Discovery medicine - the HVTN's iterative approach to developing an HIV-1 broadly neutralizing vaccine

Purpose of reviewIn the past two decades, there has been an explosion in the discovery of HIV-1 broadly neutralizing antibodies (bnAbs) and associated vaccine strategies to induce them. This abundance of approaches necessitates a system that accurately and expeditiously identifies the most promising regimens. We herein briefly review the background science of bnAbs, provide a description of the first round of phase 1 discovery medicine studies, and suggest an approach to integrate these into a comprehensive HIV-1-neutralizing vaccine.With recent preclinical success including induction of early stage bnAbs in mouse knockin models and rhesus macaques, successful priming of VRC01-class bnAbs with eOD-GT8 in a recent study in humans, and proof-of-concept that intravenous infusion of VRC01 prevents sexual transmission of virus in humans, the stage is set for a broad and comprehensive bnAb vaccine program. Leveraging significant advances in protein nanoparticle science, mRNA technology, adjuvant development, and B-cell and antibody analyses, the HVTN has reconfigured its HIV-1 vaccine strategy by developing the Discovery Medicine Program to test promising vaccine candidates targeting six key epitopes.The HVTN Discovery Medicine program is testing multiple HIV-1-neutralizing vaccine candidates.Papers of particular interest, published within the annual period of review, have been highlighted as:Despite over 20 years of intensive effort, developing an HIV-1 vaccine has proven to be one of the greatest challenges in vaccinology. Only one vaccine regimen has shown modest efficacy [1], and the efficacy has so far not been reproducible elsewhere [2]. Catalyzed by advancements in immunogen design, sequencing, and structural analyses, the field's attention has shifted to development of a multifocal broadly neutralizing antibody (bnAb) vaccine, and there is a growing pipeline of candidate products. The HIV Vaccine Trials Network (HVTN) has developed the Discovery Medicine Program to evaluate bnAb-inducing vaccine candidates efficiently and systematically, emphasizing streamlined processes for rapid vaccine design iteration.Approximately 30% of persons living with chronic HIV-1 infection develop bnAbs, often with unique features such as long heavy chain complementary determining regions (HCDR3 s), high levels of somatic hypermutation (SHM), insertions and deletions, and rare and improbable mutations [3-18]. Six known epitope regions on the HIV-1 envelope (Env) are susceptible to bnAb development, some with very high breadth and potency: CD4+-binding site (CD4bs), V2 apex, V3 glycan, gp120-gp41 interface, fusion peptide, and the membrane proximal external region (MPER) [1,3,19,20]. However, their naive B cell precursors can be extremely rare. Fortunately, the recent landmark eOD-GT8 study showed that, with the right immunogen, rare germline precursors [21,22] can be activated to induce first-step VRC01-class bnAbs in nearly all trial participants [23]. In addition, the Antibody Mediated Prevention (AMP) trials showed that passive infusion of a potent antibody like VRC01 is protective against HIV-1 strains that are neutralization-sensitive to VRC01 [24]. These results, together with the extraordinary success of the COVID-19 mRNA vaccines and improvements in immunogen design, have led to renewed enthusiasm for the development of HIV-1 neutralizing vaccines. no caption availablePurpose of reviewIn the past two decades, there has been an explosion in the discovery of HIV-1 broadly neutralizing antibodies (bnAbs) and associated vaccine strategies to induce them. This abundance of approaches necessitates a system that accurately and expeditiously identifies the most promising regimens. We herein briefly review the background science of bnAbs, provide a description of the first round of phase 1 discovery medicine studies, and suggest an approach to integrate these into a comprehensive HIV-1-neutralizing vaccine.With recent preclinical success including induction of early stage bnAbs in mouse knockin models and rhesus macaques, successful priming of VRC01-class bnAbs with eOD-GT8 in a recent study in humans, and proof-of-concept that intravenous infusion of VRC01 prevents sexual transmission of virus in humans, the stage is set for a broad and comprehensive bnAb vaccine program. Leveraging significant advances in protein nanoparticle science, mRNA technology, adjuvant development, and B-cell and antibody analyses, the HVTN has reconfigured its HIV-1 vaccine strategy by developing the Discovery Medicine Program to test promising vaccine candidates targeting six key epitopes.The HVTN Discovery Medicine program is testing multiple HIV-1-neutralizing vaccine candidates.Papers of particular interest, published within the annual period of review, have been highlighted as:Despite over 20 years of intensive effort, developing an HIV-1 vaccine has proven to be one of the greatest challenges in vaccinology. Only one vaccine regimen has shown modest efficacy [1], and the efficacy has so far not been reproducible elsewhere [2]. Catalyzed by advancements in immunogen design, sequencing, and structural analyses, the field's attention has shifted to development of a multifocal broadly neutralizing antibody (bnAb) vaccine, and there is a growing pipeline of candidate products. The HIV Vaccine Trials Network (HVTN) has developed the Discovery Medicine Program to evaluate bnAb-inducing vaccine candidates efficiently and systematically, emphasizing streamlined processes for rapid vaccine design iteration.Approximately 30% of persons living with chronic HIV-1 infection develop bnAbs, often with unique features such as long heavy chain complementary determining regions (HCDR3 s), high levels of somatic hypermutation (SHM), insertions and deletions, and rare and improbable mutations [3-18]. Six known epitope regions on the HIV-1 envelope (Env) are susceptible to bnAb development, some with very high breadth and potency: CD4+-binding site (CD4bs), V2 apex, V3 glycan, gp120-gp41 interface, fusion peptide, and the membrane proximal external region (MPER) [1,3,19,20]. However, their naive B cell precursors can be extremely rare. Fortunately, the recent landmark eOD-GT8 study showed that, with the right immunogen, rare germline precursors [21,22] can be activated to induce first-step VRC01-class bnAbs in nearly all trial participants [23]. In addition, the Antibody Mediated Prevention (AMP) trials showed that passive infusion of a potent antibody like VRC01 is protective against HIV-1 strains that are neutralization-sensitive to VRC01 [24]. These results, together with the extraordinary success of the COVID-19 mRNA vaccines and improvements in immunogen design, have led to renewed enthusiasm for the development of HIV-1 neutralizing vaccines. no caption availablePurpose of reviewIn the past two decades, there has been an explosion in the discovery of HIV-1 broadly neutralizing antibodies (bnAbs) and associated vaccine strategies to induce them. This abundance of approaches necessitates a system that accurately and expeditiously identifies the most promising regimens. We herein briefly review the background science of bnAbs, provide a description of the first round of phase 1 discovery medicine studies, and suggest an approach to integrate these into a comprehensive HIV-1-neutralizing vaccine.With recent preclinical success including induction of early stage bnAbs in mouse knockin models and rhesus macaques, successful priming of VRC01-class bnAbs with eOD-GT8 in a recent study in humans, and proof-of-concept that intravenous infusion of VRC01 prevents sexual transmission of virus in humans, the stage is set for a broad and comprehensive bnAb vaccine program. Leveraging significant advances in protein nanoparticle science, mRNA technology, adjuvant development, and B-cell and antibody analyses, the HVTN has reconfigured its HIV-1 vaccine strategy by developing the Discovery Medicine Program to test promising vaccine candidates targeting six key epitopes.The HVTN Discovery Medicine program is testing multiple HIV-1-neutralizing vaccine candidates.Papers of particular interest, published within the annual period of review, have been highlighted as:Despite over 20 years of intensive effort, developing an HIV-1 vaccine has proven to be one of the greatest challenges in vaccinology. Only one vaccine regimen has shown modest efficacy [1], and the efficacy has so far not been reproducible elsewhere [2]. Catalyzed by advancements in immunogen design, sequencing, and structural analyses, the field's attention has shifted to development of a multifocal broadly neutralizing antibody (bnAb) vaccine, and there is a growing pipeline of candidate products. The HIV Vaccine Trials Network (HVTN) has developed the Discovery Medicine Program to evaluate bnAb-inducing vaccine candidates efficiently and systematically, emphasizing streamlined processes for rapid vaccine design iteration.Approximately 30% of persons living with chronic HIV-1 infection develop bnAbs, often with unique features such as long heavy chain complementary determining regions (HCDR3 s), high levels of somatic hypermutation (SHM), insertions and deletions, and rare and improbable mutations [3-18]. Six known epitope regions on the HIV-1 envelope (Env) are susceptible to bnAb development, some with very high breadth and potency: CD4+-binding site (CD4bs), V2 apex, V3 glycan, gp120-gp41 interface, fusion peptide, and the membrane proximal external region (MPER) [1,3,19,20]. However, their naive B cell precursors can be extremely rare. Fortunately, the recent landmark eOD-GT8 study showed that, with the right immunogen, rare germline precursors [21,22] can be activated to induce first-step VRC01-class bnAbs in nearly all trial participants [23]. In addition, the Antibody Mediated Prevention (AMP) trials showed that passive infusion of a potent antibody like VRC01 is protective against HIV-1 strains that are neutralization-sensitive to VRC01 [24]. These results, together with the extraordinary success of the COVID-19 mRNA vaccines and improvements in immunogen design, have led to renewed enthusiasm for the development of HIV-1 neutralizing vaccines. no caption availablePurpose of reviewIn the past two decades, there has been an explosion in the discovery of HIV-1 broadly neutralizing antibodies (bnAbs) and associated vaccine strategies to induce them. This abundance of approaches necessitates a system that accurately and expeditiously identifies the most promising regimens. We herein briefly review the background science of bnAbs, provide a description of the first round of phase 1 discovery medicine studies, and suggest an approach to integrate these into a comprehensive HIV-1-neutralizing vaccine.With recent preclinical success including induction of early stage bnAbs in mouse knockin models and rhesus macaques, successful priming of VRC01-class bnAbs with eOD-GT8 in a recent study in humans, and proof-of-concept that intravenous infusion of VRC01 prevents sexual transmission of virus in humans, the stage is set for a broad and comprehensive bnAb vaccine program. Leveraging significant advances in protein nanoparticle science, mRNA technology, adjuvant development, and B-cell and antibody analyses, the HVTN has reconfigured its HIV-1 vaccine strategy by developing the Discovery Medicine Program to test promising vaccine candidates targeting six key epitopes.The HVTN Discovery Medicine program is testing multiple HIV-1-neutralizing vaccine candidates.Papers of particular interest, published within the annual period of review, have been highlighted as:Despite over 20 years of intensive effort, developing an HIV-1 vaccine has proven to be one of the greatest challenges in vaccinology. Only one vaccine regimen has shown modest efficacy [1], and the efficacy has so far not been reproducible elsewhere [2]. Catalyzed by advancements in immunogen design, sequencing, and structural analyses, the field's attention has shifted to development of a multifocal broadly neutralizing antibody (bnAb) vaccine, and there is a growing pipeline of candidate products. The HIV Vaccine Trials Network (HVTN) has developed the Discovery Medicine Program to evaluate bnAb-inducing vaccine candidates efficiently and systematically, emphasizing streamlined processes for rapid vaccine design iteration.Approximately 30% of persons living with chronic HIV-1 infection develop bnAbs, often with unique features such as long heavy chain complementary determining regions (HCDR3 s), high levels of somatic hypermutation (SHM), insertions and deletions, and rare and improbable mutations [3-18]. Six known epitope regions on the HIV-1 envelope (Env) are susceptible to bnAb development, some with very high breadth and potency: CD4+-binding site (CD4bs), V2 apex, V3 glycan, gp120-gp41 interface, fusion peptide, and the membrane proximal external region (MPER) [1,3,19,20]. However, their naive B cell precursors can be extremely rare. Fortunately, the recent landmark eOD-GT8 study showed that, with the right immunogen, rare germline precursors [21,22] can be activated to induce first-step VRC01-class bnAbs in nearly all trial participants [23]. In addition, the Antibody Mediated Prevention (AMP) trials showed that passive infusion of a potent antibody like VRC01 is protective against HIV-1 strains that are neutralization-sensitive to VRC01 [24]. These results, together with the extraordinary success of the COVID-19 mRNA vaccines and improvements in immunogen design, have led to renewed enthusiasm for the development of HIV-1 neutralizing vaccines. no caption availablePurpose of reviewIn the past two decades, there has been an explosion in the discovery of HIV-1 broadly neutralizing antibodies (bnAbs) and associated vaccine strategies to induce them. This abundance of approaches necessitates a system that accurately and expeditiously identifies the most promising regimens. We herein briefly review the background science of bnAbs, provide a description of the first round of phase 1 discovery medicine studies, and suggest an approach to integrate these into a comprehensive HIV-1-neutralizing vaccine.With recent preclinical success including induction of early stage bnAbs in mouse knockin models and rhesus macaques, successful priming of VRC01-class bnAbs with eOD-GT8 in a recent study in humans, and proof-of-concept that intravenous infusion of VRC01 prevents sexual transmission of virus in humans, the stage is set for a broad and comprehensive bnAb vaccine program. Leveraging significant advances in protein nanoparticle science, mRNA technology, adjuvant development, and B-cell and antibody analyses, the HVTN has reconfigured its HIV-1 vaccine strategy by developing the Discovery Medicine Program to test promising vaccine candidates targeting six key epitopes.The HVTN Discovery Medicine program is testing multiple HIV-1-neutralizing vaccine candidates.Papers of particular interest, published within the annual period of review, have been highlighted as:Despite over 20 years of intensive effort, developing an HIV-1 vaccine has proven to be one of the greatest challenges in vaccinology. Only one vaccine regimen has shown modest efficacy [1], and the efficacy has so far not been reproducible elsewhere [2]. Catalyzed by advancements in immunogen design, sequencing, and structural analyses, the field's attention has shifted to development of a multifocal broadly neutralizing antibody (bnAb) vaccine, and there is a growing pipeline of candidate products. The HIV Vaccine Trials Network (HVTN) has developed the Discovery Medicine Program to evaluate bnAb-inducing vaccine candidates efficiently and systematically, emphasizing streamlined processes for rapid vaccine design iteration.Approximately 30% of persons living with chronic HIV-1 infection develop bnAbs, often with unique features such as long heavy chain complementary determining regions (HCDR3 s), high levels of somatic hypermutation (SHM), insertions and deletions, and rare and improbable mutations [3-18]. Six known epitope regions on the HIV-1 envelope (Env) are susceptible to bnAb development, some with very high breadth and potency: CD4+-binding site (CD4bs), V2 apex, V3 glycan, gp120-gp41 interface, fusion peptide, and the membrane proximal external region (MPER) [1,3,19,20]. However, their naive B cell precursors can be extremely rare. Fortunately, the recent landmark eOD-GT8 study showed that, with the right immunogen, rare germline precursors [21,22] can be activated to induce first-step VRC01-class bnAbs in nearly all trial participants [23]. In addition, the Antibody Mediated Prevention (AMP) trials showed that passive infusion of a potent antibody like VRC01 is protective against HIV-1 strains that are neutralization-sensitive to VRC01 [24]. These results, together with the extraordinary success of the COVID-19 mRNA vaccines and improvements in immunogen design, have led to renewed enthusiasm for the development of HIV-1 neutralizing vaccines. no caption availablePurpose of reviewIn the past two decades, there has been an explosion in the discovery of HIV-1 broadly neutralizing antibodies (bnAbs) and associated vaccine strategies to induce them. This abundance of approaches necessitates a system that accurately and expeditiously identifies the most promising regimens. We herein briefly review the background science of bnAbs, provide a description of the first round of phase 1 discovery medicine studies, and suggest an approach to integrate these into a comprehensive HIV-1-neutralizing vaccine.With recent preclinical success including induction of early stage bnAbs in mouse knockin models and rhesus macaques, successful priming of VRC01-class bnAbs with eOD-GT8 in a recent study in humans, and proof-of-concept that intravenous infusion of VRC01 prevents sexual transmission of virus in humans, the stage is set for a broad and comprehensive bnAb vaccine program. Leveraging significant advances in protein nanoparticle science, mRNA technology, adjuvant development, and B-cell and antibody analyses, the HVTN has reconfigured its HIV-1 vaccine strategy by developing the Discovery Medicine Program to test promising vaccine candidates targeting six key epitopes.The HVTN Discovery Medicine program is testing multiple HIV-1-neutralizing vaccine candidates.Papers of particular interest, published within the annual period of review, have been highlighted as:Despite over 20 years of intensive effort, developing an HIV-1 vaccine has proven to be one of the greatest challenges in vaccinology. Only one vaccine regimen has shown modest efficacy [1], and the efficacy has so far not been reproducible elsewhere [2]. Catalyzed by advancements in immunogen design, sequencing, and structural analyses, the field's attention has shifted to development of a multifocal broadly neutralizing antibody (bnAb) vaccine, and there is a growing pipeline of candidate products. The HIV Vaccine Trials Network (HVTN) has developed the Discovery Medicine Program to evaluate bnAb-inducing vaccine candidates efficiently and systematically, emphasizing streamlined processes for rapid vaccine design iteration.Approximately 30% of persons living with chronic HIV-1 infection develop bnAbs, often with unique features such as long heavy chain complementary determining regions (HCDR3 s), high levels of somatic hypermutation (SHM), insertions and deletions, and rare and improbable mutations [3-18]. Six known epitope regions on the HIV-1 envelope (Env) are susceptible to bnAb development, some with very high breadth and potency: CD4+-binding site (CD4bs), V2 apex, V3 glycan, gp120-gp41 interface, fusion peptide, and the membrane proximal external region (MPER) [1,3,19,20]. However, their naive B cell precursors can be extremely rare. Fortunately, the recent landmark eOD-GT8 study showed that, with the right immunogen, rare germline precursors [21,22] can be activated to induce first-step VRC01-class bnAbs in nearly all trial participants [23]. In addition, the Antibody Mediated Prevention (AMP) trials showed that passive infusion of a potent antibody like VRC01 is protective against HIV-1 strains that are neutralization-sensitive to VRC01 [24]. These results, together with the extraordinary success of the COVID-19 mRNA vaccines and improvements in immunogen design, have led to renewed enthusiasm for the development of HIV-1 neutralizing vaccines. no caption availablePurpose of reviewIn the past two decades, there has been an explosion in the discovery of HIV-1 broadly neutralizing antibodies (bnAbs) and associated vaccine strategies to induce them. This abundance of approaches necessitates a system that accurately and expeditiously identifies the most promising regimens. We herein briefly review the background science of bnAbs, provide a description of the first round of phase 1 discovery medicine studies, and suggest an approach to integrate these into a comprehensive HIV-1-neutralizing vaccine.With recent preclinical success including induction of early stage bnAbs in mouse knockin models and rhesus macaques, successful priming of VRC01-class bnAbs with eOD-GT8 in a recent study in humans, and proof-of-concept that intravenous infusion of VRC01 prevents sexual transmission of virus in humans, the stage is set for a broad and comprehensive bnAb vaccine program. Leveraging significant advances in protein nanoparticle science, mRNA technology, adjuvant development, and B-cell and antibody analyses, the HVTN has reconfigured its HIV-1 vaccine strategy by developing the Discovery Medicine Program to test promising vaccine candidates targeting six key epitopes.The HVTN Discovery Medicine program is testing multiple HIV-1-neutralizing vaccine candidates.Papers of particular interest, published within the annual period of review, have been highlighted as:Despite over 20 years of intensive effort, developing an HIV-1 vaccine has proven to be one of the greatest challenges in vaccinology. Only one vaccine regimen has shown modest efficacy [1], and the efficacy has so far not been reproducible elsewhere [2]. Catalyzed by advancements in immunogen design, sequencing, and structural analyses, the field's attention has shifted to development of a multifocal broadly neutralizing antibody (bnAb) vaccine, and there is a growing pipeline of candidate products. The HIV Vaccine Trials Network (HVTN) has developed the Discovery Medicine Program to evaluate bnAb-inducing vaccine candidates efficiently and systematically, emphasizing streamlined processes for rapid vaccine design iteration.Approximately 30% of persons living with chronic HIV-1 infection develop bnAbs, often with unique features such as long heavy chain complementary determining regions (HCDR3 s), high levels of somatic hypermutation (SHM), insertions and deletions, and rare and improbable mutations [3-18]. Six known epitope regions on the HIV-1 envelope (Env) are susceptible to bnAb development, some with very high breadth and potency: CD4+-binding site (CD4bs), V2 apex, V3 glycan, gp120-gp41 interface, fusion peptide, and the membrane proximal external region (MPER) [1,3,19,20]. However, their naive B cell precursors can be extremely rare. Fortunately, the recent landmark eOD-GT8 study showed that, with the right immunogen, rare germline precursors [21,22] can be activated to induce first-step VRC01-class bnAbs in nearly all trial participants [23]. In addition, the Antibody Mediated Prevention (AMP) trials showed that passive infusion of a potent antibody like VRC01 is protective against HIV-1 strains that are neutralization-sensitive to VRC01 [24]. These results, together with the extraordinary success of the COVID-19 mRNA vaccines and improvements in immunogen design, have led to renewed enthusiasm for the development of HIV-1 neutralizing vaccines. no caption available