Antibodies play a greater role than immune cells in heterologous protection against secondary dengue virus infection in a mouse model

Abstract

The four serotypes of dengue virus (DENV1-4) are causative agents of dengue fever and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Previous DENV infection is a risk factor for DHF/DSS during subsequent infection by a different serotype. Nonetheless, most primary and secondary DENV infections are asymptomatic. To investigate the possible mechanisms of immune protection in vivo, 129/Pas mice lacking IFN-α/β and -γ receptors (AG129) were used to model secondary infection using both DENV1-DENV2 and DENV2-DENV4 sequences. At intervals between sequential infections of 4 to 52 weeks, protection against secondary heterologous DENV infection was observed. Passive transfer of DENV-immune serum was protective against replication of heterologous challenge virus in all tissues tested, whereas adoptive transfer of DENV-immune cells significantly protected mice from replication of the challenge virus only when a lower inoculum was administered. These findings are relevant for understanding both natural and vaccine-induced immunity to DENV.

Correlates of Protection Induced by Vaccination

“…Whereas neutralizing antibody clearly protects against a homologous serotype (157, 175), controversy has centered on what function gives heterologous serotype protec-tion in the face of the enhanced disease that occurs in the presence of antibody-dependent enhancement (ADE) (57). It appears from studies in a mouse model that heterotypic neutralizing antibodies do give heterotypic protection if they are present in concentrations sufficient to protect but insufficient to cause ADE (8,78,186).…”

Animal models for studying dengue pathogenesis and therapy

“…Sequential heterotypic DENV infection failed to induce enhanced viral load or mortality in AG129 mice (Kyle et al, 2008). Cross-reactive memory B and T cells likely contribute to protection from disease progression in mice (Zompi et al, 2012), and currently there is no model that reproduces human DHF/DSS-like disease caused by sequential infection.…”

Virus-Like Particle Secretion and Genotype-Dependent Immunogenicity of Dengue Virus Serotype 2 DNA Vaccine

“…We previously reported that a DENV-2 DNA vaccine consisting of prM and 80% E (aa 1 to 396) of DENV-2, followed by 20% E from the homologous JEV membrane-anchoring region, enhanced VLP secretion after intracellular expression and was able to generate high-titer antibodies in mice which persisted for more than 6 months (28,44). DENV-neutralizing antibodies directed against the E protein are thought to play a key role in protection against the disease, an idea supported directly by passive antibody transfer experiments in animal models and indirectly by epidemiological data from prospective studies in areas where dengue is endemic (45,46). However, the levels of antibody induction and protection for a dengue vaccine have not been established under conditions of different antigenic backbones, and these might differ depending on the phylogenetic genotype differences.…”