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Metafact Review: Influenza
The flu, like the common cold, is a viral respiratory illness and is contagious. It has taken a back-seat in recent years, but millions get sick and hundreds of thousands die each year. While the cold can be caused by a range of viruses (including rhinoviruses and seasonal coronaviruses), the flu is specifically caused by the influenza virus.
There are various types of influenza virus, helpfully called A, B, C and D. The two main types of human flu viruses are A and B - these are the ones that are responsible for seasonal human epidemics every year. Influenza viruses have three proteins sticking out of their surface: the matrix protein (M2), hemagglutinin (H) and neuraminidase (N). The two latter can change. That’s how you get H1N1, for instance, a common subtype that circulates between people. However, with up to 18 different hemagglutinin subtypes and 11 different neuraminidase subtypes, there are dozens of possible combinations the virus can choose from. Lots of mutations of influenza means vaccines have to be developed and updated each year.
We asked our experts all about influenza. Just how deadly is it? Does the vaccine work? What is ‘Flurona’? Are we more likely to get a flu if we’re out in the cold? Should we worry about catching it from other species? Does vitamin C help? Read on to learn all the facts.
1930: Year when the influenza virus was first isolated
17: Proteins encoded in the genome of influenza A viruses
130: Influenza A subtype combinations identified in nature
2: Days after catching the virus when people can start getting symptoms
889 million: Value of the global influenza medication market in 2018 (USD)
0.5: mL of vaccine in a standard jab for adults
The great pandemic
In the Spring of 1918, near the end of World War I, a minuscule threat was causing just as much damage across the world. Most of those infected had the traditional, mild symptoms of influenza, but an unusually high number died after developing pneumonia. Over the three years following the initial outbreak, a third of the world’s population (an estimated 500 million) had been infected. In the US, life expectancy dropped by over 12 years. This episode is generally referred to as the great influenza pandemic or the 1918 pandemic, although it is also known as the ‘Spanish flu’ - likely due to the fact that Spain was neutral in the War and so their press was free to report on the outbreak.
With no vaccines and only a limited understanding of the threat, quarantine measures and rudimentary cloth masks were about everything the public could do to protect themselves - this may sound all too familiar to most of us, after covid. Although the lethality of the 1918 virus was not much lower than that of the SARS-CoV-2, the shorter incubation period of influenza allowed the flu to spread even more rapidly through the population than covid would do just over a century later. It is believed that the fact that battalions of soldiers were moving around the world while staying in crowded tents also contributed to the explosive spread. Indeed, case fatality was much higher among those living in inner cities or in military training camps. Some think this could have partly contributed to the intriguing “W shape” of this pandemics, which had a huge toll on people in their 30s.
While the origin of the causing virus remained obscure for the better part of the century, we now know the pandemic was caused by a H1N1 influenza virus with genes of avian origin, and its genome was eventually sequenced - remember that influenza viruses have genomes made of RNA, much more prone to degradation than DNA, so obtaining samples were the viral genome was preserved was not free of challenges. And yet, key questions as to why this virus was so devastating are still unresolved. Controversy remains, for instance, over why this particular outbreak was linked to severe pneumonias or on the reason why healthy people in the prime of their lives were so heavily affected.
This is not the only pandemic that influenza viruses have caused, either. There have been two more, the most recent of which was the 2009 swine flu pandemic. Now, over a century after the 1918 influenza pandemic, the risk of spill-over of influenza from livestock to humans is growing, as researchers study molecular patterns that allow the virus to switch hosts and global health experts warn of the impact of environmental changes have on pandemic risk.
Is the flu vaccine effective?
Some vaccines, such as the ones against measles or mumps, need just one or two doses during our childhood to protect us from the disease. However, in the case of influenza virus, jabs are needed every year for optimal protection. What does it mean? Is the flu vaccine really working?
Yes, the flu vaccine is effective. “They do not necessarily prevent everyone who has them from getting sick – but they do help to reduce the impact of infection and prevent deaths,” writes Prof Janet Daly from the University of Nottingham. The flu vaccine can protect 60%+ of the jabbed from getting sick, says Dr Chuanxi Fu from Zhejiang Chinese Medical University, who argues that “vaccination is the most effective weapon to prevent the flu.” “Besides the direct protection of the vaccinated, receiving the flu vaccine will probably also [indirectly] benefit their relatives, friends and colleagues,” he claims.
And yet, vaccine effectiveness is higher for some influenza strains than for others. For instance, a recent meta-analysis showed that the vaccine “tends to be better against influenza B (61%) and influenza A/H1N1 (54%) than against influenza A/H3N2 (33%),” says Dr Ryan Malosh from the University of Michigan. Many studies are currently being done to figure out why, he says. For this reason, flu jabs are typically a mix. In the words of Prof Jeff Kwong from the University of Toronto, “influenza vaccines contain 3 or 4 different strains: 1 H1N1 strain, 1 H3N2 strain, and 1 or 2 B strains.” This way, we can maximise our chances of getting protection.
Prof Mark Doherty from GSK writes that “there are thousands of different strains of flu circulating at any one time.” The good news, he says, is that the bulk of the disease across the population will be caused by only a handful of common strains. The not-so-good news is, “what’s common will change from year to year.” This is exactly “why you need a new vaccination every year – to cope with the changing influenza virus population,” he concludes. “The WHO and other scientists try and predict which strains of flu are going to be circulating in a given year, and they make the vaccine to defend against those viruses,” explains Dr Larisa Labzin from the University of Queensland.
Is a universal flu vaccine possible?
Influenza kills hundreds of thousands every year, and is a medical and economical burden affecting the whole society. Unsurprisingly, health systems work hard to try and avoid people from suffering from it. Besides prevention strategies and antiviral drugs, as we have seen, the vaccine is a key weapon to achieve this. However, viruses continuously mutate and evolve. This is very much the case for the influenza virus. “The high mutation rates, and the ease of spread, have meant influenza remains a need to which researchers continue to respond,” explains Prof William Rawlinson from UNSW Sydney. That’s why people, and particularly those at greater risk, need to get a jab every year to catch up with the latest changes in the virus.
A universal vaccine that could provide lasting immunity for various flu seasons or perhaps even for life - regardless of how the virus mutates - would be a game changer. But how far are we from that, and is it even possible? “There are many researchers developing a ‘universal flu vaccine’, but I am not convinced that we will have an ideal (i.e. effective, tolerated and truly universal) vaccine in the near future,” writes Prof Daly.
An important challenge in developing a universal influenza vaccine is demonstrating that it will protect against all strains all the time, according to Dr Marc André D’Aoust from Medicago. “That demonstration requires lengthy clinical studies which will prevent the regulatory approval of an universal for several years,” says Dr D’Aoust. He remains optimistic, however. “With the progress of recombinant vaccine technologies, we can expect vaccines providing broader protection to different strains or vaccines that can be administered every 2-5 years to come to market in the foreseeable future,” he explains.
That said, many experts don’t think an universal vaccine will be developed in the short term. With this in mind, it “is a big mistake to put all the funding to this development alone,” argues Dr Larissa Rudenko from MIT. In her view, “more research on the improvement of existing vaccines is urgently needed.” In a view shared by other experts, she argues that, in fact, a universal vaccine against the flu may not even be needed. “The adjuvanted inactivated and live attenuated influenza vaccines are cross-reactive enough by themselves,” she explains, so we just need to work on their “optimization to make them more efficacious and cross-protective.”
Does influenza peak in winter just because it’s colder?
Winter is undoubtedly peak season for influenza transmission, and that has knock-on effects on hospitalizations and deaths across the world, which increase way above summer rates during the winter months. “Winter seasons often coincide with respiratory virus seasons in general—not just influenza, but other respiratory viruses like rhinovirus, adenovirus, and respiratory syncytial virus,” explains Dr Maria Sundaram from the Marshfield Clinic Research Institute. That might be why some of us see going out in the cold as a risky business. Is it really cold temperatures that make us more vulnerable to respiratory illnesses, though?
The truth is, we don’t really know. Dr Stephen Kissler from Harvard University argues that “if there is a direct link between influenza and the weather, it probably has more to do with humidity than temperature.” Influenza can thrive better in the air when humidity drops, he explains, which usually happens at low temperatures. Prof Patricia Foster from Bloomington University in Indiana agrees: “there is good evidence that the flu virus survives and transmits infection better through the air when the humidity is low, which, in temperate regions, happens both outside and inside in the winter,” she writes. “In addition, when the humidity is low people’s airways dry out and that can increase susceptibility to the virus,” she adds.
It might partly come down to how cold temperatures affect behaviour as well, as we spend more time indoors during winter months. According to Prof Anne Moore from University College Cork, “due to the cold weather people congregate more indoors, in closer surroundings with less ventilation.” This “density” allows better transmission of the virus, she explains.
The jury is still out on this, however. “We do still see flu spread in tropical regions of the globe, so this can't be the whole story,” admits Dr Kissler. Other experts we asked point to lower levels of vitamin D or melatonin during winter as additional factors that could also contribute to winter spikes of influenza.
Can influenza spread between species?
Influenza viruses can not only infect humans, of course. Because of their great diversity, some of these viruses can circulate in pigs, bats, horses, dogs or birds. Indeed, bird flu outbreaks have been in the news a lot in recent months as high infection levels are being recorded in Europe, and countries like the UK have reported their highest ever toll of avian influenza. The flu is one of the most deadly animal diseases, as it turns out, and can kill up to 90% of infected chicken. While influenza didn't affect wild birds in the past, when the H5N1 strain emerged, spillover from poultry outbreaks meant these birds - including migratory species - could become infected as well. This can set a vicious circle where the virus mutates in packed chicken or turkey farms, is spread by migratory birds and could eventually be passed on to us.
The question is, can influenza spread from one species to another? Absolutely, say the experts. For many, this calls for a “one-health” approach that considers our relationship with other species. According to Prof Ian Frazer from the University of Queensland, birds “are a major vector for spreading the flu viruses that make humans sick, and pigs are a common intermediary between birds and humans, allowing the flu viruses to adapt to infecting mammals.”
There have been episodes where a jump to humans has happened, explains Prof Foster, such as the 1968 Hong Kong flu pandemic (caused by a jump from birds) and the 2009 swine flu pandemic (caused by a jump from pigs). “This mixing up of the different strains in animals and humans allows genetic exchanges among the viruses, producing new, potentially dangerous, variants,” she warns.
Are we breeding the next pandemic? “Currently several avian influenza A strains that have already infected some humans are being closely monitored by world health organisations for their potential to cause a new pandemic,” explains Prof Foster. However, she also urges calm: “a pandemic will only erupt if one of the variants acquires the ability to efficiently transmit from person to person.”
Does Vitamin C help with the flu? Not much evidence at all that it can help against flu symptoms. A lot more has been written about whether it helps with colds, but even then experts are split.
Does zinc help against the flu? A recent study found that over-the-counter zinc supplements are associated with fewer upper respiratory infections. That said, the effect was modest (1 infection avoided for every 20), the strength of the evidence was poor, and zinc might come with side effects.
Is ‘flurona’ a new threat? No. This made-up word was all over the news a few weeks ago following a confirmed case of a flu-COVID co-infection. However, these co-infections are not new, and over 80 had already been reported so far.
Can we prevent the flu?
Yes, partially. Vaccines help to reduce the spread of flu, but their main purpose is to reduce the severity of influenza illness, making it less likely that people with flu will need medical attention. Our experience with COVID-19 has also shown that non-pharmaceutical interventions like masking and physical distancing can almost completely suppress the spread of flu; this is probably why we didn't see much flu spread at all in the winter of 2020. While we don't want to have such severe restrictions every year to eliminate the spread of the flu, this still provides good evidence that more manageable, intermediate changes to our behavior could go a long way toward reducing influenza cases.
Dr Stephen Kissler from Harvard University
Influenza poses a threat to societies across the globe. It usually gives you fever, sore throat and aches, but it can be dangerous or even deadly for some.
Jabs (developed against a mix of the strains expected to dominate) reduce serious illness and deaths. Antivirals and non-pharmaceutical measures, like mask wearing if you have symptoms, can also help us tackle spikes.
Influenza viruses mutate - a lot. Researchers are working on a universal flu vaccine so we don’t have to change the recipe and get people jabbed every year, but we are not there yet. That said, vaccines providing broader coverage are being developed.
The jury is still out on exactly why there’s a winter spike of influenza. Low temperature and humidity enhance viral transmission, but us spending more time in less ventilated indoor spaces is also likely to contribute.
Influenza can affect other species too, which encourages a “one-health” approach to deal with emerging infectious diseases. It has jumped to humans in the past, so the concern is whether it will spread between humans following animal to human transmission.