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Expert Review of Vaccines Jan 2019The search for a preventative HIV vaccine is ongoing after three decades of research. Contributions of non-human primate (NHP) models to this research are irrefutable,... (Review)
Review
INTRODUCTION
The search for a preventative HIV vaccine is ongoing after three decades of research. Contributions of non-human primate (NHP) models to this research are irrefutable, however interpreting data obtained for translation to humans has been problematic. As knowledge concerning NHP models has accumulated, their utility and value in assessing immunogenicity and efficacy of novel vaccines have become apparent. NHP models have become a critical component of vaccine design.
AREAS COVERED
Beginning with early vaccine studies, we trace the development and evolution of NHP models concurrent with changes in HIV vaccine concepts and in response to their ability to predict clinical trial efficacy. The value of NHP studies in guiding vaccine design is highlighted along with their importance in opening new areas of investigation and facilitating movement of promising approaches into the clinic.
EXPERT COMMENTARY
Due to their close relatedness to humans, NHPs are an excellent choice for immunogenicity studies. The ability of NHP models to predict clinical efficacy has improved with the introduction of low-dose challenge viruses and recognition of confounding variables in study outcomes. Use of NHP models has opened new research areas with outstanding potential for generating vaccine efficacy against HIV and other infectious agents.
Topics: AIDS Vaccines; Animals; Disease Models, Animal; Drug Design; Drug Development; HIV Infections; Humans; Immunogenicity, Vaccine; Primates; Species Specificity
PubMed: 30526159
DOI: 10.1080/14760584.2019.1557521 -
Immunity Nov 2022Eliciting broadly neutralizing antibodies (bnAbs) is the core of HIV vaccine design. bnAbs specific to the V2-apex region of the HIV envelope acquire breadth and potency...
Eliciting broadly neutralizing antibodies (bnAbs) is the core of HIV vaccine design. bnAbs specific to the V2-apex region of the HIV envelope acquire breadth and potency with modest somatic hypermutation, making them attractive vaccination targets. To evaluate Apex germline-targeting (ApexGT) vaccine candidates, we engineered knockin (KI) mouse models expressing the germline B cell receptor (BCR) of the bnAb PCT64. We found that high affinity of the ApexGT immunogen for PCT64-germline BCRs was necessary to specifically activate KI B cells at human physiological frequencies, recruit them to germinal centers, and select for mature bnAb mutations. Relative to protein, mRNA-encoded membrane-bound ApexGT immunization significantly increased activation and recruitment of PCT64 precursors to germinal centers and lowered their affinity threshold. We have thus developed additional models for HIV vaccine research, validated ApexGT immunogens for priming V2-apex bnAb precursors, and identified mRNA-LNP as a suitable approach to substantially improve the B cell response.
Topics: Mice; Humans; Animals; HIV Antibodies; AIDS Vaccines; Broadly Neutralizing Antibodies; HIV-1; Antibodies, Neutralizing; RNA, Messenger; HIV Infections; env Gene Products, Human Immunodeficiency Virus
PubMed: 36179690
DOI: 10.1016/j.immuni.2022.09.003 -
Biochemical Society Transactions Jun 2018The extensive post-translational modifications of the envelope spikes of the human immunodeficiency virus (HIV) present considerable challenges and opportunities for HIV... (Review)
Review
The extensive post-translational modifications of the envelope spikes of the human immunodeficiency virus (HIV) present considerable challenges and opportunities for HIV vaccine design. These oligomeric glycoproteins typically have over 30 disulfide bonds and around a 100 N-linked glycosylation sites, and are functionally dependent on protease cleavage within the secretory system. The resulting mature structure adopts a compact fold with the vast majority of its surface obscured by a protective shield of glycans which can be targeted by broadly neutralizing antibodies (bnAbs). Despite the notorious heterogeneity of glycosylation, rare B-cell lineages can evolve to utilize and cope with viral glycan diversity, and these structures therefore present promising targets for vaccine design. The latest generation of recombinant envelope spike mimetics contains re-engineered post-translational modifications to present stable antigens to guide the development of bnAbs by vaccination.
Topics: AIDS Vaccines; Antibodies, Neutralizing; Glycosylation; HIV; Humans; Protein Processing, Post-Translational
PubMed: 29784645
DOI: 10.1042/BST20170394 -
Current Opinion in HIV and AIDS Mar 2019CMV-vectored vaccines expressing SIV antigens have mediated unprecedented levels of virus control following SIV challenge in rhesus macaques. Remarkably, protection was... (Review)
Review
PURPOSE OF REVIEW
CMV-vectored vaccines expressing SIV antigens have mediated unprecedented levels of virus control following SIV challenge in rhesus macaques. Remarkably, protection was dependent on nonclassically restricted CD8 T cells. Here, we review the latest research in CMV-vectored vaccines in both humans and nonhuman primates as well as recent advances in the understanding nonclassically restricted T cells, particularly MHC-E-restricted CD8 T cells.
RECENT FINDINGS
Recent studies have investigated human translation of CMV-vectored vaccines including studies to ensure vaccine vector safety. Other work has focused on testing of animal models to investigate the relative contribution of MHC diversity and CMV strain on T-cell induction. Lastly, several groups have investigated MHC-E peptide binding, including HLA-E, have found that MHC-E can accommodate different peptide motifs, consistent with the original observations in CMV-vaccinated macaques.
SUMMARY
CMV remains a promising vaccine vector with the potential to be protective against multiple diseases, including HIV. However, CMV is highly species-specific and in humans, congenital infection can lead to serious birth defects. To ensure safe translation to humans, further clinical and animal studies are needed to better understand CMV-vectored immunity as well as more basic immunological questions relating to the induction of classical vs. nonclassical T cells.
Topics: AIDS Vaccines; Animals; Cytomegalovirus; Genetic Vectors; HIV; HIV Infections; Humans
PubMed: 30562176
DOI: 10.1097/COH.0000000000000524 -
Vaccine Jan 2020The potential advantages and unique challenges of the early life immune system for the development of HIV-specific broadly neutralizing antibodies were discussed during... (Review)
Review
The potential advantages and unique challenges of the early life immune system for the development of HIV-specific broadly neutralizing antibodies were discussed during a workshop entitled "Immunological Mechanisms of Inducing HIV Immunity in Infants" sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) in conjunction with the 2018 HIVR4P Conference held in Madrid, Spain. A safe and effective HIV vaccine remains a critical need in the fight against the HIV pandemic, especially to prevent emerging infections in infants, adolescents, and young adults. To successfully target these populations, a vaccine should ideally induce protective immune responses during childhood. Interestingly, several recent studies highlighting differences in immune responses between adults and children have suggested that the early life immune system could present advantages for the elicitation of broadly neutralizing antibodies (bnAbs), a response highly desired for an HIV vaccine. Notably, HIV-infected children develop bnAbs responses earlier and more frequently than infected adults; with emerging evidence that the pathways of elicitation of bnAb lineages may differ between adults and children. Moreover, there is precedent for the prevention of lifelong infections with pediatric immunization, and early life provides a unique window of opportunity for the administration of a multi-dose HIV vaccine that will likely be needed to achieve protective immunity. Further understanding of how the distinct early life immune system can be harnessed to trigger bnAb lineages for induction of durable and polyfunctional HIV-specific immunity is warranted. This strategy will include testing promising HIV vaccine candidates in pediatric populations in preclinical and clinical studies. Novel approaches to identify molecular markers of protection are also key to guide and accelerate pediatric HIV vaccine development.
Topics: AIDS Vaccines; Antibodies, Neutralizing; Education; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunization; Infant; Infant, Newborn
PubMed: 31761501
DOI: 10.1016/j.vaccine.2019.11.011 -
Frontiers of Medicine Feb 2020Remarkable progress has been achieved for prophylactic and therapeutic interventions against human immunodeficiency virus type I (HIV-1) through antiretroviral therapy.... (Review)
Review
Remarkable progress has been achieved for prophylactic and therapeutic interventions against human immunodeficiency virus type I (HIV-1) through antiretroviral therapy. However, vaccine development has remained challenging. Recent discoveries in broadly neutralizing monoclonal antibodies (bNAbs) has led to the development of multiple novel vaccine approaches for inducing bNAbs-like antibody response. Structural and dynamic studies revealed several vulnerable sites and states of the HIV-1 envelop glycoprotein (Env) during infection. Our review aims to highlight these discoveries and rejuvenate our endeavor in HIV-1 vaccine design and development.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; Drug Discovery; Drug Evaluation, Preclinical; HIV Antibodies; HIV Infections; HIV-1; Humans; env Gene Products, Human Immunodeficiency Virus
PubMed: 31858368
DOI: 10.1007/s11684-019-0721-9 -
Current Opinion in HIV and AIDS May 2017The ability to induce broadly neutralizing antibody (bNAb) responses is likely essential for development of a globally effective HIV vaccine. Unfortunately, human... (Review)
Review
PURPOSE OF REVIEW
The ability to induce broadly neutralizing antibody (bNAb) responses is likely essential for development of a globally effective HIV vaccine. Unfortunately, human vaccine trials conducted to date have failed to elicit broad plasma neutralization of primary virus isolates. Despite this limitation, in-depth analysis of the vaccine-induced memory B-cell repertoire can provide valuable insights into the presence and function of subdominant B-cell responses, and identify initiation of antibody lineages that may be on a path towards development of neutralization breadth.
RECENT FINDINGS
Characterization of the functional capabilities of monoclonal antibodies isolated from a HIV-1 vaccine trial with modest efficacy has revealed mechanisms by which non-neutralizing antibodies are presumed to have mediated protection. In addition, B-cell repertoire analysis has demonstrated that vaccine boosts shifted the HIV-specific B-cell repertoire, expanding pools of cells with long third heavy chain complementarity determining regions - a characteristic of some bNAb lineages.
SUMMARY
Detailed analysis of memory B-cell repertoires and evaluating the effector functions of isolated monoclonal antibodies expands what we can learn from human vaccine trails, and may provide knowledge that can enable rational design of novel approaches to drive maturation of subdominant disfavored bNAb lineages.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; B-Lymphocytes; Clinical Trials as Topic; HIV Antibodies; HIV Infections; HIV-1; Humans
PubMed: 28230655
DOI: 10.1097/COH.0000000000000362 -
Vaccine Nov 2015Development of an effective AIDS vaccine is crucial for the control of global human immunodeficiency virus type 1 (HIV-1) prevalence. We have developed a novel AIDS... (Review)
Review
Development of an effective AIDS vaccine is crucial for the control of global human immunodeficiency virus type 1 (HIV-1) prevalence. We have developed a novel AIDS vaccine using a Sendai virus (SeV) vector and investigated its efficacy in a macaque AIDS model of simian immunodeficiency virus (SIV) infection. Its immunogenicity and protective efficacy have been shown, indicating that the SeV vector is a promising delivery tool for AIDS vaccines. Here, we describe the potential of SeV vector as a vaccine antigen delivery tool to induce effective immune responses against HIV-1 infection.
Topics: AIDS Vaccines; Animals; Antibodies, Viral; CD8-Positive T-Lymphocytes; Clinical Trials as Topic; Genetic Vectors; HIV-1; Humans; Macaca; Models, Animal; SAIDS Vaccines; Sendai virus; Simian Acquired Immunodeficiency Syndrome; Vaccines, Synthetic
PubMed: 26232346
DOI: 10.1016/j.vaccine.2015.06.114 -
Current Opinion in HIV and AIDS Nov 2016Only four HIV-1 vaccine concepts have been tested in six efficacy trials with no product licensed to date. Several scientific and programmatic lessons can be learned... (Review)
Review
PURPOSE OF REVIEW
Only four HIV-1 vaccine concepts have been tested in six efficacy trials with no product licensed to date. Several scientific and programmatic lessons can be learned from these studies generating new hypotheses and guiding future steps.
RECENT FINDINGS
RV144 [ALVAC-HIV (canarypox vector) and AIDSVAX B/E (bivalent gp120 HIV-1 subtype B and CRF01_AE)] remains the only efficacy trial that demonstrated a modest vaccine efficacy, which led to the identification of immune correlates of risk. Progress on subtype-specific, ALVAC (canarypox vector) and gp120 vaccine prime-boost approaches has been slow, but we are finally close to the launch of an efficacy study in Africa in 2016. The quest of a globally effective HIV-1 vaccine has led to the development of new approaches. Efficacy studies of combinations of Adenovirus type 26 (Ad26)/Modified Vaccinia Ankara (MVA)/gp140 vaccines with mosaic designs will enter efficacy studies mid-2017 and cytomegalovirus (CMV)-vectored vaccines begin Phase I studies at the same time. Future HIV-1 vaccine efficacy trials face practical challenges as effective nonvaccine prevention programs are projected to decrease HIV-1 incidence.
SUMMARY
An HIV-1 vaccine is urgently needed. Increased industry involvement, mobilization of resources, expansion of a robust pipeline of new concepts, and robust preclinical challenge studies will be essential to accelerate efficacy testing of next generation HIV-1 vaccine candidates.
Topics: AIDS Vaccines; Clinical Trials as Topic; HIV Infections; Humans; Treatment Outcome
PubMed: 27537673
DOI: 10.1097/COH.0000000000000312 -
Current Opinion in HIV and AIDS Jul 2019Experimental and analytical advances have enabled systematic, high-resolution studies of humoral immune responses, and are beginning to define mechanisms of immunity to... (Review)
Review
PURPOSE OF REVIEW
Experimental and analytical advances have enabled systematic, high-resolution studies of humoral immune responses, and are beginning to define mechanisms of immunity to HIV.
RECENT FINDINGS
High-throughput, information-rich experimental and analytical methods, whether genomic, proteomic, or transcriptomic, have firmly established their value across a diversity of fields. Consideration of these tools as trawlers in 'fishing expeditions' has faded as 'data-driven discovery' has come to be valued as an irreplaceable means to develop fundamental understanding of biological systems. Collectively, studies of HIV-1 infection and vaccination including functional, biophysical, and biochemical humoral profiling approaches have provided insights into the phenotypic characteristics of individual and pools of antibodies. Relating these measures to clinical status, protection/efficacy outcomes, and cellular profiling data using machine learning has offered the possibility of identifying unanticipated mechanisms of action and gaining insights into fundamental immunological processes that might otherwise be difficult to decipher.
SUMMARY
Recent evidence establishes that systematic data collection and application of machine learning approaches can identify humoral immune correlates that are generalizable across distinct HIV-1 immunogens and vaccine regimens and translatable between model organisms and the clinic. These outcomes provide a strong rationale supporting the utility and further expansion of these approaches both in support of vaccine development and more broadly in defining mechanisms of immunity.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunity, Humoral
PubMed: 31033729
DOI: 10.1097/COH.0000000000000558