Dengue is a major public health concern in the tropical and subtropical world, with no effective treatment. The controversial live attenuated virus vaccine Dengvaxia has boosted the pursuit of subunit vaccine approaches, and nonstructural protein 1 (NS1) has recently emerged as a promising candidate. However, we found that NS1 immunization or passive transfer of NS1 antibodies failed to confer protection in symptomatic dengue mouse models using two non–mouse-adapted DENV2 strains that are highly virulent. Exogenous administration of purified NS1 also failed to worsen in vivo vascular leakage in sublethally infected mice. Neither method of NS1 immune neutralization changed the disease outcome of a chimeric strain expressing a vascular leak-potent NS1. Instead, virus chimerization involving the prME structural region indicated that these proteins play a critical role in driving in vivo fitness and virulence of the virus, through induction of key proinflammatory cytokines. This work highlights that the pathogenic role of NS1 is DENV strain dependent, which warrants reevaluation of NS1 as a universal dengue vaccine candidate.

Dengue is a major public health concern in the tropical and sub-tropical world with no effective treatment. The controversial live attenuated virus vaccine Dengvaxia has boosted the pursuit of sub-unit vaccine approaches, and the non-structural protein 1 (NS1) has recently emerged as a promising candidate. However, we found that NS1 immunization or passive transfer of NS1 antibodies failed to confer protection in symptomatic dengue mouse models using two non mouse-adapted DENV2 strains from the Cosmopolitan genotype that currently circulates in South-East Asia. Furthermore, exogenous administration of purified NS1 did not worsen in vivo vascular leakage in sub-lethally infected mice, thereby supporting that NS1 does not play a critical role in the pathogenesis of these DENV2 strains. Virus chimerization approaches indicated that the prME structural region, but not NS1, plays a critical role in driving in vivo fitness and virulence of the virus, through induction of key pro-inflammatory cytokines. This work highlights that the pathogenic role of NS1 is DENV strain-dependent, which warrants re-evaluation of NS1 as a universal dengue vaccine candidate.

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