[18-EEID US-UK DDCOVMP] Drivers of diversity and transmission of co-circulating viral lineages in host meta-populations

Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) is endemic in the USA, Asia and Europe, including the UK, and is considered the most important disease to control in swine populations. There are two distinct genotypes: PRRSV-1 mostly found in Europe and Asia, and PRRSV-2 predominating in the Americas but also in Asia and Europe. Additionally PRRSV-2 has also evolved a highly pathogenic type, which has now spread from China to other Asian countries. Vaccines against PRRSV-1 and PRRSV-2 exist, but due to the host response to PRRSV and since PRRSV is a rapidly evolving RNA virus with wide genetic variation and multiple sub-lineages, vaccines cannot be assumed to be fully protective.

In this collaborative US-UK project we will investigate how ongoing viral evolution and variable cross-immunity to different viral strains influences circulation of these rapidly evolving viruses. In particular we will evaluate how partial immunity influences evolution within and between hosts using an experimental study, where quasi-species evolution will be tracked via next generation sequencing. To quantify viral evolution and patterns of repeated invasions of different viral lineages in field settings we will monitor farms and whole genome sequence the strains over time. We will also quantify how spatial heterogeneities in cross-immunity (based on previous infection and vaccination) and population connectivity influence co-circulation and interactions among viral lineages using a dataset of exceptional spatiotemporal resolution that covers ~20% of the U.S. sow population. Finally we will use this knowledge to perform simulation modelling to elucidate how spatial and temporal variation in cross-immunity influences evolutionary dynamics of co-circulating PRRSV lineages in realistic scenarios, which will ultimately enable us to predict what the risks of infection are to up coming PRRSV strains, and thus aid selection of the most appropriate vaccines as part of PRRSV control strategies.

For genetically diverse viruses, ecological interactions between different genetic lineages can occur if infection by one lineage confers partial cross-immunity to a related lineage. In animal populations interactions amongst co-circulating viral lineages could play strong roles in shaping transmission dynamics, e.g. driving immune-mediated selection or frequency dependent fitness advantages amongst the lineages. We hypothesize that continual viral evolution and variable cross-immunity to viral variants influences circulation of rapidly evolving viruses, and this in turn shapes disease distributions between host metapopulations.

The question is particularly pertinent to the RNA virus Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) in domestic swine herds. PRRSV is highly prevalent in the United States, Asia, Europe including the UK, and is considered an important virus to control by the swine industry. High levels of genetic diversity even within the two main types, leads to semi-regular outbreaks of different variants over time and across space.

This collaborative US-UK project is about "landscapes of cross-immunity" using both experimental transmission experiments and field studies. Specifically we will (i) evaluate between and within host evolution using deep sequencing methods in a transmission experiment (ii) longitudinally monitor and obtain whole genome sequences from farms with variable levels of cross-immunity (from past infection or vaccination) (iii) quantify how spatial heterogeneities in cross-immunity and population connectivity influence co-circulation using network science and phylodynamic methods (iv) create and run realistic simulation models to show how cross-immunity influences evolutionary dynamics of co-circulating PRRSV lineages.

Our study provides the opportunity to understand and predict how vaccination can alter the ecological transmission dynamics for important animal multi-lineage pathogens such as PRRSV.

Circulation of Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) in swine populations in the USA, Asia and Europe, including the UK, causes large economic losses to the industry, and is considered the most important disease to control. In this collaborative US-UK project viral evolution in swine populations are investigated alongside the effects of natural cross-immunity or vaccine induced immunity.

The potential non-academic beneficiaries of this research include government stakeholders, pig breeding companies and producers leading to ultimately users of pig products, including retailers and consumers. There are also potential benefits to the pig vaccine sector.

Benefits from this project to the policy makers include information that could be helpful in considering control and eradication programmes, and include: insights into the diversity and evolution of the virus; factors influencing the occurrence of different strains of the virus; information on the deployment of vaccines to control diverse viral strains and how to reduce/limit future diversification and spread.

Benefits from this project to the swine industry include improved information about currently circulating and possible future strains, enabling deployment of appropriate vaccines or other control measures, and avoidance of production losses due to this disease as well as costs associated with controlling outbreaks.

By undertaking sequencing studies, this project will generate detailed genetic information about PRRSV, and this information, together with the modelling studies on the effect of animals with different immunities, could be used to inform future vaccine designs.

In addition to the wider public consumers, the benefit to the wider public from this project will be through public engagement activities relating to generating an understanding of herd immunity and disease spread and control.