Early signs of post-vaccination change in the USA rotavirus population through mutation, migration and shifting prevalence

Background/Question/Methods

An important challenge in diverse and rapidly evolving pathogens is to understand the ecological and evolutionary mechanisms that explain the response to vaccination. Here we use phylodynamics methods to specifically quantify the contribution of mutation, migration and shifting prevalence to the genetic change in the rotavirus population following the introduction of vaccination. Rotavirus, a globally distributed and genetically diverse RNA virus, was the leading cause of severe gastroenteritis among children under 5 in the United States prior to 2006, resulting in more than 400,000 outpatient visits and 50,000 hospitalizations annually. Routine vaccination in the US with two live attenuated virus vaccines began in 2006, and has substantially reduced the incidence of severe disease and hospitalization. Two antigenic outer capsid proteins VP7 (G protein), and VP4 (P protein) characterize rotavirus, and although five genotypes account for over 90% of human infections, over 60 other genotypes have been identified, and point mutations continuously accumulate on capsid antigenic sites. We compiled a large, globally representative dataset from publicly available rotavirus VP7 sequences. Bayesian phylogenetic methods, combined with stochastic mapping and ancestral state reconstruction were used to jointly estimate the migration and mutation history of each viral lineage between 2004-2012.

Results/Conclusions

To quantify the shift in the makeup of the US rotavirus population we measured the hamming distance between protein sequences of the VP7 epitopes and those of the sequence included in the vaccines. Within two years of the introduction of the vaccine, there is a clear shift in the population away (>1aa) from the sequences included in the vaccine, resulting in a population that is more different from the vaccine than prior to vaccination and compared to a global control sample. US lineages of migrant descent and lineages that have experienced a mutation event during the post vaccination period were significantly more distant (>7aa, >1aa respectively) from the vaccine compared to branches that have not undergone mutation or migration. In addition, preliminary analysis found ambiguous evidence of selection driven mutation post vaccination in the US. These findings indicate that antigenic changes in the rotavirus VP7 protein post vaccination are most likely the result of the effective migration of G genotypes which are less similar to the vaccine. Evaluating the relative contribution of migration, mutation and shifting genotype prevalence to vaccine evasion by the virus has major implications for designing a proper mitigation strategy.