VRC-RSVRGP084-00-VP / National Institute of Allergy and Infectious Diseases - LARVOL DELTA

RSV Vaccines: Targeting Prefusion F and G Proteins from Structural Design to Clinical Application. (PubMed, Vaccines (Basel)) - " Approved vaccines such as Abrysvo and Arexvy utilize structural engineering to stabilize the prefusion conformation of the F protein (PreF), thereby exposing neutralizing epitopes. Subunit vaccine candidates such as DS-Cav1 and DT-PreF enhance stability through disulfide bonds and dityrosine linkages, while ADV110 targets the conserved domain of the G protein to elicit cross-strain immunity. Virus-like particle (VLP) vaccines like IVX-A12 combine RSV and human metapneumovirus antigens to provide broad-spectrum immunity. However, challenges exist, including maintaining PreF stability, overcoming immunosenescence in the elderly, and addressing safety concerns like Guillain-Barré syndrome (GBS). Future RSV vaccine development should center on combined PreF-G protein vaccines, VLP technology, and optimizing cold-chain logistics to improve global accessibility and overcome existing challenges, thereby providing more effective prevention and control of RSV infections."

Journal • Review • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections • CAV1

Nanoparticle vaccine based on the pre-fusion F glycoprotein of respiratory syncytial virus elicits robust protective immune responses. (PubMed, J Virol) - "Here, we conjugated either the first-generation RSV pre-fusion F antigen, DS-Cav1, or the second-generation antigen, Sc9-10, to a computationally designed nanoparticle platform, NPM, via a Catcher/Tag system...These findings suggest that this vaccine design could offer a safer and more effective way to protect infants and other at-risk populations from RSV. Additionally, the nanoparticle platform may be applicable to vaccines against other infectious diseases."

Journal • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections • CAV1

Immunofocusing Design of a Fusion Glycoprotein Monomer Vaccine for Respiratory Syncytial Virus. (PubMed, Mol Ther) - "In addition, the Q74 truncated monomer not only induced neutralizing and binding antibodies with a strength comparable to that of DS-Cav1, but also focused the immune response on antigenic site Ø and site II. In summary, we found that the RSV F protein monomer designed based on immunofocusing could induce relatively immunogenicity and immune protection, providing a design strategy for RSV vaccines."

Journal • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections • CAV1

Hydrophobic residue substitutions enhance the stability and in vivo immunogenicity of respiratory syncytial virus fusion protein. (PubMed, J Virol) - "Furthermore, pre-F-IFLP induced significantly higher neutralizing antibody responses than DS-Cav1 following both the first and second booster immunizations and conferred complete protection against RSV infection in a mouse model. These findings present an alternative approach for stabilizing the trimeric prefusion F protein, enhancing its expression, and significantly improving its protective efficacy for the prevention of RSV infection in vivo."

Journal • Preclinical • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections • CAV1

Mucosal vaccines with STING-agonist liposomal formulations inhibit RSV (respiratory syncytial virus) replication in cotton rats. (PubMed, Vaccine) - "Both NanoSTING-sc9-10 DS-CaV1 and NanoSTING-SCTM vaccines protect against viral replication at the upper (nose) and lower (lung) respiratory tract of RSV-challenged cotton rats. The ability of our mucosal vaccines against RSV to elicit immunity in the respiratory tract can prevent the establishment of infection in individuals and potentially prevent disease transmission."

Journal • Preclinical • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections • CAV1

Rational design of uncleaved prefusion-closed trimer vaccines for human respiratory syncytial virus and metapneumovirus. (PubMed, Nat Commun) - "For RSV, we assess four previous prefusion F designs, including the first and second generations of DS-Cav1, SC-TM, and 847A...In mouse immunization, rationally designed RSV-F and hMPV-F UFC trimers induce robust antibody responses with high neutralizing titers. Our study provides a foundation for future prefusion F-based RSV and hMPV vaccine development."

Journal • Respiratory Diseases • Respiratory Syncytial Virus Infections • CAV1

Mutating a flexible region of the RSV F protein can stabilize the prefusion conformation. (PubMed, Science) - "We generated a series of mutants and screened them in vitro to assess their potential for forming a stable pre-F. In animals, the immunogenicity of a representative mutant F protein, with a conformation confirmed by cryo-electron microscopy, elicited levels of neutralizing antibodies and protection against RSV-induced lung damage that were comparable to those of DS-Cav1, a pre-F used in a licensed vaccine."

Journal • Respiratory Diseases • Respiratory Syncytial Virus Infections • CAV1

Development and Validation of an Enzyme-Linked Immunosorbent Assay-Based Protocol for Evaluation of Respiratory Syncytial Virus Vaccines. (PubMed, Viruses) - "Further, both antigens showed high precision (coefficient of variation < 15%). Inhibition ELISA revealed cross-reactivity of antibodies against DS-Cav1 and SC-TM, but not with the attachment (G) protein."

Journal • Respiratory Diseases • Respiratory Syncytial Virus Infections • CAV1

Age-Stratified Seroprevalence of Respiratory Syncytial Virus: Analysis Using Prefusion F and G Protein Antibodies. (PubMed, Vaccines (Basel)) - "Seroprevalence was estimated using enzyme-linked immunosorbent assays targeting two stabilized prefusion F (preF; DS-Cav1 and SC-TM) and G proteins...There was a remarkable difference in age-stratified seroprevalence rates between anti-preF and anti-G protein antibodies. Given the high disease burden and low seroprevalence in both infants and old adults, RSV vaccination would be crucial for pregnant women and people aged over 60 years."

Journal • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections • CAV1

Protection Efficacy by Rsv Pre F-m2e mRNA + DS-Cav Pref Protein in Adult Balb/c (ASM Microbe 2024) - "After challenge of vaccinated mice with RSV, F1d-dcmTM mRNA-LNP and combination group with DS-Cav1 protein provided highly effective protection by clearing lung viral loads, preventing lung histopathology and inflammation and inducing balanced T cell responses, compared to those by DS-Cav1 protein vaccination. These new RSV vaccine construct and a strategy of combination vaccination might provide safer and more effective protection than current prototype RSV pre-F protein vaccination."

Clinical • Infectious Disease • Inflammation • Respiratory Diseases • Respiratory Syncytial Virus Infections • CAV1

Engineered dityrosine-bonding of the RSV prefusion F protein imparts stability and potency advantages. (PubMed, Nat Commun) - "We show that the prefusion conformation of respiratory syncytial virus fusion protein can be stabilized with two engineered dityrosine crosslinks (DT-preF), markedly improving its stability and shelf-life. Furthermore, it has 11X greater potency as compared with the DS-Cav1 stabilized prefusion F protein in immunogenicity studies and overcomes immunosenescence in mice with simply a high-dose formulation on alum."

Journal • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections • CAV1

Vaccination with prefusion-stabilized respiratory syncytial virus fusion protein elicits antibodies targeting a membrane-proximal epitope. (PubMed, J Virol) - "An antibody repertoire analysis of a human vaccine trial investigating a prefusion-stabilized RSV fusion (F) glycoprotein antigen (DS-Cav1) identified several neutralizing antibody public clonotypes (PCs) in multiple vaccine recipients...Our results reveal that these antibodies are highly potent and recognize a previously uncharacterized antigenic site on the prefusion F protein. Vaccination with prefusion RSV F proteins appears to boost the elicitation of these neutralizing antibodies, which are not commonly elicited by natural infection."

Journal • Infectious Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections • CAV1

3D- Vaxlock Technology stabilizes the prefusion conformation of the RSV F protein resulting in a highly potent and stable subunit vaccine candidate (IVC-MG 2023) - "Dityrosine crosslinked prefusion F protein (DT-preF) maintained the prefusion conformation for 5 weeks at 4 ºC and improved shelf life in an immunogenicity experiment compared to DS-Cav1 (a traditionally stabilized prefusion F protein). DT-preF also demonstrated 9-fold higher nAbs as compared to DS-Cav1 in a mouse immunogenicity study, complete protection in cotton rats, and overcame immunosenescence in aged mice with a high dose formulation on alum."

Infectious Disease • Respiratory Syncytial Virus Infections • CAV1

Rational Design of a Highly Immunogenic Prefusion-Stabilized F Glycoprotein Antigen for a Respiratory Syncytial Virus Vaccine. (PubMed, Sci Transl Med) - "No RSV vaccine is currently available...Through in vitro and in vivo characterization studies, we identified F constructs that are more stable in the prefusion conformation and elicit ~10-fold higher serum neutralizing titers in cotton rats than DS-Cav1. The stabilizing mutations of the lead construct (847) were introduced onto F glycoprotein backbones of strains representing the dominant circulating genotypes of the two major RSV subgroups, A and B. Immunization of cotton rats with a bivalent vaccine formulation of these antigens conferred complete protection against RSV challenge, with no evidence of disease enhancement. The resulting bivalent RSV prefusion F investigational vaccine has recently been shown to be efficacious against RSV disease in two pivotal phase 3 efficacy trials, one for passive protection of infants by immunization of pregnant women and the second for active protection of older adults by direct immunization."

Journal • Geriatric Disorders • Respiratory Diseases • Respiratory Syncytial Virus Infections • CAV1

A prefusion-stabilized RSV F subunit vaccine elicits B cell responses with greater breadth and potency than a postfusion F vaccine. (PubMed, Sci Transl Med) - "B cells preferentially binding the pre-F probe were activated in DS-Cav1-vaccinated participants but not in MEDI7510-vaccinated participants. Our findings emphasize the importance of using pre-F as an immunogen in humans because of its deterministic role in eliciting highly potent neutralizing antibodies and memory B cells."

Journal • Respiratory Diseases • Respiratory Syncytial Virus Infections • CAV1 • CD27