Co-authored by Margaret I. Johnston, Ph.D., Director of the Vaccine Research Program in NIAID’s Division of AIDS
Carl W. Dieffenbach, PhD
Margaret I. Johnston, PhD
The development of a safe and effective preventive vaccine for HIV remains one of NIAID’s highest priorities. As we look to the future, we are also seeking to expand the capability of our HIV vaccine clinical research infrastructure to contribute to the development of vaccines for other infectious diseases of public health significance that impact people who are infected with HIV and those who are at risk for HIV infection.
HIV vaccine development has presented significant challenges for the scientific community. However, in late 2009, we obtained the first clinical evidence that a safe and effective HIV vaccine may indeed be possible. The RV144 Thai trial showed that an experimental “prime-boost” vaccine regimen was safe and 31 percent effective in preventing HIV infection. This information brought renewed hope and optimism to researchers and the HIV/AIDS community. Most recently, the identification by NIAID-led scientists of two new broadly neutralizing human antibodies that can prevent more than 90 percent of known HIV strains from infecting human cells will certainly help to advance HIV vaccine design. As we chart a path forward, we must keep our eye on the goal of developing a safe and effective vaccine that prevents HIV acquisition. To achieve this goal, we are following a two-pronged approach for an HIV vaccine.
The first approach grew out of the 2008 NIAID HIV vaccine summit and consists of a strengthened commitment to basic vaccine discovery for HIV. For example, investigators are actively evaluating the earliest steps during HIV infection and how a vaccine may influence the course of infection. Studies in non-human primates are addressing questions that cannot be addressed in humans. This has resulted in a proliferation of new ideas and concepts to pursue, and we must continue to encourage “out of the box” thinking and approaches to HIV prevention. As these lines of thinking and research progress, we hope that some ideas will mature into novel vaccine concepts worthy of further evaluation. Clearly, an important component of the research endeavor is the eventual evaluation of the most promising new concepts for safety and activity in humans, which includes testing candidate HIV vaccines with acquisition of infection as a clinical trial endpoint.
As we have discussed NIAID’s current HIV vaccine research agenda and potential future directions, please consider the following:
- Are there key components or activities that are missing from our two-pronged approach toward an HIV vaccine?
- Are adaptive trial designs a suitable approach for rapidly evaluating promising HIV vaccine candidates?
- Are there alternative HIV vaccine trial designs that would provide answers quickly and efficiently, so that we can quickly move towards newer, improved products with greater efficacy?
- What mechanisms should be in place to ensure that the HIV clinical vaccine research endeavor integrates product evaluation with scientific inquiry that informs and is informed by vaccine discovery and preclinical efforts?
- What mechanisms would help ensure that the best ideas for vaccine clinical research are identified and implemented?
- Aside from TB, hepatitis C and malaria, are there other infectious diseases that we should focus on for vaccine development in the HIV clinical trial network system?
Second, we need to follow up on the results of the RV144 trial to determine if the results can be extended and improved through clinical trials in higher risk populations and where different strains of HIV circulate. If a measurable sign of how vaccinated study participants were protected — what is known as a “correlate of protection” — is identified through the ongoing studies using RV144 specimens, there will be a relatively straightforward path to the improvement of vaccine design. Absent a correlate, different prime-boost strategies can be evaluated for safety and activity in “proof of concept” trials to yield additional information about what immune responses may or may not correlate with efficacy. One strategy currently under consideration is to use an adaptive trial design so that the vaccine candidates that fail early would be eliminated, resulting in a more streamlined development path. In order for these clinical trials to be performed in an expeditious manner, they will need to be conducted at sites where volunteers at high risk for HIV infection can be rapidly recruited. In addition, clinical trials that enroll volunteers with different routes of potential HIV exposure will need to be developed.
There are a number of other infectious diseases that burden populations impacted by HIV. These include, but are not limited to, tuberculosis, hepatitis C infection, and malaria. Like HIV/AIDS, finding preventive vaccines for these diseases has proven elusive as well. By integrating efforts, the best minds in infectious diseases, vaccine discovery and development can work together, so that the research processes and discoveries for each disease can inform vaccine development for other diseases. Furthermore, integration of efforts to evaluate vaccines against these diseases of public health importance would lead to a more efficient and effective use of clinical laboratory expertise and clinical trial site capacity. Our goal is to have the restructured NIAID HIV clinical trial networks make significant contributions to the development of new preventive vaccines for HIV and other diseases of critical public health importance, including those that impact the most vulnerable populations around the world (e.g., young children and pregnant women). Developing effective preventive vaccines for these diseases will greatly improve the health and well-being of people living in areas with high rates of HIV.
We welcome your thoughts and feedback with regard to this topic. In our next blog post, we will shift the discussion toward the leadership structure for a revamped NIAID HIV clinical trial network system.
Dear Dr. Carl W.Diffenbach,
Director of NIAID’s Division of AIDS
Hello
The development of a safe and effective preventive vaccine for HIV remains as a prioritiy for scientific community and its development have presented significant challenges. Why it is so? Because the development of a safe and effective preventive vaccine for HIV does not obey and follow the principles of classic vaccinlogy. The experimental reason for my claim is the elusive result from the RV144 Thai trial. I believe that some rational empiric conclusions from the RV144 Thai trial can have leading effects in your future work for development of a safe and effective HIV vaccine. But according my view, the NIH researchers have at the present time long distance from the rational empiric conclusions that it must be intended in order to upgrade the RV144 Thai trial and its results. Sincerely, I pray for them that they can evaluate and reevaluate again and again the results of the RV144 Thai trial. The RV144 Thai was the first step in rational direction, but only the first step and nothing more. The developments and the improved results are depended to the continuation of this work based on the modification of experimental methodic and strategy by the help of criticism and self criticism.
The identification of two new broadly neutralizing human antibodies that can prevent more than 90 percent of known HIV strains is good news. Their broadly neutralizing functions and effects are certainly relative to laboratory strains of HIV and not relative to the wild type strains in vivo. At the best, these antibodies can be used directly in HIV-infected patient as antibody-based therapy.
In the end I will mention some words about the new vision for the national HIV/AIDS strategy in USA. According this vision, until 2016 the United States will become a place where new HIV infections are rare and … . The vision is good but is not realistic and pragmatistic. You cannot fight a war without resources. The great resources in order to fight and curb HIV are the scientific capacities. According my view a powerful country as the United States of America lacks at the present time the scientific capacity to promises such visionary utopia indicating a USA free from new HIV infection before 2016. The incidences of miracles do not associate with scientific endeavors.
Best wishes,
Seyed Mohsen Khatami
Thank you for this post. The strategy for an organized set of adaptive trial designs is certainly a good direction to go forward as a way to test vaccines in the best experimental system currently available – i.e. human clinical trials. However, the articulation of the proposal by NIAID so far lacks sufficient detail to appreciate its potential for success or failure. This was underscored by the excellent vaccine session at the AIDS 2010 conference The Search for an HIV Vaccine: Where Are We, Where Are We Going, and How Can We Get There Faster?
http://globalhealth.kff.org/AIDS2010/July-18/The-Search-for-an-HIV-Vaccine.aspx
As Linda Gail Becker, Robin Shattock, Mark Feinberg and Alan Bernstein pointed out, a number of operational, product development, institutional and GCP issues must be integrated and publicly explained. These include:
1) Practical and meaningful use of behavioral and social science methods and design features as part of these experiments
2) Especially with the exciting results of the CAPRISA 004 study and preliminary data from CDC’s PrEP safety study, it is important to plan and articulate now how vaccine study designs will develop in a multi-intervention environment, also taking community perspectives into account
3) Although many potential adjuvants are available and likely necessary, especially supplied from industry, few have been targeted as a fully supported part of the research agenda or in ways that allow private sector involvement and sharing
4) Although NIAID itself and its US consortia have progressed much in data and materials sharing plans, those are not yet at the level for a full international effort considering the very large volume of data collected now and expected in the future.
The NIAID scheme would also benefit in the future from “blogs” or proposals that are authored and distributed from the whole range of global vaccine advocates. It would be helpful to produce ideas and systems that promote NIAID’s effort in relation to all HIV vaccine research even if NIH is the single largest funder. Efforts to bolster small company participation and others would also be welcome.
I would like to specifically comment on the question of other infectious diseases that the HIV clinical trial network system. Ideally, these should provide some similarities to HIV so that lessons can be learned and translated from the outcomes of these other vaccines to the HIV endeavors. Already, without questioning the rationale for their selection, TB and malaria are very different infections and present somewhat different vaccine challenges to HIV. That said, it would be possible to still use them to assist the HIV efforts, for example a concerted effort to use a well defined malaria or TB antigen as a platform to compare multiple different adjuvant formulations, not just to benefit malaria or TB vaccine efforts per se, but to help identify the best adjuvant for a future HIV vaccine. However, this presents challenges as people in the malaria or TB fields may resist potential dilution of their focused vaccine efforts in this way and, in any case, the correlate of vaccine protection in malaria may be very different to HIV and thereby the type of adjuvant required may also be very different. So with the current network disease focuses there appear to be limited opportunities for cross-fertilisation.
In selecting additional disease focuses for the network, I feel it would be rational to restrict these to viral infections as these will have the most similarities and utility to HIV. Therapeutic hepatitis B vaccines are the most obvious and worthy candidate. EBV, herpes simplex, and CMV, similarly present obvious similarities to HIV, can infect the same population groups and would be worth inclusion both for their own sakes but also because their success could inform successful HIV vaccine design.
I wonder why the NIAID has not approached a cocktail of at least 3 or 4 vaccines. We have seen it in HAART, and now we are seeing that it is giving encouraging results in Hepatitis C virus. Merck’s single vector vaccine failed along with other monoclonal vaccines in the past, until we had the thai trial last year as a conbination of 2 vaccines that showed a modest protection.So my question is: Why not enhance it to a 3 or 4 punch vaccine? Is it too complicated? I wish you all good hard work!
Will the slides from the ARAC meeting on the future of the clinical trials networks be posted to the blog?
Dear Dr.carl /Dr.johnson
First of all i find myself pleased to comment on the subject and let me start to say that it is very difficult and too hard to solve a problem when one aims to target with a blind eye.numerous funding and financial expenditure on HIV/AIDS vaccine development has gone waste and futile since 3 decades of its existance where millions of lives have been spoiled.The word impossible is written in the dictionary of fools ,after all scientists are closer to GOD.
Being a simple physician and researcher from INDIA i have been myself able to develop a nice alternative therapy for HIV/AIDS/HBV/HCV ,THOUGH WITHOUT facilities like research institute,laboratory,infrastructure finance and all.why could not scientists /doctors from NIH/USA and other countries find it out after expenditure of billions of dollars any cure or vaccine for the same.
i would like to suggest the authorities to make open call for proposals/invite for proposals for new ideas , from innovators /researchers /doctors or idea /thinkers throughtout globe so that if not billions/millions/but one idea from any part of the world may be able to solve this mystery by developing a foolproof effective vaccine once for all.
Thanks
yours sincerely
Dr.Shabir Qureshi
Srinagar INDIA