Zika virus is a mosquito-borne flavivirus which can cause severe disease in humans, including
microcephaly and other congenital malformations in newborns and
Guillain-Barré syndrome in adults. There are currently no approved prophylactics or
therapeutics for Zika virus; the development of a safe and effective
vaccine is an urgent priority. Preclinical studies suggest that the envelope
glycoprotein can elicit potently
neutralizing antibodies. However, such
antibodies are implicated in the phenomenon of antibody-dependent enhancement of disease. We have previously shown that
monoclonal antibodies targeting the Zika virus nonstructural NS1
protein are protective without inducing antibody-dependent enhancement of disease. Here, we investigated whether the NS1
protein itself is a viable
vaccine target. Wild-type mice were vaccinated with an NS1-expressing
DNA plasmid followed by two adjuvanted
protein boosters, which elicited high antibody titers. Passive transfer of the
immune sera was able to significantly protect STAT2 knockout mice against lethal challenge by Zika virus. In addition, long-lasting NS1-specific
IgG responses were detected in serum samples from patients in either the acute or the convalescent phase of
Zika virus infection. These NS1-specific
antibodies were able to functionally engage Fcγ receptors. In contrast, envelope-specific
antibodies did not activate Fc-mediated effector functions on infected cells. Our data suggest that the
Zika virus NS1 protein, which is expressed on infected cells, is critical for Fc-dependent cell-mediated immunity. The present study demonstrates that the
Zika virus NS1 protein is highly immunogenic and can elicit protective
antibodies, underscoring its potential for an effective Zika virus
vaccine.IMPORTANCE Zika virus is a global public health threat that causes
microcephaly and congenital malformations in newborns and
Guillain-Barré syndrome in adults. Currently, no
vaccines or treatments are available. While
antibodies targeting the envelope
glycoprotein can neutralize virus, they carry the risk of antibody-dependent enhancement of disease (ADE). In contrast,
antibodies generated against the NS1
protein can be protective without eliciting ADE. The present study demonstrates the effectiveness of an NS1-based
vaccine in eliciting high titers of protective
antibodies against
Zika virus disease in a mouse model. Sera generated by this
vaccine can elicit Fc-mediated effector functions against Zika virus-infected cells. Lastly, we provide human data suggesting that the antibody response against the
Zika virus NS1 protein is long-lasting and functionally active. Overall, our work will inform the development of a safe and effective Zika virus
vaccine.