Viral 'backbone' underlies variation in rotavirus vaccine effectiveness

The study, published today as a Reviewed Preprint in eLife, is described by the editors as an important paper. They say the novel approach to estimating rotavirus vaccine effectiveness provides convincing evidence that rotavirus vaccines should be designed based on the whole genome of circulating strains, rather than the previous use of two surface proteins. The findings will have implications for future rotavirus vaccine design, as well as type-specific vaccine evaluation more generally.

Rotavirus is a contagious gastrointestinal infection that causes inflammation of the stomach and intestines (gastroenteritis), marked by severe dehydrating diarrhea. Two main vaccines, Rotarix (RV1) and RotaTeq (RV5), have significantly reduced cases of severe illness from rotavirus in the US, but they do not provide perfect protection.

Scientists have speculated that genetic differences between circulating rotavirus strains and vaccine strains may affect how well they work. Traditionally, these differences have been quantified using two proteins on the virus' outer shell -- VP7 and VP4.

"We set out to investigate why some vaccinated children still get sick with rotavirus," says lead author Jiye Kwon, a PhD student at the Department of Epidemiology of Microbial Diseases, and the Public Health Modeling Unit, Yale School of Public Health, New Haven, US. "Previous research has focused on just the outer proteins of the virus, but rotavirus has a total of 11 genetic segments. We wanted to look at the full genome to explore whether these remaining nine segments, the viral 'backbone', may explain the variation in vaccine effectiveness against rotavirus strains."

To investigate, Kwon and colleagues examined 254 cases of rotavirus-related illness in both vaccinated and unvaccinated individuals from seven medical sites across the US between 2012 and 2016. They used the whole genome sequencing data from these cases to analyse the full genetic code of each virus strain and compare it to either the Rotarix (RV1) or the RotaTeq (RV5) vaccine. They sought to identify whether vaccine effectiveness decreased as the genetic distance between virus and vaccine strains increased, as well as to examine how the genetic diversity of rotavirus changes in areas with higher vaccine coverage.

To measure genetic distance they used a technique called sieve analysis, a flexible statistical method that allowed them to measure the percentage difference of nucleotide bases -- the molecular 'letters' that make up the genetic code -- between each case strain and the vaccine strain(s).

Their results revealed that individuals vaccinated with Rotarix (RV1) were more likely to be infected by rotavirus strains that were significantly genetically different from the vaccine -- more than 9.6% different in their full genome. Circulating viral strains that were genetically similar to the virus had a viral backbone called genogroup 1 (Wa-like). On the other hand, the genetically distant strains tended to have a different viral backbone called genogroup 2 (DS-1-like) or have mix-and-match variants known as reassortant strains.

Vaccine effectiveness results also reflected this genetic pattern. The Rotarix (RV1) vaccine provided strong protection against genetically similar viral strains, but its protection dropped significantly for more genetically distant strains. The RotaTeq (RV5) vaccine followed a similar pattern, but differences in its effectiveness were less pronounced.

Next, the team looked at whether vaccination patterns in different locations influenced the rotavirus strains circulating in the population. They found that in places where more people used Rotarix (RV1), rotavirus strains that were genetically distant dominated. This was also observed in areas with high usage of RotaTeq (RV5). This suggests that, over time, rotavirus is naturally adapting in response to vaccine-induced immunity, leading to shifts in the genetic makeup of circulating strains to favour those genetically different from the vaccine.

"Current vaccines still provide strong protection against severe illness in rotavirus, but these findings highlight the need to continually monitor viral evolution to maintain vaccine effectiveness in the long term," says Kwon.

The team caution that their study is limited by a relatively small sample size of cases, due to the requirement of whole genome sequencing data. They call for future studies to further validate their findings in other settings where whole genome sequencing data is more widely available.

"Our study shows that looking at the entire genetic structure of rotavirus gives a much clearer picture of how well vaccines work compared to just looking at the two surface proteins," says co-senior author Virginia Pitzer, Associate Professor in the Department of Epidemiology of Microbial Diseases, and the Public Health Modeling Unit, Yale School of Public Health. "This highlights the importance of incorporating the full genomic structure of viruses when designing vaccines. There are now four rotavirus vaccines currently available and more in the pipeline; our framework for using whole genome sequencing data to understand how all gene segments contribute to immune protection could be crucial for maintaining their long-term success."