Based on an analysis of 184 whole-genome dengue sequences and 408 E gene sequences from India spanning more than 60 years, a team led by Dr. Rahul Roy from the Department of Chemical Engineering at the IISc have carried out a detailed investigation of the virus diversity and evolutionary dynamics of the virus in India. They have analysed how the virus evolves from its ancestors in the presence of serotypes.
Cross-protection
While the first infection with any of the four dengue serotypes can prevent reinfection by the same serotype for a long period, the second infection by a different serotype can have a very high viral load and cause severe disease. This is because the cross-protection offered by the first infection acts as a shield against other serotypes only for two-three years and then begins to drop.
Dengue virus evolution and vaccine efficacy. | Photo Credit: The Hindu
Around one-three years after the cross-protection begins to wane is the time when antibody-dependent enhancement is most likely. This is because while the antibodies are not able to neutralise the virus belonging to different serotypes, the virus is better able to bind to the antibodies leading to higher cell infection and thus enhanced severity and viral load. This is called the antibody-dependent enhancement mediated by cross-reactive antibodies.
While the virus that is identical to the one that caused the first infection will be neutralised for a long time, viruses that are a bit look-alike of the serotype that caused the first infection have greater ability to take advantage of the weakened immune responses and bind to pre-existing antibodies and cause severe disease than the three other serotypes that did not cause the first infection, according to Suraj Jagtap from the Department of Chemical Engineering, IISc and the first author of a paper published in PLOS Pathogens.
“Several lines of evidence point to this interlinked dengue evolution driven by the underlying population-level natural immunity in India. The cross-reactive antibodies and cellular immunity from prior dengue infections can drive such co-evolution in endemic regions,” Dr. Roy elaborates.
The dominant immune selection pressure has led to the emergence of a unique Indian dengue lineage (DENV-4-Id) belonging to serotype 4 (DENV-4). “The DENV-4-Id lineage has diverged away from global sequences,” says Dr. Roy.
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South India
“The DENV-4-Id lineage is dominant in South India, and about 50% of infections in South India are due to this India-unique lineage,” says Dr. Roy. “We strongly feel that the DENV-4-Id lineage will become dominant in North India too.”
The E gene, which is seen across the dengue virus exterior, plays an important role in binding to the cell receptors. The substitution rate for the E gene was highest at 44% in genotype I of DENV-4 compared with the whole genome, suggesting high immunological pressure driving the divergence of the DENV-4 E gene. “Most of dengue virus evolution happens in the E gene. This suggests that evolution is driven primarily due to interaction with host immune system,” says Dr. Roy.
Taking a cue from the divergence of DENV-4-Id, the researchers examined whether the high seroprevalence can play a role in the evolution of dengue in India. “We identified recurring fluctuations in the divergence of envelope gene sequences of circulating dengue viruses in South India, indicating that all four serotypes are co-evolving,” says Dr. Roy.
“In South India, we find that, in general, the E gene diverges from the ancestral sequence for all serotypes, but this divergence fluctuates over time. Overall, in our dataset, the E gene sequences within a serotype and between serotypes bring the viruses closer or similar to the ancestors or drift away from the ancestors. And this happens in a coordinated fashion across all four serotypes,” says Dr. Roy. “This behaviour is pronounced in DENV-2 and DENV-4 with an estimated time period (peak-to-peak) of about three years.”
The evolution of the viruses across serotypes has implications for vaccine efficacy. The majority of strains used for developing dengue vaccines are based on strains isolated between 1964 and 1988.
“As the current Indian lineages are highly divergent from those used in all major vaccines (the genotypes used in the vaccine strains are not observed in India), there is a potentially significant reduction in vaccine efficacy,” says Dr. Roy. “Overall, about 6% of all known epitopic regions are different in Indian dengue sequences compared to the vaccine strains. Further, almost half of all the E protein variations lie either in known epitopic regions where the antibodies bind to or have a positive antigenic effect.”
Indian variants of DENV-1 and DENV-4 are distinct from all the vaccines compared to DENV-2 and DENV-3.
