Biology subjects

Acciani, M.

Publications and source records attributed to Acciani, M..

2 recordsLinked to original sources

bioRxiv2025

Stabilized Full-Length Measles Fusion Protein Elicits Potent Immunity and Protection In Vivo

Measles virus (MeV) is a highly contagious pathogen that causes significant morbidity and mortality in populations with low vaccination coverage. Infection typically leads to immune amnesia and, in rare cases, fatal neurological disease. While current live-attenuated vaccines are highly effective, they primarily elicit neutralizing antibodies against the hemagglutinin (H) glycoprotein, with a less robust response to the fusion (F) protein, a key protein for viral entry. To improve the immunogenicity of the F protein, we designed and characterized stabilized, prefusion MeV F protein antigens. We engineered both soluble ectodomains (FECTO) and full-length, membrane-embedded proteins (FFL) with mutations that confer thermal stability. Cryo-electron microscopy confirmed that these engineered antigens faithfully maintain the native prefusion conformation. When evaluated in a cotton rat model, immunization with either FECTO or FFL constructs induced neutralizing antibodies and elicited protection against viral challenge. The most stable full-length construct (FFL 3M) elicited a more potent neutralizing antibody response than its ectodomain counterpart. Importantly, no evidence of vaccine-enhanced respiratory disease was observed. These findings establish that a thermostable, full-length F protein is a superior immunogen to its soluble ectodomain. This work presents a promising candidate for next-generation, non-replicating measles vaccines intended to complement current vaccination strategies and provide a safe option for immunocompromised individuals and others who cannot receive live-virus vaccines. One-Sentence SummaryA prefusion-stabilized, full-length measles Fusion glycoprotein immunogen induces strong neutralizing responses and offers protection against challenge with wild-type virus.

immunology↗

bioRxiv2025

Structural and Mechanistic Basis for Antibody Neutralization of the Measles Fusion Protein

Measles virus (MeV) is a highly contagious viral pathogen and remains a major global health threat. Resurgent infections, driven by insufficient vaccine coverage, waning herd immunity, and the vulnerability of immunocompromised individuals, highlight the urgent need for effective countermeasures. Monoclonal antibodies (mAbs) represent a promising strategy, both as antiviral agents and as probes of viral entry mechanisms. While most vaccine-elicited neutralizing antibodies target the hemagglutinin (H) protein, emerging evidence suggests that antibodies against the fusion (F) protein are also potent inhibitors. Still, there is insufficient information on the target sites and activities of antibodies against the F protein. Like other class I fusion proteins, MeV F exists in a metastable prefusion state that undergoes dramatic conformational changes during viral entry. Here, we selected four mAbs that recognize conformational patterns of F-prefusion and/or postfusion, characterized their epitopes, specificities, and antiviral activities. Structural analyses mapped antibody interactions onto pre- and postfusion F conformations, revealing that all three neutralizing mAbs are specific for the prefusion form, while the non-neutralizing mAb recognizes only the postfusion F. Biophysical and functional assays defined distinct mechanisms: neutralization occurs either by stabilizing the prefusion protein or by preventing the extended intermediate from completing fusion. We also describe a novel mechanism of neutralization in which an antibody prematurely triggers F activation but blocks the subsequent refolding required for viral entry. Together, these findings provide the first detailed mapping of neutralizing epitopes on the MeV F protein and establish a framework for the rational design of F-targeted intervention.

immunology↗