The Making of a More Lethal Pandemic Virus – What are the Odds?

Estimates of the case fatality rate (CFR) of the current pandemic influenza virus, the new H1N1, vary greatly, from less than seasonal flu to 8%. However, no-one disputes the fact that it is less lethal than H5N1. However, relief that the new H1N1 is not H5N1 may be premature. First, the new H1N1 itself has significant killing power. In many countries, a CFR of 0.5% has been reported, much worse than seasonal flu. And there is good reason to believe that the CFR is above 1% in countries with limited access to Tamiflu. Second, the CFR of the new H1N1 could become much worse than it is today should its genetics change.

There are three ways the genes of a virus can change: mutation, reassortment and recombination. Mutation occurs when a single nucleotide, one letter in its genetic code, changes spontaneously as a result of a copying error when the virus reproduces itself. Contrary to many erroneous press reports, H1N1 is mutating, frequently. Most mutations are expected to either be disadvantageous to the virus, in which case the viruses that have them will die out, or neutral, in which case they may be preserved but will not affect the viruses ability to infect or kill.  However, it is possible at any time for a mutation favorable to the virus, but unfavorable to us, to arise. If it does, it will start to out compete the parent strain and replace it. The odds of this happening are directly proportional to the number of people infected. The more opportunities the virus has to replicate, the more likely a mutation will arise that gives the virus new, and possibly more lethal, biological properties. This is one reason why the “let it spread” policy of opposing travel restrictions and the “keep the schools open at all costs” policy are so dangerous. By increasing the number infected, these policies make the evolution of a more lethal virus more likely.

There are 8  segments which contain an influenza virus’s genetic information. If an individual is infected with two different subtypes of  flu viruses at the same time, it is possible for a new hybrid virus to be created if the two subtypes exchange genetic segments. This is how the new H1N1 virus is thought to have come into existence. Recombination, strictly defined, occurs when only parts of the genetic segments are exchanged rather than the entire segments. Unfortunately, sometimes the word “recombination” is used to include both reassortment and strictly defined recombination. Although reassortment is thought by most virologists to be more common than recombination, there is some controversy on this subject, especially in Flubogia. Since the primary risk factor for both reassortment and recombination is the same, co-infection of a host individual, I will treat these two types of genetic change together, but will use the word reassortment when discussing this risk.

There are a number of different reassortment events that could occur. The new H1N1 virus could reassort with a variety of flu viruses that infect animals. These would include some viruses that also infect humans now, but could also include a large number of viruses that currently only infect animals. Pigs and birds are often mentioned as being of particular importance because they are known to harbor flu viruses that can, and have, infected humans.This is one reason why transmittal of the new H1N1 to animals is of concern.

The new H1N1 virus could also exchange genetic material with human seasonal flu. From a statistical standpoint, this is the most likely reassortment event because both are circulating at high levels in the human population. In fact, co-infections with both viruses has likely already occurred. However, co-infection does not necessarily lead to reassortment. Both viruses must end up in the same cell. Even then, reassortment into a functioning virus is not guaranteed. It is likely that many co-infections would need to occur to create a viable hybrid. This is why the small study in ferrets that is frequently quoted in the press as proof that this sort of reassortment won’t occur is not relevant. The small number of individuals used are insufficient to detect what is expected to be a rare event.

The most dreaded reassortment event is a hybrid between the new H1N1 and H5N1. The worst case scenario would be a virus that spreads as easily the new H1N1 but which kills with the efficiency of H5N1. What are the odds of this occurring? In truth, we don’t know. But we can consider some of the relevant variables. H5N1 is endemic in animals in countries in Asia and Africa. At least 440 people have been infected; 262 of these have died (CFR = 60%). A recent paper in BMC Medicine by Boni et al. considers the risk in Vietnam.

Modelling the progression of pandemic influenza A (H1N1) in Vietnam and the opportunities for reassortment with other influenza viruses

It is likely that, in the absence of effective interventions, the introduction of a novel H1N1 into a densely populated country such as Vietnam will result in a widespread epidemic. A large epidemic in a country with intense human-animal interaction and continued co- circulation of other seasonal and avian viruses would provide substantial opportunities for H1N1 to acquire new genes.

[snip]

The new H1N1 variant has already shown that it can be transmitted from humans to pigs, and we know that the H5N1 subtype is capable of infecting humans and of successfully reassorting with human seasonal influenza viruses under in vitro and in vivo experimental conditions [7, 8]. As the population is increasing and standards of living are improving there has been an increase in livestock production and thus there is probably more contact between animals and humans than before. These contacts offer opportunities for reassortment, and, if a novel virus with the transmissibility of H1N1 and even a fraction of the virulence of H5N1 were to emerge, the consequences would be devastating.

[snip]

The overall diversity of influenza viruses in southeastern Asia ensures that an epidemic of the novel H1N1 will create many opportunities for co-infection with other subtypes circulating in the region. Genetic and antigenic data suggest that Asia is a key source of influenza viruses that cause seasonal outbreaks in the northern and southern hemispheres [45]. This region, therefore, possesses the conditions necessary for the genesis and dissemination of new influenza variants [33, 45]. Finally, the introduction of H1N1 into southeastern Asia creates an optimal evolutionarily environment for the virus, where reassortment is neither too frequent nor too rare 46]. This means the virus receives the benefits of limited reassortment (a genetic novelty) but not the penalty of high levels of reassortment (the beaking part of beneficial gene combinations).

This paper outlines clearly why events in Asia are particularly crucial for the emergence of new strains of flu virus. The lack of accurate information from many countries in the region, especially China, may result in a nasty surprise this flu season.

References

Boni et al (2009) Modelling the progression of pandemic influenza A (H1N1) in Vietnam and the opportunities for reassortment with other influenza viruses. BMC Med. 7:43

Perez et al. (2009) Fitness of Pandemic H1N1 and Seasonal influenza A viruses during Co-infection. PLoS Currents.

For a more detailed explanation of some of the genetic mechansims of change outline here, check out this page at PFI_Main:

Random Mutation, Reassortment, and Recombination

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