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Frontiers in Immunology 2020Following 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... (Review)
Review
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.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; Drug Development; HIV; HIV Infections; History, 20th Century; History, 21st Century; Humans; T-Lymphocytes
PubMed: 33193428
DOI: 10.3389/fimmu.2020.590780 -
Nature Reviews. Immunology Feb 2019Of any pathogen, HIV provides perhaps the greatest challenge to successful vaccine development. Nevertheless, progress continued to be made in 2018; new vaccine concepts... (Review)
Review
Of any pathogen, HIV provides perhaps the greatest challenge to successful vaccine development. Nevertheless, progress continued to be made in 2018; new vaccine concepts entered the clinic and new insights were obtained in basic research that will ultimately help to guide rational vaccine design against many’difficult’ pathogens.
Topics: AIDS Vaccines; Animals; HIV; Humans; Vaccinology
PubMed: 30560910
DOI: 10.1038/s41577-018-0103-6 -
Toxins Feb 2022Different mechanisms mediate the toxicity of RNA. Genomic retroviral mRNA hijacks infected host cell factors to enable virus replication. The viral genomic RNA of the... (Review)
Review
Different mechanisms mediate the toxicity of RNA. Genomic retroviral mRNA hijacks infected host cell factors to enable virus replication. The viral genomic RNA of the human immunodeficiency virus (HIV) encompasses nine genes encoding in less than 10 kb all proteins needed for replication in susceptible host cells. To do so, the genomic RNA undergoes complex alternative splicing to facilitate the synthesis of the structural, accessory, and regulatory proteins. However, HIV strongly relies on the host cell machinery recruiting cellular factors to complete its replication cycle. Antiretroviral therapy (ART) targets different steps in the cycle, preventing disease progression to the acquired immunodeficiency syndrome (AIDS). The comprehension of the host immune system interaction with the virus has fostered the development of a variety of vaccine platforms. Despite encouraging provisional results in vaccine trials, no effective vaccine has been developed, yet. However, novel promising vaccine platforms are currently under investigation.
Topics: AIDS Vaccines; Anti-Retroviral Agents; HIV; HIV Infections; Humans; Virus Replication
PubMed: 35202165
DOI: 10.3390/toxins14020138 -
Clinical Pharmacology and Therapeutics Dec 2018Human immunodeficiency virus (HIV) has infected 76 million people and killed an estimated 35 million. During its 40-year history, remarkable progress has been made on... (Review)
Review
Human immunodeficiency virus (HIV) has infected 76 million people and killed an estimated 35 million. During its 40-year history, remarkable progress has been made on antiretroviral drugs. Progress toward a vaccine has also been made, although this has yet to deliver a licensed product. In 2007, I wrote a review, HIV AIDS Vaccines: 2007. This review, HIV AIDS Vaccines: 2018, focuses on the progress in the past 11 years. I begin with key challenges for the development of an AIDS vaccine and the lessons learned from the six completed efficacy trials, only one of which has met with some success.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; Clinical Trials as Topic; Drug Development; Genotype; HIV Antibodies; HIV Antigens; HIV Infections; HIV-1; Host-Pathogen Interactions; Humans; Mutation; Phenotype; Research Design
PubMed: 30099743
DOI: 10.1002/cpt.1208 -
The New Microbiologica Apr 2022Since the beginning of the HIV/AIDS epidemy in the eighties, hundreds of phase I human immunization studies were performed, however, only nine tested efficacy in phase...
Since the beginning of the HIV/AIDS epidemy in the eighties, hundreds of phase I human immunization studies were performed, however, only nine tested efficacy in phase IIb/III clinical trials. While immunogens for SARS-CoV-2 did move along the development and clinical trial pipeline at unprecedent speed, two HIV immunization vaccine trials, started in 2016 and 2017, did meet non-efficacy criteria at the interim analysis and were thus, halted by the Data and Safety Monitoring Boards. The challenges in the quest to develop a safe, effective and durable HIV vaccine are unchanged. However, as research on HIV vaccine discovery moves forward there are many new tools and platform technologies to iterate vaccine strategies faster. Among these, there is a growing interest to conduct experimental medicine approaches where product development is directly informed by human data at an early stage of product development.
Topics: AIDS Vaccines; Acquired Immunodeficiency Syndrome; COVID-19; HIV Infections; Humans; SARS-CoV-2; Vaccination
PubMed: 35699557
DOI: No ID Found -
Immunological Reviews Jan 2017It is clear that antibodies can play a pivotal role in preventing the transmission of HIV-1 and large efforts to identify an effective antibody-based vaccine to quell... (Review)
Review
It is clear that antibodies can play a pivotal role in preventing the transmission of HIV-1 and large efforts to identify an effective antibody-based vaccine to quell the epidemic. Shortly after HIV-1 was discovered as the cause of AIDS, the search for epitopes recognized by neutralizing antibodies became the driving strategy for an antibody-based vaccine. Neutralization escape variants were discovered shortly thereafter, and, after almost three decades of investigation, it is now known that autologous neutralizing antibody responses and their selection of neutralization resistant HIV-1 variants can lead to broadly neutralizing antibodies in some infected individuals. This observation drives an intensive effort to identify a vaccine to elicit broadly neutralizing antibodies. In contrast, there has been less systematic study of antibody specificities that must rely mainly or exclusively on other protective mechanisms, although non-human primate (NHP) studies as well as the RV144 vaccine trial indicate that non-neutralizing antibodies can contribute to protection. Here we propose a novel strategy to identify new epitope targets recognized by these antibodies for which viral escape is unlikely or impossible.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; Clinical Trials as Topic; Epitopes; HIV Antibodies; HIV Antigens; HIV Infections; HIV-1; Humans; Immune Evasion; Primates
PubMed: 28133809
DOI: 10.1111/imr.12510 -
Human Vaccines & Immunotherapeutics 2014Getting to zero: zero new HIV infections, zero deaths from AIDS-related illness, zero discrimination is the theme of World AIDS Day 2012. Given the spread of the... (Review)
Review
Getting to zero: zero new HIV infections, zero deaths from AIDS-related illness, zero discrimination is the theme of World AIDS Day 2012. Given the spread of the epidemic today, getting to zero may sound difficult, but significant progress is underway. The total annual loss for the entire country due to HIV is 7% of GDP, which exceeds India's annual health expenditure in 2004. The additional loss due to loss of labor income and increased medical expenditure as measured by the external transfers, account for 5% of the country's health expenditure and 0.23% of GDP. Given that the HIV incidence rate is only 0.27% in India, these losses are quite staggering. Despite the remarkable achievements in development of anti-retroviral therapies against HIV and the recent advances in new prevention technologies, the rate of new HIV infections continue to outpace efforts on HIV prevention and control. Thus, the development of a safe and effective vaccine for prevention and control of AIDS remains a global public health priority and the greatest opportunity to eventually end the AIDS pandemic.
Topics: AIDS Vaccines; HIV Infections; Health Care Costs; Humans; India; Vaccination
PubMed: 24056755
DOI: 10.4161/hv.26243 -
Archives of Virology Aug 2018Since 1985, we have tested several immunological approaches to suppressing HIV replication in HIV-infected patients and to prevent HIV acquisition in uninfected people.... (Review)
Review
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.
Topics: AIDS Vaccines; Animals; History, 20th Century; History, 21st Century; Macaca mulatta; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; T-Lymphocytes
PubMed: 30043201
DOI: 10.1007/s00705-018-3936-1 -
Cell Host & Microbe Mar 2016Development of an effective AIDS vaccine is a global priority. However, the extreme diversity of HIV type 1 (HIV-1), which is a consequence of its propensity to mutate... (Review)
Review
Development of an effective AIDS vaccine is a global priority. However, the extreme diversity of HIV type 1 (HIV-1), which is a consequence of its propensity to mutate to escape immune responses, along with host factors that prevent the elicitation of protective immune responses, continue to hinder vaccine development. Breakthroughs in understanding of the biology of the transmitted virus, the structure and nature of its envelope trimer, vaccine-induced CD8 T cell control in primates, and host control of broadly neutralizing antibody elicitation have given rise to new vaccine strategies. Despite this promise, emerging data from preclinical trials reinforce the need for additional insight into virus-host biology in order to facilitate the development of a successful vaccine.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; CD8-Positive T-Lymphocytes; Drug Discovery; Drug Evaluation, Preclinical; HIV Antibodies; HIV-1; Host-Pathogen Interactions; Primates; Treatment Outcome
PubMed: 26922989
DOI: 10.1016/j.chom.2016.02.002 -
Frontiers in Immunology 2018It is acknowledged that vaccines remain the best hope for eliminating the HIV-1 epidemic. However, the failure to produce effective vaccine immunogens and the inability... (Review)
Review
It is acknowledged that vaccines remain the best hope for eliminating the HIV-1 epidemic. However, the failure to produce effective vaccine immunogens and the inability of conventional delivery strategies to elicit the desired immune responses remains a central theme and has ultimately led to a significant roadblock in HIV vaccine development. Consequently, significant efforts have been applied to generate novel vaccine antigens and delivery agents, which mimic viral structures for optimal immune induction. Here, we review the latest developments that have occurred in the nanoparticle vaccine field, with special emphasis on strategies that are being utilized to attain highly immunogenic, systemic, and mucosal anti-HIV humoral and cellular immune responses. This includes the design of novel immunogens, the central role of antigen-presenting cells, delivery routes, and biodistribution of nanoparticles to lymph nodes. In particular, we will focus on virus-like-particle formulations and their preclinical uses within the HIV prophylactic vaccine setting.
Topics: AIDS Vaccines; Acquired Immunodeficiency Syndrome; Animals; HIV-1; Humans; Immunity, Cellular; Immunity, Humoral; Liposomes; Nanoparticles; Vaccines, Virus-Like Particle
PubMed: 29541072
DOI: 10.3389/fimmu.2018.00345