Risk Assessment of Fifth-Wave H7N9 Influenza A Viruses in Mammalian Models

Abstract

The fifth wave of the H7N9 influenza epidemic in China was distinguished by a sudden increase in human infections, an extended geographic distribution, and the emergence of highly pathogenic avian influenza (HPAI) viruses. Genetically, some H7N9 viruses from the fifth wave have acquired novel amino acid changes at positions involved in mammalian adaptation, antigenicity, and hemagglutinin cleavability. Here, several human low-pathogenic avian influenza (LPAI) and HPAI H7N9 virus isolates from the fifth epidemic wave were assessed for their pathogenicity and transmissibility in mammalian models, as well as their ability to replicate in human airway epithelial cells. We found that an LPAI virus exhibited a similar capacity to replicate and cause disease in two animal species as viruses from previous waves. In contrast, HPAI H7N9 viruses possessed enhanced virulence, causing greater lethargy and mortality, with an extended tropism for brain tissues in both ferret and mouse models. These HPAI viruses also showed signs of adaptation to mammalian hosts by acquiring the ability to fuse at a lower pH threshold than other H7N9 viruses. All of the fifth-wave H7N9 viruses were able to transmit among cohoused ferrets but exhibited a limited capacity to transmit by respiratory droplets, and deep sequencing analysis revealed that the H7N9 viruses sampled after transmission showed a reduced amount of minor variants. Taken together, we conclude that the fifth-wave HPAI H7N9 viruses have gained the ability to cause enhanced disease in mammalian models and with further adaptation may acquire the ability to cause an H7N9 pandemic. IMPORTANCE The potential pandemic risk posed by avian influenza H7N9 viruses was heightened during the fifth epidemic wave in China due to the sudden increase in the number of human infections and the emergence of antigenically distinct LPAI and HPAI H7N9 viruses. In this study, a group of fifth-wave HPAI and LPAI viruses was evaluated for its ability to infect, cause disease, and transmit in small-animal models. The ability of HPAI H7N9 viruses to cause more severe disease and to replicate in brain tissues in animal models as well as their ability to fuse at a lower pH threshold than LPAI H7N9 viruses suggests that the fifth-wave H7N9 viruses have evolved to acquire novel traits with the potential to pose a higher risk to humans. Although the fifth-wave H7N9 viruses have not yet gained the ability to transmit efficiently by air, continuous surveillance and risk assessment remain essential parts of our pandemic preparedness efforts.

H7N9 Influenza Virus in China

“…Qi et al (2018) also reported that the H7N9 HPAIVs displayed high pathogenicity in chickens, with the human viral strains also lethal to mice. Sun et al (2018) found that the H7N9 HPAIVs exhibited enhanced lethality in mice and caused more severe infections in ferrets compared to an H7N9 LPAIV.…”

“…Guinea pigs and ferrets are two well-established animal models for the evaluation of transmissibility of influenza viruses (Gao et al 2009;Steel et al 2009;Herfst et al 2012;Imai et al 2012;Zhang et al 2013b). The H7N9 viruses, especially the human isolates, transmitted efficiently among guinea pigs or ferrets via direct contact (Belser et al 2013;Zhu et al 2013;Gabbard et al 2014;Luk et al 2015;Sun et al 2018). Compared with natural H5N1 viruses, which have never acquired respiratory droplet transmissibility, many studies have reported that both H7N9 LPAIV and HPAIV can transmit via respiratory droplets in guinea pigs and ferrets, although the efficiency of virus transmis- All six low pathogenic viruses and five of the six highly pathogenic viruses bound well to both human-type and avian-type receptors, whereas one of the six highly pathogenic viruses bound only to avian-type receptors.…”

Identification of key hemagglutinin residues responsible for cleavage, acid stability, and virulence of fifth-wave highly pathogenic avian influenza A(H7N9) viruses

“…We recently demonstrated that despite no airborne transmissibility increase compared to LPAI A(H7N9) viruses, select HPAI A(H7N9) human isolates possess heightened mammalian virulence with an extended tissue tropism in animal models and a lowered threshold pH for membrane fusion, a trait potentially associated with enhanced transmission in mammals (Sun et al, 2018). However, a comprehensive understanding of the biological properties associated with HPAI A(H7N9) virulence and mammalian transmission has yet to be identified.…”

Enhanced Potency of a Broad H7N9-Neutralizing Antibody HNIgGA6 Through Structure-Based Design

“…Neuraminidase inhibitor (NAI) resistance (R292K substitution in NA) was detected in both NA inhibitor-treated patients (Hu et al, 2013;Yen et al, 2013) and a few nonhuman-derived HP-H7N9 strains (Quan et al, 2018). Varied virulence and transmissibility has been confirmed in animal models by using circulating H7N9 viruses from wave five (Bao et al, 2019;Sun et al, 2019). Therefore, H7N9 AIV is classified as "an unusually dangerous virus for humans" by the World Health Organization (WHO, 3 ).…”