Antibody Epitopes Identified in Critical Regions of Dengue Virus Nonstructural 1 Protein in Mouse Vaccination and Natural Human Infections

Abstract

Dengue is a global public health problem and is caused by four dengue virus serotypes (DENV1-4). A major challenge in dengue vaccine development is that cross-reactive anti-DENV antibodies can be protective or potentially enhance disease via antibody-dependent enhancement (ADE). DENV nonstructural protein 1 (NS1) has long been considered a vaccine candidate as it avoids ADE. Here, we evaluated survival to challenge in a lethal DENV vascular leak model in mice immunized with NS1 combined with alum, Monophosphoryl Lipid A + AddaVax (MA), or Sigma Adjuvant System + CpG DNA, compared to mice infected with a non-lethal dose of DENV2 and mice immunized with ovalbumin (negative control). We characterized antibody responses to DENV-1, -2 and -3 NS1 using an antigen microarray tiled with 20-mer peptides overlapping by 15 amino acids and identified 5 regions of DENV NS1 with significant levels of antibody reactivity in the NS1+MA group. Additionally, we profiled the antibody responses to NS1 of humans naturally infected with DENV2 or DENV3 in serum samples from Nicaragua collected at acute, convalescent and 12-month timepoints. One region in the “wing” domain of NS1 was immunodominant in both mouse vaccination and human infection studies, and two regions were identified only in NS1-immunized mice; thus, vaccination can generate antibodies to regions that are not targeted in natural infection and could provide additional protection against lethal DENV infection. Overall, we identified a small number of immunodominant regions, which were in functionally important locations on the DENV NS1 protein and are potential correlates of protection.

Efficient Delivery of Dengue Virus Subunit Vaccines to the Skin by Microprojection Arrays

“…However, their IFN-deficient status presents some caveats to the interpretation of immune responses. Nevertheless, immune responses elicited in these animal models to various vaccine formulations have previously been shown to induce some level of protection from DENV challenge [37,38]. To the best of our knowledge, the current study is the first to assess the potential of sE subunit formulations to afford protection from DENV challenge in the AG129 mouse model.…”

Highly conserved epitopes of DENV structural and non-structural proteins: Candidates for universal vaccine targets

“…Moreover, the functions of these proteins can be used as an asset for controlling the effect of the virus on the host. For instance, NS1 is an important cofactor for the formation of replication complex, and has also been exploited for the development of vaccine (Mackenzie et al, 1996;Hertz et al, 2017) whereas NS4B regulates the helicase activity of NS3 and NS4A-NS4B complex is required for genome replication (Miller et al, 2006;Umareddy et al, 2006). NS5 is the most conserved protein of DENV and its C-terminal containing RdRp (RNA dependent RNA polymerase) domain is crucial for genomic replication (Hannemann et al, 2013: Ashour et al, 2009.…”

“…clinical trial are the live attenuated viruses (Thomas et al, 2012), chimeric vaccine (Guy et al, 2015), recombinant vaccine with adjuvants (Hertz et al, 2017), reverse vaccinology (Baliga et al, 2018), purified and inactivated virions (Fernandez et al, 2015), subunit proteins and plasmid DNA (Thisyakorn and Thisyakorn, 2014). Among these, live attenuated DENGVAXIA or CYD-TDV, a tetravalent chimeric dengue vaccine (Scott, 2016), developed by Sanofi Pasteur in December 2015, is the first licensed vaccine in some Asian and Latin American countries (Pitisuttithum and Bouckenooghe, 2016;Flaschw et al, 2016).…”

Antibody-Dependent Enhancement of Viral Infections

“…DENV EDIII induces predominantly neutralizing antibodies, thus making recombinant EDIII an attractive subunit vaccine candidate (Gil et al 2017;Frei et al 2018). DENV NS1 has also been considered as a vaccine candidate as it avoids ADE (Hertz et al 2017). Chimeric DENV constructs with pr gene replaced with Japanese Encephalitis virus pr and DNA vaccines with substitutions or removal of enhancing epitopes have demonstrated reduction in ADE (Crill et al 2012;Tang et al 2015;Wang et al 2015).…”