Boosting of HIV envelope CD4 binding site antibodies with long variable heavy third complementarity determining region in the randomized double blind RV305 HIV-1 vaccine trial
David EasterhoffM. Anthony MoodyDaniela FeraHao ChengMargaret E. AckermanKevin WieheKevin O. SaundersJustin PollaraNathan VandergriftRob ParksJérôme H. KimNelson L. MichaelRobert J. O’ConnellJean‐Louis ExclerMerlin L. RobbSandhya VasanSupachai Rerks‐NgarmJaranit KaewkungwalPunnee PitisuttithumSorachai NitayaphanFaruk SinangilJames TartagliaSanjay PhogatThomas B. KeplerS. Munir AlamHua‐Xin LiaoGuido FerrariMichael S. SeamanDavid C. MontefioriGeorgia D. TomarasStephen C. HarrisonBarton F. Haynes
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The canary pox vector and gp120 vaccine (ALVAC-HIV and AIDSVAX B/E gp120) in the RV144 HIV-1 vaccine trial conferred an estimated 31% vaccine efficacy. Although the vaccine Env AE.A244 gp120 is antigenic for the unmutated common ancestor of V1V2 broadly neutralizing antibody (bnAbs), no plasma bnAb activity was induced. The RV305 (NCT01435135) HIV-1 clinical trial was a placebo-controlled randomized double-blinded study that assessed the safety and efficacy of vaccine boosting on B cell repertoires. HIV-1-uninfected RV144 vaccine recipients were reimmunized 6–8 years later with AIDSVAX B/E gp120 alone, ALVAC-HIV alone, or a combination of ALVAC-HIV and AIDSVAX B/E gp120 in the RV305 trial. Env-specific post-RV144 and RV305 boost memory B cell VH mutation frequencies increased from 2.9% post-RV144 to 6.7% post-RV305. The vaccine was well tolerated with no adverse events reports. While post-boost plasma did not have bnAb activity, the vaccine boosts expanded a pool of envelope CD4 binding site (bs)-reactive memory B cells with long third heavy chain complementarity determining regions (HCDR3) whose germline precursors and affinity matured B cell clonal lineage members neutralized the HIV-1 CRF01 AE tier 2 (difficult to neutralize) primary isolate, CNE8. Electron microscopy of two of these antibodies bound with near-native gp140 trimers showed that they recognized an open conformation of the Env trimer. Although late boosting of RV144 vaccinees expanded a novel pool of neutralizing B cell clonal lineages, we hypothesize that boosts with stably closed trimers would be necessary to elicit antibodies with greater breadth of tier 2 HIV-1 strains. Trial Registration: ClinicalTrials.gov NCT01435135Keywords:
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Considerable HIV-1 vaccine development efforts have been deployed over the past decade. Put into perspective, the results from efficacy trials and the identification of correlates of risk have opened large and unforeseen avenues for vaccine development.
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Our study aimed to measure the levels of serotonin and oxytocin in patients affected by end-stage renal disease (ESRD), undergoing dialysis and participating in a program of animal-assisted activities (AAAs) with a dog. Ten patients with comparable levels of ESRD were enrolled. A blood sample was taken before the start of the study in order to establish basal levels. Eleven meetings were held once a week for 3 months during the last hour of dialysis, and blood samples were collected before and after AAAs. Two more meetings, one month apart from each other, were held two months later without the dog but with the same veterinarian zootherapist. Blood was drawn at the beginning and at the end of each meeting. The samples were then processed for the measurement of serotonin and oxytocin, and data obtained were analysed using analysis of variance with mixed effect models. The results show an increasing level of both serotonin and oxytocin between subsequent meetings with the dog and an increasing trend of inter-intervention levels. Overall, the results suggest that AAAs lead to modifications of serotonin and oxytocin levels, which are also accompanied by behavioural changes of patients.
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An effective HIV vaccine is a global health priority. The Merck Ad5 phase IIb T-cell vaccine failed to show efficacy and might have increased the risk of HIV acquisition in MSM. While VaxGen gp120 alone was not efficacious in groups at high risk for HIV-1 infection, the RV144 ALVAC-HIV prime and AIDSVAX gp120 B/E boost regimen showed 31% efficacy in low incidence heterosexuals in Thailand. All trials demonstrated the limitations of available laboratory and animal models to both assess relevant vaccine-induced immune responses and to predict clinical trial outcome. We have begun an intensive, broad based attempt to discover a correlate of protection from RV 144 involving over 30 investigators at 20 institutions examining the innate and adaptive responses induced in RV 144, viral sieve and host genetic studies, and non-human primate studies. Results of some of these studies will be described. A roadmap for future HIV vaccine trials will be described designed to better define RV 144 correlates of protection, improve the durability and level of protection observed, and assess protective vaccine efficacy in diverse risk groups. New strategies examining heterologous vector prime boost, universal inserts, replicating vectors, and novel protein/adjuvant immunogens should be explored to induce both T-cell and antibody responses. These new approaches will be described within the context of the roadmap for future HIV vaccine efficacy studies. HIV vaccine development requires innovative ideas and a sustained long-term commitment of scientists, governments, and the community.
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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.
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The development of a safe and effective HIV vaccine remains a challenge. The modest efficacy seen in the RV144 vaccine trial represented an important milestone for the field. Results from all efficacy studies done to date have generated new information, which has advanced the HIV vaccine field in important ways. In this article, we review the translational research insights from the vaccine efficacy trials completed and fully analyzed to date. We also describe the recent advances in the search for broadly neutralizing antibodies and discuss potential approaches to circumvent the challenge posed by the enormous diversity of HIV-1. The experience from the past 5 years highlights the importance of conducting efficacy studies that continue to move us closer toward the goal of a safe, effective, durable, and universal HIV preventive vaccine.
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Purpose of review An effective HIV vaccine is a global health priority. We describe lessons learned from four HIV vaccine trials that failed to demonstrate efficacy and one that showed modest protection as a pathway forward. Recent findings The Merck Ad5 phase IIb T-cell vaccine failed to show efficacy and might have increased the risk of HIV acquisition in men who have sex with men. Although VaxGen gp120 alone was not efficacious in groups at high risk for HIV-1 infection, the RV144 ALVAC prime and gp120 boost regimen showed 31% efficacy in low-incidence heterosexuals. All trials demonstrated the limitations of available laboratory and animal models to assess relevant vaccine-induced immune responses and predict clinical trial outcome. Analysis of innate and adaptive responses induced in RV144 will guide future trial design. Summary Future HIV vaccine trials should define the RV144 immune responses relevant to protection, improve durability and level of protection, and assess efficacy in diverse risk groups. New strategies examining heterologous vector prime–boost, universal inserts, replicating vectors, and novel protein or adjuvant immunogens should be explored to induce T-cell and antibody responses. HIV vaccine development requires innovative ideas and a sustained long-term commitment of scientists, governments, and the community.
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As of January 1998, more than 85 vaccines for 24 clinical indications are currently licensed in the United States. From the time of discovery of the etiologic agent to the development of a licensed vaccine, many years have usually been required. Although many vaccines have been licensed on the basis of one efficacy trial, multiple vaccine concepts and multiple efficacy trials (both in the United States and internationally) have at times been necessary. Over a relatively short period of time, there has been remarkable progress in human immunodeficiency virus (HIV) vaccine development, with over 34 different HIV candidate vaccines having been tested in phase 1 trials, and three having been tested in phase 2 trials. In spite of our incomplete understanding of HIV pathogenesis and correlates of protection, the first phase 3 efficacy trial has been initiated in the U.S. and tentative plans have been announced for three other phase 3 efficacy trials with the most advanced HIV candidate vaccines to begin in the next 3 years. Like many previous vaccine development efforts, these initial HIV vaccine efficacy trials could be the first of many large-scale efficacy trials in the future, testing various vaccine design concepts among different high-risk populations in both developed and developing countries. The choice of when and how to proceed to phase 3 trials remains a complex decision, but it is likely that only through such trials will further knowledge be gained to advance this important effort and reach our goal of a safe and effective HIV vaccine.
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Despite many recent advances in the HIV prevention landscape, an effective vaccine remains the most promising tool to end the HIV-1 pandemic. Areas covered: This review summarizes past HIV vaccine efficacy trials and current vaccine strategies as well as new approaches about to move into first-in-human trials. Expert opinion: Despite many setbacks in early HIV vaccine efficacy trials, the success of RV144 has provided the glimmer of hope necessary to invigorate the vaccine field, and has led to the development of a large number of vaccine strategies aiming at inducing an array of different immune responses. The follow-up pox-protein trials, developed to replicate and enhance the polyfunctional antibody responses induced by the RV144 regimen, are already reaching efficacy trials, while a large body of work providing a more complete understanding of the development of broadly neutralizing antibodies is now being translated into immunogen design using several different strategies. T-cell based vaccines, fallen out of favor after Ad5-based trials showed increased infection rates in Ad5 seropositive vaccine recipients, are experiencing a comeback based in part on the promising results from non-human primate challenge studies using rhCMV-based immunogens. This diverse array of vaccine candidates may finally allow us to identify a broadly effective HIV vaccine able to contain the epidemic.
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