Antibody Affinity Versus Dengue Morphology Influences Neutralization

Different strains within a dengue serotype (DENV1-4) can have smooth, or "bumpy" surface morphologies with different antigenic characteristics at average body temperature (37 degrees C). We determined the neutralizing properties of a serotype cross-reactive human monoclonal antibody (HMAb) 1C19 for strains with differing morphologies within the DENV1 and DENV2 serotypes. We mapped the 1C19 epitope to E protein domain II by hydrogen deuterium exchange mass spectrometry, cryoEM and molecular dynamics simulations, revealing that this epitope is likely partially hidden on the virus surface. We showed the antibody has high affinity for binding to recombinant DENV1 E proteins compared to those of DENV2, consistent with its strong neutralizing activities for all DENV1 strains tested regardless of their morphologies. This finding suggests that the antibody could out-compete E-to-E interaction for binding to its epitope. In contrast, for DENV2, HMAb 1C19 can only neutralize when the epitope becomes exposed on the bumpy-surfaced particle. Although HMAb 1C19 is not a suitable therapeutic candidate, this study with HMAb 1C19 shows the importance of choosing a high-affinity antibody that could neutralize diverse dengue virus morphologies for therapeutic purposes.Author summary Dengue virus consists of four serotypes (DENV1-4) and there are different strains within a serotype. DENV can have smooth or bumpy surface morphologies at physiological body temperature of 37 degrees C, depending on the strain. We have determined the cryoEM structures of a cross-reactive neutralizing human monoclonal antibody (HMAb) 1C19 in complex with strains of DENV1 and DENV2 that form either smooth or bumpy surface morphologies. We have mapped the epitope of HMAb 1C19 to E protein domain II and the epitope is likely partially hidden on the virus surface. We showed that the antibody has high affinity for binding to recombinant DENV1 E protein than to DENV2 E protein. This explains the strong neutralization activity for all DENV1 strains tested regardless of their morphologies at physiological temperature, whereas it can only neutralize DENV2 strain that exposes the epitope on the bumpy surface particles. These results suggest that high-affinity therapeutic antibodies could neutralize diverse dengue virus morphologies.