Commonly known as flu, influenza is a contagious respiratory condition caused by viruses. The seasonal nature of flu brings a year-round disease burden; the World Health Organisation (WHO) estimates seasonal flu can cause up to 650,000 deaths annually as a result of respiratory diseases alone.

Vaccines are the most effective way to prevent flu – particularly needed for at-risk populations, such as old people, young children and people with certain respiratory conditions. The US Centres for Disease Control and Prevention (CDC) has estimated around 40,000 deaths were avoided between 2005 and 2014 because of the seasonal flu vaccine.

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However, as the influenza viruses causing seasonal flu epidemics, Type A and Type B, are constantly genetically mutating, antibodies created due to flu vaccination will not necessarily protect those who received the vaccine the following year. Instead new vaccines have to be developed annually based on predictive modelling of how the viruses will antigenically change.

As scientists have uncovered more and more about the peculiarities of flu viruses and flu vaccination has become more widespread, vaccines to prevent flu have evolved and improved significantly both in terms of better viral coverage and more patient-friendly administration methods.

1930s – First flu vaccine developed

Following the high mortality rate of the 1919 Spanish flu pandemic, which actually caused more deaths than the First World War, scientists began to investigate the root causes of flu.

Although initially believed to be caused by bacteria, in the 1920s it became clear that a virus was the primary disease agent and in the 1930s the first influenza virus was isolated.

As a result of this work, in the mid-1930s, US virologists Jonas Salk and Thomas Francis developed the first flu vaccine. It was used to protect US military forces during the Second World War. Salk and Francis’ vaccine was an inactivated influenza A-targeting egg-based product.

1940s – Discovery of Influenza B, leading to dual-targeting vaccines

In 1940, a second flu-causing virus was discovered – it was antigenically different from the original version isolated ten years before and named influenza virus B.

Consequently, scientists began to work on creating a bivalent vaccine using the same egg culture approach that contained both type A and type B; it was first tested on humans in 1942. The dual-targeting nature of this vaccine meant it was able to better protect people against flu.

1952 – WHO starts monitoring virus strains

It became clear that not only were there two different strains of influenza, but the viruses were constantly evolving and mutating through what became known as antigenic drift. As early as 1947, it was clear that the seasonal vaccine created for the US military did not protect against all flu.

Therefore, six years after the WHO’s founding by the United Nations, the organisation’s Executive Board created the Global Influenza Surveillance and Response System (GISRS).

The GISRS was the first surveillance system to monitor the flu disease burden and the mutational changes occurring making vaccines less effective.

Over time the GISRS began to also support improved vaccine development by encouraging research to obtain suitable virus isolates to compose seasonal flu vaccines based on the epidemiology of that year’s particular disease-causing, mutated influenza virus.

1960s-70s – Further improvement of vaccines

The flu treatments developed since the 1930s had been whole virus vaccines, however, in the 1960s and 1970s researchers began to develop newer versions: split virus and subunit vaccines.

Split virus vaccines are those disrupted by a detergent and in sub-unit vaccines the HA and NA surface antigens of the viruses are isolated, meaning less of the actual virus is actually introduced through vaccination.

These two new formulations had similar efficacy to whole virus vaccines, but with reduced adverse reactions to the vaccines.

In addition, the flu vaccines being developed in the late 1970s were trivalent, rather than bivalent. Due to a major mutation observed in 1978, H1N1 appeared during the swine flu pandemic, and vaccines began to now contain two, rather than one, strain of influenza A and one strain of type B.

1980s – Global consultation on composition of seasonal vaccines

Using data from the GISRS’ monitoring, experts came together at the WHO in 1986 for the first time to review virus circulation and determine the strains most likely to spread and infect people globally that season.

Initially this was only done annually, but now it is performed twice a year with the help of predictive, computational models. The US CDC estimates the flu vaccine has an effectiveness of between 40% and 60%, depending on the accuracy of the match between the flu virus and the vaccine. Scientists are working on better forecasting models in a bid to increase the efficacy even higher.

2003 – First live attenuated influenza vaccine approved

Although clinical trials of live attenuated flu vaccines had been conducted since the 1930s, FluMist was the first of this type of vaccine to be approved in the US.

The vaccine contains a live, but weakened, version of three different strains of flu virus, which has been mixed with genes that code for surface proteins of virus strains predicted to be circulating widely that season.

Unlike flu vaccines developed up to this point, FluMist is not administered subcutaneously via an injection, but intranasally using a spray. It is cold-adapted so it can grow at lower temperatures of the nasal passages, but cannot survive in lungs where influenza developed; the technology to create it was developed by Hunein Maassab, who had been a graduate student of Thomas Francis, one of the inventors of the first flu vaccine.

2011 – Intradermal vaccines emerge

Due to patient reluctance towards traditional intramuscular vaccination, because of a dislike of needles and unpleasant adverse reactions, which impact patient adherence to flu vaccination programmes, scientists began to develop alternative administrative methods for the annual flu vaccine.

Intradermal, skin-based approaches were viewed as promising because, according to the CDC, it requires a 90% smaller needle and 40% fewer antigens in the vaccine itself, meaning more vaccine doses can be made.

This approach also provides the same immune response as a traditional intramuscular flu shot; dermal dendritic cells targeted by the vaccine are very efficient at presenting antigens against viruses.

The 2012-3 flu season saw the first use of an intradermal flu vaccine, Sanofi’s Fluzone, which was approved by the FDA in 2011.

2012 – Improving upon trivalent vaccines

To reduce the likelihood of a mismatch between the viruses seasonally circulating and the composition vaccine, while maintaining the same immunogenicity and safety as trivalent vaccines, GSK developed the first quadrivalent vaccine Fluarix. It contains two strains of influenza A and two strains of type B, one from each antigenically distinct lineage.

Quadrivalent has now become the standardised dosage approach for seasonal flu vaccine; vaccines originally created with only three viruses, such as Sanofi’s Fluzone, have been updated to contain another influenza B virus.

2013 – Creating vaccines composed of recombinant proteins

Standard practice to manufacturing flu vaccines continued to involve using an egg-based culture and weakened flu viruses. However, to make production of viruses more nimble and flexible, facilitating quicker responses to the particular demands of a flu season, a recombinant protein-based manufacturing approach was developed. This production process makes people with egg allergies also able to be protected against flu.

Sanofi’s Flublok was the first recombinant vaccine approved by the FDA in 2013. It is made from three influenza haemagglutinin proteins, which are cultured inside insect, rather than chicken, eggs.

US Department of Health and Human Services Assistant Secretary Nicole Lurie wrote in a statement: “The method used to manufacture Flublok may help meet the increased demand for flu vaccine quickly because it has the potential for faster start-up of the manufacturing process than traditional egg-based vaccine methods.”

2019 – Progress towards a needle-free version

To help overcome patient reluctance, as well as difficulty in deploying needle-based vaccination methods in developing countries, the University of Rochester Medical Centre have created a needle-free vaccine patch that can cause the same immune response as a traditional flu shot in animal models. The results of the study were published in the Journal of Investigative Dermatology.

Dean’s professor of dermatology at the University and co-author of the study Lisa Beck commented: “[Developing] countries don’t have the manpower to vaccinate entire populations. On top of that, there’s an aversion to health care in many of these communities. A needle is painful, it’s invasive, and that makes things more difficult when you are dealing with a cultural bias against preventative medicine.”

The researchers developed synthetic peptides to bind to and inhibit claudin-1, which Beck had found to be responsible for the leakiness of eczema patients’ skin barriers. They then designed a patch containing these peptides and a recombinant flu vaccine.

Unfortunately, currently the patch is primarily effective when administered to boost immunity following an intramuscular injection of flu vaccine, but the team are planning to continue to work on the patch as they perform further animal studies and eventually clinical trials.