Derek Smith explores vaccine selection

Annual influenza epidemics in humans affect 5 – 15 per cent of the population, causing an estimated half million deaths worldwide per year.

The most common treatment against flu is a preventative vaccine, recommended for the elderly and other groups at risk in most developed countries. Flu shots are administered in autumn in preparation for the winter season and have to be repeated every year. This is partly because the effect of the vaccine wears off and needs to be refreshed, but mostly because the flu virus continuously mutates, thereby escaping the defence mechanism provoked by vaccination.

Our bodies fight influenza infection by producing antibodies that attack a type of protein that sits on the surface of the virus. A flu vaccine primarily contains proteins from recent strains. These are carefully chosen, with the expectation that they will trigger the production of antibodies that will recognize the wild type virus of the upcoming winter. Protection will be strongest if the person comes into contact with the precise strain of flu that they have been vaccinated with. However, if the strain they come into contact with has changed significantly, the efficacy of the vaccine will be reduced.

Over time, all flu strains mutate and evolve. This phenomenon is known as antigenic drift, because the body’s reaction to the antigen – the protein on the virus surface – is gradually diminished as the virus evolves away from its original makeup. Roughly, the greater the difference between the vaccine strain and the strain encountered, the weaker the immunization effect will be.

Selecting vaccine strains and global surveillance
Twice a year, once for the Northern and once for the Southern hemispheres, representatives of the World Health Organisation (WHO) and the four international laboratories collaborating on influenza surveillance meet to discuss and select the season’s vaccine strains.

Over the year, thousands of influenza viruses are isolated and analysed by these centres. They have to decide how much protection vaccination with one virus will give people against others. The aim in selecting a strain for a vaccine is to identify a strain that will induce protection against the largest possible range of circulating viruses. To do this it is necessary to understand the antigenic properties of all circulating strains.

Thousands of sentinel physicians worldwide and the 112 national influenza laboratories together form the bulk of the WHO global influenza surveillance network, continuously collecting, testing, and identifying strains of flu circulating in their area. They carefully record and pass the results to one of four international collaborating centres, which use them as the basis for deciding vaccine composition.

When it is time to select strains for a flu season, a small international team of experts from various flu laboratories gathers to interpret the information collected – to identify the strains that will offer the widest range of protection. The data used as input to this collective effort can sometimes be difficult to interpret.

Mapping influenza
It is at this stage of the strain selection process that the novel method of antigenic cartography – mapping the viruses – plays a role in addition to the existing methods. In this, a computational analysis processes the collected antigenic information and converts it into a simple map that shows how distant strains are from each other.

Strains that would induce effective immunisation against one another are pictured as being close together, while those that do not offer good cross-protection are placed further apart. The figure shows an antigenic map that illustrates how influenza strains tend to form clusters that correspond to epidemics. The map helps in strain selection, because potential vaccine strains, i.e., those that are most likely to be widely protective, will be found near the centres of these clusters. 

The data collected for vaccine strain selection purposes also form a remarkable record of the evolution of influenza viruses. The application of antigenic cartography to influenza vaccine strain selection is a good example of a positive feedback in which a new research method contributes to a critical public health process and the expertise and data gathered by the public health process contributes to basic research in evolution.

These collaborative efforts have potentially wide-ranging implications for strain surveillance, for vaccine strain selection, and for research involving other highly variable pathogens such as HIV, hepatitis C, and malaria.

Dr Derek Smith is a mathematician in the Department of Zoology at the University of Cambridge. He and his colleagues recently won a £1.4 million award from the US National Institutes of Health to continue their work on mapping flu viruses