Antibodies Induced by Dengue Virus Type 1 and 2 Envelope Domain III Recombinant Proteins in Monkeys Neutralize Strains with Different Genotypes

Abstract

In the present work, we evaluated the neutralizing capacity of the antibodies induced by dengue virus type 1 and 2 envelope domain III recombinant proteins in monkeys against strains of different dengue virus type 1 and 2 genotypes. Here we demonstrated that dengue virus type 1 and 2 recombinant proteins induced high titers of neutralizing antibodies against different genotype strains.An effective humoral immune response is critical for protecting against dengue viruses (DEN) (12)(13)(14) and is the essential goal of recombinant subunit vaccines based on envelope (E) domain III. Domain III is thought to mediate interactions between the virus and cellular receptors involved in virus attachment (6,21). In addition, many of the most potent anti-DEN neutralizing monoclonal antibodies characterized to date recognize this domain (8, 9,24).There is some evidence that the antibody response to a DEN genotype does not necessarily neutralize homogenotypic DEN strains. In fact, sera from patients infected with DEN type 2 (DEN 2) or DEN 3 show variations in the neutralizing antibody responses against strains isolated early and late during the same epidemic (1, 26). Preclinical studies have exposed that the primary immune responses induced after infection of mice and monkeys with DEN 2 strains belonging to both Asian and American genotypes show differences in the responses of neutralizing antibodies against the same and different strains of infection (4, 5). Based on monoclonal antibody data, changes of specific amino acids in domain III result in the loss of binding of neutralizing monoclonal antibodies (11,19,24). A recent study has also demonstrated that monoclonal antibodies show differentiated neutralizing activities depending on the virulence of the strain (7). Based on the previously reported evidence (1, 4, 5, 7, 11,19,24,26), the humoral immune response induced by a vaccine candidate should be evaluated against strains of different genotypes of each serotype.Previously, we have reported that recombinant proteins containing domain III of DEN 1 or DEN 2 E proteins fused to the P64k protein from Neisseria meningitidis (PD10 and PD5, respectively) induce neutralizing antibodies and partial protection in immunized monkeys (3, 10). In the context of P64k, amino acid changes in E domain III included in the fusion protein have been involved in the antigenicity and immunogenicity of the resultant molecules in the mouse model (28). In the present work, we evaluate the neutralizing antibody activity in sera collected from Macaca fascicularis monkeys immunized with such recombinant proteins against strains of different genotypes.Sera from Macaca fascicularis monkeys previously immunized with DEN 1 or DEN 2 recombinant fusion proteins were evaluated by a plaque reduction neutralization test (PRNT) against DEN 1 or DEN 2 strains belonging to different genotypes of the corresponding serotype (Table 1) (17,23). The E domain III used for the PD10 or PD5 genetic construction belongs to strain DEN 1 Jamaica or DEN 2 Jamaica, respective...

The protein DIIIC‐2, aggregated with a specific oligodeoxynucleotide and adjuvanted in alum, protects mice and monkeys against DENV‐2

“…This suggests that the antibodies elicited after immunization with DIIIC‐2 should protect against infection with different strains of DENV‐2. Moreover, these findings are in agreement with previous results reported by our group, showing broad neutralization of different strains of DENV‐1 and DENV‐2 after incubation with sera from monkeys immunized with two domain III fusion proteins 14 , 15 …”

Dengue virus neutralization and antibody-dependent enhancement activities of human monoclonal antibodies derived from dengue patients at acute phase of secondary infection

“…including macaque monkeys, marmosets, and mice (Bernardo et al, 2009;Sukupolvi-Petty et al, 2010;Omatsu et al, 2011;Zompi and Harris, 2012), before they can be considered as therapeutic antibodies against DENV.…”

A broadly neutralizing germline-like human monoclonal antibody against dengue virus envelope domain III

“…In contrast, antibodies targeting DIII have proven to be the most potent neutralizing antibodies, but very few could be elicited in naturally infected individuals [18,19,[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. Despite this, previous studies indicated that anti-DENV DIII serotype-specific and cross-reactive antibodies could be elicited using DENV DIII as vaccine immunogen [36][37][38][39][40][41][42][43] and in infected humans [44][45][46][47]. It has also been demonstrated that the lysine at position 310 on DIII is the critical residue in the cross-reactive epitope [24].…”