WHO Pandemic Warning Phases.Source [pdf].

What is a pandemic?

The World Health Organization (WHO) Emergency Committee declared on August 10 that we left the pandemic phase of the H1N1 virus. “The world is no longer in phase 6 of influenza pandemic alert. We are now moving into the post-pandemic period. The new H1N1 virus has largely run its course.” But, what does it mean?

WHO classifies the severity of an emergent disease in six global warning phases. As the majority of the emergent diseases are zoonosis, the warning levels are based on how much the pathogen is circulating among humans after the transmission. Between phases 1 and 3, the disease circulates specially among animals (in phase 1 it circulates only among humans), among domestic animals and some humans in phase 2, it is also
frequently transmitted among humans in phase 3. The classification varies according to the frequency which it goes into humans. Most of the potential diseases are in this phase, such as the yellow fever, although it contaminates people in forest regions, it is restricted especially to the wild cycle, i.e. animals.

The 4th phase describes a disease which already passed from animals to humans and circulates regardless those animals. An example of this situation is the occurrence of dengue in the summer, in which many tropical climate cities has dengue outbreaks in the rainy season.

Phases 5 and 6 describe an epidemic which is already spreading more than locally, during phase 5 there is an intense transmission, but restricted to the same place, and in phase 6 the transmission is global and the pandemic is in full development. These warning levels guide the monitoring and precautions the countries must take. It is advised to monitor borders and areas of intense circulation, as well as the supply of drugs and vaccines during phases 5 and 6.

Our current condition

When phase 6 is over, since great parte of the people was already infected or vaccinated, the decease still circulates, but not as severe as before. In the case of the flu, the out of season cases stop occurring and, as it already happened in other pandemics, the virus circulates annually instead of or simultaneously with the seasonal variants.

It is in this stage that the WHO considers we just entered. According to them, people already developed immunity in many locations, in addition to the good coverage of the vaccination. From the declaration “Out-of-season outbreaks are no longer being reported in either the northern or southern hemisphere. Influenza outbreaks, including those primarily caused by the H1N1 virus, show intensity similar to that seen during seasonal epidemics.”

It is worth emphasizing that it does no mean that the H1N1 is gone. It still circulates and will probably enter the seasonal cycle common to the other variants, besides having gone back to the pigs and continue to rearrange. The committee highlights that “[...] this does not mean that the H1N1 virus has gone away. Based on experience with past pandemics, we expect the H1N1 virus to take on the behavior of a seasonal influenza virus and continue to circulate for some years to come.”

The virus that was not cruel

Still in the committee’s declaration, one phrase calls the attention: “we have been aided by pure good luck. The virus did not mutate during the pandemic to a more lethal form. Widespread resistance to oseltamivir did not develop.” In fact, and luckily as it was said, there was no serious pandemic in 2009. The number
of patients and deceased were below the expectations, and part of that can be credited to the previous immunity of the elderly, which reduced the mortality among this risk population.

The severity of this pandemic was already questioned before, especially because the phase criteria adopted does not take into consideration the spreading disease severity. Even the seasonal flu can be classified as a pandemic during the winter of the Northern Hemisphere, if it were not by the lack of prevalence of a main variant.

Criticisms about the entrance of phase 6 warning were made in June, at the British Medical Journal. According to the critics, some people involved in the panel that decided to raise the level of pandemic warning had relevant conflicts of interest, since they received funding from vaccine manufacturers. The same manufacturers that signed contracts for the production of millions of doses distributed globally. The idea is that they raised the warning level unnecessarily in order to benefit the companies.

We can not forget that when a pandemic arises, there is little time to make decisions, and in most cases the consequences for excess of zeal are much smaller than by the lack of it. It is necessary to balance the warning created around this pandemic. At the same time it is necessary to have a previous and agile preparation to stop the outbreak and reduce its impact. The collaboration of the population is also essential to make this possible. Without the correct clarification of the situation, and the comprehension of the need of the measures to be taken, problems such as rumors about the H1N1 vaccine being unnecessary or even harmful tend to grow.

Genome composition of Influenza virus sampled on Hong Kong. Source: Science 2010, reference at the end of the text.

After more than a year of the Influenza A H1N1 episode, the virus is still being monitored all over the world, both the flu cases and genetics diversity of the virus. Following up the genetic diversity helps to understand if the vaccine is still efficient and helps identifying the possible appearance of new strains.

In Hong Kong, location with an important role in the appearance of new viruses because of the bird market and high concentration of people, the virus infected raised pigs. And the sample analysis from June 2009 to February 2010 showed what was already expected: the virus is still reassorting itself.

The reassortement happens when two or more different viruses infect the same cell. The Influenza has eight genes that must be in the viruses that go out so they can be infective, and when more than one virus is present in this cell, the viruses formed are a mosaic of genes from different sources. This process was better explained here. The reassortement is worrisome because, the virus it originates has more abrupt changes than the ones acquired by the most common mutation processes, and these changes can help the virus avoid our immunological system.

In all hosts the reassortement is common. In birds, it was responsible for the creation of the H5N1 virus. In humans, it originated the pandemic viruses H2N2 on 1957 and H3N2 on 1968, and created a third strain of swine Influenza on 1997. Until 1996, there were two main strains of the swine virus: the one called classic that appeared in North American pigs around 1918 and is still there today; the Eurasian virus, also originated
on birds, that circulates in pigs since 1979. On 1997, the two swine viruses reassorted themselves as a new bird virus, originating the strain known as a triple-reassorted virus.

What the Chinese research group found, is well summarized in the figure that illustrates this post. On the left are the name of the viruses found. As it was explained here, the name contains many information. The Sw refers to the host, swine, HK is the location, Hong Kong, the number in bars is the code attributed to the sample, for tabulation, and /09 or 2010 refers to the year it was collected.

Still in the year 2009, three pure virus strains were found in pigs and contained genes of an established strain (they are not pure in fact because many were originated from reassortment events), the human Influenza A H1N1 with its eight genes in red, the Eurasian virus, with its eight genes in green, and the triple-reassorted virus, with eight genes in yellow. There were also found viruses with new reassortement standards both among Eurasian and triple-reassorted kinds, and north American classic, highlighted in blue.

In the beginning of this year, the first reassorted virus with 2009 Influenza A H1N1genes was found. It should not be an isolated problem, given the rate this event occurs and the swine origin of the virus, which already selected competent genes so that the virus multiplies in pigs.

This finding reinforces the need to monitor farm animals, specially birds and swine, to prevent the appearance of new strains and to promote the preparation when needed. Reassortment is a common event, and we are creating more and more animals and traveling around the world easily. While we do not have a vaccine that protects us against various strains of Influenza, prevention still is our best shot.

Source:
Vijaykrishna, D., Poon, L., Zhu, H., Ma, S., Li, O., Cheung, C., Smith, G., Peiris, J., & Guan, Y. (2010). Reassortment of Pandemic H1N1/2009 Influenza A Virus in Swine Science, 328 (5985), 1529-1529 DOI: 10.1126/science.1189132

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A year has passed since the first cases of Influenza A H1N1 in Mexico, we had over 18000 deaths confirmed by lab diagnosis and reported to WHO. Surely an underestimate of the total number of cases.

The average mortality was of 0.5% of the confirmed cases, close to the seasonal flu. The mortality values varied a lot from country to country, and inside a country they varied according to different studies, which show the evident necessity of more available tests and a mutual opinion on the measure to be adopted.

Different from the seasonal flu, over 90% of deaths are concentrated in people younger than 65 yeas old, consequence of the previous immunity older people have. Pregnant ladies were also the most affected, although they represent only 1 to 2% of the general population, they were 6 to 10% of the deaths caused by the flu. Other groups also have their immune systems altered like the obese and the immunocompromised and are also among the most susceptible ones.

Treatment

Although bearing the already reported drug resistance to adamantanes drug family, the Influenza of swine origin can be treated with sialidase inhibitors, the drugs Oseltamivir and Zanamivir. Oseltamivir, available to be taken orally is cheaper, is still a very effective treatment, reducing the symptom’s severity and the time of hospitalization.

Some resistance cases were found, the majority isolated cases and in patients with treatment flaw mainly of them with prolonged therapy. Rarely patients without history of contact with the drugs were found with resistant viruses; the transmission of this kind of virus was also confirmed.

Conclusions

It is still very hard to diagnose the Influenza virus as a whole. The main method, the RT-PCR technique (virus genetic material amplification) still depends on recent technology and restricted access to poorer areas. We also depend on samples collected during the period of infection. We still need cheaper and more accessible ways of detecting the virus, as well as different and cheaper ways of treatment.

Influenza A H1N1 seems to become a seasonal virus with symptoms and cases like the common flu, however the virus evolutive course is unpredictable. The prevention and survey set for the Avian Influenza and the “normal” virulence of this virus contributed for the Swine Flu not have caused bigger damage. But we are still far from being protected from more pathogenic strains, in case some of them are transmitted more easily.

Source:
Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza, Bautista E, Chotpitayasunondh T, Gao Z, Harper SA, Shaw M, Uyeki TM, Zaki SR, Hayden FG, Hui DS, Kettner JD, Kumar A, Lim M, Shindo N, Penn C, & Nicholson KG (2010). Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. The New England journal of medicine, 362 (18), 1708-19 PMID: 20445182

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The elderly, especially those older than 65 years, that is, born before 1944, constitute the part of the population less affected by H1N1. It was suggested and later confirmed by CDC that it is about the prior immunity to the virus. These people probably have been exposed to a virus similar enough to the new H1N1 for the developed antibodies to still provide protection.

And this idea was put to test by a research group from the Mount Sinai School of Medicine. Using mice as measurers in the lethal challenge, as these animals die when infected by the strain of 2009, they were able to test the protection offered by the antibodies developed against various lineages of human influenza, from 1918 to the present day.

As strange as it may seem for antibodies against human lineages to be efficient against the swine virus, a review in the history of our flus shows that this is not at all absurd. Both humans and pigs were infected by a bird lineage soon before 1918, which has evolved since then in parallel with some occasional bumps.

And this similarity was actually confirmed. Mice infected with the inactivated human virus from 1918 to 1943 in order to develop antibodies were protected against the pandemic virus of 2009, and this was also the case of mice infected with the common swine virus or with the swine lineage of the vaccine of 1976. This shows that until 1943 the human and swine lineages had not yet diverged enough to end cross immunity, and that this similarity is still present in the pig’s virus. Therefore, the people infected with the older lineages or vaccinated in 1976 already have the protective immunity against the new H1N1.

The implications of this study are several and important. Firstly, it shows that priority should be given to vaccination of the youth with the new vaccine, which is already being distributed, since the older population is immune. Another very important implication is the role of pigs. Seen before as the only intermediaries between birds and humans, they have also shown to be reservoirs of the virus that infected us, and our immune system has forgotten. This virus may leap to humans again and find another susceptible population born after the human lineage becomes more different from that of the swine.

Secondly, we can look at the evolutionary history of the influenza in humans and pigs in another way. Although both have a common origin, they went their separate ways with different rates of evolution. The human virus face a growing heterogeneous population with a life span long enough for a same person to be infected more than once, which favors the lineages able to vary enough to escape the previous immunity. However, the swine virus found a host with a smaller population, which suffer fewer migrations and is more homogeneous (once we artificially selected and crossed only the more productive individuals), which is renewed periodically.

All this contributes to pigs serving as true museums of Influenza, maintaining the lineages that have already circulated more often among persons and can be the source of new pandemic lineages, as we just discovered in practice. Among them are the viruses H1 and H3 that infected pigs since 1990 till present.

Source (via This Week in Virology):
Manicassamy, B., Medina, R., Hai, R., Tsibane, T., Stertz, S., Nistal-Villán, E., Palese, P., Basler, C., & García-Sastre, A. (2010). Protection of Mice against Lethal Challenge with 2009 H1N1 Influenza A Virus by 1918-Like and Classical Swine H1N1 Based Vaccines PLoS Pathogens, 6 (1) DOI: 10.1371/journal.ppat.1000745

copyright StockVault

One of the greater uncertanties about Avian Influenza is why it is not efficiently transmitted among humans. Thus, it is clear how likely it is that the virus is able to cross this barrier and a more efficient line appears. For example, until now the H5N1 was transmitted mainly to breeders and people in very close and extended contact with poultry.

The entrance door of Influenza in mammals is the respiratory tract, primarily ciliated cells of the respiratory epithelium, where inhaled saliva droplets come in. One of the reasons already approached for the inefficient transmission of avian viruses in humans is the difference of type of sialic acid.

In our respiratory tract, the acid α2,6 prevails in the upper part, region of nasal cavities and pharynx, while the α2,3 occurs mainly in the lower respiratory tract, alveoli, bronchi and other pulmonary cells. Human viruses have hemagglutinin (HA) with more affinity with sugars which terminate in α2,6-sialic acid and thus they can be replicated in the upper tract and better dispersed through cough and sneezes. In turn, the avian viruses have more affinity with sugars terminated in α2,3, prevailing in the digestive system of birds.

Another reason is the metabolic difference. Humans have an average body temperature of 37°C and birds between 40°C and 41°C. The temperature has a great influence in the protein structure and the virus needs several changes before getting bound to mammal receptors below 40°C. This difference is more stressed by the infection spots. While in birds the influenza virus infects the digestive system, which is at the same temperature of the body, 40-41°C, in mammals the respiratory system is cooled by the inhaled air and in the nasal region it reaches temperatures until 32°C, producing a gradient which ends in 37°C in the lungs. A recent work tested a way of adaptation.

Growing human epithelial cells, a group of American and British researchers was able to test several conditions of infection by avian and human viruses in temperatures of 32 °C and 37 °C, simulating both upper and lower respiratory tract. It was already demonstrated in avian viruses that a mutation in the amino acid 627 in the PB2 subunit of the virus polymerase (the enzyme responsible for coping its genome) has an important role in the sensitivity to temperature. The same mutation was able to make the H5N1 more infective in mice. For this reason, it was induced in human viruses in experiments in order to “avianize” the lines and test its influence in infectivity.

While the model of human virus – A/Victoria/3/75 (H3N2) – replicated both at 32°C and 37°C, the avian model – A/Dk/Eng/62 (H4N6) – replicated between one thousand and ten thousand folds less at 32°C than 37°C, where it produced almost the same number of particles than the human virus. In other words, although the avian virus grows well at a temperature equivalent to that of the lungs, the same does not occurs in the upper airway so the virus cannot be transmitted efficiently.

Given the amazing result, new human lines – A/Eng/26/99 (H3N2) and A/Udorn/307/72 (H3N2) – and avian – A/Dk/Sing/97 (H5N3) – were tested and the differences were confirmed. Human lines grew well in both temperatures and avian lines grew less in lower temperatures. Even the avian H5N1 isolated from a fatal human case (A/VN/1203/04) was tested and behaved in the same way.

When the human viruses were “avianezed” through mutation of the amino acid 627 of humans (Lysine) to the most common amino acid in birds (Glutamic Acid), in order to confirm if the mutation in PB2 would be responsible for the better growth at 32 °C, the difference was not confirmed. It was necessary to add to human viruses more characteristics of avian viruses, Hemagglutinin (HA) and Neuraminidase (NA), inducing the virus to use more the α2,3-sialic acid in order to reduce the growth in lower temperatures.

That indicates that the amino acid 627 can be an important region in the adaptation of avian viruses for humans and it should be followed during the emergence of pandemic viruses such as H5N1. However, other changes also have an important role, and a rearrangement with human viruses which could transmit HA and NA able to bind more easily to the upper ciliated epithelium could cause a big trouble.

Source:
Scull MA, Gillim-Ross L, Santos C, Roberts KL, Bordonali E, Subbarao K, Barclay WS, & Pickles RJ (2009). Avian Influenza virus glycoproteins restrict virus replication and spread through human airway epithelium at temperatures of the proximal airways. PLoS pathogens, 5 (5) PMID: 19436701

Types of sialic acid. Source: Reference 2.

As already seen before, what determines the type of cell to be infected by the influenza is the Hemagglutinin (HA), due to its preference for the sialic acid of the cell. But it is not any sialic acid that can be used. The recognition by HA depends on the position of the carbon that makes the bond between the acid and the molecule to which it is attached. The bond receives this name because of this position. In birds and mammals, occur especially in the sialic acids α2,3 and α2,6

In our respiratory tract, the α2,6 acid predominates in the upper part, region of the nasal cavity and the pharyngeal cavity, while the α2,3 occurs especially in the lower respiratory tract, in the alveoli, bronchia and other lung cells. Human virus has a hemagglutinin with higher affinity for sugars that end in an α2,6 sialic acid and therefore, can replicate in the upper tract and spread more easily through cough and sneeze. Bird virus, however, have an affinity for sugars that end with α2,3, the predominants in the digestive system of birds, where the virus replicates. – Although in mammals the influenza is predominantly a respiratory virus, in birds, it is predominantly an intestinal virus.

Influenza H5N1 shown in yellow, seen through an electronic and artificially colored microscope. Source: Wikimedia.

Therefore, when bird viruses like H5N1 infect humans, they end up bonding and replicating better in the lower respiratory tract. This explains the observed severe symptoms in the lungs, as well as the difficulty of H5N1 of being transmitted between humans. It replicates less in places that make easier its spreading, such as nasal cavities. [1]

Despite the elegance of the argument, α2,3 receptors have been found in the upper respiratory tract and α2,6 in the lower respiratory tract. What raises doubts on how significant this difference can be in order to explain the low transmission of the virus. [2]

Another important property of this virus also concerns hemagglutinin, more precisely its maturity. After being expressed by the cell, hemagglutinin still has to be digested by an external protease to work. Only the fragmented hemagglutinin in pieces can link the virus to the next cell, completing the infection, as already observed. Generally, what carries out this digestion is a protease produced in the mucus of the respiratory tract, restricting the virus to this environment.

However, the Hemagglutinin of H5N1 and other highly pathogenic viruses have a cleavage region with several basic aminoacids, which allows the digestion of the hemagglutinin by several proteases, not only those found in our respiratory tract. Like the furin protease, which occurs in almost any type of cell. Then, the influenza HPAI is able to infect and replicate in various other tissues and cause a systemic infection. [3]

Other characteristics are necessary for a virus to be highly pathogenic, such as the capacity to replicate its RNA efficiently in various cells. This occurs because the replacement of the low pathogenic viral hemagglutinin cleavage site by another site with more basic aminoacids, common in high pathogenic influenzas, was not enough for the virus to cause more severe symptoms in model animals, although it had replicated more efficiently. [4]

Constant monitoring of the virus and preventive preparation by the government is necessary to ensure that, in the case of the appearance of a highly pathogenic lineage successfully transmitted between humans, the measures to contain them are taken quickly before greater damage is caused. The possibility of the H5N1 undergoing a rearrangement with virus already adapted to humans, improving its transmission efficiency or providing dangerous properties, is very disturbing.

Due to the severity of its symptoms, diversity of hosts, circulation in animals close to humans and with dangerous properties, domestic and wild birds have been monitored since the appearance of H5N1. This threat is also the reason for the stock of antivirals, the expansion of vaccine production capacity and the conduction of diagnostic tests.

Many of these preparations are being used in this epidemic of 2009; in the USA alone over 50 thousand cases of Influenza A (H1N1), were diagnosed, a new number of tests. This amount of antivirals has never been readily available for use before. The same occurs for the quantity of vaccine doses being produced. Whatsoever as these measures have been taken against H5N1, they are effective for any Influenza. Prevention always yields returns.

Sources:

[1]van Riel, D. (2006). H5N1 Virus Attachment to Lower Respiratory Tract Science, 312 (5772), 399-399 DOI: 10.1126/science.1125548
[2] Zambon, M. (2007). Lessons from the 1918 influenza Nature Biotechnology, 25 (4), 433-434 DOI: 10.1038/nbt0407-433
[3] Steinhauer, D. (1999). Role of Hemagglutinin Cleavage for the Pathogenicity of Influenza Virus Virology, 258 (1), 1-20 DOI: 10.1006/viro.1999.9716
[4] Stech, O., Veits, J., Weber, S., Deckers, D., Schroer, D., Vahlenkamp, T., Breithaupt, A., Teifke, J., Mettenleiter, T., & Stech, J. (2009). Acquisition of a Polybasic Hemagglutinin Cleavage Site by a Low-Pathogenic Avian Influenza Virus Is Not Sufficient for Immediate Transformation into a Highly Pathogenic Strain Journal of Virology, 83 (11), 5864-5868 DOI: 10.1128/JVI.02649-08

In this context, chickens and ducks are our focus of attention. The origin and higher diversity of the Influenza is found in aquatic birds. They are the natural reservoir of Influenza and the source of all the lineages that infect humans and pigs, and their consequent mixtures such as the Influenza A (H1N1). While the human and swine Influenza lineages only have H1, H2 and H3, and N1 and N2, birds have all the known types of Hemagglutinin and Neuraminidase, H1 to 16 and N1 to 9, spread over more than 100 species already identified as carriers. [1]

Our close coexistence with these animals allows any lineage that infects them to have more chances of entering us humans. It is what has been happening to H5N1, which in most cases was transmitted to those who reared poultry birds or persons close to them. No matter how small are the chances of being transmitted to humans, as we have receptors unfavorable to the virus in our respiratory tract, the events of contact are very often.

The Asian poultry market is a place where the presence of the avian virus is constant as well as contagious. Migratory wild birds, carriers of an enormous diversity of Influenza, come in contact with domestic birds such as chickens, geese, quails and ducks that serve as intermediaries for viruses that were restricted to the wild. The coexistence of these birds with the breeders, sellers and with pigs is a high source of opportunities for the entry of new viruses. It is not by chance that Asia has been the frequent source of new Influenzas, pandemic or not. The origin of the Influenza A (H1N1) in Mexico is a bit uncommon.

The Influenza H9N2, for instance, was established as a circulating lineage in domestic birds and was isolated for the first time in turkeys in North America in 1966. In Asia, on the other hand, it circulated mostly in ducks and from then on it also began to circulate in chickens as of 1990. Although we are not concerned about H9N2, which causes mild symptoms in a few contaminated people, its presence in chickens (or quails, the virus that contains the closest genes was isolated from one) probably caused the rearrangement that generated the highly pathogenic H5N1, giving genes to an H5N1 from geese. That is, the Influenza in domestic birds can be a huge problem, even indirectly. [2]

Therefore, the transmission of new lineages of Influenza is inevitable. An event most likely to prevent and monitor, but more and more likely to happen. Our urban life style, filled with a protein rich diet from animal origin, is one of the ingredients of our long life and life quality but it is also a growing source of the problems we face.

Sources:
[1] Dugan, V., Chen, R., Spiro, D., Sengamalay, N., Zaborsky, J., Ghedin, E., Nolting, J., Swayne, D., Runstadler, J., Happ, G., Senne, D., Wang, R., Slemons, R., Holmes, E., & Taubenberger, J. (2008). The Evolutionary Genetics and Emergence of Avian Influenza Viruses in Wild Birds PLoS Pathogens, 4 (5) DOI: 10.1371/journal.ppat.1000076
[2] Guan, Y. (1999). Molecular characterization of H9N2 influenza viruses: Were they the donors of the “internal” genes of H5N1 viruses in Hong Kong? Proceedings of the National Academy of Sciences, 96 (16), 9363-9367 DOI: 10.1073/pnas.96.16.9363

Although H1N1 is circulating around us at least a little bit before 1918, we passed almost 20 years free of it. In 1957, a line of influenza virus received three genes of an avian virus, among them new HA and NA, and started to be called H2N2. With these new proteins, it did not meet previous immunity in the population and completely replaced H1N1, which circulated until then. After 11 years, it acquired a new Hemagglutinin and as H3N2 it substituted the previous H2N2.

The H1N1 continued absent in the population until 1977. In this year, it reappeared in the region of Eastern Europe and North of Asia, causing a very serious pandemic, which was called Russian Flu. Ever since, both H3N2 and H1N1 circulate between us. It is thought that the H3N2 was not replaced because there was already some immunity against the H1N1 and because the population (and consequently its hosts) was already more numerous in 1977, propitiating a bigger “space” for the circulation of the virus.

However, analyses H1N1 from 1977 disclosed something disturbing. It was very similar to the H1N1 circulating in 1950, before the emergence of the H2N2. It was like the virus had reappeared, but with some aberrant facts. If it was circulating but not being reported between 1957 and 1977, it would need to be different from the known viruses, once although being a similar virus, it still would be under evolutive pressure and in differentiation. Nevertheless, it had little mutations in HA and NA genes, and the other were identical. Even worse, although it was similar to the influenza virus circulating in 1950, it was quite different of those of 1947 and 1957.

It was like the H1N1 from 1977was the 1950 virus reintroduced in the population. If so, how would it have done such a thing? Vaccines! The only way of the virus keeping its sequences so preserved is to have passed these 27 years frozen somewhere. As a matter of fact, this is the idea of the authors of the article: the virus was kept frozen in nature. Yes, to assume that it was in some freezer and was released by mistake is something that only can be done now.

However, to contaminate the vaccine with a virus by mistake is something rare, which cannot happen currently, right?

Yes and no. It is something difficult, but possible. Insomuch that it happened in the beginning of this year. In February 2009, a company which produces vaccines in Europe sent three samples contaminated to neighboring countries which were discovered because one of the laboratories tested the vaccination line in ferrets and saw that the animals died quickly. They died because the contaminating virus was the highly pathogenic H5N1.

Fortunately, samples were confined in laboratory and neither were used in vaccination nor contaminated the personnel who had contact with it. Anyway, this kind of incident raises great concerns for all involved people and demands an immediate action to eliminate the risk and disinfect all installations. Thanks to the tests done in one of the laboratories, showing again that for Influenza the prophylaxis is the best measure.

Sources:

Zimmer, S., & Burke, D. (2009). Historical Perspective — Emergence of Influenza A (H1N1) Viruses New England Journal of Medicine, 361 (3), 279-285 DOI: 10.1056/NEJMra0904322

Scholtissek, C., von Hoyningen, V., & Rott, R. (1978). Genetic relatedness between the new 1977 epidemic strains (H1N1) of influenza and human influenza strains isolated between 1947 and 1957 (H1N1) Virology, 89 (2), 613-617 DOI: 10.1016/0042-6822(78)90203-9

Kendal, A., Noble, G., Skehel, J., & Dowdle, W. (1978). Antigenic similarity of influenza A(H1N1) viruses from epidemics in 1977–1978 to “Scandinavian” strains isolated in epidemics of 1950–1951 Virology, 89 (2), 632-636 DOI: 10.1016/0042-6822(78)90207-6

Our knowledge of Influenza in pig dates back to at least 1918 when it was observed that they could also catch the flu during a time when the human flu caused an uneven pandemic. In 1930 the virus was isolated in pigs, an H1N1 called the classic lineage, close to the human H1N1 and from the same origin: the H1N1 influenza from birds.

This virus was practically the only one circulating in pigs of North America until the end of the last century. It also circulated in pigs from Europe and Asia through a contamination in Italy in 1976, but in 1979 a new avian H1N1 completely substituted it. Since then, the history of the swine influenza and our influenza has been intercalating.

The recent world attention was more focused on the avian viruses, mostly due to the deadliness and fear caused by the H5N1, but pigs were also considered a possible source of pandemic viruses. There are several reasons that concern us about pigs, and the main ones are related to the swine physiology.

Pigs have both types of receptors for Influenza in the respiratory system, the sialic acid α2,3 and α2,6. While the virus circulating in birds have difficulties to infect us – because it uses mostly α2,3 and we only have this receptor in the lower respiratory tract (lung region), which makes the spread by cough or sneeze difficult – if this virus enters pigs it will find the α2,3 in the entire respiratory system, including the upper respiratory system. It will also find the α2,6 that, if it is able to use it, it will guarantee a higher chance of transmission among humans.

There is also the issue of temperature. Birds have a more active metabolism than ours, chickens for instance have an average temperature of 42ºC, in such a way that a virus adapted to replicate in birds generally has its enzyme functioning with less efficiency in humans. Pigs, however, have an average temperature of 39ºC, very close to ours, a convenient intermediary between birds and humans.

From an ecological point of view, the possibility of a same pig being infected by two different viruses, giving origin to a new rearranged lineage must be accounted. The chances are high given that, as pigs are able to be infected with the avian and human virus and live with both in farms, the introduction of human strains in pigs are often. Avian strains are also common in restricted cases of contamination by viruses such as H9N2, H3N3, H4N6, H1N1 and others.

This has already occurred in 1997 when the swine virus gained genes from an avian influenza and another from humans (our H3N2). This triple rearrangement circulates until today and it was one of the two viruses in pigs that gave origin to the Influenza A (H1N1) in 2009, directly demonstrating the potential of transmission to humans.

The 2009 pandemic has brought back attention to an important question. Pigs are transported around the world, bred in locations with a high density of animals, and – in many less developed places – are in direct contact with poultry birds and their owners. These animals have to be monitored and bred with some control, if we wish to reduce the chances of the appearance of new dangerous lineages.

Sources:

Olsen, C. (2002). The emergence of novel swine influenza viruses in North America Virus Research, 85 (2), 199-210 DOI: 10.1016/S0168-1702(02)00027-8

Landolt, G., & Olsen, C. (2007). Up to new tricks – A review of cross-species transmission of influenza A viruses Animal Health Research Reviews, 8 (01) DOI: 10.1017/S1466252307001272