Margaret G. McGlynn
Margaret G. McGlynn is President and CEO of IAVI
Despite the success of retroviral drugs and therapies, there are still millions of deaths a year as a result of HIV infections and ultimately AIDS. The most effective way of preventing this would be to develop a vaccine. The HIV virus is, however, a very difficult adversary. After more than two decades of trying, there are some hopeful signs of eventual success.
The origin of human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) has been traced back to non-human primates living in the forests of western and central Africa, though was not recognised until 1981 when an outbreak of Pneumocystis carinii pneumonia among young homosexual men in the USA heralded in the genesis of the global pandemic.,  Today, nearly thirty years since the identification of HIV as the etiologic agent that causes AIDS  , HIV continues to be a major global killer. The numbers are staggering, with over 2 million deaths per year due to AIDS, and over 7000 new infections daily. In some regions of the world, such as sub-Saharan Africa, life expectancy has declined significantly due to HIV, and more than ten million children are now orphans. HIV is the fourth largest killer in the world today, and the virus continues to cause significant morbidity and mortality, particularly in sub-Saharan Africa where the epidemic is most severe. Despite significant advances in HIV prevention efforts and the development of highly active anti-retroviral therapies, the rate of new HIV infections continues to outpace the combined global efforts in prevention and control. Simply put, the world needs an HIV vaccine to truly end this epidemic.
Vaccines are among the greatest successes in the history of public health, leading to the eradication of smallpox, and significant reductions in the burden of many other infectious diseases. The successful development of currently licensed vaccines has generally involved mimicry of natural infection via attenuation or inactivation of the pathogen to elicit protective immunity, such as with measles, polio, and rubella vaccines. In contrast, HIV poses significant scientific challenges that render the development of classical attenuated or killed vaccines against HIV unlikely to be successful. First of all, HIV is highly mutable, the consequences of which render the virus hyper variable – that is to say, vaccine designers face a moving target. Secondly, unlike many pathogens for which vaccines have been developed where natural infection produces clearance of the pathogen and protection from reinfection, the correlates of protection against HIV are undefined, the immune response to HIV does not clear the infection and super infection with multiple subtypes of HIV has been documented. Thirdly, there is no ideal animal model for human HIV infection; thus, long and expensive human efficacy trials are the primary option for assessment of candidate HIV vaccines. Lastly, HIV as a retrovirus infects and integrates its genome into cells of the immune system, thus compromising the host’s immune defence system shortly after infection, and providing only a short window of opportunity for vaccine-induced immune responses to be effective. While vaccines have been successfully developed against highly variable pathogens such as influenza, against pathogens where the correlates of protection were undefined such as mumps, against pathogens without an ideal animal model such as measles, and against retroviruses such as feline leukaemia virus, vaccine designers have never faced such a formidable foe as HIV, which poses the full collection of these scientific challenges.
In the absence of clearly defined correlates of protection against HIV, and in order to address the hyper variability of HIV, most efforts in HIV vaccine development are focused on the induction of broadly neutralizing antibodies to prevent infection, and/or broadly reactive cellular immune responses to control infection. Though many HIV vaccine strategies have been pursued over the past twenty-five years, including subunit recombinant proteins, viral peptides, and a range of DNA and vector approaches, only three vaccine concepts have completed all three stages of clinical development, those being safety, immunogenicity and efficacy trials.
The first concept to advance to clinical trials was patterned after the successful development of the Hepatitis B vaccine and aimed to elicit neutralising antibodies targeted to the spike protein of HIV. In preclinical studies conducted in chimpanzees, the monomeric form of HIV’s outer spike protein, termed gp120, was safe, immunogenic, neutralised a narrow subset of HIV isolates, and protected chimpanzees from infection. However, an interesting observation from the preclinical and early Phase I studies conducted in the late 1980s and early 1990s, was that sera from vaccinated animals and humans neutralised laboratory adapted isolates of HIV, but had no effect on circulating, primary isolates of HIV that had not undergone laboratory adaptation. These data led to a decision in 1994 by the National Institute for Allergy and Infectious Diseases not to provide public sector funds for human efficacy testing of this vaccine candidate. In the late 1990s, funding was eventually obtained by VaxGen, a biotechnology company championing the g120 HIV vaccine candidate, and the first HIV vaccine human efficacy trials were conducted in the US, Canada and Thailand. The results of these trials demonstrated clearly that the gp120 vaccine provided no protection against HIV infection, and had no effect on viral load on those vaccinated subjects who subsequently became infected when compared with those subjects receiving placebo.
With the realisation that development of vaccines to elicit broadly neutralising antibodies against circulating strains of HIV would be a daunting challenge, the HIV vaccine field shifted gears in the 1990s and focused greater attention of the prospects of designing vaccines to elicit cellular immune responses against HIV, with the aim not of preventing infection, but rather controlling infection. Virus-specific cellular immune responses can discriminate virus-infected from uninfected cells, and can thus target and destroy virus-infected cells. The rationale then for these cellular immune based vaccines was to prime the immune system effectively, such that when individuals become exposed and infected with HIV, that a robust, virus-specific cellular immune response would significantly blunt the infection, ideally aborting it or at minimum sufficiently blunting infection such that HIV-infected subjects would remain healthy and not progress to AIDS. Studies in non-human primates infected with hybrid HIV-simian immunodeficiency (SIV) viruses termed SHIV (simian-human-immunodeficiency virus) provided the rationale for the cellular immunity based vaccine approach. The leading candidate to advance to human efficacy trials aimed at eliciting HIV specific cellular immunity was a viral vector based vaccine developed by Merck, using a common adenovirus (adenovirus-type 5) as the vector and engineering three HIV genes into the vector (gag, pol, nef), which had previously been shown to be targets for HIV specific cellular immunity in HIV+ subjects. Preclinical studies and human safety and immunogenicity studies with this candidate demonstrated that the vaccine was safe, and that cell mediated immune responses were elicited against HIV gag, pol, and nef genes. Moreover, studies in rhesus monkeys showed that vaccinated monkeys subsequently challenged with SHIV controlled infection, providing a greater rationale for human efficacy trials. However, an analogous SIV vaccine administered to rhesus monkeys and then challenged with SIV failed to provide any benefit.
Human efficacy trials in men who have sex with men of the Merck Ad5-based HIV vaccine failed to demonstrate any efficacy in preventing or controlling infection. Moreover, a concerning observation from this efficacy trial was that more HIV infections occurred among vaccine recipients who were uncircumcised and had preexisting immunity against the vaccine vector (Ad5) compared with placebo recipients with the same characteristics, for reasons that are still not completely understood.
A third vaccine concept which advanced to human efficacy trials aimed to elicit both cell mediated immunity and antibody responses to HIV’s outer spike protein, and represented the first of a series of candidates advancing in the clinical pipeline to efficacy trials based on a prime-boost approach, ie priming or vaccinating first with one vaccine candidate, and boosting with a second vaccine candidate with the aim of stimulating more comprehensive HIV specific immune responses, than with either candidate alone. This approach, using a canarypox vector prime + monomeric gp120 boost provided the first signal for prevention of HIV infection in humans in a community based trial conducted in over 16,000 volunteers in Thailand (referred to as the RV-144 trial), albeit with a modest 31.2% efficacy. Another prime-boost vaccine concept has advanced to efficacy trials, a DNA prime + Ad5 vaccine, and data from this efficacy trial is due late in 2013.
Today, based on recent scientific advances, the HIV vaccine field is undergoing a renaissance. Newly identified broadly neutralizing antibodies against HIV have revealed new and potentially more vulnerable sites on the virus for which novel vaccine concepts are already being accelerated to clinical development. Moreover, a series of improved second generation vaccine candidates that have controlled infection in animal models have now advanced to clinical trials. Taken together, these findings are fuelling a resurgence in HIV vaccine discovery and development. In parallel, scientists are aiming to build on the modest levels of protection observed in RV-144, with related vaccine regimens focused on enhancing durability of responses, and determining whether protection can be demonstrated in populations at higher risk of HIV infection in different regions of the world.
The development of safe and effective HIV vaccines for use throughout the world will likely be accelerated by a re-commitment to clinical research as a major component of vaccine discovery. Although small animal models and non-human primate studies are important for basic science discovery, they are limited in modelling the likely outcome of human vaccine clinical trials. This is based on several reasons, including differences in host genetics and species-specificity of vaccine vectors. There are several key clinical vaccinology questions that remain to be answered for HIV, and are also likely relevant to other complex and variable pathogens such as hepatitis C, dengue and pandemic influenza. Therefore, investing in answering these key questions for HIV vaccine development would not only accelerate HIV vaccine development but also give us important information that can be applied to these other diseases to increase the probability of success. These questions include, but are not limited to: How best to generate long-lived antibody responses and cellular immune responses? How to elicit immune responses to key epitopes on a virus that are not immunodominant? How to design effective vaccine candidates based upon knowledge of the structure of the binding site of broadly neutralising antibodies in complex with the viral target? How to maintain long-lived antibody and cellular immune responses?
Looking towards the future, recent advances in new HIV prevention technologies, such as pre-exposure prophylaxis of high risk individuals with anti-retroviral drugs, early treatment of infected individuals to prevent transmission of the virus to others, progress with vaginal microbicides and improved HIV prevention counselling, may have a significant impact on HIV vaccine development in the coming years. Decreasing incidence of HIV infection will likely result in larger, longer and most costly clinical trials to demonstrate efficacy of HIV vaccines. In order to ensure that HIV vaccine efficacy trials may be undertaken and that vaccines will be effective in populations where they are most needed, clinical and laboratory capacity needs to developed and maintained in regions of the world where HIV incidence is greatest.
Development and deployment of a safe and universally effective HIV vaccine is a global public good, and will require active participation from academia, government, industry and non-governmental organisations. The International AIDS Vaccine Initiative (IAVI) is a public-private partnership, working with multiple global stakeholders towards accelerating the development of HIV vaccines. IAVI and partners over the past fifteen years have advocated for greater investment for HIV vaccine development, developed clinical capacity in sub-Saharan Africa, made seminal scientific breakthroughs in HIV vaccine science, and advanced multiple candidates to clinical trials. Large multi-national companies such as Swiss Re have the opportunity, together with their industry partners, to actively support and participate in global efforts to expedite HIV vaccine development and truly end this epidemic. Imagine a world without AIDS.
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