What are Vaccines for HIV Prevention and Therapy?
Today there are no HIV vaccines which can prevent HIV infection. All of the candidates being studied are in the experimental stage. Preventive vaccine candidates are being tested in HIV-negative people. Some of these candidates are being tested to see if they can prevent infection. Other candidates are being tested to see if they lower viral load in people who receive the vaccine before becoming HIV infected but can learn to partially fight the resulting infection.
Since 2001, global preventive HIV vaccine R&D investment has totaled US$8 billion, with an average yearly investment of US$824 million. The 2011 total investment was US$845 million, a decrease of US$14 million from 2010. As in past years, public-sector funders provided the largest part of the investment, followed by the philanthropic sector and the commercial sector.18 In 2011, the public sector provided US$702 million (83 percent), the philanthropic sector provided US$113 million (13 percent) and the commercial sector contributed US$30 million (4 percent). Investment by European governments was US$48.5 million, a decrease of over US$12 million (21 percent) from 2010, and a 40 percent decrease from the US$82 million peak in 2006. Philanthropic investments in HIV vaccine R&D increased in 2011 by US$10 million (10 percent).
In 2011, RV144 researchers revealed new findings, identifying two correlates of immunity that have the potential to move the field closer to an effective vaccine. In addition, over 30 other HIV vaccine trials were underway. Most ongoing trials are supported primarily through public-sector funding and are collaborative efforts among a range of public and private-sector entities.
RV144 researchers presented results at the AIDS Vaccine 2011 conference in Bangkok, Thailand, of a two-year effort to identify an immunological explanation for the modest 31 percent efficacy afforded by the prime-boost vaccine regimen tested in the RV144 trial. Two immune responses were found to correlate significantly with HIV infection rates in RV144 vaccine recipients: The first, involving immunoglobulin IgG antibodies that bind to the V1/V2 variable loops in the HIV envelope, correlated with a 43 percent reduction in HIV infection rate. The second involved plasma IgA antibodies that bind to the HIV envelope and correlated with a 54 percent increase in the HIV infection rate. Follow-up trials are now underway. RV305, a small immunogenicity study that aims to evaluate extended boosting regimens using the same vaccine components as RV144, began in Thailand in April 2012. RV305 is the first of two planned follow-up trials to RV144, with the second study, RV306, expected to begin later in 2012.
Additional studies evaluating a prime-boost mechanism similar to that used in RV144 are being planned for initiation in 2013 and 2014 in Thailand, Uganda and South Africa.
Broadly neutralizing antibody research is a large focus of R&D efforts and collaboration within the HIV vaccine field. The Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases (NIAID) has been focused on designing vaccines to stimulate broadly neutralizing antibodies against HIV. The VRC has completed novel research using computational biology to design immunogens capable of eliciting antibodies in animal models.
Additionally, in 2009, IAVI established the Neutralizing Antibody Center at the Scripps Research Institute dedicated to studying neutralizing antibodies. The Center is the hub for IAVI’s Neutralizing Antibody Consortium, which has isolated more than two-dozen antibodies from volunteers worldwide, deciphered some of the structures of the most potent antibodies and applied their discoveries to the design of novel vaccine candidates.
Larger pharmaceutical companies are entering into antibody research and several biotechnology companies are also engaged in R&D that has yielded promising results.
The year 2011 saw more than just the identification of new broadly neutralizing antibodies. Additional advances have been made in identifying the structures of antibodies, how they evolve and how they are produced by the immune system. These discoveries help researchers in identifying new targets, understanding how and where antibodies interact with HIV and how they are able to block the virus from infecting cells. Furthermore, VRC was able to map the way in which broadly neutralizing antibodies evolve. Collectively, these discoveries provide clues to design and evaluate vaccine candidates that can elicit such antibodies.
EuroNeut-41, funded under the European Union’s (EU) Seventh Framework Programme (FP7), aims to develop new vaccines capable of eliciting neutralizing antibodies. The EuroNeut-41 project involves 17 partners, including Sanofi Pasteur, the University of Granada in Spain, Polymun Scientific, Clinical Research Centre at the University of Surrey and PXTherapeutics.
Among other trials moving forward is HVTN 505, currently the only active vaccine efficacy trial. HVTN 505 is a Phase IIb trial evaluating a DNA prime and adenovector vaccine boost to assess whether it prevents infection or lowers the viral load of individuals who seroconvert during the trial. The regimen is being tested in over 2,000 gay men, MSM and transgender women in the US. In 2011, the trial changed its protocol to add HIV infection as an end point for analysis. HVTN 505 is expected to release results in early 2013.
Public-sector funding has accounted for the majority of funding for HIV vaccine research since research began. National research agencies, through investigator-initiated programs, have been successful in supporting basic, preclinical and clinical research. Public agencies and institutions accounted for 83 percent of all investments in 2011. Agencies in the US alone accounted for 74 percent of HIV vaccine R&D funding. The United Kingdom (UK) and Canada were the second- and third- largest contributors, investing US$18.0 million and US$13.0 million, respectively. Public agencies in eight additional countries invested more than US$1 million each. Ten public agencies increased their investment from 2010 to 2011.
The final disbursement of stimulus funding from the American Recovery and Reinvestment Act (ARRA) came in 2010, providing US$26.7 million in NIH funding for HIV vaccine R&D. While there was only a two percent drop in overall funding for HIV vaccine R&D in 2011, and a three percent drop in US funding, the current budget debates could influence funding for the NIH, the US Agency for International Development (USAID) and the US Department of Defense’s Military HIV Research Program (MHRP) in 2012 and 2013. Pressure on the US Congress to cut spending grew in 2011 and early 2012. Under the sequestration provisions of the Budget Control Act of 2011, significant cuts on the order of eight percent are proposed for the NIH starting in January 2013.
Most members of the G821 and 11 members of the G2022 supported HIV vaccine research in 2011, with China, Canada, the EU, France, the UK and the US contributing more than US$5 million. Support from Canada, France and Japan increased in 2011. Canada significantly increased its R&D investment through the Canadian Institutes of Health Research (CIHR) and is a top funder of HIV vaccine research. The CIHR HIV/AIDS Research Initiative oversees the Federal Initiative to Address HIV/AIDS in Canada and the Canadian HIV Vaccine Initiative. These initiatives provide US$22.5 million annually to support research.
Funding from the European Commission (EC) in 2011 declined dramatically from the previous year. In 2010, the EC invested US$20 million in HIV vaccine R&D. However, in 2011, EC funding decreased by approximately 50 percent to US$10 million. This is on par with the larger trend of decreased funding from European countries, with Italy, the Netherlands, the UK and Spain all reporting lower funding in 2011.
Public-sector funding has also been the backbone of many large PDP efforts and supports collaborations with other sectors, such as the commercial sector. Many commercial-sector efforts are incentivized through grants offered by the public sector. For instance, the US government supports the work of the HIV Vaccine Trials Network (HVTN), testing commercial available vaccines, through NIAID. The US NIH- supported HVTN 505 is the only vaccine efficacy trial currently underway that is testing a DNA/ Ad5 vaccine. The US NIH is supporting 20 of the 33 clinical trials that are currently underway. Additionally, the US Military HIV Research Program (MHRP) and the Walter Reed Army Institute of Research (WRAIR) are supporting additional studies on pox protein vaccines, following up on the results of the MHRP-led RV144.
France’s National Agency for Research on AIDS and Viral Hepatitis (ANRS) is also supporting a late-stage clinical trial, set to begin in September 2012, testing a DNA vaccine. Additionally, the public sectors in China, Italy, Spain, Sweden and the UK are all supporting ongoing clinical trials underway in their respective countries.
The philanthropic sector accounted for US$113 million (13 percent) of the total funds disbursed for HIV vaccine R&D in 2011, with the BMGF contributing US$78.5 million (72 percent) of that total. Overall, philanthropic contributions increased in 2011. The UK’s Wellcome Trust and the Spanish Fundació la Caixa increased their contributions in 2011.
Increases in philanthropic-sector funding offset cuts to public-sector funding in 2011. While the BMGF decreased its funding in 2011, it remains the second-largest funder and provides invaluable investments in research for HIV vaccines. The Ragon Institute, established in 2009 at Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT) and Harvard University, was founded with a five-year commitment of US$100 million from the Ragon Institute Foundation. Since its founding, the Institute has diversified its funding portfolio, bringing in funding from a variety of other sources. In 2011, funders contributed an additional US$10 million on top of the Ragon Foundation’s investment.
In 1997, there were 17 multinational pharmaceutical companies and biotechnology firms engaging in HIV vaccine R&D. While the level of company engagement has fluctuated over the past 15 years, the number of companies conducting HIV vaccine R&D remains relatively stable, with 16 private sector companies engaged during 2011.
While many biotechnology companies invest in HIV vaccine R&D, the majority of private- sector investments in vaccine R&D come from large, multinational pharmaceutical companies. Five multinationals currently have HIV vaccine programs: GlaxoSmithKline (GSK), Johnson & Johnson (through its subsidiary Crucell), Merck & Co., Novartis Vaccines and Sanofi Pasteur.
In 2011, Johnson & Johnson acquired the Dutch biotechnology company, Crucell, which has been working in collaboration to evaluate its Ad26 adenovirus vector. With the Beth Israel Deaconess Medical Center (BIDMC) and the Ragon Institute, both in Boston, Massachusetts, and the Walter Reed Army Institute of Research, in Silver Spring, Maryland, Crucell has looked at several prime-boost vaccine combinations of Ad26. In addition, Crucell, BIDMC, Ragon and the HVTN also have a collaboration with IAVI to conduct a clinical study of a Ad26/Ad35 prime boost regimen. GSK has a long history of HIV vaccine R&D, beginning with the initiation of its vaccine program in 1986. The company currently has three areas of focus in the preventive HIV vaccine field. The company is investigating an HIV-1 vaccine candidate containing a recombinant fusion protein along with their proprietary adjuvant, AS01, in collaboration with IAVI. Additionally, with the Institut Pasteur, funded in part by the EC Sixth Framework Programme, GSK is investigating a vaccine approach based on the measles vaccine.
The third area of investigation of GSK’s program is early-discovery R&D to identify new envelope antigen candidates in partnership with several academic institutions.
Merck, along with various partners, is working on an R&D program that aims to identify an HIV envelope–based protein vaccine capable of producing broadly neutralizing antibodies against HIV infection. The company continues to analyze the results of the STEP trial, which tested its adenovirus-5 vaccine, and to explore its implications for vaccine design, as well as the development of antigens to elicit protective antibodies to HIV. Despite the disappointing results of the STEP trial, the data has continued to yield important findings. In February 2011, scientists from University of Washington, who were not affiliated with the STEP trial, analyzed the genome sequences in HIV-1 isolated from newly infected STEP trial participants and found that the Step vaccine had exerted pressure on the genetic evolution of the virus.
Novartis Vaccines continues to research its alphavirus vector, and is developing different envelope proteins as well as adjuvants for use as a boost to ALVAC prime in the follow-up trials to the Thai RV144 trial or with other candidates. The company has supplied the envelope proteins for the first phase of clinical testing of a preventive HIV vaccine study launched in June by the National Center of the Istituto Superiore di Sanità (ISS) in Italy, part of a collaboration of the AIDS Vaccine Integrated Project (AIVP).
Sanofi Pasteur, the vaccines division of the Sanofi- Aventis Group, is engaging in follow-up studies to RV144 with multiple partners in Thailand and South Africa. In 2011, Sanofi Pasteur signed an agreement with Novartis Vaccines to collaborate on an HIV vaccine prime-boost regimen to build and improve on the efficacy level obtained in the RV144 study in Thailand. The focus will be on the development and clinical evaluation of the HIV prime-boost approach in South Africa and Thailand. Novartis Vaccines and Sanofi Pasteur are working in partnership with the Pox-Protein Public-Private Partnership (P5), which includes the US NIAID, the BMGF, the HIV Vaccine Trials Network (HVTN) and the US MHRP.
Sanofi Pasteur also contributed expertise and funding to the BMGF’s Collaboration for AIDS Vaccine Discovery (CAVD) project, which contributes funds, expertise and products to the EuroVacc Foundation, and is a member of EuroNeut-41, the European consortium on neutralizing antibodies. with a small decrease in preclinical research and an increase in clinical research. Further information about the categories used to define R&D can be found in the Methodology page.
Therapeutic vaccines enhance immune responses for HIV-positive individuals to help them better control infection. Investment toward research for therapeutic HIV vaccines for HIV-positive individuals increased in 2011 to US$21.2 million, a change of US$9.6 million from 2010.
Investment from public-sector sources increased. Investors included the US NIH (62 percent), France’s Institut Pasteur (8 percent), Australia’s National Health and Medical Research Council (NHMRC) (7 percent), the Australian Research Council (ARC) (6 percent), the UK Medical Research Council (2 percent), the Canadian Institutes for Health Research (CIHR) (1.4 percent), the Canadian HIV Vaccine Initiative (1.2 percent) and the Swedish Research Council (SRC) and Estonia Research Council (less than one percent each).
Philanthropic sources began funding therapeutic vaccine research, with funding from the BMGF, the Campbell Foundation and amfAR (3 percent).
Funding from pharmaceutical and biotechnology companies is likely underrepresented, since only a few biotechnology firms reported their investment in 2011. Companies involved in R&D for therapeutic vaccines in 2011 include Argos Therapeutics, Bionor Immuno, FIT Biotech, Genetic Immunity, GeoVax, GSK, Invio Pharmaceuticals, Profectus Biosciences and VIRxSYS.