Influenza viruses circulating in humans constantly acquire small changes to their surface glycoproteins – haemagglutinin (HA) and neuraminidase (NA). These changes alter the antigenicity of the HA and NA – known as antigenic drift.
Because influenza viruses can evade the immune system in this way people need an updated seasonal influenza vaccine every year.
It is estimated that there are between three million and five million cases of influenza each year globally, including between 250,000 and 500,000 deaths.
Influenza is seasonal and reaches its peak in winter, so there are two different influenza seasons each year – one in the northern hemisphere and one in the southern hemisphere.
The World Health Organisation (WHO) makes separate recommendations for two different vaccine formulations every year – one for each hemisphere.
The influenza vaccine life cycle begins with these recommendations in February for the northern hemisphere vaccine and in September for the southern hemisphere vaccine.
Most influenza vaccines worldwide are inactivated trivalent vaccines. They contain antigen from three strains of influenza every year, two influenza A strains (H1N1 and H3N2) and one influenza B strain.
More recently new quadrivalent vaccines have been developed that also contain an extra influenza B strain.
Surveillance data is collected worldwide on influenza viruses that have been circulating during the previous winter months.
We source and distribute serum panels used for the serology assays to the other WHO laboratories. We also perform serological assays to assess how well the current vaccine matches the newly circulating influenza virus strains.
A World Health Organisation (WHO) expert panel – including a NIBSC representative – reviews and assesses our data together with data from a number of other WHO laboratories worldwide and decides on which strains will be most appropriate for the next winter season.
Once the strains for the next winter season have been selected, CVVs need to be generated.
Wild-type influenza viruses – the viruses that circulate in nature including those infecting humans – are not usually suitable to make a vaccine. This is because they do not grow well enough in the substrates used by manufacturers to produce the required amount of vaccine in the time available.
CVVs are viruses which have both the required antigenicity to match the circulating strains and which grow better.
NIBSC is one of only three laboratories worldwide that produce influenza CVVs for seasonal influenza vaccine production.
The process we use is called classical reassortment. It involves infecting hens’ eggs with two influenza viruses at the same time – the wild-type virus which has the antigenic properties required and a laboratory-adapted influenza strain that grows to high titres in eggs.
The segmented genome of the influenza virus leads to a natural ‘mix and match’, so that the resulting viruses from the mixed infection can contain all possible gene combinations.
We then use antibodies directed against the HA and NA of the laboratory virus to select for viruses that have the new wild-type HA and NA we need, but with other genes from the laboratory strain to give high growth.
Once we have generated the new CVV we test its growth properties and confirm it is suitable antigenically before sending it to vaccine manufacturers for vaccine production.
As well as generating our own CVVs, we also distribute both wild-type seasonal influenza strains and CVVs made in the other reassorting laboratories.
We routinely ship viruses to manufacturers and research laboratories all over the world.
Once the vaccine has been produced there needs to be a reliable way to confirm the potency of the vaccine – that there is enough antigen in the vaccine dose to generate an immune response.
For influenza virus the gold standard assay for this is the single radial immune diffusion (SRD) assay. This involves producing an antiserum and a calibrated antigen reagent.
Othmar Engelhardt, Principal ScientistJason Long, Principal ScientistCarolyn Nicolson, Senior ScientistVictoria Burrows, Scientist