Thursday, July 30, 2015

CDC Study: Pathogenesis & Transmissibility Of HPAI H5 In Mice & Ferrets



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Its effects on poultry are well established, but determining the pathogenesis (progression of disease) and degree of transmissibility of our recently arrived HPAI H5 viruses among mammals is a  high priority.  While it’s been encouraging that we’ve seen hundreds of poultry outbreaks over the past 18 months without seeing any human cases, a more precise measurement of their pandemic potential is needed.


Despite this lack of human cases, we have seen reports of dogs being infected with H5N8 (see MAFRA: H5N8 Antibodies Detected In South Korean Dogs (Again)).   The ability to infect canines does not automatically make it a human threat, but it does raise some concerns (see Study: Dogs As Potential `Mixing Vessels’ For Influenza).


Earlier this year, in Virology: Pathogenesis Of Avian A/H5N8 In Ferrets, we saw that that ferrets intranasally inoculated  with the Korean H5N8 strain suffered no mortality or serious respiratory symptoms, but that ferrets intratracheally infected showed `dose-dependent mortality’.


Yesterday the CDC published a new study in the Journal of Virology (the bulk of which, alas, is behind a pay wall) that further explores both the pathogenicity (in mice) and transmissibility (in ferrets) of both the North American H5N8 and H5N2 viruses.


The CDC has provided a lengthy summary, and for the most part the news remains good.  Some highlights:

  • The severity of disease in inoculated mice was dose dependent, with severe disease only in mice given a very high dose of the virus.  And while the virus was detected in the lungs, laboratory mice experienced a less severe, more moderate disease than seen when exposed to the Asian H5N1 virus.
  • Illness in ferrets was described as mild, and the virus did not spread to flu naïve ferrets placed in the same cage as infected ferrets, suggesting the risk of human-to-human transmission is low.
  • H5Nx viruses replicated in human lung and airway cell cultures - but not as vigorously as with the Asian H5N1 virus – comparable to what is seen with seasonal H1N1.


While none of this precludes the possibility that human infection with one of these viruses might occur, this does reinforce the CDC’s assessment that these viruses currently pose a low risk to human health.   Influenza viruses are always changing, however, and new reassortants could appear, so ongoing vigilance is required.


More from the CDC below:


New CDC Laboratory Study Suggests U.S. H5 Bird Flu Viruses Currently Pose Low Risk to People

A new CDC study describes findings from a series of CDC laboratory experiments designed to improve understanding of the human health risk posed by two H5 bird flu viruses detected in birds in the United States: H5N2 and H5N8. Findings of this study indicate that the H5N2 and H5N8 bird flu viruses detected in the United States were less lethal in mammals and replicated (made copies of themselves during infection) at a lower level than the H5 bird flu viruses from Asia that have caused infections, serious illness and deaths in people. Overall findings suggest that these new U.S. bird flu viruses are unlikely to easily infect or spread between people in their current form and are likely to be associated with mild to moderate illness compared to the more severe illness associated with Asian H5 viruses. These U.S. bird flu viruses would need to undergo additional changes in order to pose a pandemic health risk to people.

This study, published today in the Journal of Virology, involved a combination of laboratory tests, some of which included animals and others that involved human lung cells grown in the laboratory via cell culture. CDC often uses such tests to infer how newly detected flu viruses can impact human health. These studies are part of a routine public health risk assessment process that CDC undertakes whenever a new virus with pandemic potential is identified.

Experiments conducted in this study include the following: tests in mice to determine the severity of disease associated with these viruses, tests in ferrets to determine characteristics of how these viruses spread between mammals and within the body, and tests using cell culture to measure the ability of these viruses to grow in human airway/lung cells (specifically human airway epithelial Calu-3 cells) in a laboratory setting.

Results in mice showed that mice infected with these viruses did not experience severe disease unless given very high doses of the virus. Virus was detectable in the lungs of mice, though, which is a characteristic that can be associated with more serious illness. However, compared to Asian H5 viruses, these U.S. H5 bird flu viruses demonstrated less severe, more moderate disease characteristics. Health researchers consider mice to be a reliable model for how disease associated with H5 bird flu viruses develops and progresses in mammals.

Transmission experiments involving ferrets showed that these U.S. H5 bird flu viruses did not spread between flu naïve ferrets (i.e., ferrets that had never been exposed to flu viruses previously) placed in the same cage as infected ferrets. This indicates that the virus is unlikely to spread efficiently among people, if they were to become infected by close contact with H5N2- or H5N8-infected poultry. Also, illness in the infected ferrets was generally mild, and the viruses did not spread systemically to multiple organs, which is a characteristic associated with more severe disease. These results are consistent with previous studies of H5N8 bird flu viruses in South Korea, which also showed low to moderate virulence in mammals. Ferrets are considered an excellent model for studying flu transmission and they also exhibit signs of disease that are similar to people infected with the flu.

Researchers also evaluated the ability of these bird flu viruses to replicate in human lung cells in laboratory experiments involving cell culture. The ability of a virus to infect human lung and airway cells is a trait that can be associated with more severe illness. These tests showed that H5N2 and H5N8 viruses replicated in human lung and airway cells at significantly lower levels compared to the Asian H5N1 viruses that have caused human deaths in Asia and elsewhere. While replication did occur, it was at a level comparable to human seasonal H1N1 flu virus.

Outbreaks in birds of H5N2, H5N8 and a new H5N1 bird flu virus were detected in the United States first in late 2014. Both of the bird flu viruses involved in this study were detected in Washington State: the H5N8 bird flu virus was obtained from an infected gyrfalcon and the H5N2 virus was obtained from a northern pintail duck. Most of the U.S. poultry outbreaks reported this year have been associated with the H5N2 virus, resulting in the loss of nearly 50 million chickens and turkeys on over 200 farms since the virus was first identified in December 2014. No human infections with these viruses have been detected at this time.

These findings reaffirm CDC’s current assessment that these viruses pose a low risk to the general public. CDC will continue to closely monitor and assess the risk of these viruses to human health as part of its routine pandemic preparedness responsibilities and activities.




Pathogenesis and transmission of novel HPAI H5N2 and H5N8 avian influenza viruses in ferrets and mice

Joanna A. Pulit-Penaloza, Xiangjie Sun, Hannah M. Creager, Hui Zeng, Jessica A. Belser, Taronna R. Maines and Terrence M. Tumpey

A novel highly pathogenic avian influenza (HPAI) H5N8 virus, first detected in January 2014 in poultry and wild birds in South Korea, has spread throughout Asia and Europe, and caused outbreaks in Canada and the United States by the end of the year. The spread of H5N8 and the novel reassortant viruses, H5N2 and H5N1 (H5Nx), in domestic poultry across multiple states in the U.S. pose a potential public health risk. To evaluate the potential of cross-species infection, we determined the pathogenesis and transmissibility of two Asian-origin H5Nx viruses in mammalian animal models. The newly isolated H5N2 and H5N8 viruses were able to cause severe disease in mice only at high doses. Both viruses replicated efficiently in the upper and lower respiratory tracts of ferrets; however clinical symptoms were generally mild and there was no evidence of systemic dissemination of virus to multiple organs. Moreover, these influenza H5Nx viruses lacked the ability to transmit between ferrets in a direct contact setting. We further assessed viral replication kinetics of the novel H5Nx viruses in a human bronchial epithelium cell line, Calu-3. Both H5Nx viruses replicated to a level comparable to a human seasonal H1N1 virus, but significantly lower than a virulent Asian-lineage H5N1 HPAI virus. Although the recently isolated H5N2 and H5N8 viruses displayed moderate pathogenicity in mammalian models, their ability to rapidly spread among avian species, reassort, and generate novel strains underscores the need for continued risk assessment in mammals.

(Continue . . .)

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