Antigenic evolution of influenza A under immune pressure in mice.

Identification: Chu, Julie


Antigenic evolution of influenza A under immune pressure in mice  
Julie TS Chu, Leo Poon
University of Hong Kong, School of Public Health, Hong Kong
Influenza A viruses are highly mutable human respiratory pathogens that cause significant morbidity and mortality worldwide. Seasonal vaccination is currently the most effective countermeasures against influenza infection, but is limited by continuous antigenic drift of the viruses. As a result, there is a constantly need to reformulate the composition of vaccines. Unpredictable periodical antigenic changes in influenza are thought to be partially driven by herd immunity in human populations. Due to various practical and biological limitations, effects of immune pressure on influenza antigenic drift in humans is difficult to quantify and study.
To understand influenza antigenic changes that occur under in vivo selection pressures, several animal models were developed. However, these previous animal studies had some limitations. The animals were often immunised with inactivated vaccines, thus vaccine-induced responses may not fully mimic those caused by influenza virus infections. Moreover, some of the viruses used for infection were not well adapted to the animal models, resulting in selection by other factors irrelevant to antigenic drift.
In this project, we plan to develop a sequencing pipeline that can be used to carry out early detection of mutations associated with antigenic changes. Specifically, we want to
study the effects of immune pressure on antigenic drift. By decoding the sequential changes that lead to antigenic drift, we may achieve a better understanding of antigenic evolution of influenza under immune pressure.
The objectives of this study are:
1. Serially passage a mouse-adapted influenza virus in mice with pre-existing immunities against influenza viruses
2. Study the viruses from each passage with a single-molecule sequencing approach
3. Characterise the detected antigenic variants and their precursor/derivatives in vitro and in vivo
We have successfully established a working inbred model with non-sterile immunity by optimising vaccination and challenge virus, dose, route and frequency. We have carried out serial blind passages of the selected virus in five separate mouse groups. The full length genetic sequence of viruses from passage four were analysed through deep sequencing. SNPs identified in HA and NA regions will be characterised in depth for identification of potential immune epitopes.  
Existing progeny viruses will be serially blind-passaged in similarly treated mice for another five times, which may yield a greater number of detectable mutations, and possibly present major escape variants that can be identified and characterised through in vitro neutralisation assays and deep sequencing techniques.


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