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  • 1
    Online Resource
    Online Resource
    Robustness of the Ferret Model for Influenza Risk Assessment Studies: a Cross-Laboratory Exercise
    American Society for Microbiology ; 2022
    In:  mBio Vol. 13, No. 4 ( 2022-08-30)
    Details
    In: mBio, American Society for Microbiology, Vol. 13, No. 4 ( 2022-08-30)
    Abstract: Past pandemic influenza viruses with sustained human-to-human transmissibility have emerged from animal influenza viruses. Employment of experimental models to assess the pandemic risk of emerging zoonotic influenza viruses provides critical information supporting public health efforts. Ferret transmission experiments have been utilized to predict the human-to-human transmission potential of novel influenza viruses. However, small sample sizes and a lack of standardized protocols can introduce interlaboratory variability, complicating interpretation of transmission experimental data. To assess the range of variation in ferret transmission experiments, a global exercise was conducted by 11 laboratories using two common stock H1N1 influenza viruses with different transmission characteristics in ferrets. Parameters known to affect transmission were standardized, including the inoculation route, dose, and volume, as well as a strict 1:1 donor/contact ratio for respiratory droplet transmission. Additional host and environmental parameters likely to affect influenza transmission kinetics were monitored and analyzed. The overall transmission outcomes for both viruses across 11 laboratories were concordant, suggesting the robustness of the ferret model for zoonotic influenza risk assessment. Among environmental parameters that varied across laboratories, donor-to-contact airflow directionality was associated with increased transmissibility. To attain high confidence in identifying viruses with moderate to high transmissibility or low transmissibility under a smaller number of participating laboratories, our analyses support the notion that as few as three but as many as five laboratories, respectively, would need to independently perform viral transmission experiments with concordant results. This exercise facilitates the development of a more homogenous protocol for ferret transmission experiments that are employed for the purposes of risk assessment. IMPORTANCE Following detection of a novel virus, rapid characterization efforts (both in vitro and in vivo ) are undertaken at numerous laboratories worldwide to evaluate the relative risk posed to human health. Aggregation of these data are critical, but the use of nonstandardized protocols can make interpretation of divergent results a challenge. For evaluation of virus transmissibility, a multifactorial trait which can only be evaluated in vivo , identifying intrinsic levels of variability between groups can improve the utility of these data, as well as ensure that experiments are performed with sufficient replication to ensure high confidence in compiled results. Using the ferret transmission model and two influenza A viruses, we conducted a multicenter standardization exercise to improve the interpretation of transmission data generated during risk assessment activities; this exercise serves as a model for future efforts employing both in vitro and in vivo models against possible pandemic pathogens.
    Type of Medium: Online Resource
    ISSN: 2150-7511
    URL: Article
    DOI: 10.1128/mbio.01174-22
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2022
    detail.hit.zdb_id: 2557172-2
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  • 2
    Online Resource
    Online Resource
    Sequential Transmission of Influenza Viruses in Ferrets Does Not Enhance Infectivity and Does Not Predict Transmissibility in Humans
    American Society for Microbiology ; 2022
    In:  mBio Vol. 13, No. 6 ( 2022-12-20)
    Details
    In: mBio, American Society for Microbiology, Vol. 13, No. 6 ( 2022-12-20)
    Abstract: Airborne transmission in ferrets is a key component of pandemic risk assessment. However, some emerging avian influenza viruses transmit between ferrets but do not spread in humans. Therefore, we evaluated sequential rounds of airborne transmission as an approach to enhance the predictive accuracy of the ferret model. We reasoned that infection of ferrets via the respiratory route and onward transmission would more closely model transmission in humans. We hypothesized that pandemic and seasonal viruses would transmit efficiently over two rounds of transmission, while emerging avian viruses would fail to transmit in a second round. The 2009 pandemic H1N1 (pdm09) and seasonal H3N2 viruses were compared to avian-origin H7N9 and H3N8 viruses. Depending on the virus strain, transmission efficiency varied from 50 to 100% during the first round of transmission; the efficiency for each virus did not change during the second round, and viral replication kinetics in both rounds of transmission were similar. Both the H1N1pdm09 and H7N9 viruses acquired specific mutations during sequential transmission, while the H3N2 and H3N8 viruses did not; however, a global analysis of host-adaptive mutations revealed that minimal changes were associated with transmission of H1N1 and H3N2 viruses, while a greater number of changes occurred in the avian H3N8 and H7N9 viruses. Thus, influenza viruses that transmit in ferrets maintain their transmission efficiency through serial rounds of transmission. This answers the question of whether ferrets can propagate viruses through more than one round of airborne transmission and emphasizes that transmission in ferrets is necessary but not sufficient to infer transmissibility in humans. IMPORTANCE Airborne transmission in ferrets is used to gauge the pandemic potential of emerging influenza viruses; however, some emerging influenza viruses that transmit between ferrets do not spread between humans. Therefore, we evaluated sequential rounds of airborne transmission in ferrets as a strategy to enhance the predictive accuracy of the ferret model. Human influenza viruses transmitted efficiently ( 〉 83%) over two rounds of airborne transmission, demonstrating that, like humans, ferrets infected by the respiratory route can propagate the infection onward through the air. However, emerging avian influenza viruses with associated host-adaptive mutations also transmitted through sequential transmission. Thus, airborne transmission in ferrets is necessary but not sufficient to infer transmissibility in humans, and sequential transmission did not enhance pandemic risk assessment.
    Type of Medium: Online Resource
    ISSN: 2150-7511
    URL: Article
    DOI: 10.1128/mbio.02540-22
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2022
    detail.hit.zdb_id: 2557172-2
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  • 3
    Online Resource
    Online Resource
    Evaluation of the Biological Properties and Cross-Reactive Antibody Response to H10 Influenza Viruses in Ferrets
    American Society for Microbiology ; 2017
    In:  Journal of Virology Vol. 91, No. 19 ( 2017-10)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 91, No. 19 ( 2017-10)
    Abstract: The recent outbreak of avian origin H10N7 influenza among seals in northern Europe and two fatal human infections with an avian H10N8 virus in China have demonstrated that H10 viruses can spread between mammals and cause severe disease in humans. To gain insight into the potential for H10 viruses to cross the species barrier and to identify a candidate vaccine strain, we evaluated the in vitro and in vivo properties and antibody response in ferrets to 20 diverse H10 viruses. H10 virus infection of ferrets caused variable weight loss, and all 20 viruses replicated throughout the respiratory tract; however, replication in the lungs was highly variable. In glycan-binding assays, the H10 viruses preferentially bound “avian-like” α2,3-linked sialic acids. Importantly, several isolates also displayed strong binding to long-chain “human-like” α2,6-linked sialic acids and exhibited comparable or elevated neuraminidase activity relative to human H1N1, H2N2, and H3N2 viruses. In hemagglutination inhibition assays, 12 antisera cross-reacted with ≥14 of 20 H10 viruses, and 7 viruses induced neutralizing activity against ≥15 of the 20 viruses. By combining data on weight loss, viral replication, and the cross-reactive antibody response, we identified A/mallard/Portugal/79906/2009 (H10N7) as a suitable virus for vaccine development. Collectively, our findings suggest that H10 viruses may continue to sporadically infect humans and other mammals, underscoring the importance of developing an H10 vaccine for pandemic preparedness. IMPORTANCE Avian origin H10 influenza viruses sporadically infect humans and other mammals; however, little is known about viruses of this subtype. Thus, we characterized the biological properties of 20 H10 viruses in vitro and in ferrets. Infection caused mild to moderate weight loss (5 to 15%), with robust viral replication in the nasal tissues and variable replication in the lung. H10 viruses preferentially bind “avian-like” sialic acids, although several isolates also displayed binding to “human-like” sialic acid receptors. This is consistent with the ability of H10 viruses to cross the species barrier and warrants selection of an H10 vaccine strain. By evaluating the cross-reactive antibody response to the H10 viruses and combining this analysis with viral replication and weight loss findings, we identified A/mallard/Portugal/79906/2009 (H10N7) as a suitable H10 vaccine strain.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.00895-17
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2017
    detail.hit.zdb_id: 1495529-5
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  • 4
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    Online Resource
    Protective efficacy of influenza group 2 hemagglutinin stem-fragment immunogen vaccines
    Springer Science and Business Media LLC ; 2017
    In:  npj Vaccines Vol. 2, No. 1 ( 2017-12-15)
    Details
    In: npj Vaccines, Springer Science and Business Media LLC, Vol. 2, No. 1 ( 2017-12-15)
    Abstract: The stem of the influenza A virus hemagglutinin (HA) is highly conserved and represents an attractive target for a universal influenza vaccine. The 18 HA subtypes of influenza A are phylogenetically divided into two groups, and while protection with group 1 HA stem vaccines has been demonstrated in animal models, studies on group 2 stem vaccines are limited. Thus, we engineered group 2 HA stem-immunogen (SI) vaccines targeting the epitope for the broadly neutralizing monoclonal antibody CR9114 and evaluated vaccine efficacy in mice and ferrets. Immunization induced antibodies that bound to recombinant HA protein and viral particles, and competed with CR9114 for binding to the HA stem. Mice vaccinated with H3 and H7-SI were protected from lethal homologous challenge with X-79 (H3N2) or A/Anhui/1/2013 (H7N9), and displayed moderate heterologous protection. In ferrets, H7-SI vaccination did not significantly reduce weight loss or nasal wash titers after robust 10 7 TCID 50 H7N9 virus challenge. Epitope mapping revealed ferrets developed lower titers of antibodies that bound a narrow range of HA stem epitopes compared to mice, and this likely explains the lower efficacy in ferrets. Collectively, these findings indicate that while group 2 SI vaccines show promise, their immunogenicity and efficacy are reduced in larger outbred species, and will have to be enhanced for successful translation to a universal vaccine.
    Type of Medium: Online Resource
    ISSN: 2059-0105
    URL: Article
    DOI: 10.1038/s41541-017-0036-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2882262-6
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  • 5
    Online Resource
    Online Resource
    Development of animal models against emerging coronaviruses: From SARS to MERS coronavirus
    Elsevier BV ; 2015
    In:  Virology Vol. 479-480 ( 2015-05), p. 247-258
    Details
    In: Virology, Elsevier BV, Vol. 479-480 ( 2015-05), p. 247-258
    Type of Medium: Online Resource
    ISSN: 0042-6822
    URL: Article
    DOI: 10.1016/j.virol.2015.02.030
    RVK:
    WA 15000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2015
    detail.hit.zdb_id: 1471925-3
    SSG: 12
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  • 6
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    Online Resource
    In Vitro Neutralization Is Not Predictive of Prophylactic Efficacy of Broadly Neutralizing Monoclonal Antibodies CR6261 and CR9114 against Lethal H2 Influenza Virus Challenge in Mice
    American Society for Microbiology ; 2017
    In:  Journal of Virology Vol. 91, No. 24 ( 2017-12-15)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 91, No. 24 ( 2017-12-15)
    Abstract: Influenza viruses of the H1N1, H2N2, and H3N2 subtypes have caused previous pandemics. H2 influenza viruses represent a pandemic threat due to continued circulation in wild birds and limited immunity in the human population. In the event of a pandemic, antiviral agents are the mainstay for treatment, but broadly neutralizing antibodies (bNAbs) may be a viable alternative for short-term prophylaxis or treatment. The hemagglutinin stem binding bNAbs CR6261 and CR9114 have been shown to protect mice from severe disease following challenge with H1N1 and H5N1 and with H1N1, H3N2, and influenza B viruses, respectively. Early studies with CR6261 and CR9114 showed weak in vitro activity against human H2 influenza viruses, but the in vivo efficacy against H2 viruses is unknown. Therefore, we evaluated these antibodies against human- and animal-origin H2 viruses A/Ann Arbor/6/1960 (H2N2) (AA60) and A/swine/MO/4296424/06 (H2N3) (Sw06). In vitro , CR6261 neutralized both H2 viruses, while CR9114 only neutralized Sw06. To evaluate prophylactic efficacy, mice were given CR6261 or CR9114 and intranasally challenged 24 h later with lethal doses of AA60 or Sw06. Both antibodies reduced mortality, weight loss, airway inflammation, and pulmonary viral load. Using engineered bNAb variants, antibody-mediated cell cytotoxicity reporter assays, and Fcγ receptor-deficient ( Fcer1g −/− ) mice, we show that the in vivo efficacy of CR9114 against AA60 is mediated by Fcγ receptor-dependent mechanisms. Collectively, these findings demonstrate the in vivo efficacy of CR6261 and CR9114 against H2 viruses and emphasize the need for in vivo evaluation of bNAbs. IMPORTANCE bNAbs represent a strategy to prevent or treat infection by a wide range of influenza viruses. The evaluation of these antibodies against H2 viruses is important because H2 viruses caused a pandemic in 1957 and could cross into humans again. We demonstrate that CR6261 and CR9114 are effective against infection with H2 viruses of both human and animal origin in mice, despite the finding that CR9114 did not display in vitro neutralizing activity against the human H2 virus. These findings emphasize the importance of in vivo evaluation and testing of bNAbs.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.01603-17
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2017
    detail.hit.zdb_id: 1495529-5
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  • 7
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    Online Resource
    Virology under the Microscope—a Call for Rational Discourse
    American Society for Microbiology ; 2023
    In:  Journal of Virology Vol. 97, No. 2 ( 2023-02-28)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 97, No. 2 ( 2023-02-28)
    Abstract: Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns – conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we – a broad group of working virologists – seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/jvi.00089-23
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2023
    detail.hit.zdb_id: 1495529-5
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  • 8
    Online Resource
    Online Resource
    Virology under the Microscope—a Call for Rational Discourse
    American Society for Microbiology ; 2023
    In:  mBio Vol. 14, No. 1 ( 2023-02-28)
    Details
    In: mBio, American Society for Microbiology, Vol. 14, No. 1 ( 2023-02-28)
    Abstract: Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns – conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we – a broad group of working virologists – seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.
    Type of Medium: Online Resource
    ISSN: 2150-7511
    URL: Article
    DOI: 10.1128/mbio.00188-23
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2023
    detail.hit.zdb_id: 2557172-2
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  • 9
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    Online Resource
    Virology under the Microscope—a Call for Rational Discourse
    American Society for Microbiology ; 2023
    In:  mSphere Vol. 8, No. 2 ( 2023-04-20)
    Details
    In: mSphere, American Society for Microbiology, Vol. 8, No. 2 ( 2023-04-20)
    Abstract: Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns – conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we – a broad group of working virologists – seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.
    Type of Medium: Online Resource
    ISSN: 2379-5042
    URL: Article
    DOI: 10.1128/msphere.00034-23
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2023
    detail.hit.zdb_id: 2844248-9
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