scholarly journals V2-Specific Antibodies in HIV-1 Vaccine Research and Natural Infection: Controllers or Surrogate Markers

Animals ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 526 ◽  
Author(s):  
Duerr ◽  
Gorny
Keyword(s):  
Vaccine Efficacy ◽  
Natural Infection ◽  
Vaccine Trial ◽  
Clinical Findings ◽  
Hiv Vaccine ◽  
Model Systems ◽  
Potential Contribution ◽  
Vaccine Research ◽  
Specific Antibodies ◽  
Hiv 1

Most human immunodeficiency virus (HIV) vaccine trials have lacked efficacy and empirical vaccine lead targets are scarce. Thus far, the only independent correlate of reduced risk of HIV-1 acquisition in humans is elevated levels of V2-specific antibodies identified in the modestly protective RV144 vaccine trial. Ten years after RV144, human and non-human primate vaccine studies have reassessed the potential contribution of V2-specific antibodies to vaccine efficacy. In addition, studies of natural HIV-1 infection in humans have provided insight into the development of V1V2-directed antibody responses and their impact on clinical parameters and disease progression. Functionally diverse anti-V2 monoclonal antibodies were isolated and their structurally distinct V2 epitope regions characterized. After RV144, a plethora of research studies were performed using different model systems, immunogens, protocols, and challenge viruses. These diverse studies failed to provide a clear picture regarding the contribution of V2 antibodies to vaccine efficacy. Here, we summarize the biological functions and clinical findings associated with V2-specific antibodies and discuss their impact on HIV vaccine research.

scholarly journals V2-Specific Antibodies in HIV-1 Vaccine Research and Natural Infection: Controllers or Surrogate Markers

Vaccines ◽  
2019 ◽  
Vol 7 (3) ◽  
pp. 82 ◽  
Author(s):  
Ralf Duerr ◽  
Miroslaw K. Gorny
Keyword(s):  
Vaccine Efficacy ◽  
Natural Infection ◽  
Vaccine Trial ◽  
Clinical Findings ◽  
Hiv Vaccine ◽  
Model Systems ◽  
Potential Contribution ◽  
Vaccine Research ◽  
Specific Antibodies ◽  
Hiv 1

Most human immunodeficiency virus (HIV) vaccine trials have lacked efficacy and empirical vaccine lead targets are scarce. Thus far, the only independent correlate of reduced risk of HIV-1 acquisition in humans is elevated levels of V2-specific antibodies identified in the modestly protective RV144 vaccine trial. Ten years after RV144, human and non-human primate vaccine studies have reassessed the potential contribution of V2-specific antibodies to vaccine efficacy. In addition, studies of natural HIV-1 infection in humans have provided insight into the development of V1V2-directed antibody responses and their impact on clinical parameters and disease progression. Functionally diverse anti-V2 monoclonal antibodies were isolated and their structurally distinct V2 epitope regions characterized. After RV144, a plethora of research studies were performed using different model systems, immunogens, protocols, and challenge viruses. These diverse studies failed to provide a clear picture regarding the contribution of V2 antibodies to vaccine efficacy. Here, we summarize the biological functions and clinical findings associated with V2-specific antibodies and discuss their impact on HIV vaccine research.

scholarly journals Recognition Patterns of the C1/C2 Epitopes Involved in Fc-Mediated Response in HIV-1 Natural Infection and the RV114 Vaccine Trial

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
William D. Tolbert ◽  
Verna Van ◽  
Rebekah Sherburn ◽  
Marina Tuyishime ◽  
Fang Yan ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Vaccine Efficacy ◽  
Natural Infection ◽  
Vaccine Trial ◽  
Constant Region ◽  
Cellular Cytotoxicity ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Hiv 1 ◽  
Rv144 Vaccine ◽  
Reduced Risk

ABSTRACT Antibodies (Abs) specific for CD4-induced envelope (Env) epitopes within constant region 1 and 2 (C1/C2) were induced in the RV144 vaccine trial, where antibody-dependent cellular cytotoxicity (ADCC) correlated with reduced risk of HIV-1 infection. We combined X-ray crystallography and fluorescence resonance energy transfer-fluorescence correlation spectroscopy to describe the molecular basis for epitopes of seven RV144 Abs and compared them to A32 and C11, C1/C2 Abs induced in HIV infection. Our data indicate that most vaccine Abs recognize the 7-stranded β-sandwich of gp120, a unique hybrid epitope bridging A32 and C11 binding sites. Although primarily directed at the 7-stranded β-sandwich, some accommodate the gp120 N terminus in C11-bound 8-stranded conformation and therefore recognize a broader range of CD4-triggered Env conformations. Our data also suggest that Abs of RV144 and RV305, the RV144 follow-up study, although likely initially induced by the ALVAC-HIV prime encoding full-length gp120, matured through boosting with truncated AIDSVAX gp120 variants. IMPORTANCE Antibody-dependent cellular cytotoxicity (ADCC) correlated with a reduced risk of infection from HIV-1 in the RV144 vaccine trial, the only HIV-1 vaccine trial to date to show any efficacy. Antibodies specific for CD4-induced envelope (Env) epitopes within constant region 1 and 2 (cluster A region) were induced in the RV144 trial and their ADCC activities were implicated in the vaccine efficacy. We present structural analyses of the antigen epitope targets of several RV144 antibodies specific for this region and C11, an antibody induced in natural infection, to show what the differences are in epitope specificities, mechanism of antigen recognition, and ADCC activities of antibodies induced by vaccination and during the course of HIV infection. Our data suggest that the truncated AIDSVAX gp120 variants used in the boost of the RV144 regimen may have shaped the vaccine response to this region, which could also have contributed to vaccine efficacy.

scholarly journals Impact of Herpes Simplex Virus Type 2 on HIV-1 Acquisition and Progression in an HIV Vaccine Trial (the Step Study)

2011 ◽  
Vol 57 (3) ◽  
pp. 238-244 ◽  
Author(s):  
Ruanne V Barnabas ◽  
Judith N Wasserheit ◽  
Yunda Huang ◽  
Holly Janes ◽  
Rhoda Morrow ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Vaccine Trial ◽  
Hiv Vaccine ◽  
Simplex Virus ◽  
Step Study ◽  
Hiv 1

scholarly journals Erratum for Tolbert et al., “Recognition Patterns of the C1/C2 Epitopes Involved in Fc-Mediated Response in HIV-1 Natural Infection and the RV114 Vaccine Trial”

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
William D. Tolbert ◽  
Verna Van ◽  
Rebekah Sherburn ◽  
Marina Tuyishime ◽  
Fang Yan ◽  
...  
Keyword(s):  
Natural Infection ◽  
Vaccine Trial ◽  
Hiv 1

scholarly journals Fc Receptor-Mediated Activities of Env-Specific Human Monoclonal Antibodies Generated from Volunteers Receiving the DNA Prime-Protein Boost HIV Vaccine DP6-001

2016 ◽  
Vol 90 (22) ◽  
pp. 10362-10378 ◽  
Author(s):  
Matthew R. Costa ◽  
Justin Pollara ◽  
Regina Whitney Edwards ◽  
Michael S. Seaman ◽  
Miroslaw K. Gorny ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Neutralizing Antibodies ◽  
Fc Receptor ◽  
Hiv Vaccine ◽  
Small Subset ◽  
Potential Contribution ◽  
Human Monoclonal Antibodies ◽  
Initial Report ◽  
Protein Boost ◽  
Hiv 1

ABSTRACTHIV-1 is able to elicit broadly potent neutralizing antibodies in a very small subset of individuals only after several years of infection, and therefore, vaccines that elicit these types of antibodies have been difficult to design. The RV144 trial showed that moderate protection is possible and that this protection may correlate with antibody-dependent cellular cytotoxicity (ADCC) activity. Our previous studies demonstrated that in an HIV vaccine phase I trial, the DP6-001 trial, a polyvalent Env DNA prime-protein boost formulation could elicit potent and broadly reactive, gp120-specific antibodies with positive neutralization activities. Here we report on the production and analysis of HIV-1 Env-specific human monoclonal antibodies (hMAbs) isolated from vaccinees in the DP6-001 trial. For this initial report, 13 hMAbs from four vaccinees in the DP6-001 trial showed broad binding to gp120 proteins of diverse subtypes both autologous and heterologous to vaccine immunogens. Equally cross-reactive Fc receptor-mediated functional activities, including ADCC and antibody-dependent cellular phagocytosis (ADCP) activities, were present with both immune sera and isolated MAbs, confirming the induction of nonneutralizing functional hMAbs by the DNA prime-protein boost vaccination. Elicitation of broadly reactive hMAbs by vaccination in healthy human volunteers confirms the value of the polyvalent formulation in this HIV vaccine design.IMPORTANCEThe roles of Fc receptor-mediated protective antibody responses are gaining more attention due to their potential contribution to the low-level protection against HIV-1 infection that they provided in the RV144 trial. At the same time, information about hMabs from other human HIV vaccine studies is very limited. In the current study, both immune sera and monoclonal antibodies from vaccinated humans showed not only high-level ADCC and ADCP activities but also cross-subtype ADCC and ADCP activities when a polyvalent DNA prime-protein boost vaccine formulation was used.

scholarly journals Generation and Characterization of a Bivalent HIV-1 Subtype C gp120 Protein Boost for Proof-of-Concept HIV Vaccine Efficacy Trials in Southern Africa

PLoS ONE ◽  
2016 ◽  
Vol 11 (7) ◽  
pp. e0157391 ◽  
Author(s):  
Carlo Zambonelli ◽  
Antu K. Dey ◽  
Susan Hilt ◽  
Samuel Stephenson ◽  
Eden P. Go ◽  
...  
Keyword(s):  
Southern Africa ◽  
Vaccine Efficacy ◽  
Hiv Vaccine ◽  
Proof Of Concept ◽  
Subtype C ◽  
Efficacy Trials ◽  
Gp120 Protein ◽  
Protein Boost ◽  
Hiv 1

scholarly journals OC 8491 PREPVACC: A PHASE III, MAMS ADAPTIVE PROPHYLACTIC HIV VACCINE TRIAL WITH A SECOND RANDOMISATION TO COMPARE F/TAF WITH TDF/FTC PREP

2019 ◽  
Vol 4 (Suppl 3) ◽  
pp. A10.1-A10
Author(s):  
Sarah Joseph ◽  
Pontiano Kaleebu ◽  
Eugene Ruzagira ◽  
Christian Holm Hansen ◽  
Janet Seeley ◽  
...  
Keyword(s):  
Vaccine Efficacy ◽  
Vaccine Trial ◽  
Final Analysis ◽  
Standard Of Care ◽  
Hiv Vaccine ◽  
Phase Iii ◽  
Hiv Incidence ◽  
Multi Stage ◽  
Adaptive Trial Design ◽  
Env Protein

BackgroundThere remains an urgent need for a prophylactic HIV vaccine to control generalised epidemics. PrEP has demonstrated effectiveness of 86% and is recommended by WHO; uptake is generally high, but retention is disappointing in some settings. The EDCTP2 project PrEPVacc will assess the efficacy of two combination prophylactic vaccine regimens (DNA, MVA and Env protein/adjuvant) each compared to placebo and the proportion of infections averted by F/TAF in comparison to TDF/FTC. A Registration Cohort, recruiting HIV negative volunteers at risk of HIV will precede the trial.MethodsThe PrEPVacc partnership agreed that 70% vaccine efficacy had public health relevance. The trial uses nstage software for multi-arm, multi-stage designs (MAMS) and the averted infections ratio (AIR) methodology with participants randomised (i) 1:1:1 to active product or placebo (ii) 1:1 to TDF/FTC : F/TAF until week 26 (presumed peak immunogenicity). Access to PrEP in the Registration Cohort and after week 26 will be standard of care. HIV seroconversions occurring between weeks 0–26 will inform the PrEP analysis, incorporating HIV incidence amongst those who do not take up PrEP locally in the Registration Cohort. Seroconversions after week 26 will inform vaccine analyses.ResultsUp to 556 participants per group affords 92% power to detect vaccine efficacy of 70% at the final analysis, assuming incidence of 4/100-person years and 10% loss with 81% and 97% power to conclude that F/TAF can avert half or more of the infections prevented by TDF/FTC if effectiveness of TDF/FTC is 70% and 80%, respectively.ConclusionPrEPVacc adopts a pragmatic approach to uncertainties around HIV incidence in settings where PrEP is increasingly available. This innovative adaptive trial design uses validated software to determine vaccine efficacy and a novel methodology to evaluate a new PrEP agent, overcoming the challenge of demonstrating non-inferiority when adherence to TDF/FTC is high and the number of outcome events very low.

scholarly journals Anti-V2 Antibody Deficiency in Individuals Infected With HIV-1

2018 ◽  
Author(s):  
Lily Liu ◽  
Liuzhe Li ◽  
Aubin Nanfack ◽  
Luzia M. Mayr ◽  
Sonal Soni ◽  
...  
Keyword(s):  
Vaccine Efficacy ◽  
Hiv Vaccine ◽  
Phase Iii ◽  
Dominant Factor ◽  
Plasma Samples ◽  
Electrostatic Charges ◽  
Glycosylation Sites ◽  
Significant Difference ◽  
Hiv 1 ◽  
Rv144 Vaccine

ABSTRACTThe positive correlation of high levels of plasma anti-V2 antibodies (Abs) with protective immunity in the Phase III anti-HIV RV144 vaccine trial generated interest in the induction of these Abs for HIV vaccine development. We analyzed plasma samples from 79 chronically infected Cameroonian individuals for Ab reactivity against three V1V2 fusion proteins and five cyclic V2 peptides and found that HIV-1 infection induces different levels of anti-V2 Abs. While the majority of plasma samples reacted strongly with one or more V2 antigens, 10% (8) of the samples were nonreactive. Deficiency of anti-V2 Abs was consistently found in longitudinal plasma samples tested over 8 to 54 months of HIV infection. There was a strong correlation between binding activities of plasma anti-V2 Abs and anti-gp120 and anti-gp41 Abs, suggesting that deficiency of V2 Abs could be related, in part, to a limited ability to elicit strong Ab responses. Analysis of gp120 sequences revealed that the V2 region of viruses from donors with V2-deficient versus V2-reactive Abs displayed a tendency toward longer length, more glycans, and lower isoelectric point and charge. No differences between these two patient groups were noted in the same parameters measured in the V1 region. These data suggest that immunogens containing a shorter V2 region with fewer glycosylation sites and higher electrostatic charges would be beneficial for induction of anti-V2 Abs, but the ability to mount a strong general Ab response to HIV-1 appears to be a dominant factor.IMPORTANCEThe results of the RV144 vaccine clinical trial showed a correlation between plasma Abs against a V1V2 fusion protein and a decreased risk of acquiring HIV-1 infection. This turned the focus of some HIV vaccine design to the induction of elevated levels of anti-V2 Abs to increase vaccine efficacy. In plasma samples from Cameroonian individuals infected with HIV-1, we observed broad variations in levels of anti-V2 Abs, and 8 of the 79 plasma samples tested displayed substantial deficiency of V2 Abs. Sequence analysis of the V2 region from plasma viruses and multivariate analyses of V2 characteristics showed a significant difference in several features between V2-deficient and V2-reactive plasma Abs. These results suggest that HIV vaccine immunogens containing a V2 region with shorter length, fewer glycosylation sites, and higher electrostatic charges may be beneficial for induction of a higher level of anti-V2 Abs and thus contribute to HIV vaccine efficacy.

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