Therapeutic Vaccine Research Toward a Functional Cure Shows Promise
by Jeannie Wraight
Until recently, therapeutic vaccines and immune-based therapies (IBTs) were all but shunned by the HIV research community due to poor or mixed results in clinical trials. This helped to facilitate an environment where novel therapies, including the search for a functional cure, had all but been abandoned as unobtainable. Fortunately, the cure of Timothy Brown (a.k.a. the Berlin Patient), has created a paradigm shift in the thought process of many researchers. That is, although the method used with Timothy could not be reproduced in the very large majority of people with HIV, the idea of a cure or the development of a therapeutic vaccine once again seems plausible.
At the same time, most researchers believe, after continual vaccine failures and the recent data from the RV144 preventative vaccine trial, that the direction of HIV vaccines needs to be reevaluated.
The controversial RV144 study is the first preventative HIV vaccine that may show a partial protective benefit (31.2 percent) against HIV transmission. The RV144 data is viewed by many as a first step in devising hypotheses of where to go from here in the development of an HIV vaccine.
Ongoing analysis of the trial results found that vaccine recipients with high levels of one type of antibody response had the lowest rate of HIV infection, and those with high levels of another type had the highest rate of infection. If shown to be truly, partially effective, RV144 may refocus attention on B-cell responses and non-neutralizing antibodies, providing a possible investigational path worthy of exploration.
Conversely, the statistical analysis of the RV144 data has left many researchers questioning the protective benefit seen. Some believe that the partial benefit may be due to chance alone because of the relatively small number of infected individuals in the placebo and vaccine groups. When using a different model of statistical analysis to interpret the trial results, the level of efficacy is substantially decreased. An abstract published in the April 2011 issue of the Journal of Infectious Disease titled “Statistical interpretation of the RV144 HIV vaccine efficacy trial in Thailand: a case study for statistical issues in efficacy trials” looks closely at the factors in question.
With further data interpretation and a follow-up trial the true level of efficacy from RV144 could help determine the next steps in HIV vaccine research.
Advances in either a preventative or therapeutic HIV vaccine could assist in the development of the other, helping to determine the immune responses necessary to convey protection from HIV infection. To date, most HIV therapeutic vaccines have failed to show, or have only partially shown, the benefit they hoped to achieve. Many believe this is because we are not looking at the right immune responses or the viral proteins needed to achieve these responses. Essentially, the questions that need to be answered in order to do so simply have not been asked.
“The field has tested several failed therapeutic vaccines in the past to show, as in prophylactic vaccine efforts, that we do not yet understand what type of response is needed to develop host-mediated control of HIV-1 in the absence of therapy. With what we know now, therapeutic vaccine efforts remain wishful thinking until such a time we can design them having gained new knowledge of what makes elite controllers control, what makes an immune response after therapy interruption control HIV-1 to levels similar to ART (functional cure), or how to generate an immunogen for which immune escape is not expected. Until then therapeutic vaccine studies will remain a hit or miss exercise with a score to date of 100-percent misses,” stated Dr. Luis J. Montaner, immunology professor and director of the HIV-1 Immunopathogenesis Laboratory at The Wistar Institute in Philadelphia.
Although HIV antiretrovirals have saved or prolonged the lives of millions living with HIV, the high cost of lifelong treatment both financially and physically makes antiretroviral therapy (ART) only a stopgap to a cure or less invasive, less expensive therapy. There is no doubt in the benefit that would be achieved for HIV-positive people globally with the discovery of a functional HIV therapeutic vaccine.
Although much research needs to be done, there is some new therapeutic vaccine research that does look promising.
PENNVAX-B is a Phase I therapeutic vaccine candidate which has completed one NIH sponsored clinical trial, with another company sponsored trial in progress. In addition, a trial on PENNVAX-G, a preventative vaccine candidate, sponsored by the NIH is enrolling.
Inovio’s PENNVAX HIV vaccines are based on their proprietary SynCon design, which aims to provide universal protection against known and newly emergent strains within a subtype of a virus. PENNVAX-B targets the HIV subtypes, or clades, common to North America and Europe. This synthetically created vaccine is highly optimized to maximize the production of HIV-specific antigens by cells of the body and induce broad antibody and T-cell immune responses. Combined with Inovio’s proprietary CELLECTRA electroporation delivery technology, which maximizes the uptake of the synthetic vaccine into cells, this vaccine platform has achieved T-cell immune responses not seen with other vaccine platforms to-date, and with a favorable safety profile. The research of this technology should be supported and followed by HIV researchers, activists and treatment advocacy groups to determine whether it is a progressive step in vaccine research.
“Therapeutic vaccines and immunotherapeutic approaches with their potential to stimulate the body’s own defense mechanisms continue to offer promise for hard to treat diseases like cancer and chronic diseases like HIV, HBV, and HCV. The issues and costs of long-term drug treatment and adherence to a drug regimen make the simplicity of a potential vaccine approach combined with ART optimal for HIV. Historically the immune potency of HIV vaccines has been one of the barriers to effective vaccine development for treatment and/or prophylaxis,” said Niranjan Sardesai, PhD, Senior Vice President of Research and Development at Inovio. “Inovio’s vaccine technology is the first new platform to raise potent antigen specific T-cell responses in people, creating new excitement in the field of therapeutic vaccines and their potential development for treating HIV.”
In an article regarding recent data on Vpx, an HIV protein, Professor Françoise Barré-Sinoussi, 2008 Nobel Laureate in Medicine and IAS President-elect, states: “New findings on innate control of HIV have implications for treatments and can provide insight into therapeutic vaccine development, bringing us one step closer to finding better strategies to address HIV infection.”
Promising advances in the search for a functional cure are also occurring. Calimmune, co-founded by Nobel Prize Laureate Dr. David Baltimore, has engineered a CCR5 gene therapy which would render cells immune to HIV. CCR5 is the main co-receptor that allows HIV to enter cells. Approximately one percent of Europeans possess a hereditary mutation that cannot produce CCR5, rendering them immune to HIV infection. When only one parent has this mutation it makes it more difficult for an individual to become infected with HIV and they experience a three- to five-year delay in disease progression. This approach is about to enter Phase I clinical trials to test its viability.
Although extremely promising, approaches such as Calimmune’s would result in a decrease in the need for ART but most likely would not result in fully ending the HIV pandemic. When viewing a sustainable, successful and durable solution, we must consider the issue of drug access and cost as well as efficaciousness.
Even if a gene therapy or cell therapy such as Calimmune’s were found to be effective, the task of providing it to everyone living with HIV on a level that would result in controlling present infections and eradicating new HIV infections would be unlikely.
A successful approach would have to be a one-time, or a limited boost therapy where only one vaccination or one vaccination and a follow-up, or booster, shot could be produced in syringes and distributed throughout all areas including those with limited access and medical facilities. Therapies such as Calimmune’s would require cells to be removed and engineered with the CCR5 protein on-site.
Therapies such as Calimmune’s and other gene and cell therapies would be a significant advance in HIV treatment for a large percentage of people living with HIV, resulting in the preservation of life for those already HIV-positive and a dramatic decrease in new infections. However, the most viable approach for preserving immune function remains easy-to-administer, prepackaged therapies.
Supporting advances in technology and research such as these would progress us toward a better understanding of immune responses and vaccination. Entities such as the NIH, universities, institutions and foundations are not funding on any substantial level promising therapeutic vaccine candidates or the basic research needed to better our understanding so we can move towards a viable therapeutic vaccine that would eliminate the need for lifelong or continual antiretroviral therapy.
Research of therapeutic vaccines is essential to produce therapies that at worst can prolong the need for ongoing treatment and at best, act as a functional cure. As with any research, financial support and a clear understanding of the present data are essential.
Advocacy groups such as amfAR, the National Minority AIDS Council (NMAC), The AIDS Institute, Project Inform, and other AIDS organizations should be rallying for therapeutic vaccine research if we are to ever see an end to the AIDS pandemic.
In 2011 Congress failed to support any initiatives that would provide funding for therapeutic vaccine research. Supporting the allocation of funding for biotechnology companies with promising new therapeutic vaccines would help ensure the initiation and continuation of valuable research for a more viable solution then the currently available ARTs.
A House resolution (H.RES 906) passed in November 2009 recognized the need for the development of a Clade B preventative vaccine for the United States. An authorization that could have provided funding for such research was never passed. When a budget for HIV vaccine research is approved, therapeutic vaccines must be provided a fair share. Why is Congress not taking an active role in supporting the needed funding for therapeutic vaccine research? The development of such would offer a permanent solution to the shortfall in drug access, save the United States government billions of dollars on the provision of ART for U.S. citizens alone, and would dramatically reduce or eliminate the ADAP waiting list.
A preventative vaccine will most likely not be developed until we have a clearer understanding of immune responses, which we can obtain through the investigation of therapeutic vaccines. The HIV Vaccine Trials Network and U.S. Military HIV Research Program, two of the largest-funded HIV vaccine programs, focus only on preventative vaccines. Discoveries made in the pursuit of a therapeutic vaccine would dramatically increase the likelihood of a preventative vaccine.
In the absence of a cure, and without such research and support, we may be destined to lifelong treatment—that is, for those of us who can access it.
IAS article: www.iasociety.org/Default.aspx?pageId=556
Jeannie Wraight has been an AIDS treatment activist and HIV writer for over fifteen years. She lives in New York City.