mRNA-LNP Vaccines Encoding for Dengue Optimized prM/ENV Proteins Induce Protective Immunity without ADE

Area of Science:

• Virology
• Immunology
• Vaccine Development

Background:

• Dengue virus (DENV) causes ~400 million infections yearly, with no approved vaccines for naive individuals.
• Four DENV serotypes (DENV 1-4) exist, complicating vaccine development due to potential antibody-dependent enhancement (ADE).
• Previous work showed a DENV-1 mRNA vaccine lacking the fusion loop (FL) protected against DENV and avoided ADE.

Purpose of the Study:

• To develop and evaluate mRNA-LNP vaccines for DENV serotypes 2, 3, and 4.
• To create a tetravalent vaccine combining monotypic DENV vaccines.
• To assess the immunogenicity, protective efficacy, and ADE potential of the tetravalent vaccine.

Main Methods:

• Designed mRNA-LNP vaccines encoding prM-E proteins for DENV 2, 3, and 4, incorporating ΔFL modifications and chimeric E proteins.
• Assessed vaccine immunogenicity and protection against lethal homotypic DENV challenge in mice.
• Formulated monotypic vaccines into a tetravalent vaccine and evaluated its performance in mice.

Main Results:

• Monovalent mRNA-LNP vaccines for DENV 2, 3, and 4 elicited serotype-specific neutralizing antibodies and protected against lethal homotypic challenge.
• Fusion loop mutation reduced ADE in vaccinated mouse sera.
• The tetravalent vaccine induced neutralizing responses against all DENV serotypes and provided protection against lethal challenges.

Conclusions:

• Monovalent DENV mRNA-LNP vaccines generate protective immunity and mitigate ADE risk.
• A first-generation ADE-altered tetravalent DENV vaccine has been developed.
• This approach offers a promising strategy for a safe and effective pan-Dengue vaccine.