mRNA-1644 / IAVI, Moderna - LARVOL DELTA

Simultaneous priming of HIV broadly neutralizing antibody precursors to multiple epitopes by germline-targeting mRNA-LNP immunogens in mouse models. (PubMed, Sci Immunol) - "Simultaneous delivery of immunogens encoded by mRNA-LNPs, however, drove maturation across different precursor frequencies and immunogen doses. Furthermore, administration of a cocktail of mRNA-LNP immunogens (N332-GT5 gp151, ApexGT5 gp151, eOD-GT8 60mer, and 10E8-GT12 24mer) led to balanced activation of four distinct bnAb precursor classes, indicating that multiepitope HIV bnAb precursor priming might be successfully implemented in humans but might be immunogen dependent."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease

Structural insights into VRC01-class bnAb precursors with diverse light chains elicited in the IAVI G001 human vaccine trial. (PubMed, Proc Natl Acad Sci U S A) - "Here, we report on structural characterization of vaccine-elicited VRC01-class bnAb precursors in the IAVI G001 Phase 1 clinical trial with the eOD-GT8 60mer nanoparticle as immunogen. The structures highlight how germline-encoded features drive bnAb-like recognition at early stages. This work provides molecular evidence supporting germline targeting in humans and provides guidance for designing booster immunogens to shepherd affinity maturation toward broad neutralization."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Structural insights into VRC01-class bnAb precursors with diverse light chains elicited in the IAVI G001 human vaccine trial. (PubMed, bioRxiv) - "Here, we report on structural characterization of vaccine-elicited VRC01-class bnAb precursors in the IAVI G001 Phase 1 clinical trial with the eOD-GT8 60mer nanoparticle as immunogen. The structures highlight how germline-encoded features drive bnAb-like recognition at early stages. This work provides molecular evidence supporting germline-targeting in humans and provides guidance for designing booster immunogens to shepherd affinity maturation toward broad neutralization."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Safety and Immunogenicity of mRNAs Encoding HIV Immunogens (eOD-GT8 60mer, Core-g28v2 60mer, N332-GT5 gp151) in Adult Participants Without HIV and in Overall Good Health in South Africa (HVTN 317) (clinicaltrials.gov) - P1 | N=96 | Not yet recruiting | Sponsor: HIV Vaccine Trials Network | Initiation date: Feb 2025 ➔ Sep 2025

Trial initiation date • Human Immunodeficiency Virus • Infectious Disease

Safety and Immunogenicity of MRNAs Encoding HIV Immunogens (eOD-GT8 60mer, Core-g28v2 60mer, N332-GT5 Gp151) in Adult Participants Without HIV and in Overall Good Health in South Africa (HVTN 317) (clinicaltrials.gov) - P1 | N=96 | Not yet recruiting | Sponsor: HIV Vaccine Trials Network

New P1 trial • Human Immunodeficiency Virus • Infectious Disease

Breaking new ground: exploring volunteer acceptance of sampling techniques in IAVI-G003 (HIVR4P 2024) - "Our study, within the IAVI G003 trial, a Phase 1 study evaluating the safety and immunogenicity of the eOD-GT8 60mer mRNA vaccine (mRNA-1644), sought to explore participants' perceptions of non-conventional sampling techniques in Rwanda and South Africa... The study highlights the necessity for increased clinical trial literacy, particularly concerning non-conventional sampling techniques within research communities in Africa. Our work underscores the importance of developing tailored interventions and communication strategies to better manage participant expectations and experiences in trials involving non-conventional sampling techniques."

Mood Disorders • Pain • Psychiatry

Use of Transient Transfection for cGMP Manufacturing of eOD-GT8 60mer, a Self-Assembling Nanoparticle Germline-Targeting HIV-1 Vaccine Candidate. (PubMed, Pharmaceutics) - P1 | "The cGMP clinical trial material was tested in a Phase 1 clinical trial (NCT03547245), is currently being stored at -80 °C, and is on a stability testing program as per regulatory guidelines. The methods described here illustrate the utility of transient transfection for cGMP production of complex products such as glycosylated self-assembling nanoparticles."

Journal • Human Immunodeficiency Virus • Infectious Disease

mRNA-LNP prime boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models. (PubMed, Sci Immunol) - "Here, we preclinically validated a lipid nanoparticle-encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 60mer as a soluble self-assembling nanoparticle in mouse models. Boosts drove precursor B cell participation in germinal centers; the accumulation of somatic hypermutations, including in key VRC01-class positions; and affinity maturation to boost and native-like antigens in two of the three precursor lineages. We have preclinically validated a prime-boost regimen of soluble self-assembling nanoparticles encoded by mRNA-LNP, demonstrating that multiple lineages can be primed, boosted, and diversified along the bnAb pathway."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease • CD4

Heterologous prime-boost vaccination drives early maturation of HIV broadly neutralizing antibody precursors in humanized mice. (PubMed, Sci Transl Med) - "Vaccination with the germline-targeting immunogen eOD-GT8 60mer adjuvanted with AS01B was found to induce VRC01-class bnAb precursors in 97% of vaccine recipients in the IAVI G001 phase 1 clinical trial; however, heterologous boost immunizations with antigens more similar to the native glycoprotein will be required to induce bnAbs. We further showed that VRC01-class antibodies induced by mRNA-based regimens could neutralize pseudoviruses lacking the N276 glycan. These results demonstrated that heterologous boosting can drive maturation toward VRC01-class bnAb development and supported the initiation of the IAVI G002 phase 1 trial testing mRNA-encoded nanoparticle prime-boost regimens."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease

A Phase 1 Study to Evaluate the Safety and Immunogenicity of eOD-GT8 60mer mRNA Vaccine (mRNA-1644) and Core-g28v2 60mer mRNA Vaccine (mRNA-1644v2-Core) (clinicaltrials.gov) - P1 | N=56 | Active, not recruiting | Sponsor: International AIDS Vaccine Initiative | Trial completion date: Jul 2023 ➔ Jul 2024

Trial completion date • Human Immunodeficiency Virus • Infectious Disease • CD4

Human immunoglobulin gene allelic variation impacts germline-targeting vaccine priming. (PubMed, NPJ Vaccines) - "In a clinical trial of the eOD-GT8 60mer germline-targeting immunogen, higher frequencies of vaccine-induced VRC01-class bnAb-precursor B cells were observed in the high dose compared to the low dose group. Through immunoglobulin heavy chain variable (IGHV) genotyping, statistical modeling, quantification of IGHV1-2 allele usage and B cell frequencies in the naive repertoire for each trial participant, and antibody affinity analyses, we found that the difference between dose groups in VRC01-class response frequency was best explained by IGHV1-2 genotype rather than dose and was most likely due to differences in IGHV1-2 B cell frequencies for different genotypes. The results demonstrate the need to define population-level immunoglobulin allelic variations when designing germline-targeting immunogens and evaluating them in clinical trials."

Journal • IGH

Humanized V(D)J-rearranging and TdT-expressing mouse vaccine models with physiological HIV-1 broadly neutralizing antibody precursors. (PubMed, Proc Natl Acad Sci U S A) - "Priming immunization with eOD-GT8 60mer, which strongly engages VRC01 precursors, induced robust VRC01-class germinal center B cell responses...VRC01-class-rearranging models should facilitate further evaluation of VRC01-class prime and boost immunogens. These new VRC01-class mouse models establish a prototype for the generation of vaccine-testing mouse models for other HIV-1 bnAb lineages that employ different HC or LC Vs."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease • CD4

Vaccination induces HIV broadly neutralizing antibody precursors in humans. (PubMed, Science) - "In a randomized, double-blind, placebo-controlled phase 1 clinical trial, the HIV vaccine-priming candidate eOD-GT8 60mer adjuvanted with AS01 had a favorable safety profile and induced VRC01-class bnAb precursors in 97% of vaccine recipients with median frequencies reaching 0.1% among immunoglobulin G B cells in blood. bnAb precursors shared properties with bnAbs and gained somatic hypermutation and affinity with the boost. The results establish clinical proof of concept for germline-targeting vaccine priming, support development of boosting regimens to induce bnAbs, and encourage application of the germline-targeting strategy to other targets in HIV and other pathogens."

Clinical • Journal • Human Immunodeficiency Virus • Infectious Disease

A Phase 1 Study to Evaluate the Safety and Immunogenicity of eOD-GT8 60mer mRNA Vaccine (mRNA-1644) and Core-g28v2 60mer mRNA Vaccine (mRNA-1644v2-Core) (clinicaltrials.gov) - P1 | N=56 | Active, not recruiting | Sponsor: International AIDS Vaccine Initiative | Recruiting ➔ Active, not recruiting

Enrollment closed • Human Immunodeficiency Virus • Infectious Disease

A Study to Evaluate the Safety and Immunogenicity of eOD-GT8 60mer mRNA Vaccine (mRNA-1644) (clinicaltrials.gov) - P1 | N=20 | Active, not recruiting | Sponsor: International AIDS Vaccine Initiative | Recruiting ➔ Active, not recruiting

Enrollment closed • Human Immunodeficiency Virus • Infectious Disease

A Study to Evaluate the Safety and Immunogenicity of eOD-GT8 60mer mRNA Vaccine (mRNA-1644) (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: International AIDS Vaccine Initiative

New P1 trial • Human Immunodeficiency Virus • Infectious Disease

A Phase I Trial to Evaluate the Safety and Immunogenicity of eOD-GT8 60mer Vaccine, Adjuvanted (clinicaltrials.gov) - P1 | N=46 | Completed | Sponsor: International AIDS Vaccine Initiative | Active, not recruiting ➔ Completed | Trial completion date: Nov 2021 ➔ Aug 2021

Trial completion • Trial completion date • Human Immunodeficiency Virus • Infectious Disease

A Phase 1 Study to Evaluate the Safety and Immunogenicity of eOD-GT8 60mer mRNA Vaccine (mRNA-1644) and Core-g28v2 60mer mRNA Vaccine (mRNA-1644v2-Core) (clinicaltrials.gov) - P1; N=56; Recruiting; Sponsor: International AIDS Vaccine Initiative; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Human Immunodeficiency Virus • Infectious Disease

A Phase I Trial to Evaluate the Safety and Immunogenicity of eOD-GT8 60mer Vaccine, Adjuvanted (clinicaltrials.gov) - P1; N=48; Active, not recruiting; Sponsor: International AIDS Vaccine Initiative; Trial completion date: Dec 2020 ➔ Nov 2021

Clinical • Trial completion date • Human Immunodeficiency Virus • Infectious Disease

A Phase 1 Study to Evaluate the Safety and Immunogenicity of eOD-GT8 60mer mRNA Vaccine (mRNA-1644) and Core-g28v2 60mer mRNA Vaccine (mRNA-1644v2-Core) (clinicaltrials.gov) - P1; N=56; Not yet recruiting; Sponsor: International AIDS Vaccine Initiative

New P1 trial • Human Immunodeficiency Virus • Infectious Disease

[VIRTUAL] Vaccination induces maturation of diverse unmutated VRC01-class precursors to HIV-1 broadly neutralizing antibodies in an Ig-humanized mouse model (HIVR4P 2021) - "Overall, our study provides proof-of-concept for the induction of VRC01-class bnAbs of greater than 50%-neutralization breadth by sequential immunization, succeeds in eliciting antibodies capable of recognizing glycan276-bearing strains, and uses longitudinal analysis to pinpoint the development of specific SHM in response to specific immunogens."

Preclinical • Human Immunodeficiency Virus • Infectious Disease • CD4

Multiplexed CRISPR/CAS9-mediated engineering of pre-clinical mouse models bearing native human B cell receptors. (PubMed, EMBO J) - "We demonstrate that B cells from these mice are fully functional: upon transfer to congenic, wild type mice at controlled frequencies, such B cells can be primed by eOD-GT8 60mer, a germline-targeting immunogen currently in clinical trials, recruited to germinal centers, secrete class-switched antibodies, undergo somatic hypermutation, and differentiate into memory B cells. KI mice expressing functional human BCRs promise to accelerate the development of vaccines for HIV and other infectious diseases."

Journal • Human Immunodeficiency Virus • Immunology • Infectious Disease

B cells expressing authentic naive human VRC01-class BCRs can be recruited to germinal centers and affinity mature in multiple independent mouse models. (PubMed, Proc Natl Acad Sci U S A) - "The germline-targeting HIV immunogen eOD-GT8 60mer is currently in clinical trial as a candidate bnAb vaccine priming immunogen. Precursor frequency and affinity interdependently influenced responses. Taken together, these experiments utilizing authentic naive human VRC01-class BCRs validate a central tenet of germline-targeting vaccine design and extend the overall concept of the reverse vaccinology approach to vaccine development."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease

A Phase I Trial to Evaluate the Safety and Immunogenicity of eOD-GT8 60mer Vaccine, Adjuvanted (clinicaltrials.gov) - P1; N=48; Active, not recruiting; Sponsor: International AIDS Vaccine Initiative; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed