Fifteen years have elapsed since the former U.S. president Bill Clinton predicted in 1997 the introduction of a vaccine for AIDS "within a decade." Unfortunately, instead of the prediction becoming a reality, 2007 represented a particularly low point for HIV vaccine research. During that year Merck & Co. Inc. announced that it was discontinuing its HIV vaccine trial. Merck, along with the AIDS community had high hopes for the drug, which had been in development for almost a decade. Its failure caused researchers to become pessimistic about the prospects of ever achieving an effective HIV vaccine in the foreseeable future.

The feelings of the time was summed up at the 2008 annual meeting of the American Association for the Advancement of Science, where AAAS president David Baltimore called an AIDS vaccine "a sad topic" and added that the development of a vaccine "has been 10 years away for the past 20 years." (See BioWorld Today, Feb 15, 2008.)

However, a spate of recent discoveries has fueled expectations that the development of an effective HIV vaccine may now be within reach.

At the XIX International AIDS Conference last week, for example, Gary Nabel, director of the Vaccine Research Institute at the National Institute of Allergies and Infectious Disease (NIAID), said that he hopes that by 2020, "we will be in the midst of an efficacy trial for a vaccine candidate that could really work." (See BioWorld Today, July 25, 2012.)

The mood has definitely become more positive in the research community, Carl Dieffenbach told BioWorld Insight. Although developing an HIV vaccine still poses an exceptional challenge, Dieffenbach, director of the Division of AIDS at the NIAID at the National Institutes of Health (NIH), said the modest results from the RV144 16,000-participant Thai HIV vaccine trial was a turning point. It galvanized a new enthusiasm for the prospects of learning how to induce broad neutralizing antibodies to HIV-1 by a vaccine. The study showed that those who received the vaccine were about 31 percent less likely to be infected than those who did not.

The total number of broadly neutralizing antibodies known to the scientific community was four 15 years ago and "now we have hundreds" of such antibodies said Nabel.

This is where the thrust of the work will be going forward for preventative and therapeutic vaccines, noted Dieffenbach.

It is clear that significant investments in research and development will be required. The HIV Vaccines and Microbicides Resource Tracking Working Group latest report released this month found that since 2001, global preventive HIV vaccine research and development investment has totaled $8 billion, with an average yearly investment of $824 million. The 2011 investment was $845 million – $14 million lower than in 2010. The public sector provided 83 percent of funding in 2011, at $702 million, with the NIH leading the way.

HIV Vaccine Consortium

In July the NIH awarded $31 million in first-year funding for the establishment of a new consortium called the Centers for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID). The initiative, which will be led by Duke University and Scripps Research Institute, is projected to receive up to $186 million over the next six years. The goal is to accelerate HIV vaccine development by supporting multidisciplinary research into immune responses that prevent or contain HIV infection and generating model vaccine components that can induce these protective immune responses.

Duke researchers will attempt to identify and target the vulnerabilities of HIV to specific immune system responses and use that information to design vaccines that induce protective immunity at the time and location of HIV transmission. Their work will largely focus on inducing broadly neutralizing antibodies that can prevent HIV infection as well as on generating protective T-cell and innate immune system responses. One strategy will be to evaluate the maturation pathways of these rarely occurring neutralizing antibodies, and use those pathways to help design vaccines that can elicit protective antibody responses.

For their part, Scripps researchers will conduct B-cell and antibody research to guide the development of immunogens. Additionally, the scientists will concentrate on CD4-positive T-cell research and try to harness these cells' direct antiviral activity, as well as their ability to help other cells produce antibodies.

Role of Private Sector

The private sector also is playing its part. Robert McNally, president and CEO of Atlanta–based GeoVax Labs Inc. told BioWorld Insight that although the FDA approval of Gilead Science Inc.'s anti-viral medication, Truvada, for prevention of HIV in adults who are at high risk for contracting the disease is an important development, he believes that the best preventative solution lies in a vaccine approach. "The company's preventive vaccine is considered a leading candidate for the version of the virus most prevalent in North and South America, and Europe."

In May GeoVax Labs said that the NIH-funded HIV Vaccine Trials Network (HVTN) had opened enrollment for a Phase I trial for its second-generation HIV vaccine, which is identical to its first generation (currently in a Phase IIa clinical trial) except for the inclusion of granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjuvant to enhance vaccine responses. (See BioWorld Today, May 23, 2012.)

In the non-human primate model, co-expression of GM-CSF in the DNA prime achieved a 90 percent exposure reduction in infection, McNally noted.

Bionor Pharma ASA, of Oslo, Norway, is another company working in the field. It presented immunological data from a large exploratory Phase II study of Vacc-4x at the "Towards an HIV Cure" workshop sponsored by the International AIDS Society.

The results showed improved quality of immune cells, that can in part explain killing of HIV infected cells leading to the reduction in viral load in patients receiving Vacc-4x.

"This shows that Vacc-4x works differently than antiretroviral therapies (ART)," said Jürgen Rockstroh, a member of Bionor Pharma's Clinical Advisory Board in a statement. "If a patient stops taking ART, the virus normally returns within few weeks, but with Vacc-4x we see a sustained response."

Bionor's second therapeutic HIV vaccine, Vacc-C5, is developed to induce antibodies to HIV that can reduce viral production (lowering the set point) and the hyperactivation of the immune system that leads to AIDS. Recently, a clinical Phase I/II study with Vacc-C5 was approved by the Norwegian regulatory authorities.

The company completed a private placement of approximately $10 million in June to fund its research programs.