Sep 22nd 2021
IN SEPTEMBER 2020 doctors and public-health officials in the northern hemisphere were on high alert. They did not know how co-19 would behave in the first winter of the pandemic. Respiratory viruses tend to surge during cold weather. And there were the usual concerns about influenza, the shape-shifting virus that sickens and kills many people every year. At worst, doctors feared they would see simultaneous outbreaks of co-19 and flu which would overwhelm hospitals and send deaths soaring—a “twindemic”.
It never materialised. Co-19 cases continued to rise in much of the world in late 2020 and early 2021 but the wave of influenza never struck. And yet today those same experts are worried once again. Flu’s absence in 2020-21 has probably made the prospects for 2021-22 worse: outbreaks could occur sooner, last longer and affect many more people than usual.
Seasonal flu is caused by a group of viruses that circulate around the world in and between birds, humans and other mammals. The flu season in the northern hemisphere—loosely defined for this purpose as North America, Europe, north Africa and West Asia—usually starts around October each year and peaks the following January or February. In the southern hemisphere the season begins around May and peaks between June and August.
Two types of virus cause winter flu. Influenza A viruses originate in birds and pigs. The H1N1 and H3N2 subtypes (named for the structures of two proteins on their surfaces, also infect humans. Influenza B infects only humans.
As these viruses mutate and spread, they are adept at reconfiguring the proteins that sit on their surfaces, making them less recognisable to people’s immune systems, even those that have encountered similar viruses before. As a result, flu vaccines need to be updated and re-administered every year.
It takes manufacturers at least six months to create, test and manufacture large quantities of flu vaccines, so they need to decide well ahead of the flu season which versions of which viruses vaccines should target. It is at this point that the World Health Organisation (WHO) steps in.
The Global Influenza Surveillance and Response System (GISRS) is a network of laboratories and public-health institutions in 123 countries that collect respiratory samples throughout the year. They sequence the genes of any influenza viruses and characterise the proteins on their surfaces to build a detailed picture of the most prevalent influenza viruses in circulation, how those viruses are evolving and which new ones are emerging.
Armed with these data, every February and September the WHO brings together experts to recommend which strains of flu should be targeted by the forthcoming vaccines for the northern and southern hemispheres respectively.
In February 2021 those experts, using information from the viruses circulating in previous months in the southern hemisphere, selected four viruses for this year’s vaccines for the northern hemisphere. By the start of October, those vaccines should start going into arms.
The first big uncertainty for the coming winter is whether they picked the right viruses. This is always a problem but it is especially acute this year. Far less information was available from GISRS because the 2020-21 flu season was such a non-event across the world (see chart). Less than 0.2% of samples globally tested positive for influenza between September 2020 and January 2021, according to the WHO. Between 2017 and 2020 the rate was 17%. The number of flu hospitalisations in America in the 2020-21 season was the lowest since such records began in 2005. The Centres for Disease Control and Prevention said it received one report of a child dying of flu in the 2020-21 season in America, compared with 199 in 2019-20.
What explains such low levels of flu? Because of co-19, people were wearing face masks, social distancing, washing their hands, avoiding public transport and staying at home. This also helped limit the spread of other respiratory viruses, including influenza.
This happy result has a troubling corollary. Vaccines for influenza are generally less effective than those for co-19; they prevent about 70% of detectable infections in healthy adults and about 50% in the elderly. How well a vaccine works is a function of how well its components match the viral strains that a person actually encounters. When they are poorly matched, vaccines are less effective at preventing both infection and severe disease, resulting in worse epidemics. Given the paucity of information available about which strains of flu are circulating, the Academy of Medical Sciences (AMS) in Britain reckons the likelihood of mismatches is higher this year.
A second big unknown is how people’s immune systems, which have largely avoided influenza for more than a year, will respond when they do encounter it. The mild or non-existent influenza season of 2020-21 was probably welcome at a time when co-19 was killing tens of thousands of people and putting many more in hospitals. But it also means that many fewer people will have been exposed to the circulating flu viruses in the past year so the levels of natural immunity in populations will be relatively low. A wave of influenza in such an environment “could be problematic”, warned the AMS.
Even those who have previously been exposed are at risk. Immunity diminishes over time. Worse, flu viruses change rapidly, so the immune system’s memory of one season’s flu may be of limited use against new viruses. Some have little or no protection against flu—babies and young children who have never been exposed to it.
Research on previous flu outbreaks in America proes some clues for what might happen in 2021. A study in 2013 examined what happened after mild winters, when rates of influenza transmission tended to be lower than usual and therefore resulted in lower-intensity epidemics. The researchers found that 72% of the subsequent epidemics were more severe than average. They started 11 days sooner and the epidemic growth rate was 40% higher. Their severity was probably exacerbated by their earlier onset because fewer people would have been vaccinated at that point.
Modelling by the AMS has shown that, if Britons returned to their pre-pandemic way of life, the country could at worst face a winter influenza epidemic 2.2 times more deadly than normal. In recent years flu has typically killed 10,000-30,000 people annually in England. The 2017-18 season was the most recent bad season, with about 26,000 deaths.
Respiratory syncytial virus (RSV) proes more clues as to what could be in store for the northern hemisphere. RSV is a major cause of hospitalisation and death in young children, particularly those less than a year old. Reports from around the world showed a 98% reduction in cases of RSV during the pandemic. But researchers in Australia also found that, after physical distancing restrictions had been relaxed in the last few months of 2021, RSV cases shot up. They peaked in December (the country’s summer), instead of the usual June or July (its autumn/winter). The peak itself was almost three times higher than usual and there were many more cases of infection in older children. Doctors in New York City found similar results after March 2021.
In the grippe of winter
If influenza or RSV surge when co-19 levels are high, some doctors worry that people could be struck by several respiratory viruses at once. Around a fifth of children who end up in hospitals with bad lung disease are infected with multiple viruses, says Stephen Holgate, a pharmacologist at the University of Southampton. Growing eence suggests that influenza and sars-cov-2 can coexist and that they interact negatively, he explains. The AMS reckons that being infected with influenza A makes people more susceptible to sars-cov-2. It also worries that the wider circulation of other respiratory viruses could lead to more dangerous variants of sars-cov-2.
Preventing a “twindemic” in 2021-22 will take three steps, argues Dame Anne Johnson, an epidemiologist at University College London and president of the AMS.
First, a concerted effort to get more vaccines—for both co-19 and influenza—into arms. Since natural immunity to flu is probably at its lowest for years around the world, immunity via vaccines will need to make up the shortfall. That will mean jabbing those normally at high risk, such as the elderly, pregnant women and health-care workers, but also children, who are prodigious spreaders of infection.
Second, since the symptoms of various respiratory illnesses including co-19 are similar, doctors and clinicians need routine access to multiplex testing, where throat swabs are tested for different viruses at the same time. Rapid tests for influenza should readily be available in hospitals, clinics, care homes and pharmacies, says Professor Johnson. Identifying infections is useful—the timely use of antivirals can shorten an episode of flu.
The third way to fend off the bug is for ordinary people to practise what Professor Johnson calls “respiratory hygiene”. Social-distancing rules may no longer be in force in much of the world, but people should still wear masks in crowded indoor environments. They should also work from home where possible and socialise outdoors, she says.
Scientists will face the coming flu season using the tools they know work. But the current process for making flu vaccines is slow—it takes six months and involves incubating viruses in chickens’ eggs or mammalian cells before carefully extracting and purifying proteins that go on to make the building blocks of the vaccines.
The success of messenger RNA (mRNA) vaccines for co-19 has spurred scientists to investigate how to use the same technology against flu. mRNA should speed up the process, leaving less time between concocting the vaccine and the viruses mutating. And mRNA vaccines should be easier to tweak if new strains emerge.
In July Moderna, an American firm that developed a successful mrna co-19 jab, began a trial of its mrna flu jab, which targets all four virus strains recommended by the WHO. Pfizer, the other American mRNA co-19 vaccine-maker, has also adapted its technology to make a candidate flu vaccine. Seqirus, a British drug firm, has announced plans to begin clinical trials of its mRNA flu vaccine in late 2022. It wants to use self-amplifying messenger RNA (SA-mRNA). A typical mRNA vaccine tells a person’s cells to make an antigen (against which their immune system can then make antibodies). SA-mRNA vaccines also instruct the body’s cells to replicate the mRNA itself. That should mean a much smaller vaccine dose can elicit the same immunological result, useful if you need to vaccinate people against multiple flu viruses at once—or keep boosting immunity for co-19, which is set to join influenza as a regular visitor every winter. ■