Evolution and Vaccination of Influenza Virus

Abstract

In this study, we present an application paradigm in which an unsupervised machine learning approach is applied to the high-dimensional influenza genetic sequences to investigate whether vaccine is a driving force to the evolution of influenza virus. We first used a visualization approach to visualize the evolutionary paths of vaccine-controlled and non-vaccine-controlled influenza viruses in a low-dimensional space. We then quantified the evolutionary differences between their evolutionary trajectories through the use of within- and between-scatter matrices computation to provide the statistical confidence to support the visualization results. We used the influenza surface Hemagglutinin (HA) gene for this study as the HA gene is the major target of the immune system. The visualization is achieved without using any clustering methods or prior information about the influenza sequences. Our results clearly showed that the evolutionary trajectories between vaccine-controlled and non-vaccine-controlled influenza viruses are different and vaccine as an evolution driving force cannot be completely eliminated.

Keywords: influenza; machine learning; visualization..

FIG. 1.

Seasonal human A/H3N2 influenza ratio analysis against time of vaccine introduction. A constant shift of positively selected site location when a new vaccine was introduced. Horizontal axis represents the position of HA1 domain of the HA gene. Vertical axis represents time progression from 1971 (bottom) to 2016 (top) when each new (green square) and repeated (black square) vaccine was introduced. Red color bars denote the range of positions, with ratio from 0.8 to 1. Blue color bars denote the range of positions, with ratio greater than 1. HA, hemagglutinin.

FIG. 2.

Seasonal human A/H3N2 influenza virus evolution trajectory. Each arrow points to a vaccine seed strain (red dot). The directional evolution can be seen as traveling from lower left to the top and then coming down to the lower right.

FIG. 3.

Seasonal human Type B influenza virus evolution trajectory. Two separate lineages (Victoria and Yamagata) are evolving simultaneously: (a) top to lower left and to lower right and diverging further (b). Vaccine introductions are indicated by year labels in (a) and shown as black circles in (b).

FIG. 4.

Seasonal human H1N1 influenza virus evolution trajectory in three dimensions. Vaccine strains are black crosses.

FIG. 5.

Vaccine-controlled avian H5 influenza virus evolution trajectory in three dimensions. The vaccine was introduced in early 1990s, and the virus slowly evolved away from the vaccine strain and established two separate lineages.

FIG. 6.

Non-vaccine-controlled human H5N1 influenza virus evolution trajectory in three dimensions. The virus has evolved into a few dominant lineages since 1997. Three major evolutionary lineages can be seen originating from the center cluster, which contains viruses from 1997. However, the specific H5 HA gene identified in 1997 has remained present in these days.

FIG. 7.

Non-vaccine-controlled avian H5 influenza virus evolution trajectory in three dimensions. Multiple clusters scattered throughout, sharing almost the same time periods, thus suggesting the co-circulation of multiple clades or sublineages of the avian H5 subtype.