a higher number of HIV-positive people. This would reduce the global community viral load along with the number of new HIV infections. Finally, advances in therapeutic vaccine research would likely equate to a gained knowledge for vaccine researchers, possibly helping in the slow and hard-won search for a preventative vaccine for HIV.

Jeannie Wraight contributed to this article.

Mariel Selbovitz, MPH, serves as the Chair of the Cornell ACTG Community Advisory Board and has authored over thirty abstracts and articles.

A former member of ACT UP NY, David Miller is an AIDS treatment activist and current member of the Cornell ACTG CAB. He is on the Community Access Board of OyaGen, one of the subjects of this article.