Evolutionary dynamics of dengue virus in India

Abstract

More than a hundred thousand dengue cases are diagnosed in India annually, and about half of the country’s population carries dengue virus-specific antibodies. Dengue propagates and adapts to the selection pressures imposed by a multitude of factors that can lead to the emergence of new variants. Yet, there has been no systematic analysis of the evolution of the dengue virus in the country. Here, we present a comprehensive analysis of all DENV gene sequences collected between 1956 and 2018 from India. We examine the spatio-temporal dynamics of India-specific genotypes, their evolutionary relationship with global and local dengue virus strains, interserotype dynamics and their divergence from the vaccine strains. Our analysis highlights the co-circulation of all DENV serotypes in India with cyclical outbreaks every 3–4 years. Since 2000, genotype III of DENV-1, cosmopolitan genotype of DENV-2, genotype III of DENV-3 and genotype I of DENV-4 have been dominating across the country. Substitution rates are comparable across the serotypes, suggesting a lack of serotype-specific evolutionary divergence. Yet, the envelope (E) protein displays strong signatures of evolution under immune selection. Apart from drifting away from its ancestors and other contemporary serotypes in general, we find evidence for recurring interserotype drift towards each other, suggesting selection via cross-reactive antibody-dependent enhancement. We identify the emergence of the highly divergent DENV-4-Id lineage in South India, which has acquired half of all E gene mutations in the antigenic sites. Moreover, the DENV-4-Id is drifting towards DENV-1 and DENV-3 clades, suggesting the role of cross-reactive antibodies in its evolution. Due to the regional restriction of the Indian genotypes and immunity-driven virus evolution in the country, ~50% of all E gene differences with the current vaccines are focused on the antigenic sites. Our study shows how the dengue virus evolution in India is being shaped in complex ways.

Antigenic distance between primary and secondary dengue infections correlates with disease risk

“…Systematically quantifying the properties of human serum against previous and current circulating strains will help discern the changes in immune profiles and pathogenesis after natural infection and vaccination ( 31 – 33 ). This will become increasingly important as dengue vaccines begin to get used ( 12 , 17 , 18 ). The antigenic distance between vaccine strains and locally circulating strains may help explain underlying differences in the efficacy of vaccines across populations, with the potential of a long-term goal of tailored vaccines based on local antigenic profiles.…”

“…It would also provide biological insight into a role for antigenic imprinting to explain an individual’s long-term disease risk, where the specific virus that first infects an individual largely determines future disease risk when they are exposed to antigenically different viruses ( 14 – 16 ). Further, the specific antigenic properties of strains used in vaccines could be evaluated for their potential to cause disease from generating sub-neutralization titers, the magnitude of which may differ across settings because of heterogeneity in strain-specific immune histories and the antigenic characteristics of circulating viruses ( 17 , 18 ).…”

Genetic Diversity and Dispersal of DENGUE Virus among Three Main Island Groups of the Philippines during 2015–2017

“…However, the genetic diversity was more pronounced within each genotype and included 12 distinct clades among 4 serotypes. This observation is characteristic of DENV epidemiology in which a single genotype generally dominates within each serotype in a cyclical pattern [ 41 , 42 ], yet high genetic diversity is maintained within genotypes through co-circulating clades and in situ evolution [ 43 ]. A similar pattern has also been reported in previous studies in the Philippines [ 22 , 44 ].…”

Antigenic diversity and dengue disease risk

“…Systematically quantifying the properties of human sera against previous and current circulating strains will help discern the changes in immune profiles and pathogenesis after natural infection and vaccination [29][30][31] . This will become increasingly important as dengue vaccines begin to get used 12,17,18 . The antigenic distance between vaccine strains and locally circulating strains may help explain underlying differences in the efficacy of vaccines across populations, with the potential of a long-term goal of tailored vaccines based on local antigenic profiles.…”

“…It would also provide biological insight into a role for antigenic imprinting to explain an individual's long-term disease risk, where the specific virus that first infects an individual largely determines future disease risk when they are exposed to antigenically different viruses [14][15][16] . Further, the specific antigenic properties of strains used in vaccines could be evaluated for their potential to cause disease from generating sub-neutralisation titres, the magnitude of which may differ across settings due to heterogeneity in strain-specific immune histories and the antigenic characteristics of circulating viruses 17,18 .…”