Structure-guided design of a prefusion GPC trimer induces neutralizing responses against LASV

Area of Science:

• Virology
• Immunology
• Vaccine Development

Background:

• Lassa virus (LASV) causes severe hemorrhagic fever, with no approved vaccines currently available.
• The LASV precursor glycoprotein complex (GPC) is a key target for vaccine development, but eliciting effective neutralizing antibodies remains challenging.
• Existing vaccine candidates often struggle to induce robust immune responses against LASV.

Purpose of the Study:

• To design and produce a stable prefusion trimeric form of the LASV GPC antigen.
• To evaluate the immunogenicity and protective efficacy of the novel GPC antigen against Lassa fever.
• To investigate the immune response elicited by the GPC antigen.

Main Methods:

• Engineered a prefusion GPC trimer (GPCv2) by introducing proline substitution and a trimerization domain.
• Assessed GPCv2 expression, stability, and conformational epitope retention.
• Vaccinated mice with GPCv2 and challenged with LASV pseudovirus.
• Analyzed immune repertoire sequencing to compare immune responses to trimeric and monomeric antigens.

Main Results:

• The modified GPCv2 antigen formed a stable prefusion trimer with high expression levels.
• GPCv2 vaccination induced higher levels of neutralizing antibodies compared to monomeric forms.
• Mice vaccinated with GPCv2 demonstrated protection against LASV pseudovirus challenge.
• Immune repertoire sequencing revealed convergent immune clones and unique V-J pairing biases in the trimeric GPCv2 group.

Conclusions:

• The prefusion GPC trimer antigen (GPCv2) is a promising candidate for Lassa fever vaccine development.
• GPCv2 elicits a strong neutralizing antibody response and provides protection in a mouse model.
• Structural modifications leading to a stable prefusion trimer enhance vaccine efficacy against Lassa virus.