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Pandemic flu: A national framework for responding to an influenza pandemic

Influenza pandemics are natural phenomena which occurred three times in the last century. Their severity has ranged from something similar to seasonal influenza to a major threat, with many millions of people worldwide becoming ill and a proportion of these dying. No country can expect to escape the impact of a pandemic entirely, and when it arrives most people are likely to be exposed to an increased risk of catching the virus at some point. Influenza pandemics therefore pose a unique international and national challenge. As well as their potential to cause serious harm to human health, they threaten wider social and economic damage and disruption. Measures to prevent, detect and control them require coordinated international effort and cooperation, with one countrys action or inaction potentially affecting many others.
Although it is highly likely that another influenza pandemic will occur at some time, it is impossible to forecast its exact timing or the precise nature of its impact. This uncertainty is one of the main challenges for policy makers and planners. Even if as seems likely a pandemic originates abroad, it will probably affect the UK within two to four weeks of becoming an epidemic in its country of origin, and could then take only one or two more weeks to spread to all major population centres here. In addition to collaborating actively in multi-national prevention, detection and research, the Governments aims at a national level are to ensure that the UK is prepared to limit the internal spread of a pandemic and to minimise health, economic and social harm as far as possible.
This framework sets out the Governments strategic approach to achieving these aims and is intended for use by all those involved in planning for and responding to an influenza pandemic. It builds upon and supersedes the most recent version of the UK Health Departments UK Influenza Pandemic Contingency Plan (published in October 2005), expanding it to cover a more comprehensive range of impacts and responses. The framework will also inform the development of community and organisational arrangements that are appropriate to local circumstances and are sufficiently consistent to ensure an equitable and sustainable national response. It includes information to support planning and, where necessary, provides signposts to additional sources of technical information and guidance.

Related:

• Newsflash: H5N1 Influenza in Suffolk again
• H5N1 influenza is no longer “bird flu”
• Global migration of influenza viruses
• The Biology of Influenza
• Influenza pandemic – when?

Defra has confirmed that the type of bird flu found in turkeys on a Suffolk farm is the virulent H5N1 strain.

RNA interference, RNAi, is a natural antiviral mechanism in plants and invertebrates. Based on the results obtained in plants, Drosophila and worms and because the RNAi machinery is present in all animals from nematodes to mammals, RNAi has often been proposed to be involved in the response to viral infection in vertebrates. In mammals the interferon (IFN) system is a central innate antiviral defence mechanism, while the involvement of RNA interference (RNAi) in antiviral response against RNA viruses is uncertain. Here, we tested whether RNAi is involved in the antiviral response in mammalian cells. To investigate the role of RNAi in influenza A virus-infected cells in the absence of IFN, we used Vero cells that lack IFN-alpha and IFN-beta genes. Our results demonstrate that knockdown of a key RNAi component, Dicer, led to a modest increase of virus production and accelerated apoptosis of influenza A virus-infected cells. These effects were much weaker in the presence of IFN. The results also show that in both Vero cells and the IFN-producing alveolar epithelial A549 cell line influenza A virus targets Dicer at mRNA and protein levels. Thus, RNAi is involved in antiviral response, and Dicer is important for protection against influenza A virus infection.

Dicer is involved in protection against influenza A virus infection
J Gen Virol. 2007 88: 2627-2635

In temperate regions influenza epidemics recur with marked seasonality: in the northern hemisphere the influenza season spans November to March, while in the southern hemisphere epidemics last from May until September. Although seasonality is one of the most familiar features of influenza, it is also one of the least understood. Indoor crowding during cold weather, seasonal fluctuations in host immune responses, and environmental factors, including relative humidity, temperature, and UV radiation have all been suggested to account for this phenomenon, but none of these hypotheses has been tested directly. Using the guinea pig model, these authors evaluated the effects of temperature and relative humidity on influenza virus spread. By housing infected and nave guinea pigs together in an environmental chamber, they carried out transmission experiments under conditions of controlled temperature and humidity. They found that low relative humidities of 20%-35% were most favorable, while transmission was completely blocked at a high relative humidity of 80%. Furthermore, when guinea pigs were kept at 5°C, transmission occurred with greater frequency than at 20°C, while at 30°C, no transmission was detected. The data implicate low relative humidities produced by indoor heating and cold temperatures as features of winter that favor influenza virus spread.
To investigate the mechanism permitting prolonged viral growth, expression levels in the upper respiratory tract of several innate immune mediators were determined. Innate responses proved to be comparable between animals housed at 5°C and 20°C, suggesting that cold temperature (5°C) does not impair the innate immune response in this system. Although the seasonal epidemiology of influenza is well characterized, the underlying reasons for predominant wintertime spread are not clear. This provides direct experimental evidence to support the role of weather conditions in the dynamics of influenza and thereby address a long-standing question fundamental to the understanding of influenza epidemiology and evolution.

Influenza virus transmission is dependent on relative humidity and temperature
PLoS Pathog 3(10): e151

Related:

• Global migration of influenza viruses
• The Biology of Influenza

Highly pathogenic avian H5N1 influenza viruses have spread throughout Asia, Europe, and Africa, raising serious worldwide concern about their pandemic potential. Although more than 250 people have been infected with these viruses, with a high rate of mortality, the molecular mechanisms responsible for the efficient transmission of H5N1 viruses among humans remain elusive. We used a mouse model to examine the role of the amino acid at position 627 of the PB2 viral protein in efficient replication of H5N1 viruses in the mammalian respiratory tract. Viruses possessing Lys at position 627 of PB2 replicated efficiently in lungs and nasal turbinates, as well as in cells, even at the lower temperature of 33°C. Those viruses possessing Glu at this position replicated less well in nasal turbinates than in lungs, and less well in cells at the lower temperature. These results suggest that Lys at PB2–627 confers to avian H5N1 viruses the advantage of efficient growth in the upper and lower respiratory tracts of mammals. Therefore, efficient viral growth in the upper respiratory tract may provide a platform for the adaptation of avian H5N1 influenza viruses to humans and for efficient person-to-person virus transmission, in the context of changes in other viral properties including specificity for human receptors.

Growth of H5N1 Influenza A Viruses in the Upper Respiratory Tracts of Mice
PLoS Pathogens 2007 3 (10) e133

What does this all mean?
The H5N1 influenza virus (formerly known as “bird flu”) has mutated to infect people more easily, although it still has not transformed into a pandemic strain. In order to acquire the capacity for efficient human-to-human transmission, H5N1 avian influenza viruses must undergo a series of genetic changes resulting in the ability to replicate at lower temperatures, in a wider range of cell types, to recognize human receptors, and other unknown phenotypic changes controlled by virus proteins. Birds usually have a body temperature of 41°C, and humans 37°C. The human nose and throat, where flu viruses usually enter, is usually around 33°C, so the virus doesn’t grow well in the nose or throat of humans. This research identifes a mutation which allows H5N1 to replicate in the cooler temperatures of the human upper respiratory tract. The H5N1 viruses circulating in Europe and Africa all have this mutation. What we don’t know at present is how many additional mutations are needed for these humanized viruses to become a pandemic strain, or how long that process will take.

Influenza A virus is able to persistently re-infect human populations by continually evading host immunity through the continuous and rapid evolution of surface antigens. This process is known as antigenic drift. Influenza virus epidemics affect temperate latitudes of the world each winter, from November to March in the northern hemisphere and from May to September in the southern hemisphere. In the United States alone, these influenza epidemics are associated with an annual average of 36,000 human deaths and 226,000 hospitalizations. Globally, the virus is associated with as many as half a million annual deaths. While rapid antigenic change is characteristic of influenza, recent studies have failed to detect antigenic drift over a single epidemic season, suggesting that important evolutionary processes may occur during non-epidemic periods, either locally or perhaps elsewhere. However, surveillance during non-epidemic periods is not conducted routinely by the network of World Health Organization influenza reference centers and, consequently, little is known about how and where the virus persists in the human population in between winter epidemics at low levels. A key question is therefore whether the virus remains locally within its host population in between epidemics, perhaps persisting within hosts in a latent state, or whether the virus migrates to other reservoirs, such as the tropics, and is later reintroduced.

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Although influenza virus has long been regarded a “cold-weather” pathogen due to its marked winter epidemics in temperate zones, recent studies show that tropical regions experience significant year-round influenza virus activity. In theory, such a “tropical belt” could serve as a year-round reservoir that harbors endemic populations of influenza virus that seasonally reintroduce viral isolates into temperate zones to trigger new epidemics. Whereas population crashes at the end of seasonal epidemics create severe evolutionary bottlenecks that limit genetic diversity, tropical zones may function as permanent mixing pools for viruses from around the world. Historically, Southeast Asia has been considered a potential epicenter for emergence of pandemic viruses due to the proximity with which humans live with their domestic animals. However, abundant data from these regions is currently unavailable, so the origins of influenza pandemics and epidemics remain unclear.

Given the ease and speed with which the influenza virus is thought to spread between humans, it is generally accepted that global chains of direct person-to-person transmission are sufficient to maintain influenza virus in the human population. However, a complete understanding of how the influenza virus transmits between humans is lacking, and whether human-to-human spread alone accounts for the seasonal emergence of epidemics has been questioned. The simultaneous appearance of influenza outbreaks separated by large distances, as well as sporadic influenza cases during summer months, suggests that the virus may instead already be “seeded” and somehow reactivated by environmental stimuli. The alternating pattern of northern and southern hemisphere epidemics could, in principle, also result from opposite climatic forces independently reactivating viral activity in these two hemispheres at alternating six-month intervals. Hence instead of continually migrating across the equator, separate virus populations could persist locally in an asymptomatic latent state over the summer months until climatic stimuli sufficiently increase host susceptibility and/or viral transmissibility to induce another epidemic. However, hypotheses of how climatic change may directly or indirectly influence viral activity and/or host susceptibility remain largely untested.

Some theories for influenza seasonality produce testable hypotheses. On one hand, if influenza virus persists locally over the summer in a latent state, then isolates sampled over multiple seasons from a single locality would cluster together on a phylogenetic tree, separate from isolates from other geographic regions. Alternatively, if the virus did not evolve locally between epidemic seasons, but rather traveled globally between epidemics, then the resulting phylogeny would show extensive intermixing of isolates from different localities. To determine whether influenza virus migrates between the northern and southern hemispheres during non-epidemic summer months or remains localized, a recent paper in PLoS Pathogens reports on an extensive phylogenetic analysis of 399 influenza A viruses sampled from New Zealand from 2000 to 2005, 88 virus sequences from Australia from 1999 to 2005, and a carefully selected sample of 52 isolates which are representative of the types present in a larger sample of 413 viruses in the USA from 1998 and 2005 (Phylogenetic Analysis Reveals the Global Migration of Seasonal Influenza A Viruses. PLoS Pathog 3(9): e131).

The results show that even in areas as relatively geographically isolated as New Zealand’s South Island and in Western Australia, global virus migration contributes significantly to the seasonal emergence of influenza A epidemics, and that this migration has no clear directional pattern. These observations run counter to suggestions that local epidemics are triggered by the climate-driven reactivation of influenza viruses that remain latent within hosts between seasons or transmit at low efficiency between seasons. However, a complete understanding of the seasonal movements of influenza A virus will require greatly expanded global surveillance, particularly of tropical regions where the virus circulates year-round, and during non-epidemic periods in temperate climate areas.

Related:

• This is the End
• Influenza: H5N1 Updates
• The Biology of Influenza
• Influenza pandemic – when?

During the period 20 May to 15 Sep 2007, a total of 21 human cases of avian influenza A (H5N1) infection was reported to WHO from four countries (China, Egypt, Indonesia, and Vietnam). Fourteen (67%) of these cases were fatal.

Since 1 Dec 2003, a total of 328 human avian influenza A (H5N1) infection have been reported to WHO. Of these, 200 (61%) were fatal. All the human cases were reported from Asia (Azerbaijan, Cambodia, China, Indonesia, Iraq, Laos, Thailand, Turkey, and Vietnam) and Africa (Djibouti, Egypt, and Nigeria).

MMWR Weekly 28 Sep 2007 56 (3)

H5N1 influenza virus can also pass through a pregnant woman’s placenta to infect the foetus. Researchers also found evidence that the virus not only affects the lungs, but passes throughout the body into the gastrointestinal tract, the brain, liver and blood cells.

Related:

• The Biology of Influenza
• Influenza pandemic – when?
• This is the End

This post is from regular guest blogger:

Ed Rybicki, Department of Molecular and Cell Biology, University of Cape Town, South Africa.

This is the End. Or the beginning of the end. Or possibly, the end of the beginning?
To misquote the immortal Bill Shankly: “It’s not a matter of life and death: it’s much more important than that”.

Having hopefully alarmed you, let me explain: a group of mainly Thai researchers has, in the latest Journal of Virology, just published a paper entitled “An Avian Influenza H5N1 Virus That Binds to a Human-Type Receptor“. They say, nice and succinctly in their abstract, that “We describe here substitutions at position 129 and 134 identified in a virus isolated from a fatal human case that could change the receptor-binding preference of HA of H5N1 virus“.

And this is a big deal, why?

Well, wild birds are the natural reservoir of just about the entire genetic repertoire of influenza viruses – and particularly of Influenza A viruses, the nastiest ones that get into humans. In fact, humans have been infected to our sure knowledge with viruses which have only 3 of 9 neuraminidase (N) and 5 of 15 or more haemagglutinin (H) gene combinations – and human pandemics in the last 100 years have only been caused by H1N1 (twice), H2N2 and H3N2 viruses. Of course, other viruses have been picked up in humans, but usually as a result of direct human-animal or human-bird contact: these include cases of H7N7, H7N3, H9N2 and H10N3 infection, which pop up, and then disappear.

And then, of course, everyone’s favourite candidate for the next Big One: H5N1 highly pathogenic avian influenza. Far from being a transient phenomenon, this has established itself as an endemic virus in chickens and other domestic fowl in Indonesia, Vietnam, Thailand and possibly Egypt, and keeps popping up in western Europe, mainly in migratory waterfowl. It has also infected over 320 people worldwide – and killed more than 190 of them, which is what makes it so sinister a threat.

One of the reasons that we are not constantly overrun with avian flu viruses popping straight out of birds and into people, and why we haven’t yet had a human H5N1 pandemic, is that bird-infecting flu virus H proteins bind to a sialic acid (SA) α2,3Gal(actose) receptor – which in birds is predominantly found in the enteric tract, which is why the virus is shed prolifically via faeces in birds, but is not much found in humans except for deep in the respiratory tract, which is difficult to reach. Thus, while humans can be infected by H5N1 viruses, this is rare, and so far onward transmission to other humans has not been reliably documented. Human-adapted flu viruses, on the other hand, bind preferentially to an SAα2,6Gal receptor – which is found predominantly in the upper respiratory tract, meaning the virus can much more easily infect and be transmitted. The frightening thing is that it takes only a few mutations in the H gene – 3 in the case of the legendary H1N1 Spanish Flu pandemic virus – to change from one type to the other, and only 2 to bind both types relatively weakly.

So Prasert Auewarakul and colleagues have isolated, from a fatal infection of a 5-year-old boy, a population of H5 HA sequences which are distributed evenly between the bird type (SAα2,3Gal-binding) and a mutant type (SAα2,3Gal- and SAα2,6Gal-binding). The mutant HA protein had two substitutions, at positions 129 and 134 (lL129V and A134V). These two residues are located close to part of the receptor binding domain, and apparently alter the binding specificity by changing the configuration of the binding pocket.

The implications of this are very worrying indeed: a lethal virus which can bind both bird and human receptors was selected for in a single bird-human transmission event – just like the Spanish Flu H1N1 HA reconstructed from archival tissue samples, which we should need no reminding, went on to kill in excess of 60 million people. In the age of the steam train and ship…. This means that we could be just one infection away from The Big One – with death tolls predicted to be in the range of tens of millions.

…of our elaborate plans, the end
Of everything that stands, the end…

Thanks to Jim Morrison and The Doors

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Related:

• Influenza: H5N1 Updates
• UK preparedness for pandemic influenza
• The Biology of Influenza
• Influenza pandemic – when?

Today’s post is another from regular guest blogger:

Ed Rybicki, Department of Molecular and Cell Biology, University of Cape Town, South Africa.

While fossilized viruses have never been found, we can often infer probable lines of evolutionary descent by analysis of extant genomic sequences. This sort of molecular phylogenetic approach has thrown up all sorts of interesting findings for a number of important viruses: for example, it is possible that the divergence of Herpes simplex types 1 and 2 (orofacial vs genital herpes viruses) occurred during the time humans separated from our nearest chimpanzee relatives – and possibly because the development of face-to-face sex in humans reduced the frequency of facial-genital contact, although this may only be idle speculation! Herpesviruses in general seem to have evolved along with us since before the separation of invertebrate and vertebrate lineages, and possibly since a prokaryote origin: herpesvirus capsid proteins are distantly related to tailed phage proteins, and thus possibly have a common – and very evolutionarily deep – origin. Human papillomaviruses have speciated along with us primates as well, and viruses preferring particular locations are often more closely related to viruses infecting the same locus on another primate than they are to other human viruses. I have speculated in print elsewhere on the “Gondwanan” distribution of geminivirus ancestors, and how their development can be traced back for at least several hundred million years.

But while this may be academically fascinating, how is it relevant to the real world? One special-case example – that of the re-awakening of a “fossil” endogenous human retrovirus – was covered on this site recently. This has all sorts of interesting implications for the evolution of new retroviruses by recombination, and for taking a good hard look at xenotransplants. However, a more recent development in the field of HIV evolution is even more important, inasmuch as it has very important implications for HIV vaccines.

An often-quoted factoid is that the extent of variation of HIV genotypes in one individual in a year is equivalent to the worldwide variation in influenza A viruses in the same time. If one considers that the rate of flu virus antigenic change requires annual redevelopment of flu vaccines, what does this mean for HIV? James Mullins’ group in Seattle and their co-workers in Pennsylvania have gone a ways towards answering this in their just-published paper in Journal of Virology entitled “Reconstruction and function of ancestral center-of-tree human immunodeficiency virus type 1 proteins”. They used phylogenetic analysis of many whole-virus sequences together with a new algorithm to computationally derive “centre of tree” (COT) ancestral protein sequences for HIV subtype B, as part of a strategy to design immunogens for use as vaccines that would elicit the broadest possible immune recognition of circulating HIV strains. The thinking behind this strategy is that use of ancestral sequences would minimise the genetic distance between a vaccine and circulating strains that could feasibly have speciated from it, compared to using any one of those strains, or even a consensus sequence.

Their Gag polyprotein sequence was capable of forming budded virus-like particles (VLPs); the ancestral Tat and Nef proteins retained appropriate function, and the proteins were immunogenic in terms of eliciting cytotoxic T-cell responses in mice. More importantly, the COT Gag elicited strong cross-subtype CTL responses when tested against peptide pools derived from subtypes A and M – and there was evidence that CD4 help was improved for these antigens. These are very important results when one considers the rate of change of HIV isolates: given that HIV phylogenetic variation can be depicted by starburst-like trees, and that the genetic distance between any two branch tips goes through a node, using the derived nodal sequences as vaccines could be a highly useful means of reducing the breadth of antigenic variation necessary to cover the current HIV spectrum – or even only part of it, given the geographic clustering of certain HIV subtypes. One could speculate that, when the correlates of protection for HIV vaccines are known (or in other words, when we finally know just what an HIV vaccine should look like), it could be possible to formulate COT-derived vaccine sequences on a yearly basis, as is routinely done for flu, based on up-to-date variation data. And given that subtype C – the target of the South African AIDS Vaccine Initiative and other vaccine development efforts – seems to be the prevalent form of HIV worldwide right now…it is possible that a single vaccine COULD protect people at risk in southern Africa, India and China. One lives in hope!

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