The first influenza pandemic was recorded in 1580; since this time, various methods have been employed to eradicate its cause. The etiological cause of influenza, the orthomyxoviridae was finally discovered by the Medical Research Council (MRC) of the United Kingdom in 1933.

In the world wide Spanish flu pandemic of 1918, "Physicians tried everything they knew, everything they had ever heard of, from the ancient art of bleeding patients, to administering oxygen, to developing new vaccines and sera (chiefly against what we now call Hemophilus influenzae—a name derived from the fact that it was originally considered the etiological agent—and several types of pneumococci). Only one therapeutic measure, transfusing blood from recovered patients to new victims, showed any hint of success."In 1931, viral growth in embryonated hens' eggs was reported by Ernest William Goodpasture and colleagues at Vanderbilt University. The work was extended to growth of influenza virus by several workers, including Thomas Frances, Wilson Smith and Macfarlane Burnet, leading to the first experimental influenza vaccines. In the 1940s, the US military developed the first approved inactivated vaccines for influenza, which were used in the Second World War. Greater advances were made in vaccinology and immunology, and vaccines became safer and mass-produced. Today, thanks to the advances of molecular technology, we are on the verge of making influenza vaccines through the genetic manipulation of influenza genes (see figure 1).

Flu vaccine is usually grown in fertilized chicken eggs (see figure 2). In February preceding each fall's flu season (in the Northern hemisphere), three strains of flu are selected and chicken eggs inoculated.

As of November 2007, both the conventional injection and the nasal spray are manufactured using chicken eggs. The European Union has also approved Optaflu, a vaccine produced by Novartis using vats of animal cells. This technique is expected to be more scalable and avoid problems with eggs, such as allergic reactions and incompatibility with strains that affect avians like chickens. A DNA-based vaccination, which is hoped to be even faster to manufacture, is currently in clinical trials, but has not yet been proven safe and effective. Research continues into the idea of a "universal" influenza vaccine (but no vaccine candidates have been announced) which would not need to be tailored to work on particular strains, but would be effective against a broad variety of influenza viruses.

Figure 2. Researchers infect eggs and sort through eggs used for the cultivation of flu vaccine. Vaccines are made the same way they've been made for half a century, relying on tens of millions of chicken eggs to grow the virus.

In a 2007 report, the current global capacity of approximately 826 million seasonal influenza vaccine doses (inactivated and live) was double the current production of 413 million doses. In an aggressive scenario of producing pandemic influenza vaccines by 2013, only 2.8 billion courses could be produced in a six-month time frame. If all high- and upper-middle-income countries sought vaccines for their entire populations in a pandemic, nearly 2 billion courses would be required. If China pursued this goal as well, more than 3 billion courses would be required to serve these populations. Vaccine research and development is ongoing to identify novel vaccine approaches that could produce much greater quantities of vaccine at a price that is affordable to the global population.

An effective method of vaccine generation that bypasses the need for eggs is the construction of "influenza virus-like particle (VLP)". VLP is a non-egg, non-mammalian cell culture-based vaccine, purified from the supernatants of Spodoptera frugiperda Sf9 insect cells following infection of baculovirus vectors encoding an expression cassette made up of only three influenza virus structural proteins, hemagglutinin (HA), neuraminidase (NA), and matrix (M1) VLPs elicit antibodies that recognize a broader panel of antigenically distinct viral isolates compared to other vaccines in the hemagglutination-inhibition (HAI) assay.

Each year, three strains are chosen for selection in that year's flu vaccination by the WHO Global Influenza Surveillance Network. The chosen strains are the H1N1, H3N2, and Type-B strains thought most likely to cause significant human suffering in the coming season. Due to the high mutation rate of the virus a particular vaccine formulation is effective for at most about a year. The World Health Organization coordinates the contents of the vaccine each year to contain the most likely strains of the virus to attack the next year.

"The WHO Global Influenza Surveillance Network was established in 1952. The network comprises 4 WHO Collaborating Centres (WHO CCs) and 112 institutions in 83 countries, which are recognized by WHO as WHO National Influenza Centres (NICs). These NICs collect specimens in their country, perform primary virus isolation and preliminary antigenic characterization. They ship newly isolated strains to WHO CCs for high level antigenic and genetic analysis, the result of which forms the basis for WHO recommendations on the composition of influenza vaccine for the Northern and Southern Hemisphere each year."

The Global Influenza Surveillance Network's selection of viruses for the vaccine manufacturing process is based on its best estimate of which strains will be predominant the next year, amounting in the end to well-informed but fallible guesswork.

Formal WHO recommendations first issued in 1973; beginning 1999 there have been two recommendations per year, one for the northern hemisphere (N) and the other for the southern hemisphere (S).