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Influenza and the Holy Grail Vaccine

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The influenza virus caused between 941 million illnesses and 12–52,000 deaths in the United States each year between 2010 and 2020. In a “bad” flu year, around 30,000 people die in the UK from flu and pneumonia. A 2018 study estimated that 30% of the burden of infectious disease in Europe is due to influenza. The World Health Organization (WHO) estimates 3–5 million severe flu cases and 290,000 to 650,000 respiratory deaths occur worldwide each year.

Those at high risk of flu complications are children younger than two years and adults aged 65 years and above, as well as pregnant women and people with certain chronic medical conditions. The best strategy for avoiding flu is to get a vaccine shot, with current vaccines offering protection against four strains of the virus: two type B and two type A strains. The WHO recommends vaccination as the main measure for preventing the disease and advises that healthcare workers receive a flu jab.

Egg-based vaccines rule the roost

Most flu jabs consist of key proteins from viruses replicated in eggs. “It is pretty old school. The virus is grown in eggs, harvested and chemically treated and then it’s purified to some degree,” says Kim Roberts, virologist at Trinity College Dublin. The most important component is the hemagglutinin (H) glycoprotein at the viral surface, which is quantified after manufacture. “That’s the bit that your immune response generates most neutralizing antibodies against,” Roberts explains.

There are some other types of flu vaccines. In 2011, a live attenuated vaccine for intranasal use was approved in Europe for children and adolescents. The UK vaccinated over 3 million children with this nasal spray in 2020–21. “This virus replicates a little bit in the nose and that stimulates a really good immune response,” says Roberts. In the US this vaccine is also licensed for adults. The US FDA approved one inactivated flu vaccine that is made in mammalian cells, rather than eggs, but production is limited. Egg-based vaccines rule the roost, and account for ~82% of the US supply chain this year. They dominate in Europe too. The process of making them has incrementally improved over 70 years, but still takes around six months. “There are multiple problems [with this production method],” affirms Roberts, one example being, “decisions in selecting strains have to be made eight months in advance.”

Strains are selected by WHO experts in February for the Northern Hemisphere winter season, for example. However, rapid viral evolution can mean the vaccine does not match the circulating strains well the following season. Also, some strains do not grow well in eggs. “It’s a compromise between the strain that’s going to give you a good antibody response, and a strain that will grow well in eggs,” Roberts explains. Also, the chosen strains may adapt to replicate well in eggs, a disadvantage since we want them to closely mirror wild type viruses, rather than evolve into superior egg viruses.

“Flu vaccines could be improved in many ways,” says Rebecca Cox, head of the influenza centre at the University of Bergen in Norway. “But at the end of the day it has to be cost effective.” One major issue is that the vaccines don’t boast impressive efficacy, especially amongst the elderly; CDC figures for the last 10 years suggest efficacy between 10–60%. “Moderately effective,” is how Cox sums up flu vaccines, though it reduced the risk of an adult being admitted with flu to a general ward by 37% and an ICU by 82%, a 2018 study found. Approaches to improve efficacy in the elderly include higher doses or adding an immune-boosting adjuvant. There is limited evidence thus far that newer flu vaccines are more effective, according to a 2020 study from the European Centre for Disease Control.

Quest for the Holy Grail

Since strain antigens drift and immunity wanes, it is recommended that vulnerable people get a flu jab every year. “Every three to four years you really need to update the vaccine, but the vaccine efficacy is low anyway, and some years the vaccine does not match the current strain well and you can have really low efficacy,” says Sunetra Gupta, evolutionary biologist at the University of Oxford. This problem has long been recognized, and it has led researchers to pursue a universal flu vaccine, the “Holy Grail” of flu vaccinology. This is a vaccine that works against current and future strains. “Efforts to develop a universal flu vaccine have been going on for decades,” says Roberts.

Such a vaccine could allow stockpiling for the emergence of a pandemic influenza strain. The last pandemic occurred in 2009, but there were flu pandemics also in 1918, 1957 and 1968. It will happen again, and the six-month process of making egg-based flu vaccines leaves the world vulnerable.

Different strategies for a universal flu vaccine are being tried. There was one universal flu vaccine in Phase III clinical trials from BiondVax in Israel, but it reported disappointing results in October 2020. Another experimental vaccine (FLU-v from Imutex) stimulates killer T cells to target conserved internal proteins common to all flu viruses, which are not as variable as surface proteins. It has reported positive results in a Phase IIb challenge study. Such efforts are noted in this tracker from the Influenza Vaccines Roadmap initiative.

Another approach is to redirect the immune system to more conserved areas of the hemagglutinin protein to get around its shape shifting that evades antibodies. Florian Krammer at Icahn School of Medicine at Mount Sinai, New York, has focused on the stalk portion, close to the viral membrane. He recently reported positive results from a Phase I clinical trial on healthy US adults. This tested the safety and ability of a chimeric vaccine that consists of different hemagglutinin stalks and head parts from avian flu subtypes, along with the AS03 adjuvant.

The hope here is that antibodies raised by the vaccine would work against different strains, or even entirely new strains, of the virus. But this is not easy task. “It is difficult to do something that doesn’t happen in nature,” says Roberts. “Whether it’s a natural infection or a vaccine, most people don’t generate cross-reacting immune responses,” meaning responses that tackle different strains of the virus.

Nevertheless, Gupta at Oxford has also been on the hunt for a universal flu vaccine. She noted that the receptor binding domain of flu hemagglutinin contains flexible loops that shape-shift to throw off antibody attachment. “The dogma was that anything that the immune system naturally sees in flu is highly diverse,” says Gupta, and therefore not suitable for a universal vaccine. She wondered if there were targets of natural immunity that varied, but were not highly diverse, and asked why certain strains persist for years, only to be completely replaced by another unique strain.

Her research revealed parts of the head of the hemagglutinin protein that seemed to come in four to five flavors, which the virus shifted through over the decades. Changes alter the configuration of the receptor binding domain and mean antibodies for previous strains no longer bind so well. “It always has to circle back or keep reusing these epitopes,” says Gupta. “Once [the virus] mutated this region, [antibody] neutralization dropped dramatically.” She reported that young children were naturally immune to some historical strains, including from the 1930s, and that this was partly due to having the same epitopes close to the receptor binding domain.  

By including the four variations into one vaccine, Supta generated immune protection in mice to human H1N1 strains that have circulated since 1918. “We’d be able to vaccinate with a cocktail of four different epitopes and it focuses immunity on an area naturally recognized by the immune system,” she says. This is now being licensed by Blue Water Vaccines, who will fund clinical trials.

Another trial planned for early 2022 will see four inactivated strains of avian flu either injected or sprayed into the noses of volunteers. “These are low pathogenic avian flu influenza viruses, chosen because they are the phylogenetic precursors to most groups of human influenza A viruses,” says Matthew Memoli, flu virologist at the National Institutes of Allergy & Infections Diseases. His hope is that deploying a cocktail of whole inactivated viruses will protect the old, the young and immune compromised. “A universal vaccine shouldn’t be just universal in the viruses in covers, but also in terms of the types of people it can protect,” says Memoli.

Potential pandemic silver linings

Unfortunately, the pandemic has significantly slowed R&D on influenza vaccines, admit researchers. But SARS-CoV-2 accelerated two new platforms – viral vector and mRNA vaccines – a potential silver lining. “It will be interesting to see what happens with adenovirus vector-based vaccines and the messenger RNA and how that transforms the landscape,” says Cox. But she warns, “It’s not a given that they will be more successful for influenza.” What is a sure bet, however, is that they will be faster to design and manufacture – especially the mRNA vaccines. “Once you’ve identified the strain of virus that you want to base your vaccine on, it is much faster to make that messenger RNA,” says Roberts. This could drastically cut the eight-month time lag in generating new seasonal vaccines, meaning that the strains chosen would be a closer match to what is circulating in the community.

Moreover, there have already been studies on flu vaccines using mRNA. “The results were okay, but weren’t fantastic,” notes Cox. Pfizer recently announced a trial planned for 2022, and Moderna is reportedly working on a COVID-19 and flu combo shot. Flu vaccine researchers are optimistic. “I think this will probably be a paradigm shift in vaccinology for influenza, in terms of these technologies now being adapted for large-scale production, which they weren’t before,” says Cox. It might even assist in the development of a universal flu vaccine.

Flu vaccination will continue to be needed. “The flu situation is never stable. It changes every year, and we get periodic pandemics,” says virologist Elly Gaunt at the University of Edinburgh. “We are never getting rid of flu, because it has got a reservoir in wildfowl, and we can’t vaccinate every migratory bird in the world. Flu is not going anywhere.” A universal flu vaccine would be a perennial boon for public health. In the meantime, faster vaccine production using the newly validated platforms, may offer a superior vaccine, if their costs can be kept competitive.