Major Scientific Hurdles in HIV Vaccine Development: Historical Perspective and Future Directions.

Following the discovery of HIV as a causative agent of AIDS, the expectation was to rapidly develop a vaccine; but thirty years later, we still do not have a licensed vaccine. Progress has been hindered by the extensive genetic variability of HIV and our limited understanding of immune responses required to protect against HIV acquisition. Nonetheless, valuable knowledge accrued from numerous basic and translational science research studies and vaccine trials has provided insight into the structural biology of the virus, immunogen design and novel vaccine delivery systems that will likely constitute an effective vaccine. Furthermore, stakeholders now appreciate the daunting scientific challenges of developing an effective HIV vaccine, hence the increased advocacy for collaborative efforts among academic research scientists, governments, pharmaceutical industry, philanthropy, and regulatory entities. In this review, we highlight the history of HIV vaccine development efforts, highlighting major challenges and future directions.

A 30-year journey of trial and error towards a tolerogenic AIDS vaccine.

Since 1985, we have tested several immunological approaches to suppressing HIV replication in HIV-infected patients and to prevent HIV acquisition in uninfected people. Here, after briefly reviewing our studies on immunosuppressive treatments and therapeutic dendritic cell-based therapies, we examine in more detail our work on the tolerogenic vaccines we developed against AIDS in Chinese macaques. The vaccine consisted of inactivated SIVmac239 particles adjuvanted with the Bacillus of Calmette and Guerin (BCG), Lactobacillus plantarum (LP), or Lactobacillus rhamnosus (LR). Without adjuvant, the vaccine administered by the intragastric route induced the usual simian immunodeficiency virus (SIV)-specific humoral immune responses but no post-challenge protection. In contrast, out of 24 macaques that were immunized with the adjuvanted vaccine and challenged intrarectally with SIVmac239 or SIVB670, 23 were sterilely protected for up to 5 years, while all control macaques were infected. On the other hand, all macaques of Indian origin that were immunized with the same adjuvanted vaccine were not protected. We then discovered that vaccinated Chinese macaques developed a previously unrecognized class of non-cytolytic MHC-Ib/E-restricted CD8+ T cells (or CD8+ T-Regs) that suppressed the activation of SIV RNA-infected CD4+ T cells and thereby inhibited the (activation-dependent) reverse transcription of the virus and prevented the establishment of SIV infection. Finally, we found a similar population of HLA-E-restricted CD8+ T-Regs in human elite controllers (a small group of HIV-infected patients whose viral replication is naturally inhibited). Ex vivo, their CD8+ T-Regs suppressed viral replication in the same manner as those of vaccinated Chinese macaques. It is noteworthy that all of these elite controllers had a homo- or heterozygous HLA-Bw4-80I genotype. Taking into account the longevity and the high percentage of vaccine-protected Chinese macaques together with the concomitant identification of a robust ex vivo correlate of protection and the discovery of similar CD8+ T-Regs in human elite controllers, preventive and therapeutic HIV vaccines should be envisaged in humans.

South African HIV-1 vaccine candidates - the journey from the bench to clinical trials.

Around 2.5 million people become infected with human immunodeficiency virus (HIV) each year. This extraordinary toll in human life and public health worldwide will only be reversed with effective prevention. Vaccination is regarded as the most effective way to prevent infectious disease. However, there are many challenges to overcome before a successful prophylactic HIV vaccine will be available. We are participating in a global effort to develop and test candidate HIV vaccines. Two candidate prophylactic HIV vaccines that were designed and developed at the University of Cape Town (UCT) entered phase 1 clinical trials in the USA and South Africa in 2009, after a 9-year development period. In addition to the vaccines in clinical trial, there is a pipeline of candidate HIV-1 subtype C vaccines including virus-like particles, novel DNA vaccines, capripoxvirus and Bacillus Calmette-Guérin (BCG)-vectored vaccines. This article describes the history of HIV vaccine research at UCT, and the partnerships that made the project possible.

Cytokine adjuvants for vaccine therapy of neoplastic and infectious disease.

Vaccination, the revolutionary prophylactic immunotherapy developed in the eighteenth century, has become the most successful and cost-effective of medical remedies available to modern society. Due to the remarkable accomplishments of the past century, the number of diseases and pathogens for which a traditional vaccine approach might reasonably be employed has dwindled to unprecedented levels. While this happy scenario bodes well for the future of public health, modern immunologists and vaccinologists face significant challenges if we are to address the scourge of recalcitrant pathogens like HIV and HCV and well as the significant obstacles to immunotherapy imposed by neoplastic self. Here, the authors review the clinical and preclinical literature to highlight the manner by which the host immune system can be successfully manipulated by cytokine adjuvants, thereby significantly enhancing the efficacy of a wide variety of vaccination platforms.

HIV vaccine development: past, present and future.

The search for an HIV vaccine began following the discovery of the virus more than 25 years ago. Despite important progress, an effective vaccine remains an elusive goal that will likely require many more years of R&D to achieve. Following recent advances in research, however, there has been increased optimism that a prophylactic HIV vaccine is feasible. A consensus is forming among researchers to support a larger role for proof-of-concept efficacy clinical trials, conducted in parallel with invigorated basic research efforts and testing in animal models, to accelerate the discovery of key principles that will guide rational vaccine development.

Toward an AIDS vaccine.

A quarter century of scientific discovery has been applied to developing an AIDS vaccine, yet this goal remains elusive. Specific characteristics of the virus, including the extreme genetic variability in circulating viral isolates worldwide, biological properties of HIV that impede immune attack, and a high mutation rate that allows for rapid escape from adaptive immune responses, render this a huge challenge. However, evidence of protection against AIDS viruses in animal models and control of HIV in humans under certain circumstances, together with scientific advances in understanding disease pathogenesis, provide a strong rationale and objective paths to continue the pursuit of an effective AIDS vaccine to stem the global epidemic.

A reflection on HIV/AIDS research after 25 years.

Dr. Robert C. Gallo provides a personal reflection on the 25 year history of AIDS.

The evolution of HIV and its consequences.

Since the beginning of the AIDS epidemic in 1981, HIV-1 has demonstrated an amazing ability to mutate. HIV-1 was introduced into the human population in the early to mid twentieth century in central Africa. During ensuing decades, this extraordinary mutational capacity has resulted in the circulation of HIV-1 strains that are quite different from one another, yet still remarkably pathogenic. The potential impact of this viral diversity on treatment, monitoring,and vaccine development is discussed.

Twenty years of therapy for HIV-1 infection.

Antiretroviral therapy, where available, has transformed HIV-1 disease into a treatable and somewhat chronic infection. This article summarizes the accomplishments thus far and what lies ahead in our struggle to improve the treatment of, and possibly eliminate, HIV-1 infection.

The past, present and future of HIV-vaccine development: a critical view.

Despite the extensive efforts that have been made to combat AIDS, the global number of HIV-1 infections is still increasing. There is major consent among scientists worldwide, that the development of successful HIV vaccine strategies requires a profound understanding of the epidemiological principles of a viral pandemic, as well as deep insights into the molecular and immunological mechanisms of HIV pathogenesis. This review provides an overview of past and present developments, as well as future aspects of HIV vaccines, and also provides a summary of current clinical trials in man.