Influenza A virus subtype H7N9

Influenza A virus subtype H7N9
Virus classification
(unranked):	Virus
Realm:	Riboviria
Kingdom:	Orthornavirae
Phylum:	Negarnaviricota
Class:	Insthoviricetes
Order:	Articulavirales
Family:	Orthomyxoviridae
Genus:	Alphainfluenzavirus
Species:	Influenza A virus
Serotype:	Influenza A virus subtype H7N9

Influenza (flu)
Types Avian A/H5N1 subtype Canine Equine Swine A/H1N1 subtype
Vaccines 2009 pandemic Pandemrix Live attenuated Seasonal flu vaccine brands
Treatment Amantadine Baloxavir marboxil Laninamivir Oseltamivir Peramivir Rimantadine Umifenovir Zanamivir
Pandemics 1889-1890 Russian flu 1918 Spanish flu 1957-1958 Asian flu 1968 Hong Kong flu 1977 Russian flu 2009 swine flu
Outbreaks 1976 swine flu 2006 H5N1 India 2007 Australian equine 2007 Bernard Matthews H5N1 2008 West Bengal 2015 United States H5N2 outbreak 2020–2022 H5N8 outbreak
See also Flu season Influenza evolution Influenza research Influenza-like illness Vaccine reformulations
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Influenza A virus subtype H7N9 (A/H7N9) is a subtype of the influenza A virus, which causes influenza (flu), predominantly in birds. It is enzootic (maintained in the population) in many bird populations.^[1] A/H7N9 virus is shed in the saliva, mucous, and feces of infected birds.^[2] The virus can spread rapidly through poultry flocks and among wild birds; it can also infect humans that have been exposed to infected birds.^[2]

A/H7N9 virus is shed in the saliva, mucous, and feces of infected birds; other infected animals may shed bird flu viruses in respiratory secretions and other body fluids.^[3] The virus can spread rapidly through poultry flocks and among wild birds.^[3]

Symptoms of A/H7N9 influenza vary according to both the strain of virus underlying the infection and on the species of bird or mammal affected.^[4][5] Classification as either Low Pathogenic Avian Influenza (LPAI) or High Pathogenic Avian Influenza (HPAI) is based on the severity of symptoms in domestic chickens and does not predict the severity of symptoms in humans.^[6] Chickens infected with LPAI A/H7N9 virus display mild symptoms or are asymptomatic, whereas HPAI A/H7N9 causes serious breathing difficulties, a significant drop in egg production, and sudden death.^[7]

In mammals, including humans, A/H7N9 influenza (whether LPAI or HPAI) is rare; it can usually be traced to close contact with infected poultry or contaminated material such as feces.^[8] Symptoms of infection vary from mild to severe, including fever, diarrhoea, and cough; the disease can often be fatal.^[9][10]

The A/H7N9 virus is considered to be enzootic (continually present) in wild aquatic birds, which may carry the virus over large distances during their migration.^[11] The first known case of A/H7N9 influenza infecting humans was reported in March 2013, in China.^[12] Cases continued to be recorded in poultry and humans in China over the course of the next 5 years. Between February 2013 and February 2019 there were 1,568 confirmed human cases and 616 deaths associated with the outbreak in China.^[13] Initially the virus was low pathogenic to poultry, however around 2017 a highly pathogenic strain developed which became dominant. The outbreak in China has been partially contained by a program of poultry vaccination which commenced in 2017.^[14]

Bird-adapted A/H7N9 transmits relatively easily from poultry to humans, although human to human transmission is rare. Its ability to cross the species barrier renders it a potential pandemic threat, especially if it should acquire genetic material from a human-adapted strain.^[15][16]

H7N9 is a subtype of Influenza A virus. Like all subtypes it is an enveloped negative-sense RNA virus, with a segmented genome.^[17] Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses.^[18] The segmentation of its genome facilitates genetic recombination by reassortment in hosts infected with two different strains of influenza viruses at the same time.^[19][20] Through a combination of mutation and genetic reassortment the virus can evolve to acquire new characteristics, enabling it to evade host immunity and occasionally to jump from one species of host to another.^[21][22]

Most human infections with avian influenza viruses, including A/H7N9, occur after exposure to infected poultry or contaminated environments. A/H7N9 viruses continue^[when?] to circulate in poultry in China. Most reported patients with A/H7N9 virus infection have had severe respiratory illness (e.g., pneumonia). Rare instances of limited person-to-person spread of this virus have been identified in China, but there is no evidence of sustained person-to-person spread.^{[citation needed]} Some human infections with A/H7N9 virus have been reported outside of mainland China, Hong Kong or Macao but all of these infections have occurred among people who had traveled to China before becoming ill. A/H7N9 viruses have not been detected in people or birds in the United States.^[23]

Prior to 2013, A/H7N9 had previously been isolated only in birds, with outbreaks reported in the Netherlands, Japan, and the United States. Until the 2013 outbreak in China, no human infections with A/H7N9 had been reported.^[8][24]

A significant outbreak of Influenza A virus subtype H7N9 (A/H7N9) started in March 2013 when severe influenza affected 18 humans in China; six subsequently died.^[15] It was discovered that a low pathogenic strain of A/H7N9 was circulating among chickens, and that all the affected people had been exposed in poultry markets. Further cases among humans and poultry in mainland China continued to be identified sporadically throughout the year, followed by a peak around the festival season of Chinese New Year (January and February) in early 2014 which was attributed to the seasonal surge in poultry production. Up to December 2013, there had been 139 cases with 47 deaths.^[25]

Infections among humans and poultry continued during the next few years, again with peaks around the new year. In 2016 a virus strain emerged which was highly pathogenic to chickens.^[14][26] In order to contain the HPAI outbreak, the Chinese authorities in 2017 initiated a large scale vaccination campaign against avian influenza in poultry. Since then, the number of outbreaks in poultry, as well as the number of human cases, dropped significantly. In humans, symptoms and mortality for both LPAI and HPAI strains have been similar.^[14] Although no human H7N9 infections have been reported since February 2019, the virus is still circulating in poultry, particularly in laying hens. It has demonstrated antigenic drift to evade vaccines, and remains a potential threat to the poultry industry and public health.^[26]

Genetic characterisation of this strain of avian influenza A/7N9 shows that it was not related to A/H7N9 strains previously identified in Europe and North America. This new strain resulted from the recombination of genes between several parent viruses noted in poultry and wild birds in Asia. The H7 gene is most closely related to sequences found in samples from ducks in Zhejiang province in 2011.The N9 gene was closely related to isolated wild ducks in South Korea in 2011. Other genes resembled samples collected in Beijing and Shanghai in 2012. The genes would have been carried along the East Asian flyway by wild birds during their annual migration.^{[27][28][27][29]}

The genetic characteristics of A/H7N9 virus are of concern because of their pandemic potential, e.g. their potential to recognise human and avian influenza virus receptors which affects the ability to cause sustained human-to-human transmission, or the ability to replicate in the human host.^[15][14]

During early 2017, outbreaks of avian influenza A(H7N9) occurred in poultry in the USA. The strain in these outbreaks was of North American origin and is unrelated to the Asian lineage H7N9 which is associated with human infections in China.^[30]

In May 2024, an HPAI A/H7N9 was detected on a poultry farm with 160,000 birds in Terang, Australia. There were 14,000 clinically affected birds. It is presumed that migratory wild birds were the source of the outbreak.^[31]

Avian flu viruses, both HPAI and LPAI, can infect humans who are in close, unprotected contact with infected poultry. Incidents of cross-species transmission are rare, with symptoms ranging in severity from no symptoms or mild illness, to severe disease that resulted in death.^[32][33] As of February, 2024 there have been very few instances of human-to-human transmission, and each outbreak has been limited to a few people.^[34] All subtypes of avian Influenza A have potential to cross the species barrier, with H5N1 and H7N9 considered the biggest threats.^[35][36]

As of 2019, the case fatality rate of the Chinese strain of A/H7N9 is 39%.^[37]

Information released in 2014 indicated that 75% of those that came down with H7N9 influenza had previously been exposed to domestic poultry, often in live bird markets.^[38][39] However, Chinese scientists found evidence that person-to-person transmission was possible, but would not transmit easily.^[40]

Although China has been praised for its quick response,^[12] some experts believe that there would be great difficulty providing adequate supplies of a vaccine if the virus were to develop into a pandemic. According to an article in the Journal of the American Medical Association (JAMA) in May 2013, "Even with additional vaccine manufacturing capacity... the global public health community remains woefully underprepared for an effective vaccine response to a pandemic...There is no reason to believe that a yet-to-be-developed pandemic A(H7N9) vaccine will perform any better than existing seasonal vaccines or the A(H1N1)pdm09 vaccines [about 60% to 70% effectiveness], particularly with regard to vaccine efficacy in persons older than 65 years."^[41]

On October 26, 2013, Chinese scientists announced that they had successfully produced an H7N9 vaccine, the first influenza vaccine to be developed entirely in China.^[42] It was developed jointly by researchers from Zhejiang University, Hong Kong University, the Chinese Center for Disease Control and Prevention, China's National Institute for Food and Drug Control, and the Chinese Academy of Medical Sciences. Chinese National Influenza Center director Shu Yuelong said the vaccine passed tests on ferrets and had been approved for humans, but H7N9 has not spread far enough to merit widespread vaccination. The vaccine was developed from a throat swab of an infected patient taken April 3.^[43]

On November 12, 2013, US scientists at Novavax, Inc. announced their successful clinical testing of an H7N9 vaccine in the New England Journal of Medicine. They had previously described the development, manufacture, and efficacy in mice of an A/Anhui/1/13 (H7N9) viruslike particle (VLP) vaccine produced in insect cells with the use of recombinant baculovirus. The vaccine combined the HA and neuraminidase (NA) of A/Anhui/1/13 with the matrix 1 protein (M1) of A/Indonesia/5/05. The study enrolled 284 adults (≥18 years of age) in a randomized, observer-blinded, placebo-controlled clinical trial of this vaccine.^[44]

The Centers for Disease Control and Prevention (CDC) began sequencing and development of a vaccine as routine procedure for any new transgenic virus.^[45] The CDC and vaccine manufacturers are developing a candidate virus to be used in vaccine manufacturing if there is widespread transmission.^[8][46] On September 18, 2013, NIH announced that researchers have begun testing an investigational H7N9 influenza vaccine in humans. Two Phase II trials are collecting data about the safety of the vaccine, immune system responses to different vaccine dosages, both with and without adjuvants. Healthy adults 19 to 64 years of age will be enrolled in the two studies. The inactivated-virus vaccine was made with H7N9 virus that was isolated in Shanghai, China. Adjuvants are being tested with the vaccine to determine if an adequate immune response can be produced. In addition, during a pandemic, adjuvants may be used as part of a "dose-sparing strategy".^[47]

In response to a request from the CDC and the Biomedical Advanced Research and Development Authority, following the unprecedented immediate release of the H7N9 flu virus gene sequences from the first human cases, by scientists at the China CDC^[48] through the GISAID Initiative,^[49][50] the J. Craig Venter Institute, and Synthetic Genomics Vaccines, Inc. began working with Novartis to synthesize the genes of the new viral strain, and supplied these synthesized genes to the CDC.^[51][52][53]

The scientific community has praised China for its transparency and rapid response to the outbreak of H7N9.^[54] In an editorial on April 24, 2013, the journal Nature said "China deserves credit for its rapid response to the outbreaks of H7N9 avian influenza, and its early openness in the reporting and sharing of data."^[12] This, in spite of initial worries by Chinese scientists and officials that they might lose credit for their work in isolating and sequencing the novel H7N9 virus, after learning that pharmaceutical company Novartis and the J. Craig Venter Institute had used their sequences to develop US-funded H7N9 vaccine without offering to collaborate with the Chinese team, according to Nature.^[55] They believed, the usage of their data was initially not handled in the spirit of the GISAID sharing mechanism, which requires scientists who use the sequences to credit and propose collaboration with those who deposited the data in GISAID. Nature cited a Chinese official who concluded that this situation was quickly mitigated once communication channels were opened and the parties agreed to collaborate, thanks to GISAID president Peter Bogner.^[56][57]

Despite concerns that vaccination of poultry against the H5N1 avian influenza virus over the last decade might have made it harder for Chinese veterinary technicians to spot the recent spread of the H7N9 virus, China's Agriculture Ministry defended its policy of large-scale vaccination of poultry against the earlier bird flu strain, saying that it was not interfering with its efforts now to identify the emerging H7N9 virus.^[58]

On April 15, 2013, the RIWI Corporation, led by researcher Neil Seeman of the University of Toronto released data on 7,016 Chinese “fresh” (i.e. non-panel based) Internet users – with a 24.08% response rate – over 20 hours. The level of contagion awareness was 31% in Beijing, 38% in Hangzhou, 33% in Nanjing, 40% in Shanghai, 52% in Ürümqi, and 28% in Zhengzhou (Chi Square; P = 0.05). The result far exceeds that of other internet surveys, suggesting an intense relevancy of interest and sense of urgency related to the current disease outbreak in the minds of average Chinese citizens.^[59]

In April 2013, Shanghai's health ministry ordered culling of birds after pigeon samples collected at the Huhuai wholesale agricultural products market in Songjiang District of Shanghai showed H7N9^[60][61] On April 4, 2013, Shanghai authorities closed a live-poultry-trading zone and began slaughtering all birds. Poultry trading areas in two other areas of the Minhang district were also closed.^[62] On April 6, 2013, all Shanghai live poultry markets closed temporarily in response to the H7N9 found in the pigeon samples.^[8][60][63] The same day, Hangzhou also closed its live poultry markets.^[63]

After gene sequence analysis, the national avian flu reference laboratory concluded that the strain of the H7N9 virus found on pigeons was highly congenic with those found on persons infected with H7N9 virus, the ministry said.^[61] On April 22, 2013, Forbes quoted Chinese state media reporting $2.7 billion in poultry industry losses.^[64]

When January 2014 brought a dramatic increase in reports of disease, the Chinese government responded by halting live poultry trading in three cities in Zhejiang province where 49 cases and 12 deaths had been reported. In addition, live poultry trading in Shanghai was halted for three months. In Hong Kong, authorities reacted to the discovery of H7N9 in live chickens from the province of Guangdong by suspending imports of fresh poultry from mainland China for 21 days, culling 20,000 chickens, and other measures in an effort to control the spread of the virus.^[65]

On February 18, 2014, it was announced that the Chinese government would extend the ban for four months. The health minister also said that they plan to prevent diseased birds from entering the market by setting up a facility where imported poultry can be quarantined to ensure they are disease-free.^[66]

The WHO did not advise against travel to China at that point in time, as there was no evidence of human-to-human transmission of the virus.^[67]

United States

On April 9, 2013, the Centers for Disease Control and Prevention (CDC) activated its Emergency Operations Center (EOC) in Atlanta at Level II, the second-highest level of alert.^[68] Activation was prompted because the novel H7N9 avian influenza virus has never been seen before in animals or humans and because reports from China have linked it to severe human disease. EOC activation will "ensure that internal connections are developed and maintained and that CDC staff are kept informed and up to date with regard to the changing situation."^[69]

Canada

On April 10, 2013, the Public Health Agency of Canada (PHAC) and the Canadian Food Inspection Agency (CFIA) spelled out bio-safety guidance for handling the H7N9 virus.^[70] They stated that work with live cultures must be conducted in biosafety level 3 (BSL-3) containment. They also said that studies growing H7N9 virus should not be done in labs that culture human influenza viruses and that personnel should not have contact with susceptible animals for 5 days after handling H7N9 samples.^[71]

Malaysia

Malaysia announced that it would temporarily ban Chinese chicken imports.^[72]

Vietnam

Vietnam announced that it would temporarily ban Chinese poultry imports.^[73][74]

Singapore

All hospitals were informed to remain vigilant, and to notify Singapore's Ministry of Health (MOH) immediately of any suspected cases of avian influenza in individuals who have recently returned from affected areas in China.^[67] MOH advised returning travellers from affected areas in China (Shanghai, Anhui, Jiangsu, and Zhejiang) to look out for signs and symptoms of respiratory illness, such as fever and cough, and seek early medical attention if they are ill with such symptoms.^[67] MOH also advised individuals to inform their doctors of their travel history, should they develop these symptoms after returning to Singapore.^[67]

Taiwan

On 3 April 2013, the Executive Yuan activated Taiwan's Central Epidemic Command Center (CECC) in response to the epidemic in mainland China.^[75][76] The Executive Yuan deactivated the CECC for H7N9 influenza on 11 April 2014.^[75]

During this period, 24 meetings were convened with representatives from 24 central government agencies including the Council of Agriculture, the Ministry of Transportation and Communications, and the Ministry of Education, along with 22 city and county governments. Meetings were attended by regional commanding officers and deputy commanding officers of the Communicable Disease Control Network.^[75]

On 17 May 2013, a ban became effective on the slaughtering of live poultry at traditional wet markets, which eliminated the risk of animal-to-human transmission of avian influenza.^[75]

• Antigenic shift
• Influenza A virus subtype H9N2
• Influenza A virus subtype H5N1
• Pandemic H1N1/09 virus
• Influenza research
• Zoonosis