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The Ascent of H7N9

Amesh A. Adalja, MD, FACP, FACEP, FIDSA, November 1, 2017

The relatively new avian influenza, H7N9, is now considered to be the most concerning of all pandemic threats. To cope with the myriad influenza viruses that circulate in humans and animals, the US Centers for Disease Control and Prevention (CDC) developed an Influenza Rapid Assessment Tool (IRAT) to rank order viruses that pose the biggest threat to humans. In recent iterations of this tool, the H7N9 influenza A virus has topped the list, surpassing all other flu viruses, including H5N1. Several important aspects that underlie this ranking are vital to understanding for pandemic preparedness.1 


The Trajectory of the Fifth Wave

The epidemic of H7N9 began in 2013, with cases occurring in southern China, predominantly among individuals with close contact with poultry markets. Taiwan has reported 1 case imported from China. These cases have occurred over the past 4 years in annual epidemic waves, culminating with the largest wavethe fifthwhich southern China is currently experiencing. To date, there has been no sustained human-to-human transmission, but more than 1,500 cases have occurred, with a case fatality rate reaching 40%. This wave of the epidemic has been characterized by more cases than the other 4 waves combined in addition to having a larger geographic spread.2 


High-Pathogenicity Variant in Chickens Emerges; Human Adaptation

In past years of this outbreak, H7N9 was characterized as having low pathogenicity in chickens—meaning that they exhibited no symptoms of infection. “Low path” viruses pose problems with disease tracking because the birds are not obviously sick. Thus, it falls to human cases to serve as sentinel events to gauge the spread of the virus. However, high-pathogenicity viruses are easier to spot in chicken populations because most or all of the birds suddenly die. Even though high-pathogenicity outbreaks are easier to detect, they are cause for concern because, in addition to being lethal to poultry, they are also more virulent in mammals. 

A new study from the Kawoaka lab has recently confirmed that high-pathogenicity variants of H7N9 can transmit efficiently with lethal results in a ferret model3ferrets being the standard animal model for human influenza.

Though the virus has not yet acquired the capacity for sustained, efficient human-to-human transmission, another paper revealed that just 3 mutations are needed for the avian-adapted virus to switch its receptor specificity to human versions.4 


Another Lineage Poses Challenge for Vaccines

Another concerning development in this wave surrounds the divergence of H7N9 strains into 2 distinct lineagesPearl River Delta and Yangtze River Deltawith Yangtze predominating. Such an event calls into question the efficacy of the stockpiled H7N9 vaccine, which has considerable antigenic differences from this lineage. This is prompting the development of new candidate vaccine viruses for an updated vaccine. It is also important to note that because of the immunological naïveté of the human population to H7N9 viruses, 2 doses of the vaccine will be required for significant immunity to be achieved.2 


Neuraminidase Resistance

A cornerstone of influenza pandemic response will be the employment of antiviral medications. Of the 2 classes of licensed influenza antiviral medications in the United States, drug resistance to the adamantane class is now widespread. The remaining drugs belong to the neuraminidase inhibitors class. Evidence from the fifth wave reveals that neuraminidase inhibitor resistance is occurring in H7N9, which is especially concerning in a disease with a 40% fatality rate. This reinforces the need for the development and deployment of new antiviral therapies with disparate mechanisms of actions, such as favipiravir.2 


The Window of Opportunity May Be Closing

The ascent of H7N9 to the top of the most concerning influenza viruses is the result of multiple lines of converging evidence. That these epidemiologic and virologic changes are occurring during the largest H7N9 epidemic wave to date adds to the urgency with which this threat needs to be addressed. If H7N9 achieves sustained human-to-human transmission, it would arguably be the worst health and national security threat faced by the world in literally a century. An H7N9 pandemic could well be worse—perhaps much worse—than the great pandemic of 1918. There still is time, however, to develop new vaccines, more comprehensive surveillance programs, and new antiviral treatment paradigms.



  1. Centers for Disease Control and Prevention. Summary of influenza risk assessment tool (IRAT) results. CDC website. Updated October 23, 2017. Accessed October 31, 2017.
  2. Kile JC, Ren R, Liu L, et al. Update: increase in human infections with novel Asian lineage avian influenza A(H7N9) viruses during the fifth epidemic—China, October 1, 2016-August 7, 2017. MMWR Morb Mortal Wkly Rep 2017;66(35):928-932.
  3. Imai M, Watanabe T, Kiso M, et al. A highly pathogenic avian H7N9 influenza virus isolated from a human is lethal in some ferrets infected via respiratory droplets. Cell Host Microbe 2017. Accessed October 31, 2017.
  4. de Vries RP, Peng W, Grant OC, et al. Three mutations switch H7N9 influenza to human-type receptor specificity. PLoS Pathog 2017;13(6):e1006390. Accessed October 31, 2017.