VIROLOGY


around the receptor binding pocket and are therefore a good surrogate measure of neutralising antibodies. If the surface of the virus protein changes, as a result of viral evolution, the antibodies can no longer bind to the viral surface. The ability of antibody to bind is measured through the assays mentioned above. If there is a reduction of more than four- to eight-fold in antibody binding compared to a reference strain, it is recognised that there is a virus present which has significant change on the HA surface, otherwise known as a drift variant. It has been recognised that the titre of anti-HA antibodies present in serum correlates with protection from infection. Hence, vaccines atempt to induce high levels of HA antibody to provide protection, but these antibodies need to be directed towards the head of the globular protein in order to prevent infection.


Vaccine effectiveness (VE) analysis. Assessed at a population level, this provides an estimate of the ability of vaccines in use to prevent illness or infection, allows comparisons of efficacy against different sub-types and, if sufficient data is available, may allow an assessment of clade/sub-clade specific VE estimates to be made which can be used to infer which circulating strain is least well-protected against by current vaccines. Recent WHO publications, such as the Full Value of improved Influenza Vaccine Assessment (FVIVA), explain how such analyses may be used to estimate deaths prevented or hospitalisations averted.


Data integration. Compiling information from multiple different data sources at different locations in the world is done to provide an overview of the most important changes in circulating viruses which have happened since the last snapshot. Advanced analytical techniques, such as antigenic cartography, are used to provide visualisation of information about strain variation, compared to current vaccine strains, helping to consolidate information about strain divergence. Fitness forecasting can also be undertaken to estimate the growth of different virus lineages (increase in frequency over time) as means of prediction of the fastest growing lineages.


Selecting strains The goal of the strain selection commitee, under the umbrella of WHO, is to use the foregoing information to identify influenza


Egg-based vaccines an A/Missouri/11/2025 (H1N1)pdm09-like virus; an A/Darwin/1454/2025 (H3N2)-like virus; and a B/Tokyo/EIS13-175/2025 (B/Victoria lineage)-like virus.


Cell culture-, recombinant protein- or nucleic-acid based vaccines an A/Missouri/11/2025 (H1N1)pdm09-like virus; an A/Darwin/1415/2025 (H3N2)-like virus; and a B/Pennsylvania/14/2025 (B/Victoria lineage)-like virus.


WHO Recommendations for influenza vaccine composition for the 2026-2027 northern hemisphere season


viral antigens that will elicit the best and most cross-protective immunity against diverse and diverging viruses using a probability assessment of what will be co-circulating in the next 12 months. The ideal vaccine viral antigens confer a broad breadth of immunity to multiple subclades of viruses, thus reducing the risk of a vaccine mismatch. The strain selection process has evolved from a more simplistic atempt to provide the best match to circulating strains towards a strain which induces more cross-reactive immunity. The key questions are what genetic clades and subclades are in circulation and where in the world? What genetic diversity has been observed within subclades, are the viruses with new genetic changes spreading geographically, and are these distinct from prior or other contemporary viruses? What is the proportion of the new groups and is it possible to see trends over time? Do current vaccines induce antibodies in humans that protect against emerging viruses? Which of the currently available viral antigens provides the best and most comprehensive recognition of potential emerging strains?


What types of vaccines are used? Vaccine use is concentrated in high- and middle-income countries, but there has been a gradual expansion in vaccine use since the early 2000s when the pandemic threat of H5N1 was first recognised. Since this time, there has been incremental increase in production capacity and production sites in different parts of the world, mainly for trivalent vaccines produced in embryonated eggs. Influenza virus vaccines have become increasingly diverse in recent decades. The very youngest and the very oldest


members of society are most affected by influenza. Vaccines intended for the elderly are often described as ‘enhanced vaccines’ as they may include either a higher dose of viral antigen to increase the antibody response (high dose), or they may include


adjuvants to improve the overall immune response. Vaccines for children include the use of live atenuated virus strains which induce a broad humoral and cellular immunity. Different vaccine platforms provide different challenges for vaccine strain selection. Although over 90% of all influenza


vaccines used globally are still grown in eggs, the technology platforms for production of influenza vaccines have become increasingly sophisticated. One of the key problems of producing flu vaccine in eggs is that, during virus growth, adaptive mutations occur to improve the virus growth in this substrate. Unfortunately, many of these mutations – termed egg adaptations – may affect the antigenicity of the final vaccine product. Antibodies raised to egg-derived vaccines may induce antibodies that react to the egg adaptations seen in vaccine strains, but are not reactive with circulating strains, which means that they are less effective as vaccines. This can be overcome by growing


vaccines in mammalian cell culture, or producing recombinant protein vaccines where the vaccine antigen does not have any egg adaptive mutations and is a closer match to the circulating strains. Vaccines are therefore produced in cell culture, or as recombinant protein, which gives increasing diversity of available products and the ability to tailor vaccines to different segments of the population, as is seen in seasonal campaigns in England. Given the diversity of platforms for


vaccine production, strains are now selected for use in either cell-derived or recombinant vaccines or for egg-derived vaccines.


Manufacturing process Influenza vaccines cannot be produced at pace or at scale without a strong and commited private-public partnership. Following the announcement of vaccine strain choices, there are many different production processes undertaken by manufacturers before vaccines are


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