Flavivirus NS1 and Its Potential in Vaccine Development

Abstract

The Flavivirus genus contains many important human pathogens, including dengue, Japanese encephalitis (JE), tick-borne encephalitis (TBE), West Nile (WN), yellow fever (YF) and Zika (ZIK) viruses. While there are effective vaccines for a few flavivirus diseases (JE, TBE and YF), the majority do not have vaccines, including WN and ZIK. The flavivirus nonstructural 1 (NS1) protein has an unusual structure–function because it is glycosylated and forms different structures to facilitate different roles intracellularly and extracellularly, including roles in the replication complex, assisting in virus assembly, and complement antagonism. It also plays a role in protective immunity through antibody-mediated cellular cytotoxicity, and anti-NS1 antibodies elicit passive protection in animal models against a virus challenge. Historically, NS1 has been used as a diagnostic marker for the flavivirus infection due to its complement fixing properties and specificity. Its role in disease pathogenesis, and the strong humoral immune response resulting from infection, makes NS1 an excellent target for inclusion in candidate flavivirus vaccines.

Secreted dengue virus NS1 from infection is predominantly dimeric and in complex with high-density lipoprotein

“…Mature NS1 is 352 amino acids long with an apparent molecular mass between 40 – 50 kDa depending on its glycosylation state at asparagine residues 130 and 207 for the majority of flaviviruses ( 4 ). All flavivirus NS1 species contain 12 conserved cysteine residues that form six intra-chain disulphide bonds, two at the N-terminus and four at the C-terminus, that are crucial for non-covalent dimer formation which remain stable to reduction but are heat-labile ( 5 ).…”

CryoEM structures of the multimeric secreted NS1, a major factor for dengue hemorrhagic fever

“…NS1 is secreted alongside dengue virus particles during an infection. It is a multifunctional protein which exists in different oligomeric forms intracellularly and extracellularly 5 , and they play distinctly different roles. The intracellular NS1 (iNS1), exists as membrane associated dimeric form and is a part of the viral replication complex.…”

Cross-reactive antibodies targeting surface-exposed non-structural protein 1 (NS1) of dengue virus-infected cells recognize epitopes on the spaghetti loop of the β-ladder domain

“…One aspect of this work is to define DENV NS1 epitopes targeted by DENV cross-reactive anti-NS1 antibodies derived from B-cell repertoires of dengue patients. Prior studies have identified several immunodominant epitopes located on the wing and C-terminal half of the β-ladder domains [ 37 ]. Biering et.al.…”

“…The functional basis of these domains is not thoroughly understood and target epitopes for antibody-mediated protection are not comprehensive. To date, several NS1 epitopes have been identified from naturally infected humans and immunized mice [ 36 , 37 ], but the functions of only a few have been demonstrated. Immuno-dominant regions of the NS1 protein associated with cell binding have been identified solely on the wing and the C-terminal end of the β-ladder domains [ 33 , 38 ].…”