Search

The relationship between humans and viruses has a long history. Since the first identification of viruses in the 19th century, we have considered them to be 'pathogens' and have studied their mechanisms of replication and pathogenicity to combat the diseases that they cause. However, the relationships between hosts and viruses are various and virus infections do not necessarily cause diseases in their hosts. Rather, recent studies have shown that viral infections sometimes have beneficial effects on the biological functions and/or evolution of hosts. Here, we provide some insight into the positive side of viruses. [ABSTRACT FROM AUTHOR]

Background: Reverse genetics systems to rescue viruses from modified DNA are useful tools to investigate the molecular mechanisms of viruses. The COVID‐19 pandemic prompted the development of several reverse genetics systems for SARS‐CoV‐2. The circular polymerase extension reaction (CPER) method enables the rapid generation of recombinant SARS‐CoV‐2; however, such PCR‐based approaches could introduce unwanted mutations due to PCR errors. Methods: To compare the accuracy of CPER and a classic reverse genetics method using bacterial artificial chromosome (BAC), SARS‐CoV‐2 Wuhan/Hu‐1/2019 was generated five times using BAC and five times using CPER. These 10 independent virus stocks were then deep sequencing, and the number of substitutions for which the frequency was greater than 10% was counted. Results: No nucleotide substitutions with a frequency of greater than 10% were observed in all five independent virus stocks generated by the BAC method. In contrast, three to five unwanted nucleotide substitutions with a frequency of more than 10% were detected in four of the five virus stocks generated by the CPER. Furthermore, four substitutions with frequencies greater than 20% were generated in three virus stocks by using the CPER. Conclusions: We found that the accuracy of the CPER method is lower than that of the BAC method. Our findings suggest care should be used when employing the CPER method. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Neumann G, Kawaoka Y. (2011) The first influenza pandemic of the new millennium. Influenza and Other Respiratory Viruses DOI: 10.1111/j.1750-2659.2011.00202.x. In the spring of 2009, a novel influenza A virus of the H1N1 subtype emerged that transmitted efficiently among humans; by June of 2009, the outbreak reached pandemic status. The pandemic virus possesses six viral RNA segments from so-called triple reassortant swine viruses that emerged in North American pig populations in the late 1990s and two viral RNA segments from Eurasian avian-like swine influenza viruses. Most human infections with the virus have been mild; however, severe and fatal infections occurred among certain risk groups, but also among those without any known risk factors. Here, we summarize the evolutionary, epidemiological, clinical, and molecular findings on the pandemic virus. We also discuss the arsenal of antiviral compounds and vaccines available to prevent and treat infections with the virus. [ABSTRACT FROM AUTHOR]

Vaccination is the most effective strategy to combat influenza. Ideally, potent and persistent vaccine effects would be induced with a single vaccine dose. Here, we designed a virus‐like particle (VLP)‐based vaccine presenting multiple copies of the influenza hemagglutinin (HA) from A/Puerto Rico/8/1934 (PR8HA‐VLP) and examined its immunogenicity and protective efficacy in ferrets. Serum‐neutralizing antibodies were effectively induced against the homologous virus at 3‐week post‐vaccination with a single dose of PR8HA‐VLP with or without adjuvants. When the single‐immunized ferrets were challenged with the homologous virus, virus replication in the nasal mucosa was significantly reduced. Long‐term monitoring of serum titers revealed that after adjuvanted vaccination with PR8HA‐VLP, neutralizing antibodies were retained at similar levels 20‐ to 183‐week post‐vaccination, although a 4‐ to 8‐fold titer decline was observed from 3‐ to 20‐week post‐vaccination. Boost immunization at 183 weeks after the first immunization elicited higher neutralizing antibody titers than those at 3 weeks after the initial immunization in most of the animals. These results confirm that nanoparticle‐based vaccines are a promising approach to effectively elicit durable multiyear neutralizing antibody responses against influenza viruses. [ABSTRACT FROM AUTHOR]

Background: Influenza viruses can cause zoonotic infections that pose public health risks. Surveillance of influenza A and B viruses is conducted globally; however, information on influenza C and D viruses is limited. Longitudinal monitoring of influenza C virus in humans has been conducted in several countries, but there has been no long‐term monitoring of influenza D virus in humans. The public health risks associated with the influenza D virus therefore remain unknown. Methods: We established a duplex real‐time RT‐PCR to detect influenza C and D viruses and analyzed respiratory specimens collected from 2144 patients in Japan with respiratory diseases between January 2018 and March 2023. We isolated viruses and conducted hemagglutination inhibition tests to examine antigenicity and focus reduction assays to determine susceptibility to the cap‐dependent endonuclease inhibitor baloxavir marboxil. Results: We detected three influenza C viruses belonging to the C/Kanagawa‐ or C/Sao Paulo‐lineages, which recently circulated globally. None of the specimens was positive for the influenza D virus. The C/Yokohama/1/2022 strain, isolated from the specimen with the highest viral RNA load and belonging to the C/Kanagawa‐lineage, showed similar antigenicity to the reference C/Kanagawa‐lineage strain and was susceptible to baloxavir. Conclusions: Our duplex real‐time RT‐PCR is useful for the simultaneous detection of influenza C and D viruses from the same specimen. Adding the influenza D virus to the monitoring of the influenza C virus would help in assessing the public health risks posed by this virus. [ABSTRACT FROM AUTHOR]

Background: US recommendations for COVID‐19 vaccine boosters have expanded in terms of age groups covered and numbers of doses recommended, whereas evolution of Omicron sublineages raises questions about ongoing vaccine effectiveness. Methods: We estimated effectiveness of monovalent COVID‐19 mRNA booster vaccination versus two‐dose primary series during a period of Omicron variant virus circulation in a community cohort with active illness surveillance. Hazard ratios comparing SARS‐CoV‐2 infection between booster versus primary series vaccinated individuals were estimated using Cox proportional hazards models with time‐varying booster status. Models were adjusted for age and prior SARS‐CoV‐2 infection. The effectiveness of a second booster among adults ≥50 years of age was similarly estimated. Results: The analysis included 883 participants ranging in age, from 5 to >90 years. Relative effectiveness was 51% (95% CI: 34%, 64%) favoring the booster compared with primary series vaccination and did not vary by prior infection status. Relative effectiveness was 74% (95% CI: 57%, 84%) at 15 to 90 days after booster receipt, but declined to 42% (95% CI: 16%, 61%) after 91 to 180 days, and to 36% (95% CI: 3%, 58%) after 180 days. The relative effectiveness of a second booster compared to a single booster was 24% (95% CI: −40% to 61%). Conclusions: An mRNA vaccine booster dose added significant protection against SARS‐CoV‐2 infection, but protection decreased over time. A second booster did not add significant protection for adults ≥50 years of age. Uptake of recommended bivalent boosters should be encouraged to increase protection against Omicron BA.4/BA.5 sublineages. [ABSTRACT FROM AUTHOR]

The emergence and spread of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which causes coronavirus disease (COVID‐19), prompted worldwide COVID‐19 surveillance. To investigate the impact of COVID‐19 on influenza activity, we used global surveillance data collected since 2019 to compare the number of cases positive for COVID‐19 and for influenza across 22 representative countries (Australia, Brazil, Canada, China, Egypt, France, Germany, India, Israel, Italy, Japan, Mexico, The Netherlands, The Philippines, Poland, The Republic of Korea, South Africa, Spain, Thailand, The United Kingdom, The United States, and Vietnam). Our results demonstrate alternating prevalence of SARS‐CoV‐2 and influenza virus. [ABSTRACT FROM AUTHOR]

Reduced COVID‐19 vaccine effectiveness (VE) has been observed with increasing predominance of SARS‐CoV‐2 Delta (B.1.617.2) variant. Two‐dose VE against laboratory‐confirmed SARS‐CoV‐2 infection (symptomatic and asymptomatic) was estimated using Cox proportional hazards models with time‐varying vaccination status in a prospective rural community cohort of 1266 participants aged ≥12 years. Between November 3, 2020 and December 7, 2021, VE was 56% for mRNA COVID‐19 vaccines overall, 65% for Moderna, and 50% for Pfizer‐BioNTech. VE when Delta predominated (June to December 2021) was 54% for mRNA COVID‐19 vaccines overall, 59% for Moderna, and 52% for Pfizer‐BioNTech. [ABSTRACT FROM AUTHOR]

The post‐translational acetylation of lysine residues is found in many nonhistone proteins and is involved in a wide range of biological processes. Recently, we showed that the nucleoprotein of the influenza A virus is acetylated by histone acetyltransferases (HATs), a phenomenon that affects viral transcription. Here, we report that the PA subunit of influenza A virus RNA‐dependent RNA polymerase is acetylated by the HATs, P300/CREB‐binding protein‐associated factor (PCAF), and general control nonderepressible 5 (GCN5), resulting in accelerated endonuclease activity. Specifically, the full‐length PA subunit expressed in cultured 293T cells was found to be strongly acetylated. Moreover, the partial recombinant protein of the PA N‐terminal region containing the endonuclease domain was also acetylated by PCAF and GCN5 in vitro, which facilitated its endonuclease activity. Mass spectrometry analyses identified K19 as a candidate acetylation target in the PA N‐terminal region. Notably, the substitution of the lysine residue at position 19 with glutamine, a mimic of the acetyl‐lysine residue, enhanced its endonuclease activity in vitro; this point mutation also accelerated influenza A virus RNA‐dependent RNA polymerase activity in the cell. Our findings suggest that PA acetylation is important for the regulation of the endonuclease and RNA polymerase activities of the influenza A virus. [ABSTRACT FROM AUTHOR]

The persistence of the global severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic has brought to the forefront the need for safe and effective vaccination strategies. In particular, the emergence of several variants with greater infectivity and resistance to current vaccines has motivated the development of a vaccine that elicits a broadly neutralizing immune response against all variants. In this study, we used a nanoparticle‐based vaccine platform for the multivalent display of the receptor‐binding domain (RBD) of the SARS‐CoV‐2 spike (S) protein, the primary target of neutralizing antibodies. Multiple copies of RBD were conjugated to the SpyCatcher‐mi3 protein nanoparticle to produce a highly immunogenic nanoparticle‐based vaccine. RBD‐SpyCatcher‐mi3 vaccines elicited broadly cross‐reactive antibodies that recognized the spike proteins of not just an early isolate of SARS‐CoV‐2, but also three SARS‐CoV‐2 variants of concern as well as SARS‐CoV‐1. Moreover, immunization elicited high neutralizing antibody titers against an early isolate of SARS‐CoV‐2 as well as four variants of concern, including the delta variant. These results reveal the potential of RBD‐SpyCatcher‐mi3 as a broadly protective vaccination strategy. [ABSTRACT FROM AUTHOR]

For nuclear export of proteins, the formation of a ternary export complex composed of the export substrate, a cellular export factor and Ran-GTP is crucial. CRM1 is a cellular export factor for proteins containing leucine-rich nuclear export signals (NESs). Although the NES sequence is crucial for nuclear export, its exact role in the formation of the ternary export complex is controversial. Here we demonstrate an interaction between human CRMI (hCRM1) and influenza A virus NS2 protein, which contains an NES motif in its N-terminal region. Replacement of the hydrophobic amino acids in the NES motif did not abolish NS2's interaction with hCRM1. Using our recently established systems for the generation of influenza virus or virus-like particles from cloned cDNAs, we found that NS2 is essential for nuclear export of influenza virus ribonucleoprotein (RNP) complexes, and that alteration of the NS2-NES abrogated this event and influenza virus generation. These findings suggest that the NS2-NES is not crucial for the interaction of this protein with hCRM1, but is for the formation of the ternary export complex with Ran-GTP. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Here, we genetically and antigenically analyzed influenza B viruses (IBVs) isolated in Japan during the 2017‐2018 and 2018‐2019 influenza seasons. Methods: A total of 68 IBVs (61 B/Yamagata/16/88‐like [B/Yamagata]‐lineage and 7 B/Victoria/2/87‐like [B/Victoria]‐lineage) were antigenically and genetically characterized by using hemagglutination inhibition (HI) assays and phylogenetic analysis, respectively. The susceptibility of IBVs to neuraminidase (NA) inhibitors was assessed by using a fluorescence‐based NA inhibition assay. Results: All 61 B/Yamagata‐lineage isolates were genetically closely related to B/Phuket/3073/2013, the vaccine strain for these two seasons. Eleven B/Yamagata‐lineage isolates tested were antigenically similar to B/Phuket/3073/2013 by the HI test. Seven B/Victoria‐lineage isolates were genetically closely related to B/Texas/02/2013, the WHO‐recommended vaccine strain for the 2017‐2018 season; however, they were antigenically distinct from B/Texas/02/2013 with an eightfold or 16‐fold difference in HI titer. Of these 7 isolates, 4 possessed a two‐amino‐acid deletion at positions 162 and 163 in hemagglutinin (HA) and the other 3 had a three‐amino‐acid deletion at positions 162‐164 in HA. Importantly, the variants with the three‐amino‐acid deletion appeared to be antigenically different from the B/Colorado/06/2017 virus with the two‐amino‐acid deletion, the vaccine strain for the 2018‐2019 season with a fourfold or eightfold difference in HI titer. One B/Yamagata‐lineage isolate carrying a G407S mutation in its NA showed a marked reduction in susceptibility to zanamivir, peramivir, and laninamivir. Conclusions: These results highlight the need for continued monitoring for the prevalence of the antigenic variant with the three‐amino‐acid deletion and the variant with reduced NA inhibitor susceptibility. [ABSTRACT FROM AUTHOR]

Objectives To examine cross-reactivity between hemagglutinin ( HA) derived from A/California/7/09 ( CA/09) virus and that derived from representative Eurasian 'avian-like' ( EA) H1N1 swine viruses isolated in Italy between 1999 and 2008 during virological surveillance in pigs. Design Modified vaccinia virus Ankara ( MVA) expressing the HA gene of CA/09 virus ( MVA- HA- CA/09) was used as a vaccine to investigate cross-protective immunity against H1N1 swine viruses in mice. Sample Two classical swine H1N1 ( CS) viruses and four representative EA-like H1N1 swine viruses previously isolated during outbreaks of respiratory disease in pigs on farms in Northern Italy were used in this study. Setting Female C57 BL/6 mice were vaccinated with MVA/ HA/ CA/09 and then challenged intranasally with H1N1 swine viruses. Main outcome measures Cross-reactive antibody responses were determined by hemagglutination- inhibition ( HI) and virus microneutralizing ( MN) assays of sera from MVA-vaccinated mice. The extent of protective immunity against infection with H1N1 swine viruses was determined by measuring lung viral load on days 2 and 4 post-challenge. Results and Conclusions Systemic immunization of mice with CA/09-derived HA, vectored by MVA, elicited cross-protective immunity against recent EA-like swine viruses. This immune protection was related to the levels of cross-reactive HI antibodies in the sera of the immunized mice and was dependent on the similarity of the antigenic site Sa of H1 HAs. Our findings suggest that the herd immunity elicited in humans by the pandemic (H1N1) 2009 virus could limit the transmission of recent EA-like swine HA genes into the influenza A virus gene pool in humans. [ABSTRACT FROM AUTHOR]

Abstract: To identify a determinant of human H3 hemagglutinin (HA) amino acid residues linked to the recognition of molecular species of sialic acid, we generated six mutant viruses possessing either the wild-type HA gene from A/Memphis/1/71 (H3N2) or a genetically single-mutated HA gene at position 137, 144, 155, 158 or 193 from a genetic backbone of A/WSN/33 (H1N1) by reverse genetics. We evaluated the binding ability with four types of synthetic sialylglycolipids. The results indicate that the amino acid substitutions Thr155 to Tyr and Glu158 to Gly in H3 HA facilitate virus binding to N-glycolylneuraminic acid. [Copyright &y& Elsevier]

We investigated whether a vaccine derived from an apathogenic reassortant type A H5N1 influenza strain could induce immune responses in vivo that mediated protection from highly pathogenic avian influenza virus infection in mice. After two subcutaneous immunizations with formalin-inactivated H5N1 whole virus particles (whole particle vaccine), significant killing specific for cells presenting a nucleoprotein peptide from the vaccine strain of the virus was observed. Similar vaccination with viruses treated with ether and formalin, which are commonly used for humans as ether-split vaccines, induced little or no cytotoxic T-cell response. Furthermore, whole particle vaccines of the apathogenic H5N1 strain were more effective than ether-split vaccines at inducing antibody production able to neutralize a highly pathogenic H5N1 strain. Finally, whole particle vaccines of H5N1 protected mice against infection by an H5N1 highly pathogenic avian influenza virus more effectively than did ether-split vaccines. These results suggest that formalin-inactivated virus particles of apathogenic strains are effective for induction of both cytotoxic T-lymphocyte and antibody responses against highly pathogenic avian influenza viruses in vivo, resulting in protection from infection by a highly pathogenic H5N1 virus. [ABSTRACT FROM AUTHOR]