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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 -
Current Opinion in HIV and AIDS May 2019Although HIV-1 diversity is a critical barrier to HIV-1 vaccine development, implementing vaccine strategies that directly address HIV-1 genetic specificities has been... (Review)
Review
PURPOSE OF REVIEW
Although HIV-1 diversity is a critical barrier to HIV-1 vaccine development, implementing vaccine strategies that directly address HIV-1 genetic specificities has been challenging. Here, we discuss the intersection between HIV-1 phylogenetics and vaccine development.
RECENT FINDINGS
We describe the vaccine regimens that are currently tested in two vaccine efficacy trials and recent research highlighting HIV-1 genetic features that were associated with the development of broadly neutralizing antibodies.
SUMMARY
Compared with how widely HIV-1 diversity is recognized as a critical issue for vaccine research, relatively few genetically informed vaccine solutions have been compared, in part because the lack of correlates of protection against HIV-1 limits the ability to develop and test multiple vaccine candidates in a fully rational manner. Yet, recent findings have provided a better understanding of the viral features associated with the development of broad and potent neutralizing antibodies, offering new avenues for engineering vaccine candidates. Future research should also plan to address potential consequences associated with the rollout of an efficacious vaccine, including the possibility of vaccine resistance spreading in the population.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; HIV Antibodies; HIV Infections; HIV-1; Humans; Phylogeny
PubMed: 30925535
DOI: 10.1097/COH.0000000000000545 -
Cell Jan 2024The CD4-binding site (CD4bs) is a conserved epitope on HIV-1 envelope (Env) that can be targeted by protective broadly neutralizing antibodies (bnAbs). HIV-1 vaccines...
The CD4-binding site (CD4bs) is a conserved epitope on HIV-1 envelope (Env) that can be targeted by protective broadly neutralizing antibodies (bnAbs). HIV-1 vaccines have not elicited CD4bs bnAbs for many reasons, including the occlusion of CD4bs by glycans, expansion of appropriate naive B cells with immunogens, and selection of functional antibody mutations. Here, we demonstrate that immunization of macaques with a CD4bs-targeting immunogen elicits neutralizing bnAb precursors with structural and genetic features of CD4-mimicking bnAbs. Structures of the CD4bs nAb bound to HIV-1 Env demonstrated binding angles and heavy-chain interactions characteristic of all known human CD4-mimicking bnAbs. Macaque nAb were derived from variable and joining gene segments orthologous to the genes of human VH1-46-class bnAb. This vaccine study initiated in primates the B cells from which CD4bs bnAbs can derive, accomplishing the key first step in the development of an effective HIV-1 vaccine.
Topics: Animals; Humans; Broadly Neutralizing Antibodies; CD4 Antigens; Cell Adhesion Molecules; HIV-1; Macaca; AIDS Vaccines
PubMed: 38181743
DOI: 10.1016/j.cell.2023.12.002 -
Proceedings of the National Academy of... Aug 2014With the 2010s declared the Decade of Vaccines, and Millennium Development Goals 4 and 5 focused on reducing diseases that are potentially vaccine preventable, now is an...
With the 2010s declared the Decade of Vaccines, and Millennium Development Goals 4 and 5 focused on reducing diseases that are potentially vaccine preventable, now is an exciting time for vaccines against poverty, that is, vaccines against diseases that disproportionately affect low- and middle-income countries (LMICs). The Global Burden of Disease Study 2010 has helped better understand which vaccines are most needed. In 2012, US$1.3 billion was spent on research and development for new vaccines for neglected infectious diseases. However, the majority of this went to three diseases: HIV/AIDS, malaria, and tuberculosis, and not neglected diseases. Much of it went to basic research rather than development, with an ongoing decline in funding for product development partnerships. Further investment in vaccines against diarrheal diseases, hepatitis C, and group A Streptococcus could lead to a major health impact in LMICs, along with vaccines to prevent sepsis, particularly among mothers and neonates. The Advanced Market Commitment strategy of the Global Alliance for Vaccines and Immunisation (GAVI) Alliance is helping to implement vaccines against rotavirus and pneumococcus in LMICs, and the roll out of the MenAfriVac meningococcal A vaccine in the African Meningitis Belt represents a paradigm shift in vaccines against poverty: the development of a vaccine primarily targeted at LMICs. Global health vaccine institutes and increasing capacity of vaccine manufacturers in emerging economies are helping drive forward new vaccines for LMICs. Above all, partnership is needed between those developing and manufacturing LMIC vaccines and the scientists, health care professionals, and policy makers in LMICs where such vaccines will be implemented.
Topics: AIDS Vaccines; Communicable Disease Control; Developing Countries; Diarrhea; Global Health; Humans; Malaria Vaccines; Neglected Diseases; Poverty Areas; Respiratory Tract Infections; Tuberculosis Vaccines; Vaccines
PubMed: 25136089
DOI: 10.1073/pnas.1400473111 -
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 -
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