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 like the 1918 Spanish influenza, with such 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.
At the time of writing, it was evident that as long as the second bird flu virus – the H7N9 strain – continues to circulate in the domestic poultry of China, it will continue to be a pandemic threat. Let us suppose that H7N9 acquires human-to-human transmissibility and retains its lethal nature for humans, causing a 30 per cent or higher mortality rate. How well prepared are we to deal with such an event? Certainly better than people were in 1918, but not as well as we need to be.
Immediate strategies to deal with the problem would include:
1.Administering stockpiled anti-influenza medicines known as neuraminidase (N) inhibitors. As mentioned earlier, to be effective, these drugs must be administered within two to three days of a person’s becoming infected.
2.Vaccinating to protect the population against the virus. Unfortunately, any prepared and stockpiled vaccines against H7N9 would probably be outdated, because all viruses continue to change. Those vaccines might well prevent death but might not protect against infection. It would be essential to make a new H7N9 vaccine as quickly as possible.
3.Using stockpiled universal anti-influenza antibody. This antibody is still at the experimental stage of development. It protects animals against all known influenza viruses and, most importantly, the protection lasts for longer after infection than that of the neuraminidase drugs. It would be a gigantic undertaking to get enough of such an antibody stockpiled, but it must be considered.
4.Using universal influenza vaccine on humans worldwide once the vaccine has been thoroughly safety tested. This would be the best strategy, but it will not be feasible until sometime in the future, perhaps 10 years or more, because the initial tests of universal vaccines in humans has just begun.
We would definitely handle a pandemic now better than the world could in 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. The viruses of greatest concern are the H2, H5, H7 and H9 subtypes. The H2 group caused a human influenza pandemic from 1957 to 1968. The H5, H7 and H9 influenza viruses have periodically spread to humans, causing disease, but have not yet caused pandemics. The H5N1 viruses have become established in the domestic poultry of many countries, including China, Indonesia, Vietnam, Bangladesh and Egypt. It is noteworthy that the H5 group of highly pathogenic influenza viruses were never reported in humans before the mid-1990s; now they are found in humans in several countries every year.
It could be argued that the apparent increased incidence of influenza in pigs and poultry is in fact due to more intense surveillance. It is true that influenza surveillance in these animals has vastly improved since the mid-1990s, but that is not the only reason for the increase. Another reason is that the global populations of intermediary hosts for influenza – ducks, chickens and pigs – have grown to meet increasing demand for protein as the world population rises. The Food and Agriculture Organization of the United Nations estimates that the global population of chickens increased more than sixfold between 1961 and 2013, while domestic ducks increased fivefold, pigs more than doubled and the human population did the same. The continued presence of highly pathogenic H5N1 and H7N9 and the less pathogenic H7N9 and H9N2, which periodically spread to humans in live bird markets, is of continuing concern.
Since we know that influenza pandemics originate from the aquatic bird reservoirs of the world and that the viruses spread through live poultry markets, or via pigs, to humans, it makes sense to attempt to prevent that initial spread. Prevention would seem to be the best policy. The closure of all the LBMs in Hong Kong in 1997 immediately interrupted the spread of H5N1 to humans. After the LBMs were reopened, the virus returned. After the emergence of the second bird flu (H7N9) in Shanghai in 2013, the number of human cases similarly fell quickly after the LBMs were closed.
From a public health perspective, permanently closing LBMs worldwide makes good sense. And it will be too late to do so after any of the bird flu viruses (H2, H5, H7, H9) have acquired the ability to spread from human to human. However, many countries are highly dependent on these markets. Closing them would be problematic in nations where household refrigeration is limited; LBMs are traditionally the safest way for consumers to obtain fresh meat.
The experience in Hong Kong has shown that the situation can change over time, however. There, the number of LBMs has fallen from over 1000 in 1997 to 132 in 2017, and people no longer depend completely on such markets. While the older members of society in Hong Kong firmly believe that live-bought chicken tastes much better than the frozen equivalent, the younger generation is moving to consumption of refrigerated or frozen chicken. One goal would be to encourage other countries to rely less on LBMs. Another goal should be to encourage countries like China and the US, where alternatives are plentiful, to begin working towards permanent closure of their LBMs for poultry.
Another way to help prevent the spread of influenza viruses to humans is to develop poultry and pigs that are resistant to influenza. We know that some animals (such as sheep) and some duck breeds (such as mallards) are naturally resistant. In Chapter 11 we saw that these ducks showed no disease when infected with a strain of H5N1 bird flu that kills 100 per cent of infected chickens and turkeys.
We now know that during the evolution of the domestic chicken from the jungle fowl, the gene for interferon, the first line of defence against influenza, was lost. All ducks have this gene. If we were to transfer this duck gene (RIG-I) to chickens, then chickens would probably not be killed by the H5N1 virus. The downside of course would be that the chicken would then become the ultimate Trojan horse in the spread of influenza – a carrier with no visible signs!
The gene for interferon is only one of many providing some protection. A better strategy would be to make chickens (and/or pigs) completely resistant to influenza. As we define all the genes that make a sheep naturally resistant to influenza, these genes could be transferred to chickens and/or pigs. This in turn of course raises the issue of the ethics – along with the risks and benefits – of the genetic engineering of animals and the manipulation of human genes. These decisions are for the future, and the possibility of influenza-resistant animals is part of that future.
Universal vaccines are much closer to being realised than influenza-resistant pigs and poultry. Scientists have discovered that all subtypes of influenza A viruses contain common or universal parts of the haemagglutinin (H) component. Figure 2.2 in Chapter 2 of the H component is useful here: the common region of this club-shaped spike would be the stalk (the head, sitting on top of the stalk, projects outside the virus). Universal antibodies have been prepared that attach to these common regions and halt infection by all subtypes of influenza viruses. The difficulty is that lower animals and humans make the vast majority of their protective antibodies to attach to the head of the club. Only a tiny proportion of antibodies are made for the common regions. Although scientists have successfully cultured generations of cells that produce antibodies to these common regions, those cell lines are extremely rare. However, many pharmaceutical companies have prepared universal antibodies and have begun to market them. While these will be useful for treating severe cases of influenza infection in humans, there are not enough available to control a rapidly spreading influenza pandemic.
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 to the stalk of the H spike. Many approaches are being tested in animals and humans, each attempting to direct the body’s immune response to these common regions. The approaches include cutting off the head of the H spike and putting on different heads, using only the stalk region to make a vaccine and creating a length of DNA that specifies the common region and then priming the human body with a DNA-based vaccine.
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.
This all sounds like an extremely protracted undertaking, but our experience from the 2013 bird flu (caused by the H7N9 virus) suggests that it may not necessarily be. After Chinese scientists published the virus’s complete genetic code, commercial companies immediately started to make the haemagglutinin and neuraminidase surface components of the influenza virus using the genetic information. As a result, a DNA vaccine to the virus was available within weeks. This effort demonstrated the wisdom of sharing information.
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. Many other anti-influenza drugs are also under development, so a well-equipped drug toolkit is in the pipeline. And we are already much better off than the world population in 1918.
Another advantage we have today is antibiotics. Bacterial pneumonia, which was responsible for many of the deaths in the 1918 Spanish influenza pandemic, can now be treated with antibiotics, and pneumococcal vaccines can be used to prevent infection caused by the bacteriumStreptococcus pneumoniae. 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 and should receive both the pneumonia and yearly influenza vaccines. As a senior myself, I strongly recommend both to all my contemporaries – the benefits are scientifically proven and the risks are extremely low.
A question I am frequently asked is, will we be able to predict the next influenza pandemic? Currently, we cannot do so; however, I am an optimist. I remember the weather forecasts of 70 years ago – they were often wrong and rarely even predicted major storms. Forecasters simply did not have the information they needed. Fast forward to today, when weather forecasts are much more precise and often even correct!
When the influenza forecasters are able to get information of equivalent quality and quantity, I am optimistic that they will be able to predict the next influenza epidemic or pandemic. But there is so much more we need to know. 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. And of course many other species are involved, adding complexity to the issue.
While pandemic influenza has been the central theme of this book, seasonal influenza is also of serious concern. Cumulatively seasonal influenza kills more people globally than pandemics (with the exception of 1918). The 2017–18 seasonal outbreaks of influenza in Britain and the US illustrate the point. These outbreaks were dominated by an H3N2 influenza virus that was dubbed ‘Aussie flu’ by the British press. Genetically the virus could be traced back to Australia from Britain and the US. The H3N2 virus was similar to the virus from the previous season, but the severity of the disease was greatly increased. It killed over 100 children in the US and filled hospitals. The recommended vaccine provided limited protection (10–30 per cent efficacy). Antigenically the H3N2 virus was similar to the virus from the previous season, but the severity was greatly increased. Much better vaccines are urgently needed, and we need to understand why severity can vary so greatly and how to treat severe cases.
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. We have made huge advances in our understanding, and in the development of medicines and vaccines, but we are not there yet.
It is a very exciting time in biological sciences – we have the power to play God, to make changes in the genetic codes of viruses, animals and humans and help make better medicines, vaccines and resistant animals. The challenge will be to regulate ourselves sufficiently to protect society from mistakes but not so far as to stifle our ability to generate scientific knowledge. For nature will eventually again challenge mankind with an equivalent of the 1918 influenza virus. We need to be careful, but we also need to be prepared.