Influenza viruses continuously mutate and evolve, and consequently different strains can cause epidemics each year. To ensure that vaccines contain the most appropriate circulating strains, and thereby improve influenza control measures, WHO founded the Global Influenza Surveillance Network (GISN) in 1952. This WHO system also ensures that vaccines have equivalent efficacy through the use of standardized potency testing reagents.

The GISN is complex, comprising more than 100 National Influenza Centres, four Collaborating Centres based in Australia, Japan, the United Kingdom and USA, and three Reference Laboratories in Australia (TGA), the UK (NIBSC) and America (CBER). These work with academic laboratories, regulatory agencies and manufacturers, as part of a highly time-constrained process designed to ensure vaccines are available each year.

1. Virus collection: physicians take swabs from sick patients, from which local National Influenza Centres isolate influenza viruses.

2. Virus characterization: Collaborating Centres analyse these viruses, and compare them to previous viruses to monitor any differences.

3. WHO vaccine strain selection: the Collaborating Centres and influenza experts review this surveillance data twice a year, and WHO recommends the most appropriate viruses for inclusion in vaccines for the coming season (currently, two ‘A’ subtypes and a single ‘B’ type).

4. Confirmation by regulatory authorities: local regulatory agencies consider the WHO information and make the final decision on which strains should be included in vaccines used in their territories that year.

5. Viruses for manufacture: financed predominantly by industry, the Collaborating Centres in Australia and the US isolate the selected viruses in eggs specifically for vaccine manufacture, as required by regulatory agencies.

6. High-growth vaccine strains: as influenza ‘A’ viruses often grow poorly during manufacture, industry funds the New York Medical College and the UK’s WHO Reference Laboratory (and the vaccine manufacturer CSL covers its own costs) to produce high-growth strains, using genetic reassortment. These strains are freely available to all manufacturers. The vaccine producer MedImmune undertakes similar processes at its own expense for the manufacture of live-attenuated vaccines.

7. Vaccine manufacture: following further processing, manufacturers grow the three vaccine strains in eggs (although several producers are establishing alternative processes using cell culture rather than eggs). These are then killed (except for vaccines containing live-attenuated viruses), purified, processed and filled into vials, syringes or sprayers.

8. Vaccine standardization: to ensure vaccines have comparable efficacy, manufacturers use potency testing reagents standardized by the WHO Reference Laboratories and the Collaborating Centre in Japan. To support this process manufacturers supply Reference Laboratories with reagents or provide materials for their production, and are charged for the service by the UK Reference Laboratory, which provides most of the reagents used globally, to recover its costs.

9. Regulatory control and vaccine release: to ensure that each batch conforms to the required quality standards they must pass local regulatory agencies’ confirmatory testing, which is carried out throughout the production process, before vaccines can be released for use.

The WHO network is also responsible for identifying any unusual influenza ‘A’ viruses with the potential to cause a pandemic. Due to the danger posed by these viruses, additional steps are required for their safe monitoring and use in vaccine strain production.

A. Virus isolation: appropriate containment facilities (biosafety level 3 / 4) are required for safe virus isolation and handling.

B. High-growth vaccine strains: for H5N1 viruses only the WHO Collaborating Centre in the US, Reference Laboratory in the UK and the laboratory at St Judes Children’s Hospital in the USA have the appropriate facilities to prepare high-growth strains for vaccine manufacture. In addition, these viruses require strict safety testing, and genetic modification to prevent them killing the eggs used in production.

C. Vaccine production: some countries treat these strains as genetically modified organisms and impose restrictions on their import, handling and production, making research and manufacture more complicated and time consuming.

Influenza vaccine production is a complex, highly time-constrained process. From the WHO strain recommendation to the release of the first vaccine batches takes 5-6 months. As a result, it is the flexibility and collaborative approach of all those involved that ensures vaccine is available each year. In the event of a pandemic, the time pressures will be even more intense. Therefore, maintaining and strengthening the system must be a key priority, to enhance the world’s ability to address the continuing threat posed by influenza.