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Nature Medicine Nov 2023Human immunodeficiency virus type 1 (HIV-1)-neutralizing antibodies (nAbs) that prevent infection are the main goal of HIV vaccine discovery. But as no nAb-eliciting...
Human immunodeficiency virus type 1 (HIV-1)-neutralizing antibodies (nAbs) that prevent infection are the main goal of HIV vaccine discovery. But as no nAb-eliciting vaccines are yet available, only data from HIV-1 neutralizers-persons with HIV-1 who naturally develop broad and potent nAbs-can inform about the dynamics and durability of nAb responses in humans, knowledge which is crucial for the design of future HIV-1 vaccine regimens. To address this, we assessed HIV-1-neutralizing immunoglobulin G (IgG) from 2,354 persons with HIV-1 on or off antiretroviral therapy (ART). Infection with non-clade B viruses, CD4 T cell counts <200 µl, being off ART and a longer time off ART were independent predictors of a more potent and broad neutralization. In longitudinal analyses, we found nAb half-lives of 9.3 and 16.9 years in individuals with no- or low-level viremia, respectively, and 4.0 years in persons who newly initiated ART. Finally, in a potent HIV-1 neutralizer, we identified lower fractions of serum nAbs and of nAb-encoding memory B cells after ART initiation, suggesting that a decreasing neutralizing serum activity after antigen withdrawal is due to lower levels of nAbs. These results collectively show that HIV-1-neutralizing responses can persist for several years, even at low antigen levels, suggesting that an HIV-1 vaccine may elicit a durable nAb response.
Topics: Humans; HIV-1; HIV Infections; HIV Antibodies; Antibodies, Neutralizing; AIDS Vaccines; Virus Replication
PubMed: 37957379
DOI: 10.1038/s41591-023-02582-3 -
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 -
PLoS Pathogens Nov 2021Despite the advent of long-acting anti-retroviral therapy able to control and prevent infection, a preventative vaccine remains a global priority for the elimination of...
Despite the advent of long-acting anti-retroviral therapy able to control and prevent infection, a preventative vaccine remains a global priority for the elimination of HIV. The moderately protective RV144 vaccine trial suggested functional IgG1 and IgG3 antibodies were a potential correlate of protection, but the RV144-inspired HVTN702 validation trial failed to demonstrate efficacy despite inducing targeted levels of IgG1/IgG3. Alterations in inserts, and antigens, adjuvant, and regimen also resulted in vaccine induced target quantitative levels of the immune correlates, but drove qualitative changes to the humoral immune response, pointing to the urgent need to define the influence of vaccine strategies on shaping antibody quality, not just quantity. Thus, defining how distinct prime/boost approaches tune long-lived functional antibodies represents an important goal in vaccine development. Here, we compared vaccine responses in Phase I and II studies in humans utilizing various combinations of DNA/vector, vector/vector and DNA/protein HIV vaccines. We found that adenoviral vector immunization, compared to pox-viral vectors, resulted in the most potent IgG1 and IgG3 responses, linked to highly functional antibody activity, including assisting NK cell related functions. Minimal differences were observed in the durability of the functional humoral immune response across vaccine regimens, except for antibody dependent phagocytic function, which persisted for longer periods in the DNA/rAd5 and rAd35/rAd5 regimen, likely driven by higher IgG1 levels. Collectively, these findings suggest adenoviral vectors drive superior antibody quality and durability that could inform future clinical vaccine studies. Trial registration: ClinicalTrials.gov NCT00801697, NCT00961883, NCT02207920, NCT00125970, NCT02852005).
Topics: AIDS Vaccines; Adenoviridae; Adult; Female; Genetic Vectors; HIV Antibodies; HIV Antigens; HIV Infections; HIV-1; Humans; Immunity, Humoral; Immunoglobulin G; Male; Vaccine Development; Vaccines, DNA; Young Adult
PubMed: 34843602
DOI: 10.1371/journal.ppat.1010016 -
Annual Review of Immunology Apr 2020Development of improved approaches for HIV-1 prevention will likely be required for a durable end to the global AIDS pandemic. Recent advances in preclinical studies and... (Review)
Review
Development of improved approaches for HIV-1 prevention will likely be required for a durable end to the global AIDS pandemic. Recent advances in preclinical studies and early phase clinical trials offer renewed promise for immunologic strategies for blocking acquisition of HIV-1 infection. Clinical trials are currently underway to evaluate the efficacy of two vaccine candidates and a broadly neutralizing antibody (bNAb) to prevent HIV-1 infection in humans. However, the vast diversity of HIV-1 is a major challenge for both active and passive immunization. Here we review current immunologic strategies for HIV-1 prevention, with a focus on current and next-generation vaccines and bNAbs.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; Clinical Trials as Topic; Disease Management; Genetic Variation; HIV Antibodies; HIV Infections; HIV-1; Host-Pathogen Interactions; Humans; Immunization, Passive; RNA, Viral; Structure-Activity Relationship; T-Lymphocytes; Viral Proteins
PubMed: 32340576
DOI: 10.1146/annurev-immunol-080219-023629 -
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 -
Current Opinion in HIV and AIDS Sep 2020Recent work defining Fc-mediated effector functions for both viral control and protection against infection is summarized and considered along with new strategies to... (Review)
Review
PURPOSE OF REVIEW
Recent work defining Fc-mediated effector functions for both viral control and protection against infection is summarized and considered along with new strategies to drive robust Fc-mediated responses.
RECENT FINDINGS
In new human and nonhuman primate (NHP) vaccine trials as well as studies of natural infection, Fc-mediated effector responses have sometimes been observed to correlate with decreased risk of infection or with better clinical outcomes, suggesting a potential role for these responses in HIV-1 prevention and therapy. Recent highlights include use of antibody-dependent cellular cytotoxicity-sensitizing CD4-induced mimetic compounds, novel V1V2 immunogens, passive transfer studies, and vaccine regimens that successfully elicited Fc-mediated responses and were reported to decrease risk of infection in challenge studies in NHPs. Lastly, detailed studies of IgG3 forms of HIV-specific antibodies have reported that both neutralizing and Fc-mediated responses can be increased relative to the more prevalent IgG1 subclass.
SUMMARY
Successful harmonization of neutralizing and Fc-mediated responses may make key contributions to the goal of reducing HIV-1 infection via active and passive vaccination. New studies continue to highlight the importance of Fc-mediated antibody responses as correlates of decreased risk of infection and suggest enhanced phagocytosis is a potential mechanism of reduced risk of infection associated with human IgG3 responses. Results from recent studies may help guide the rational design of therapies and vaccines that aim to specifically leverage antibody effector function.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; Antibody-Dependent Cell Cytotoxicity; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunoglobulin Fc Fragments
PubMed: 32675573
DOI: 10.1097/COH.0000000000000638 -
EBioMedicine Mar 2020Antiretroviral therapy (ART) suppresses human immunodeficiency virus (HIV) infection. Research seeking to transform viral suppression into elimination has generated... (Review)
Review
Antiretroviral therapy (ART) suppresses human immunodeficiency virus (HIV) infection. Research seeking to transform viral suppression into elimination has generated novel immune, chemical and molecular antiviral agents. However, none, to date, have excised latent integrated proviral DNA or removed infected cells from infected persons. These efforts included, but are not limited to, broadly neutralizing antibodies, "shock" and "kill" latency-reversing agents, innate immune regulators, and sequential long-acting antiretroviral nanoformulated prodrugs and CRISPR-Cas9 gene editing. While, the latter, enabled the complete excision of latent HIV-1 from the host genome success was so far limited. We contend that improvements in antiretroviral delivery, potency, agent specificity, or combinatorial therapies can provide a pathway towards complete HIV elimination.
Topics: AIDS Vaccines; Anti-HIV Agents; Disease Eradication; HIV Infections; HIV-1; Humans
PubMed: 32114397
DOI: 10.1016/j.ebiom.2020.102667 -
Human Vaccines & Immunotherapeutics Mar 2020Despite 30 years of effort, we do not have an effective HIV-1 vaccine. Over the past decade, the HIV-1 vaccine field has shifted emphasis toward antibody-based vaccine...
Despite 30 years of effort, we do not have an effective HIV-1 vaccine. Over the past decade, the HIV-1 vaccine field has shifted emphasis toward antibody-based vaccine strategies, following a lack of efficacy in CD8+ T-cell-based vaccine trials. Several lines of evidence, however, suggest that improved CD8+ T-cell-directed strategies could benefit an HIV-1 vaccine. First, T-cell responses often correlate with good outcomes in non-human primate (NHP) challenge models. Second, subgroup studies of two no-efficacy human clinical vaccine trials found associations between CD8+ T-cell responses and protective effects. Finally, improved strategies can increase the breadth and potency of CD8+ T-cell responses, direct them toward preferred epitopes (that are highly conserved and/or associated with viral control), or both. Optimized CD8+ T-cell vaccine strategies are promising in both prophylactic and therapeutic settings. This commentary briefly outlines some encouraging findings from T-cell vaccine studies, and then directly compares key features of some T-cell vaccine candidates currently in the clinical pipeline.
Topics: AIDS Vaccines; CD8-Positive T-Lymphocytes; Epitopes; HIV Infections; HIV-1; Humans
PubMed: 31584318
DOI: 10.1080/21645515.2019.1666957 -
The FEBS Journal Jun 2022Protection from human immunodeficiency virus (HIV) acquisition will likely require an effective vaccine that elicits antibodies against the HIV-1 envelope glycoproteins... (Review)
Review
Protection from human immunodeficiency virus (HIV) acquisition will likely require an effective vaccine that elicits antibodies against the HIV-1 envelope glycoproteins (Envs), which are the sole target of neutralizing antibodies and a main focus of vaccine development. Adjuvants have been widely used to augment the magnitude and longevity of the adaptive immune responses to immunizations with HIV-1 Envs and to guide the development of specific immune responses. Here, we review the adjuvants that have been used in combination with HIV-1 Envs in several preclinical and human clinical trials in recent years. We summarize the interactions between the HIV-1 Envs and adjuvants, and highlight the routes of vaccine administration for various formulations. We then discuss the use of combinations of different adjuvants, the potential effect of adjuvants on the elicitation of antibodies enriched in somatic hypermutation and containing long complementarity-determining region 3 of the antibody heavy chain, and the elicitation of non-neutralizing antibodies.
Topics: AIDS Vaccines; Adjuvants, Immunologic; Antibodies, Neutralizing; HIV Infections; HIV-1; Humans; Immunity; env Gene Products, Human Immunodeficiency Virus
PubMed: 33705608
DOI: 10.1111/febs.15814