The flu expert who predicted a pandemic: “Millions of people would die”

Otago University researcher Robert G Webster's book on influenza was published in December. It included a terrifyingly prescient chapter about pandemics.

The question uppermost in my mind as we look at the past 100 years of influenza pandemics, epidemics and control strategies is whether another pandemic with a deadly and disruptive impact on society is possible.

The answer is yes: it is not only possible, it is just a matter of time.

We would definitely handle a pandemic now better than the world could during the Spanish influenza of 1918, but would we do any better than we did in controlling the relatively rather mild H1N1 pandemic of 2009, when close to 300,000 people perished? A reality check suggests that we are marginally better prepared now, but that we could not stop an influenza pandemic.

Millions of people would die before we could bring it under control or modify its effect.

From where might such a pandemic spring? Since the mid-1990s, influenza has occurred more and more frequently in intermediate hosts, including pigs and poultry.

We urgently need a universal vaccine, but this is still a pipe dream. The challenge is to make a vaccine that will persuade the human body to preferentially make antibodies. Many approaches are being tested in animals and humans, each attempting to direct the body’s immune response to these common regions.

Eventually one or more of these strategies will be shown to provide universal protection to all influenza viruses. The next challenges will be to determine and then demonstrate that these vaccines are safe and have no downside, such as making the virus more easily taken into cells. Once all the safety and effectiveness goals are achieved, influenza scientists’ dream of a universal vaccine may well be realised.

Unfortunately, there are very few anti-influenza drugs available that make much impact. Currently we have one ancient family of ‘plug drugs’ (amantadine and rimantadine), which plug up the tiny pipeline into the virus’s core – the M2 protein. While they do work, influenza viruses rapidly become resistant to them, and they are rarely used. The more effective family of drugs targets the neuraminidase component (Tamiflu, Relenza, Rapivab and Inavir). These drugs block the enzyme so the virus remains stuck to the host cell and cannot spread. They are very effective if administered immediately a person becomes infected but are not helpful after about two days. However, they are the best we have so far.

Two new drugs, T-705 (favipiravir) and Baloxavir marboxil (Xofluza), are showing considerable promise for treatment of influenza. These drugs target different components of the polymerase complex. Both drugs are approved for human use in Japan: T-705 was approved for emergency use against oseltamivir (Tamiflu) resistant viruses in 2014 and Xofluza was approved for treatment of influenza in February 2018. T-705 is what we call a nucleotide analogue – it looks like one of the building blocks of a virus genome, but when incorporated into the virus’s RNA it makes it non-functional. Xofluza binds to a pocket in the PA protein and blocks its function in replication. A single oral dose of this drug is sufficient to treat influenza infection in humans, making it very convenient.

Each of these drugs targets a different vital pathway in the replication of an influenza virus. Used in combination with a neuraminidase inhibitor (Tamiflu), they would have real impact on reducing the spread of an influenza pandemic.

Bacterial pneumonia, which was responsible for many of the deaths in the 1918 Spanish influenza pandemic, can now be treated with antibiotics. But there are two difficulties: the population’s increasing resistance to antibiotics, and the fact that not enough people are vaccinated against bacterial infection. The elderly are at particular risk.

A question I am frequently asked is, will we be able to predict the next influenza pandemic? At one point we thought that finding the genetic code of the influenza virus would give us the answer. Well, it gave us some information, but to find the full answer we had to remake the virus. This process in turn provided valuable information on the many techniques the virus uses to circumvent the defence mechanisms of the human body. We discovered that because the 1918 virus made such vast amounts of virus in the host’s body, the body overproduced its own toxic protective chemicals, thus turning the guns on itself.

To fully understand the mechanisms involved there, we need to know the full genetic code of humans and the myriad different pathways of interplay between it and the virus.

It is sobering to realise that, after nearly 100 years of studying the 1918 influenza, we still do not know precisely why the virus was such a killer; nor are we significantly better prepared to deal with a repeat event.

Nature will eventually again challenge mankind with an equivalent of the 1918 influenza virus. We need to be prepared.

An edited version of the concluding chapter to Flu Hunter: Unlocking the secrets of a virus by Robert G Webster (Otago University Press, $35)

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