Vesicular Stomatitis Virus and DNA Vaccines Expressing Zika Virus Nonstructural Protein 1 Induce Substantial but Not Sterilizing Protection against Zika Virus Infection

Abstract

The nonstructural protein 1 (NS1) of several flaviviruses, including West Nile, dengue, and yellow fever viruses, is capable of inducing variable degrees of protection against flavivirus infection in animal models. However, the immunogenicity of NS1 protein of Zika virus (ZIKV) is less understood. Here, we determined the efficacy of ZIKV NS1-based vaccine candidates using two delivery platforms, methyltransferase-defective recombinant vesicular stomatitis virus (mtdVSV) and a DNA vaccine. We first show that expression of ZIKV NS1 could be significantly enhanced by optimizing the signal peptide. A single dose of mtdVSV-NS1-based vaccine or two doses of DNA vaccine induced high levels of NS1-specfic antibody and T cell immune responses but provided only partial protection against ZIKV viremia in BALB/c mice. In Ifnar1-/- mice, neither NS1-based vaccine provided protection against a lethal high dose (105 PFU) ZIKV challenge, but mtdVSV-NS1-based vaccine prevented deaths from a low dose (103 PFU) challenge, though they experienced viremia and body weight loss. We conclude that ZIKV NS1 alone conferred substantial, but not complete, protection against ZIKV infection. Nevertheless, these results highlight the value of ZIKV NS1 for vaccine development. Importance Most Zika virus (ZIKV) vaccine research has focused on the E or prM-E proteins and the induction of high levels of neutralizing antibodies. However, these ZIKV neutralizing antibodies cross react with other flaviviruses, which may aggravate the disease via an Antibody Dependent Enhancement (ADE) mechanism. ZIKV NS1 protein may be an alternative antigen for vaccine development, as antibodies to NS1 do not bind to the virion, thereby eliminating the risk of ADE. Here we show that recombinant VSV and DNA vaccines expressing NS1, alone, confer partial protection against ZIKV infection in both immunocompetent and immunodeficient mice, highlighting the value of NS1 as a potential vaccine candidate.

Flavivirus NS1 and Its Potential in Vaccine Development

“…When this vaccine was administered by the IM route to Ifnar −/− (interferon-αβ receptor knockout) mice, with boosting two and five weeks later, four/five mice developed high levels of NS1-specific antibodies. However, all of the mice developed severe disease after a 10 5 PFU ZIKV challenge [107]. Additional studies suggest an NS1 DNA vaccine can confer protection against ZIKV infection in BALB/c mice as long as NS1 is effectively secreted.…”

“…In contrast, intranasal inoculation of the rVSV vaccine expressing only NS1 induced high levels of anti-NS1 antibodies, a T-cell response, and partial protection against ZIKV viremia in BALB/c mice. The vaccine given by the IM route did not protect Ifnar1 -/mice against a 10 5 PFU ZIKV challenge, while a 10 3 PFU challenge caused viremia and weight loss [107]. Alternatively, a ZIKV-NS1 vaccine was generated using a modified vaccinia Ankara (MVA) vector and was able to protect 100% of IM-vaccinated CD-1/ICR mice from IC challenge [116].…”

A Methyltransferase-Defective Vesicular Stomatitis Virus-Based SARS-CoV-2 Vaccine Candidate Provides Complete Protection against SARS-CoV-2 Infection in Hamsters

“…Thus, a single mutation (such as D1762A) in the MTase catalytic site abolished both G-N-7 and 29-O methylations (28,36). Previously, we showed that rVSV-D1762A is the most attenuated virus among all the mtdVSVs (26), and the rVSV-D1762A backbone has been recently used as a vector to deliver Zika virus antigen (37). Functionally, G-N-7 methylation is essential for mRNA stability and viral protein translation, whereas 29-O methylation serves as a molecular signature for host innate immunity to discriminate self from nonself RNA (27,38).…”

Vesicular Stomatitis Virus: From Agricultural Pathogen to Vaccine Vector

“…Methyltransferase defective (mtd) rVSVs expressing either the ZIKV pre-membrane protein (mtdVSV-ZIKVprM) or the pre-membrane protein, in addition to the envelope and non-structural 1 (NS1) proteins (mtdVSV-ZIKVprM-E-NS1), were able to elicit potent humoral and cellular immune responses and protect BALB/c and A129 mice from disease associated with ZIKV challenge. Interestingly, a vaccine expressing only NS1, mtdVSV-ZIKVNS1, was able to partially protect A129 and IFNAR -/- mice from ZIKV challenge, likely owing to a robust T cell response since a neutralizing antibody response was absent [ 131 , 132 ].…”