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

Area of Science:

• Virology
• Vaccinology
• Structural Biology

Background:

• Measles virus (MeV) causes significant morbidity and mortality, especially in under-vaccinated populations.
• Current live-attenuated vaccines primarily target the hemagglutinin (H) glycoprotein, with a weaker response to the fusion (F) protein.
• The F protein is crucial for MeV entry into host cells.

Purpose of the Study:

• To engineer and characterize stabilized, prefusion MeV F protein antigens to enhance immunogenicity.
• To compare the immunogenicity and protective efficacy of soluble ectodomain (F_ECTO) and full-length (F_FL) F protein constructs.
• To evaluate the potential of these antigens as next-generation, non-replicating measles vaccines.

Main Methods:

• Engineered stabilized F_ECTO and F_FL constructs with mutations for thermal stability.
• Utilized cryo-electron microscopy to confirm prefusion conformation of engineered antigens.
• Assessed immunogenicity and protective efficacy in a cotton rat model following immunization and viral challenge.

Main Results:

• Engineered F_ECTO and F_FL constructs maintained native prefusion conformation.
• Immunization with both F_ECTO and F_FL induced neutralizing antibodies and protection against MeV challenge.
• The most stable full-length construct (F_FL 3M) showed a more potent neutralizing antibody response than its ectodomain counterpart.
• No vaccine-enhanced respiratory disease was observed.

Conclusions:

• Thermostable, full-length MeV F protein is a superior immunogen compared to its soluble ectodomain.
• These stabilized F protein antigens represent promising candidates for next-generation, non-replicating measles vaccines.
• This approach offers a safe alternative for immunocompromised individuals and those unable to receive live-virus vaccines.