Key Amino Acid Substitution for Infection-Enhancing Activity-Free Designer Dengue Vaccines

Dengue is a globally important disease caused by four serotypes of dengue virus. Dengue vaccine development has been hampered by antigenic cross-reactivity among serotypes, which potentially causes antibody-dependent enhancement of infection and disease severity. Here we found that a single amino acid substitution in the envelope protein at position 87 from aspartic acid to asparagine or at position 107 from leucine to phenylalanine is critical for suppressing the induction of infection-enhancing antibody in a mouse model. The site and type of amino acid substitution were determined via neutralization escape using an enhancing-activity-only monoclonal antibody that was engineered to reveal neutralizing activity. Mutated dengue type 1 DNA vaccines containing either or both amino acid substitutions induced neutralizing antibodies devoid of enhancing activity against all serotypes. The effect of substitution was further demonstrated using other serotypes and a tetravalent formulation. This finding may contribute to the development of infection-enhancing-activity-free dengue vaccines.