'Mix and Match' vaccination: Is dengue next?

The severity of the COVID-19 pandemic and the development of multiple SARS-CoV-2 vaccines expedited vaccine 'mix and match' trials in humans and demonstrated the benefits of mixing vaccines that vary in formulation, strength, and immunogenicity. Heterologous sequential vaccination may be an effective approach for protecting against dengue, as this strategy would mimic the natural route to broad dengue protection and may overcome the imbalances in efficacy of the individual leading live attenuated dengue vaccines. Here we review 'mix and match' vaccination trials against SARS-CoV-2, HIV, and dengue virus and discuss the possible advantages and concerns of future heterologous immunization with the leading dengue vaccines. COVID-19 trials suggest that priming with a vaccine that induces strong cellular responses, such as an adenoviral vectored product, followed by heterologous boost may optimize T cell immunity. Moreover, heterologous vaccination may induce superior humoral immunity compared to homologous vaccination when the priming vaccine induces a narrower response than the boost. The HIV trials reported that heterologous vaccination was associated with broadened antigen responses and that the sequence of the vaccines significantly impacts the regimen's immunogenicity and efficacy. In heterologous dengue immunization trials, where at least one dose was with a live attenuated vaccine, all reported equivalent or increased immunogenicity compared to homologous boost, although one study reported increased reactogenicity. The three leading dengue vaccines have been evaluated for safety and efficacy in thousands of study participants but not in combination in heterologous dengue vaccine trials. Various heterologous regimens including different combinations and sequences should be trialed to optimize cellular and humoral immunity and the breadth of the response while limiting reactogenicity. A blossoming field dedicated to more accurate correlates of protection and enhancement will help confirm the safety and efficacy of these strategies.