Issue #46: COVID-19 and influenza

Written by Nobel Laureate Professor Peter Doherty

Early on in the course of this pandemic, much of our thinking about COVID-19 was conditioned by our long confrontation with influenza (flu). I’ve been writing a lot about the coronaviruses and, as I think there are lessons to be learned from comparing flu and COVID-19, I’ll devote this essay to providing some background on human influenza. Next week, we’ll probe the link between immunity and pathogenesis for these two diseases. Hopefully, that will illuminate how COVID-19 vaccines work.

All nations are accustomed to regular ‘seasonal’ flu epidemics, which are essentially global pandemics caused by mutated versions of influenza viruses that circulated in the previous year. When it comes to pandemic versus epidemic, there’s no consistency in nomenclature across the public health spectrum. For example, people who work with the noroviruses, the ones that cause disastrous outbreaks of three-day diarrhea aboard cruise ships, refer to mutants from existing viruses (equivalent to a ‘seasonal’ flu) as new pandemic strains.

With influenza, the word ‘pandemic’ is reserved for novel variants that (like SARS-CoV-2) jump across into us from other species, then spread from person to person. The worst such event we know about was the 1918/19 ‘Spanish flu’ that likely originated in birds. At least 50 million people died in a global population that was less than a third of that today. The most recent was the 2009/10 H1N1 swine flu, which emerged in Mexico when two viruses that normally circulate in pigs reassorted to give a new virus that was highly infectious for us.

Once that 2009 H1N1 virus had infected people in nations across the planet, the World Health Organization (WHO) followed their established protocol for influenza and declared that we had a pandemic. But, in the minds of many people, the word ‘pandemic’ translates to severe disease and that 2009 swine flu seemed no worse than a seasonal flu. That led some to accuse the WHO of ‘scaremongering’: it may be why the WHO was slow to call COVID-19 as a pandemic.

What is an H1N1 virus? The influenza A viruses, the ones that cause pandemics, are characterised primarily by the hemagglutinin (H) and neuraminidase (N ) molecules on their surface. In all, there are 18 different H and 11 N types. Though, when they jump into us, we usually contract them from domestic chickens or pigs, their primary maintaining hosts in nature are wild aquatic birds that normally experience inapparent gastrointestinal tract infections. As the flu A viruses survive well in fresh water and infect just about all bird species, this is a great strategy for the long-term survival of these viruses. In addition, influenza A virus strains circulate in a number of different vertebrate species, particularly human beings (H1N1 and H3N2), pigs (H1N1, H3N2 and H1N2) – pigs can infect us and we infect them – and domestic chickens (H5N1, H7N7 and more).

What does reassortment mean? The influenza virus genome is in eight different segments. If a single cell in our (or a bird) lung becomes infected with, say, an H1N1 virus that is circulating in humans and an H9N2 virus from chickens, there is potential for the emergence of novel H9N1 or H1N2 viruses that might spread from human to human. This would then be a new pandemic strain. At the moment, there is some concern re people contracting an H5N8 virus from close contact with domestic chickens, an experience we’ve also had over the past 20 years with H5N1 and H7N9 viruses – often with fatal consequences – but they did not establish in human populations.

Apart from the influenza A viruses, we are also infected with influenza B viruses that circulate only in humans. And both the A and B flu viruses mutate at a high rate, with new ‘seasonal’ variants emerging from a myriad of potential escape mutants that are not neutralised by the circulating antibodies, or immunoglobulins (Igs) elicited by infection with, or vaccination against, currently (and previously) circulating strains. As a consequence of this extraordinary complexity, the WHO network of six collaborating centres across the planet – there is one at the Doherty Institute led by Professor Kanta Subbarao and Professor Ian Barr – is among the best organised and most effective of all WHO activities. Among their major roles is the identification of candidate viruses for next year’s vaccines. Currently, there are discussions about developing a comparable network for coronaviruses, which may well build on the existing flu centres.  

Just as SARS-CoV-2 enters respiratory epithelial cells after the virus spike protein receptor binding domain (RBD) grabs the angiotensin converting enzyme 2 – also called the ACE2 receptor – flu viruses infect when the H molecule attaches to cell surface sialic acids (SA, sugars). Then, once progeny flu virions are made in an infected ‘factory cell’, the N breaks that H-SA bond and allows the virus particles to ‘escape’. The anti-influenza neuraminidase inhibitor drugs ‘Relenza’ and ‘Tamiflu’ that work for all influenza A and B viruses – we need similar, class-specific antivirals for the coronaviruses – block the N so that it can’t operate. As a consequence, the newly made flu virions ‘hang-up’ on the cell surface and can’t break free to infect more cells in us, or in other people. Drugs are great, but vaccines are a lot cheaper and more readily rolled out across the planet. Back to immunity and vaccines next week.