Accepted Manuscript Birds of ill omen - is H7N9 the harbinger of the next pandemic? Sophia Häfner PII: S1286-4579(13)00092-0 DOI: 10.1016/j.micinf.2013.04.011 Reference: MICINF 4022 To appear in: Microbes and Infection Received Date: 22 April 2013 Accepted Date: 25 April 2013 Please cite this article as: S. Häfner, Birds of ill omen - is H7N9 the harbinger of the next pandemic?, Microbes and Infection (2013), doi: 10.1016/j.micinf.2013.04.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Transcript
Accepted Manuscript
Birds of ill omen - is H7N9 the harbinger of the next pandemic?
Sophia Häfner
PII: S1286-4579(13)00092-0
DOI: 10.1016/j.micinf.2013.04.011
Reference: MICINF 4022
To appear in: Microbes and Infection
Received Date: 22 April 2013
Accepted Date: 25 April 2013
Please cite this article as: S. Häfner, Birds of ill omen - is H7N9 the harbinger of the next pandemic?,Microbes and Infection (2013), doi: 10.1016/j.micinf.2013.04.011.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service toour customers we are providing this early version of the manuscript. The manuscript will undergocopyediting, typesetting, and review of the resulting proof before it is published in its final form. Pleasenote that during the production process errors may be discovered which could affect the content, and alllegal disclaimers that apply to the journal pertain.
Abstract: In February 2013, a novel avian virus appeared in Humans in China and caused several fatalities since. The rapidity and efficiency of the orgainsations in charge led to the quick identification of H7N9 and the triggering of preventive measures. However, the sequencing of the viral genome holds good and bad news and it is not clear yet if we face an emerging pandemic. Keywords: H7N9, avian flu, virus
Close to the inexorable centenary of recorded influenza A infections and pandemics, it seems as if we are entitled to a revised edition of avian flu: H7N9, a phylogenetic patchwork of viruses from Chinese ducks, brambling birds and Korean wild birds, appeared around February 2013 in humans in China, infected about 80 and killed 17 individuals up to date, with the international medical community being quickly on alert.
Most threatening infectious diseases worldwide are zoonoses, pathogens transmissible from animals to humans difficult to eradicate because of their large and persistent reservoir. Viruses emerging regularly from swine and birds are no exception. Influenza A viruses (AIV) have caused regularly major health problems since 1918 (H1N1), the most recent ones date from 2003 (H7N7 and H5N1) and 2009 (H1N1), H5N1 alone causing over 90 deaths between 2003 and 2006 and panicked citizens leaving only their homes when wearing a face mask [1,2].
The good thing about things happening over and over again, is that one might say that we learnt a little lesson there in the meantime: birds fly and so do humans, enabling pathogens to spread quickly over the world and to become quickly everyone’s problem [3]. Thus, the two trump cards against emerging viruses are rapidity and information. The ones who deserve special credit in the recent events are the Chinese medical attendants and researchers for the speed and efficiency of identification and publication of the novel virus in less than a week, notably the Shanghai Fifth Hospital, who executed instantly the guidelines of the nation-wide alert network for the diagnosis of respiratory infectious diseases created in 2008 when confronted with the first two patients. Throat- swab specimens were sent to the Laboratory of Pathogen Diagnosis and Biosafety of Shanghai Public Health Clinical Center who determined the viral subtype by real-time RT-PCR. The Chinese Center for Disease Control confirmed the results and isolated the H7N9 virus, the National Health and Family Planning Commission notified the World Health Organization (WHO) [4] and on March 29, the Chinese National Influenza Center (CNIC) made the full genome sequences publicly available on the website of the Global Initiative on Sharing Avian Influenza Data (GISAID) [3,5]. The latter, a scientific consortium promoting international free sharing of influenza virus sequences and clinical or epidemiological data, was created in 2006 as a reaction to the H5N1 outbreak and the increasing concerns about a pandemic scenario. The data can be used for research as well as for the development of diagnostic tools and vaccines [6]. Virtual worldwide data sharing became indeed common practice, the latest up-to-date information concerning H7N9 is instantly available to anyone on numerous websites such as the Influenza Virus Resources of the National Center for Biotechnology Information (NCBI), the Influenza Sequence Database (ISD), GenBank, the Influenza Research F-Database or the WHO, not to mention the non professional spread of
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
information through various blogs and social networks like Twitter.
Speaking of computers – the latest hopes to be slightly ahead of threatening mutations of the novel virus took the form of keyboards. In order to elucidate the road to become a human virus, the team of Shin-Ru Shih came up with a computational approach designed to identify host-species associated amino acids in all 8 genomic segments and 11 encoded protein sequences of human or avian influenza viruses [2]. Drawing in the previously mentioned online datasets, the authors identified 52 species-associated signatures, most of them in the functional domains of essential proteins for viral replication or interaction with host cell proteins. Mutations of these points from the avian to the human consensus amino acids could reflect crucial changes in host cell tropism and in the ability to efficiently infect humans. Many have been already correlated with increased virulence, transmission type and enhanced ability to infect mammalian cells [5]. The minimal amount of mutations required to render an influenza virus a pandemic strain is still unknown, but monitoring closely the evolution of key signature residues offers the possibility to foresee changes
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
in the viral behaviour. Biological experiments should be performed to back up the theories linked to each signature [2].
Shibo Jiang and colleagues applied the technique directly to the H7N9 sequences [1] and published the results in this issue of Microbes and Infection. Their findings hold both good and bad news. Despite some mutations enhancing mammalian adaptation (E627K in the PB2 protein and Q226L mutation in the hemagglutinin protein), conferring resistance to M2 channel blockers amantadine and rimantadine (N31S) and correlating with higher virulence (deletion in the stalk of the neuraminidase protein), H7N9 remains mainly avian-type, with low pathogenicity and sensitive to oseltavimir, zanamivir. The other side of the coin is that the clinical spectrum of symptoms, ranging from fulminant pneumonia and acute respiratory distress syndrome (ARDS) to multiorgan failure and ultimately death, is none of the gentle ones and that we have to add “not yet” to any of the previous statements. Additional mutations of the key signature amino acids identified by Shih and colleagues could boost H7N9's virulence and drug resistance.
The main sword of Damocles is the possible gain of human-to-human transmissibility synonym of the beginning of a serious pandemic. As a consequence, scientists lately focused anxiously on a putative family cluster when a female patient who died from the infection and a male patient still in hospital turned out to be wife and husband. Likewise, the “Li family case” of a father and a son in Shanghai who contracted the H7N9 virus with a fatal outcome for the father, is still an issue of debate. Although there is no direct evidence for human-to-human transmission, there is also no evidence that all H7N9 patients had contact history with avian species, suggesting that non- sustained human transmission – through prolonged, close contact between family members, unlike sustained transmission by respiratory droplets for example - could occur. Limited human transmission had already been observed during the H5N1 and the H7N7 outbreaks and the risk of acquisition of an efficient human transmissibility increases proportionally with the number of infected individuals by supplying the virus with an ideal training ground for further adaptive mutations to the human organism [3,5].
Right now, the primordial measure is not to lower one’s guard. As infections with N9 subtypes have not occurred in humans before and those with N7 being rare, the population lacks immunity to this new virus and people of all ages and both sexes are at risk. On the agenda figure, in big red letters, enhanced surveillance and strict monitoring of all potential cases, family members, health care workers and occurring mutations, rapid clinical data collection and worldwide sharing [3]. The WHO published a real-time RT-PCR protocol for the detection of the H7N9 virus, insisting strongly that any not subtypeable specimen should be sent urgently to one of the six WHO Collaborating Centres for Influenza in the Global Influenza Surveillance and Response System (GISRS) [7]. In parallel, rapid strategies to combat the virus need to be developed. A vaccine against H7N9 does not yet exist and existing H7 vaccines turned out to be poorly immunogenic in mammals [3, 5]. Sharing viruses worldwide will certainly accelerate vaccine development; nevertheless its release can’t be expected before months. Eyes should be kept also on the animal reservoir because a virus causing only mild or asymptomatic disease could spread silently among birds and potentially other hosts in China and neighboring countries.
The last measure, of equal importance than fighting the virus is fighting panic among the population. Successful prevention and control of the situation requires the clear communication of main messages to the civilian and clinical community [3]. A preventive campaign has already been initiated by the Chinese government by closing poultry markets and by covering public spaces with image-rich posters passing on the message to stay away from poultry and how to wash your hands correctly.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Anyway, the coming weeks hold great suspense as they will decide if H7N9 settles for another zoonosis or if it aims at the title of the next pandemic.
References
[1] Q. Liu, L. Lu, Z. Sun, G-W. Chen, Y. Wen, S. Jiang, Genomic signature and protein sequence analysis of novel influenza A (H7N9) virus that causes an outbreak in humans in China, Microbes Infect. 15 (2013) ahead of print. [2] G-W. Chen, S-C. Chang, C-K. Mok, Y-L Lo, Y-N. Kung, J-H. Huang, Y-H. Shih, J-Y. Wang, C. Chiang, C-J. Chen and S-R. Shih, Genomic signatures of human versus avian influenza A viruses, Emerg. Infect. Dis. 12 (2006) 1353-1360. [3] T. Uyeki, N. Cox, Global concerns regarding novel influenza A (H7N7) virus infections, N. Engl. J. Med. (2013), ahead of print. [4] Y-M. Wen, H-D. Klenk, H7N9 avian influenza virus – search and re-search, Emerg. Microbes Infect. 2 (2013) 1-2. [5] R. Gao, B. Cao, Y. Hu, Z. Feng, D. Wang, W. Hu, J. Chen, Z. Jie, H. qiu, K. Xu, X. Xu, H. Lu, W. Zhu, Z. Gao, N. Xiang, Y. Shen, Z. He, Y. Gu, Z. ahang, Y. Yang, X. Zhao, L. Zhou, X. Li, S. Zou, Y. Zhang, X. Li, L. Yang, J. Guo, J. Dong, Q. Li, L. Dong, Y. zhu, T. Bai, s. Wang, P. Hao, W. Yang, Y., zhang, J. Han, H. Yu, D. Li, G. Gao, G. Wu, Y. Wang, z. Yuan and Y. Shu, Human Infection with a novel avian-origin influenza A (H7N9) virus, N. Engl. J. Med. (2013), ahead of print. [6] http://en.wikipedia.org/wiki/GISAID [7] http://www.who.int/influenza/gisrs_laboratory/cnic_realtime_rt_pcr_protocol_a_h7n 9.pdf
