Large-scale recoding of an arbovirus genome to rebalance its insect versus mammalian preference

Arboviruses (arthropod-borne viruses), a large group of RNA viruses, replicate in insects that transmit them to mammals, their second host. Insects and mammals have evolved different protein encoding strategies (codon pair bias); hence, arboviruses must delicately balance their encodings between two phyla. Using dengue virus (DENV), the most important human arbovirus pathogen, as a model, we have, by computer design and chemical synthesis, undone this balance in codon pair bias in favor of insects. Recoded DENVs grow well in insect cells but are highly attenuated in mammalian cells and in suckling mice. This unique approach offers a previously unidentified possibility to rapidly develop new vaccine candidates against DENV and perhaps against many different human arboviruses.