Summary Avian influenza A viruses rarely infect humans, but if they do and transmit among them, worldwide outbreaks (pandemics) can result. The recent sporadic infections of humans in China with a previously unrecognized avian influenza A virus of the H7N9 subtype (A(H7N9)) have caused concern due to the appreciable case fatality rate associated with these infections (>25%), potential instances of human-to-human transmission1, and the lack of pre-existing immunity among humans to viruses of this subtype. Here, we therefore characterized two early human A(H7N9) isolates, A/Anhui/1/2013 and A/Shanghai/1/2013 (H7N9; hereafter referred to as Anhui/1 and Shanghai/1, respectively). In mice, Anhui/1 and Shanghai/1 were more pathogenic than a control avian H7N9 virus (A/duck/Gunma/466/2011; H7N9; Dk/GM466) and a representative pandemic 2009 H1N1 virus (A/California/04/2009; H1N1; CA04). Anhui/1, Shanghai/1, and Dk/GM466 replicated well in the nasal turbinates of ferrets. In nonhuman primates (NHPs), Anhui/1 and Dk/GM466 replicated efficiently in the upper and lower respiratory tracts, whereas the replicative ability of conventional human influenza viruses is typically restricted to the upper respiratory tract of infected primates. By contrast, Anhui/1 did not replicate well in miniature pigs upon intranasal inoculation. Most critically, Anhui/1 transmitted via respiratory droplets in one of three pairs of ferrets. Glycan arrays demonstrated that Anhui/1, Shanghai/1, and A/Hangzhou/1/2013 (a third human A(H7N9) virus tested in this assay) bind to human virus-type receptors, a property that may be critical for virus transmissibility in ferrets. Anhui/1 was less sensitive than a pandemic 2009 H1N1 virus to neuraminidase inhibitors, although both viruses were equally susceptible to an experimental antiviral polymerase inhibitor. The robust replicative ability in mice, ferrets, and NHPs and the limited transmissibility in ferrets of Anhui/1 suggest that A(H7N9) viruses have pandemic potential.

No abstract

No abstract

The hemagglutinin (HA) of influenza A virus is a homotrimeric glycoprotein with an ectodomain composed of a globular head and stem region (26). Both regions carry N-linked oligosaccharide chains. The appearance or disappearance of oligosaccharides on the globular head has been reported to occur naturally during antigenic drift of influenza A/H3N2 viruses from 1968 to 1975 (15, 24, 25). The acquisition of new oligosaccharides is an important mechanism underlying the antigenic drift of HA. Antigenic drift occurs by accumulation of a series of point mutations resulting in amino acid substitutions in antigenic sites on the surface of the HA (1, 25). These substitutions prevent neutralization by antibodies directed against previous epidemic strains.Based on analysis of the HA sequences of A/H3N2 viruses isolated from 1968 to 2002, the oligosaccharide chains on the globular head show large variations in number among different A/H3N2 isolates, although five glycosylation sites at Asn residues 8, 22, 38, 285, and 483 on the stem region are strictly conserved. Most of the A/H3N2 viruses that circulated between 1968 and 1974 (represented by A/Aichi/2/68) had only two oligosaccharides at residues 81 and 165 on the globular head of the HA (Fig. 1A). However, viruses isolated in 1975 (represented by A/Victoria/3/75) had lost a glycosylation site at residue 81 and gained two new sites at residues 63 and 126. The 1986 isolates (represented by A/Memphis/6/86) had acquired a new carbohydrate attachment site at residue 246, and the 1997 isolates (represented by A/Sydney/5/97) had obtained two additional sites at residues 122 and 133. Some recent isolates (represented by A/Panama/2007/99) had often obtained a novel site at residue 144. Thus, the A/H3N2 viruses recently circulating have six or seven glycosylation sites on the globular head of the HA, although whether these are glycosylated is not known. Moreover, the HAs of influenza A/H1N1 viruses and influenza B viruses isolated recently also possess several oligosaccharide chains on their globular head. These observations suggest that the addition of new oligosaccharides to the globular head of the HA may provide influenza viruses with an increased ability to prevail among humans (14). Interestingly, however, examination of the available HA sequences of influenza A/H2N2 viruses showed that none of the HAs had obtained a new glycosylation site on the globular head, and they had only one carbohydrate chain at position 169 (21).We previously studied the antigenic structure of the HA of A/H2N2 virus and revealed that most of the escape mutants selected by monoclonal antibodies had acquired a new glycosylation site at position 131, 160, or 187 on the tip of the HA (21,22,23). The results indicated that A/H2N2 viruses have the potential to gain at least one additional oligosaccharide on the globular head of the HA, although this has never occurred during 11 years of its circulation in humans. We constructed HA glycosylation site mutants containing one to three oligosaccharides at posi...

No abstract

The recent emergence of SARS-CoV-2 Omicron (B.1.1.529 lineage) variants possessing numerous mutations has raised concerns of decreased effectiveness of current vaccines, therapeutic monoclonal antibodies and antiviral drugs for COVID-19 against these variants 1,2 . The original Omicron lineage, BA.1, prevailed in many countries, but more recently, BA.2 has become dominant in at least 68 countries 3 . Here we evaluated the replicative ability and pathogenicity of authentic infectious BA.2 isolates in immunocompetent and human ACE2-expressing mice and hamsters. In contrast to recent data with chimeric, recombinant SARS-CoV-2 strains expressing the spike proteins of BA.1 and BA.2 on an ancestral WK-521 backbone 4 , we observed similar infectivity and pathogenicity in mice and hamsters for BA.2 and BA.1, and less pathogenicity compared with early SARS-CoV-2 strains. We also observed a marked and significant reduction in the neutralizing activity of plasma from individuals who had recovered from COVID-19 and vaccine recipients against BA.2 compared to ancestral and Delta variant strains. In addition, we found that some therapeutic monoclonal antibodies (REGN10987 plus REGN10933, COV2-2196 plus COV2-2130, and S309) and antiviral drugs (molnupiravir, nirmatrelvir and S-217622) can restrict viral infection in the respiratory organs of BA.2-infected hamsters. These findings suggest that the replication and pathogenicity of BA.2 is similar to that of BA.1 in rodents and that several therapeutic monoclonal antibodies and antiviral compounds are effective against Omicron BA.2 variants.The Omicron variant of SARS-CoV-2, the virus responsible for COVID-19, was first detected in late November 2021 and has spread rapidly around the world. Omicron variants have been classified into four different sublineages: BA.1, BA.1.1, BA.2 and BA.3. The original Omicron lineage, BA.1, rapidly became the prevailing variant circulating in many countries; however, BA.2 variants have become dominant in at least 68 countries 3 . Moreover, the prevalence of BA.2 is increasing rapidly in several other countries including South Africa, Sweden, Austria, Singapore, Georgia and Sri Lanka (https://covariants.org/per-variant). Preliminary data indicate that the BA.2 variant may be more transmissible than the BA.1 variant 5,6 .Recently, we and others have shown that BA.1 variants are less pathogenic in animal models than previously circulating variants of concern 7-9 (VOC), consistent with preliminary clinical data in humans 10 . Moreover, other studies have reported that BA.1 variants show reduced sensitivity to vaccine-or infection-induced antibodies, as well as some therapeutic monoclonal antibodies [11][12][13][14][15] . The spike (S) protein of SARS-CoV-2 mediates viral receptor binding and membrane fusion, both of which are essential for viral infection of host cells. The S protein is also the principal antigen targeted by the host neutralizing antibody response 16 . Notably, mutations in the S protein, such as E484K, N501Y, D614G and P681H/R, have ...

SUMMARY Low pathogenic H7N9 influenza has recently evolved to become highly pathogenic, raising concerns of a pandemic, particularly if these viruses acquire efficient human-to-human transmissibility. We compared a low pathogenic H7N9 virus with a highly pathogenic isolate, and two of its variants that represent neuraminidase inhibitor-sensitive and -resistant subpopulations detected within the isolate. The highly pathogenic H7N9 viruses replicated efficiently in mice, ferrets, and/or nonhuman primates, and were more pathogenic in mice and ferrets than the low pathogenic H7N9 virus, with the exception of the neuraminidase inhibitor-resistant virus, which showed mild-to-moderate attenuation. All viruses transmitted among ferrets via respiratory droplets, and the neuraminidase-sensitive variant killed several of the infected and exposed animals. Neuraminidase inhibitors showed limited effectiveness against these viruses in vivo, but the viruses were susceptible to a polymerase inhibitor. These results suggest that the highly pathogenic H7N9 virus has pandemic potential and should be closely monitored.

Background Coronavirus disease (COVID‐19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), was first detected in Japan in January 2020 and has spread throughout the country. Previous studies have reported that viral interference among influenza virus, rhinovirus, and other respiratory viruses can affect viral infections at the host and population level. Methods To investigate the impact of COVID‐19 on influenza and other respiratory virus infections, we analyzed clinical specimens collected from 2244 patients in Japan with respiratory diseases between January 2018 and September 2020. Results The frequency of influenza and other respiratory viruses (coxsackievirus A and B; echovirus; enterovirus; human coronavirus 229E, HKU1, NL63, and OC43; human metapneumovirus; human parainfluenza virus 1, 2, 3, and 4; human parechovirus; human respiratory syncytial virus; human adenovirus; human bocavirus; human parvovirus B19; herpes simplex virus type 1; and varicella‐zoster virus) was appreciably reduced among all patients during the COVID‐19 pandemic except for that of rhinovirus in children younger than 10 years, which was appreciably increased. COVID‐19 has not spread among this age group, suggesting an increased risk of rhinovirus infection in children. Conclusions Rhinovirus infections should be continuously monitored to understand their increased risk during the COVID‐19 pandemic and viral interference with SARS‐CoV‐2.