Monday, May 13, 2013

ProMed: H3N2 Pandemic Potential (2 articles - 1 from MIT & 1 from Nature)

Subject: PRO/AH> Influenza (31): H3N2 pandemic potential
Archive Number: 20130513.1710144
INFLUENZA (31): H3N2 PANDEMIC POTENTIAL
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[1]
Date: Fri 10 May 2013
Source: MIT News [edited]
http://web.mit.edu/newsoffice/2013/potential-flu-pandemic-lurks-0510.html


Potential flu pandemic lurks
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In the summer of 1968, a new strain of influenza appeared in Hong Kong. This strain, known as H3N2, spread around the globe and eventually killed an estimated 1 million people. A new study from MIT [Massachusetts Institute of Technology] reveals that there are many strains of H3N2 circulating in birds and pigs that are genetically similar to the 1968 strain and have the potential to generate a pandemic if they leap to humans. The researchers, led by Ram Sasisekharan, the Alfred H Caspary Professor of Biological Engineering at MIT, also found that current flu vaccines might not offer protection against these strains. "There are indeed examples of H3N2 that we need to be concerned about," says Sasisekharan, who is also a member of MIT's Koch Institute for Integrative Cancer Research. "From a pandemic-preparedness point of view, we should potentially start including some of these H3 strains as part of influenza vaccines." The study, which appears in the [10 May 2013] issue of the journal Scientific Reports, also offers the World Health Organization and public health agencies' insight into viral strains that should raise red flags if detected.

Influenza evolution
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In the past 100 years, influenza viruses that emerged from pigs or birds have caused several notable flu pandemics. When one of these avian or swine viruses gains the ability to infect humans, it can often evade the immune system, which is primed to recognize only strains that commonly infect humans. Strains of H3N2 have been circulating in humans since the 1968 pandemic, but they have evolved to a less dangerous form that produces a nasty seasonal flu. However, H3N2 strains are also circulating in pigs and birds. Sasisekharan and his colleagues wanted to determine the risk of H3N2 strains re-emerging in humans, whose immune systems would no longer recognize the more dangerous forms of H3N2. This type of event has a recent precedent: In 2009, a strain of H1N1 emerged that was very similar to the virus that caused a 1918 pandemic that killed 50 million to 100 million people. "We asked if that could happen with H3," Sasisekharan says. "You would think it's more readily possible with H3 because we observe that there seems to be a lot more mixing of H3 between humans and swine."

Genetic similarities
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In the new study, the researchers compared the 1968 H3N2 strain and about 1100 H3 strains now circulating in pigs and birds, focusing on the gene that codes for the viral hemagglutinin (HA) protein. After comparing HA genetic sequences in five key locations that control the viruses' interactions with infected hosts, the researchers calculated an "antigenic index" for each strain. This value indicates the percentage of these genetic regions identical to those of the 1968 pandemic strain and helps determine how well an influenza virus can evade a host's immune response. The researchers also took into account the patterns of attachment of the HA protein to sugar molecules called glycans. The virus' ability to attach to glycan receptors found on human respiratory-tract cells is key to infecting humans.

Seeking viruses with an antigenic index of at least 49 percent and glycan-attachment patterns identical to those of the 1968 virus, the research team identified 581 H3 viruses isolated since 2000 that could potentially cause a pandemic. Of these, 549 came from birds and 32 from pigs.

The researchers then exposed some of these strains to antibodies provoked by the current H3 seasonal-flu vaccines. As they predicted, these antibodies were unable to recognize or attack these H3 strains. Of the 581 HA sequences, 6 swine strains already contain the standard HA mutations necessary for human adaptation, and are thus capable of entering the human population either directly or via genetic reassortment, Sasisekharan says.

"One of the amazing things about the influenza virus is its ability to grab genes from different pools," he says. "There could be viral genes that mix among pigs, or between birds and pigs." The findings from this study will raise our awareness for potential H3N2 flu pandemics and will at the same time help us to monitor, prevent and prepare for such events," says Yizhi Jane Tao, an assistant professor of biochemistry and cell biology at Rice University who was not part of the research team. Sasisekharan and colleagues are now doing a similar genetic study of H5 influenza strains. The H3 study was funded by the National Institutes of Health and the National Science Foundation.

[Byline: Anne Trafton]

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Communicated by:
ProMED-mail Rapporteur Kunihiko Iizuka

[The introductory and discussion sections from the scientific publication on which the commentary above is based are summarised below. - Mod.CP]

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[2]
Date: Fri 10 May 2013
Source: Nature, Scientific Reports [edited]
http://www.nature.com/srep/2013/130510/srep01822/full/srep01822.html


[Ref: Tharakaraman K, Raman R, Stebbins NW, Viswanathan K , Sasisekharan V, Sasisekharan R: Antigenically intact hemagglutinin in circulating avian and swine influenza viruses and potential for H3N2 pandemic. Scientific Reports, 2013; 3 DOI: 10.1038/srep01822]
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Background
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The 2009 swine-origin H1N1 influenza, though antigenically novel to the population at the time, was antigenically similar to the 1918 H1N1 pandemic influenza, and consequently was considered to be "archived" in the swine species before reemerging in humans. Given that the H3N2 is another subtype that currently circulates in the human population and is high on WHO pandemic preparedness list, we assessed the likelihood of reemergence of H3N2 from a non-human host. Using HA sequence features relevant to immune recognition, receptor binding and transmission we have identified several recent H3 strains in avian and swine that present hallmarks of a reemerging virus. IgG polyclonal raised in rabbit with recent seasonal vaccine H3 fail to recognize these swine H3 strains suggesting that existing vaccines may not be effective in protecting against these strains. Vaccine strategies can mitigate risks associated with a potential H3N2 pandemic in humans.

[Interested readers are recommended to access the original text at the source URL above to view the impressive volume of data processed in this analysis, and the excellent diagrams and images accompanying the text. - Mod.CP]

Discussion
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The H3 HA of some of the recent avian strains share approximately 86 percent overall sequence identity with the HA of the avian progenitor of the 1968 pandemic virus (A/duck/Ukraine/1/1963), reflecting antigenic intactness within birds. Many sequences from swine, some collected as recently as 2001, were also found to have high homology with the A/duck/Ukraine/1/1963 HA, indicating avian to swine transfer. For reasons that remain unclear, the more recent swine H3 HAs (2006 and later) have diverged significantly from the 1968 pandemic H3N2 HA while in contrast the majority of swine H1 HAs remained antigenically stable from 1918 to the 1990s. Unlike the 1918 H1N1 virus which crossed to swine soon after and remained in swine, the human H3N2 viruses have repeatedly crossed from humans to swine for some time -- quite possibly, this could be the reason why swine H3 viruses appear to manifest the antigenic drift that human strains underwent during this period. In fact, the AI [antigenic identity] values of human H3 in the last decade are comparable to the AI values of some swine H3 HAs of the same period; interestingly, the recent human and swine HAs show differential binding to polyclonal antibodies generated against seasonal vaccine strain (Fig. 2). This apparent discrepancy may be explained in part by the presence of certain key antigenic "hotspot" locations, where amino acid substitutions can lead to disproportionately large changes in antigenicity. Our observation is supported by other studies on H3 antigenic evolution. The frequent interspecies transmission of H3 viruses might also explain why this subtype is associated with the highest rates of mortality.

The importance of glycosylation in antigenic site masking leading to a new pandemic cycle and viral evolution became apparent after the 2009 pandemic. It was observed that the seasonal H1N1 HA carries antigenic site-masking glycosylation sites not present in the 2009 pandemic H1N1 HA (and 1918 H1N1 HA) and the exposure of the unprotected antigenic surface is believed to be the reason underpinning the severity of the 2009 H1N1 pandemic. Akin to H1 subtype, the additional glycosylation sites on the recent seasonal H3 appear to have a role in antigenic site masking. For instance, the glycosylation at position 63 masks antigenic site E, and glycosylation at sites, and protect antigenic A. The shielding nature of these glycosylation sites is evident from the gradual decline in the mutation rate of the masked antigenic sites following their appearance (Fig. S2), portending a 2009 H1N1-like H3N2 pandemic. If a virus carrying a HA similar to the ones identified by this analysis makes its way into humans, it would need to evolve rapidly in response to selective pressures from vaccination and herd immunity. The ability of H3 subtype to add glycosylation sites will be a key factor enabling the virus to achieve sustained circulation in the next cycle. In contrast, a previous study using nucleotide sequence analysis concluded that H2 has an intrinsically lower capacity to add glycosylation sites. Taking these factors together, we assert that it is less likely for an avian or swine H2 virus (antigenically similar to 1957-58 pandemic H2N2) to gain a foothold for sustained circulation in humans when compared to H3 viruses.

The rapid antigenic drift that human H3N2 HA underwent during the early adaptation period of the virus (1968-76) appears to have slowed down after 1977. Interestingly, this time period also coincides with the reemergence of H1N1 in the human population. The (re-) emerging H1N1 subtype could have imposed strong selective pressures on the H3N2 to stop circulating in humans after 1977. The evolution of human H3N2 HA after 1977 is characterized by glycosylation accrual, low-level site-specific antigenic changes, and variations at other non-immunodominant sites. Additionally, a recent study found that the affinity of human H3 viruses for human receptors has reduced drastically since 2001. These observations suggest that currently circulating viruses are not as dominant as the earlier viruses. Based on this trend, one can argue that human H3N2 HA presently is "antigenically drained", which poses a substantially high barrier to evolution via antigenic drift. However, the presence of antigenically intact H3 in avian and swine suggests that, as with 2009 H1N1 pandemic, reassortment can result in 'resetting and shifting' the antigenicity back to that of the 1968 pandemic and hence facilitate sustained evolution of this subtype in humans.

Influenza A viruses of other subtypes (H5, H7, H9) that have caused sporadic infections in humans over the past decade also pose equal risk of a pandemic, especially since they represent completely novel HA subtypes. Although antigenic phenotypes could be predicted from HA sequences, the genetic signatures in influenza viruses that lead to a sustained human-to-human transmission cannot be accurately predicted. Although an antigenically novel HA is necessary, it is not the only determining factor for a pandemic. While gain of host receptor specificity is a key determinant, changes in influenza proteins other than HA such as the polymerase (PB2) are typically involved, making predictions of the timing of future pandemics more complex. Nevertheless, our study facilitates setting the stage for future work aimed at designing vaccination studies with animal models using a cocktail of H3 antigens from strains of current avian and swine origin along with specific past strains. Such studies would augment the preparedness in the event of potential re-emergence of H3N2 pandemic.

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Communicated by:
ProMED-mail Rapporteur Kunihiko Iizuka

[Unlike the 1918 H1N1 virus which crossed to swine soon after and remained in swine, the human H3N2 viruses appear to have repeatedly crossed from humans to swine for some time, which could be the reason why swine H3 viruses appear to manifest the antigenic drift that human strains underwent during this period.

The affinity of human H3 viruses for human receptors has reduced drastically since 2001. Such observations suggest that currently circulating viruses are not as dominant as the earlier viruses. Based on this trend, the author suggest that human H3N2 HA presently is "antigenically drained", which poses a substantially high barrier to evolution via antigenic drift. However, the presence of antigenically intact H3 in avian and swine suggests that, as with 2009 H1N1 pandemic, reassortment can result in 'resetting and shifting' the antigenicity back to that of the 1968 pandemic and hence facilitate sustained evolution of this subtype in humans.

The authors concede that while gain of host receptor specificity is a key determinant, changes in influenza proteins other than HA such as the polymerase (PB2) are typically involved, making predictions of the timing of future pandemics more complex. Nevertheless, the authors claim that this study facilitates setting the stage for future work aimed at designing vaccination studies with animal models using a cocktail of H3 antigens from strains of current avian and swine origin along with specific past strains. Such studies would augment the preparedness in the event of potential re-emergence of H3N2 pandemic. - Mod.CP]

http://www.news.gov.hk/tc/categories/health/index.lin.shtml

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