Harnessing cells and antibodies—a two-pronged assault on HIV
In 2012, our researchers and partners advanced the design and evaluation of vaccine candidates that target HIV in two important ways: by eliciting neutralizing antibodies that can stop HIV from invading target cells, and inducing specialized cells of the immune system to destroy cells that become infected.
HIV has evolved multiple mechanisms to evade recognition and destruction by the immune system but the RV144 clinical trial, completed in Thailand in 2009, established the feasibility of an AIDS vaccine. In pursuit of the goal to develop a vaccine capable of preventing infection by a wider variety of the HIV subtypes that circulate in different regions of the world, researchers at IAVI and elsewhere have, among other things, isolated and analyzed scores of antibodies that appear to be able to stop a broad spectrum of HIV variants from infecting cells in the laboratory. They are now racing to apply what they have learned from these antibodies to develop a new generation of vaccines.
IAVI's R&D program covers a variety of activities essential to the development of HIV vaccines, including:
- The design and preclinical development of HIV vaccine candidates to elicit effective antibody and cell-mediated immune responses against HIV, and to target those responses to appropriate tissues
- The clinical evaluation of novel HIV vaccine candidates
- Epidemiological research to prepare for such trials, especially in key populations
Validating a new strategy for vaccine design
In 2012, researchers at and affiliated with IAVI stepped up their efforts to devise vaccines that might elicit bNAbs against HIV, and established that the molecular targets of antibodies can be synthetically reconstructed to make immunogens—the active ingredients of vaccines (see box).
Scientists have long been aware that a minority of HIV-infected people make bNAbs to the virus. These antibodies do not appear to arrest an existing infection, but they may be able to prevent infection if they are present when HIV enters the body for the first time.
In 2012, the quest to develop vaccines based on bNAbs was expanded into India in partnership with the government's Translational Health Sciences and Technology Institute of the Indian Government's Department of Biotechnology, which is working with IAVI on increasing the speed and scale of such immunogen design. Meanwhile, NAC researchers screened more than 60 potential immunogens designed on the basis of bNAb studies, and selected two to advance into preclinical development.
Further, IAVI and affiliated researchers showed in 2012 that it is possible to create synthetic immunogens based on a close study of the mechanisms by which antibodies neutralize viruses. One of the approaches NAC researchers have employed to do this applies sophisticated computational and protein engineering techniques to recreate complex molecular structures found on HIV that are uniquely targeted by bNAbs. The hope is that, if given as part of a vaccine, such immunogens might elicit bNAbs. To prove that this novel approach to vaccine design is viable, NAC researchers and their partners reconstructed a molecular structure found on the respiratory syncytial virus (RSV)—which causes respiratory disease in infants—that is effectively targeted by a known antibody. They then demonstrated that this structure could elicit similar antibodies when it was injected into animals. This proof of concept also has implications for the design of vaccines against other variable viruses, such as hepatitis C and influenza.
Sharing our expertise in antibodies and product development
IAVI is also contributing to studies that will investigate whether bNAbs can prevent HIV infection in humans using an approach known as gene transfer, in which a gene that encodes a useful protein is transiently expressed in people. In a Phase I trial that will be sponsored by IAVI and is being supported by the US Agency for International Development (USAID), the Bill & Melinda Gates Foundation and NIAID, researchers will use a harmless viral vector (under-associated virus, or AAV) to deliver the gene that encodes a bNAb against HIV, named PG9, which was isolated by IAVI and affiliated researchers in 2009. Researchers will examine whether the antibody is safe, produced at acceptable levels, and how long it persists. Manufacturing of the vector carrying PG9 was completed in 2012.
In partnership with the Gates Foundation, a pilot program was launched in 2012 to assess the feasibility and impact of a Vaccine Product Development Center, Central Services Facility (CSF), to help principal investigators (PIs) supported through the Gates Foundation-funded CAVD to advance vaccine concepts into human trials and to prepare for such studies. For example, the CSF worked with a CAVD PI at Rockefeller University to devise a clinical development plan to assess a new, highly potent, broadly neutralizing antibody as a possible therapeutic agent for HIV infection. Similarly, another CAVD PI and his team at the Harvard Medical School worked with the CSF to fashion a preclinical and clinical development plan for an adenoviral replicating vector bearing a novel mosaic HIV antigen—which is computationally designed and engineered to elicit immune responses against a broad range of circulating HIV subtypes. The pilot CSF, which began as a contract with four participating PIs, was later expanded to a total of six and is now being reviewed by the Gates Foundation for long-term support.
In 2012, IAVI supported a project led by the Global HIV Vaccine Enterprise, along with a number of other product development experts, to develop a webbased tool, From Bench to Clinic, to help researchers efficiently move candidate vaccines into clinical trials in the US, Canada and the European Union. The guide acquaints researchers, funders and advocates with the practical steps, processes, costs and timelines typical to biomedical product development.
Vaccines help the immune system detect and destroy pathogens (viruses, bacteria and parasites) before they can cause disease—and to remember them for future targeting. Many vaccines do this either by exposing the body to a weakened or dead pathogen, or to molecules derived from targeted pathogens, which are known as immunogens. Intact weakened HIV is not used to make vaccines because of the risk of disease. Instead, the immunogens used to make candidate HIV vaccines are either HIV protein molecules, or HIV genes that are taken up by cells of the body, which then produce the proteins encoded by the genes. Such genes might be delivered in a circle of DNA (a DNA vaccine). They may alternatively be incorporated into an unrelated virus, or vector. In any case, HIV vaccine candidates cannot cause HIV infection, since they only contain or encode fragments of the virus.
IAVI and its partners also continued a third Phase I trial evaluating the Ad35 vaccine candidates given in a prime-boost regimen with a DNA vaccine candidate made by Profectus. The DNA vaccine was given with a novel adjuvant—a substance that enhances the immune response—and delivered by electroporation, in which a small voltage is applied to improve uptake of DNA by cells.
Improving data integrity and the safety of volunteers
In 2012, IAVI piloted the use of a fingerprint-reading technology to better identify participants in clinical trials and HIV research. Such technology can help protect both the safety of volunteers and the integrity of data collected in clinical research by enhancing the ability to follow study participants and prevent enrollment of individuals in multiple studies. This technology is also being used to explore whether volunteers can be followed in a "virtual cohort."
IAVI and partners have developed an improved assessment of understanding (AoU) tool through the application of social science studies supported by IAVI. The new tool is designed to better measure volunteers' understanding of their risks, rights and responsibilities, which is essential to the ethical conduct of clinical research. It was employed in multiple IAVI studies in 2012.
IAVI also worked with the Global HIV Vaccine Enterprise and other partners to convene dozens of representatives from academia, civil society, government, industry and NGOs from around the world for a consultation on the challenges associated with vaccine-induced sero-positivity—the presence of antibodies against HIV in participants from AIDS vaccine clinical trials, which can result in false positives in future HIV tests. As a result, the WHO's Vaccine Advisory Committee unanimously agreed to develop formal guidelines to support volunteers.
Replicating vectors in Africa
In 2012, IAVI and partners prepared for the clinical evaluation of a novel vector-born HIV vaccine candidate based on a measles-like Sendai virus, which does not cause illness in humans. Unlike most HIV vaccine vectors, this vector can replicate inside the human body, and so might elicit more durable and vigorous immune responses. Further, the vector targets mucosal tissues—the lining of inner body cavities—where HIV establishes a foothold in the earliest stages of infection, and where effective immune responses could thwart HIV as it enters the body. IAVI also advanced another replicating viral vector, derived from the canine distemper virus (CDV) vaccine, into preclinical evaluation in primates. Like the Sendai virus, CDV does not cause illness in humans but does infect key cells in the gut, eliciting a mucosal response which can be helpful as HIV establishes an infection in immune cells found in the gut.
Domino effects of technical capacity
In preparation for the Sendai trial, IAVI partners in Rwanda and Kenya, including the Kenya AIDS Vaccine Initiative (KAVI) refined techniques and assessed mucosal immune responses in volunteers, including some who are currently participating in trials. KAVI in Nairobi has become a regional center of excellence for mucosal immunology, a capability that will contribute to its efforts to become a hub for clinical research in Africa.
IAVI continued to help partners to build technical capacity for research and ensure that their data are of the consistency and quality required to pass regulatory review. With support from USAID, for example, clinical researchers working with IAVI in Africa have over the years been trained in Good Clinical Practices (GCP). The HIL and partner labs in Africa have also received accreditation in Good Clinical Laboratory Practices (GCLP). By the end of 2012, IAVI and its partners had trained more than 800 people in GCLP since the training started nine years ago. In 2012, IAVI also joined a Gates Foundation initiative to provide GCP and GCLP training to 142 researchers from 17 countries. Some of IAVI's research partners have, further, extended such training to laboratories across the region, participating in major efforts funded by the European & Developing Countries Clinical Trials Partnership (EDCTP) and others to develop research capacity in Africa.
Parsing HIV dynamics in severe epidemics and preparing for vaccine trials
Throughout 2012, IAVI evaluated the incidence of new HIV infections in regional epidemics, focusing mainly on groups in Africa at high risk for HIV. IAVI's incidence studies, which provide information essential to both vaccine trials and public health policy, have enrolled 16,000 volunteers since 2004. They have extended HIV testing and counseling services to more than 300,000 people. Thanks to support and funding from EDCTP and USAID, IAVI's partners at the Uganda Virus Research Institute have conducted groundbreaking epidemiological, virological and social science studies with Uganda's Lake Victoria fishing communities. This work has brought into focus a high-risk population with an HIV prevalence up to five times higher than that of the general population in Uganda and HIV incidence rates that are among the highest in the region.
A subset of volunteers in IAVI's incidence studies who were previously found to have acquired HIV have been followed from the earliest stages of infection in a study named Protocol C. Access to a group of people who have been followed from the earliest days of infection is of great value to studying a variety of issues related to HIV infection, diagnosis and transmission. In 2012 alone, IAVI's Protocol C cohort contributed to more than two dozen other HIV research projects around the world.
In 2012, IAVI stepped up its focus on populations particularly vulnerable to HIV infection in South Africa, Kenya and Uganda, in some cases testing novel approaches to tracking new infections. Such studies are essential to selecting populations for future large-scale trials. At the same time, participation in research can help explain why certain populations are particularly vulnerable to HIV and provide information to people as to how to reduce their risk for HIV infection. In 2012, IAVI and partners provided support to two government clinics in Uganda to improve provision of health services and HIV counseling and testing in fishing communities and helped a hospital that refers people to IAVI studies to improve its services for HIV testing and voluntary male circumcision, an important preventive measure.
In the coastal Kenyan cities of Kilifi and Mtwapa, IAVI and partners have supported public health workers in their effort to tailor their care and counseling outreach to men who have sex with men. Our focused advocacy has encouraged Kenyan public health agencies to improve their HIV prevention outreach to this typically marginalized and stigmatized group.
In Uganda, IAVI provided in-kind support for a mock vaccine trial using a licensed hepatitis B vaccine. The study determined that volunteers from fishing communities along Lake Victoria, whose members tend to be highly mobile, can be recruited and retained in such studies.