Last data update: Jan 27, 2025. (Total: 48650 publications since 2009)
Records 1-30 (of 36 Records) |
Query Trace: Brock N[original query] |
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Dissecting the role of the HA1-226 leucine residue in the fitness and airborne transmission of an A(H9N2) avian influenza virus
Sun X , Belser JA , Pulit-Penaloza JA , Brock N , Kieran TJ , Pappas C , Zeng H , Tumpey TM , Maines TR . J Virol 2024 e0092824 ![]() ![]() A better understanding of viral factors that contribute to influenza A virus (IAV) airborne transmission is crucial for pandemic preparedness. A limited capacity for airborne transmission was recently observed in a human A(H9N2) virus isolate (A/Anhui-Lujiang/39/2018, AL/39) that possesses a leucine (L) residue at position HA1-226 (H3 numbering), indicative of human-like receptor binding potential. To evaluate the roles of the residue at this position in virus fitness and airborne transmission, a wild-type AL/39 (AL/39-wt) and a mutant virus (AL/39-HA1-L226Q) with a single substitution at position HA1-226 from leucine to glutamine (Q), a consensus residue in avian influenza viruses, were rescued and assessed in the ferret model. The AL/39-HA1-L226Q virus lost the ability to transmit by air, although the virus had a comparable capacity for replication, induced similar levels of host innate immune responses, and was detected at comparable levels in the air surrounding the inoculated ferrets relative to AL/39-wt virus. However, ferrets showed a lower susceptibility to AL/39-HA1-L226Q virus infection compared to the AL/39-wt virus. Furthermore, the AL/39-wt and AL/39-HA1-L226Q viruses each gained dominance in different anatomic sites in the respiratory tract in a co-infection competition model in ferrets. Taken together, our findings demonstrate that the increasing dominance of HA1-L226 residue in an avian A(H9N2) virus plays multifaceted roles in virus infection and transmission in the ferret model, including improved virus fitness and infectivity. IMPORTANCE: Although the capacity for human-like receptor binding is a key prerequisite for non-human origin influenza A virus (IAV) to become airborne transmissible in mammalian hosts, the underlying molecular basis is not well understood. In this study, we investigated a naturally occurring substitution (leucine to glutamine) at residue 226 in the HA of an avian-origin A(H9N2) virus and assessed the impact on virus replication and airborne transmission in the ferret model. We demonstrate that the enhanced airborne transmission associated with the HA1-L226 virus was mainly due to the increased infectivity of the virus. Interestingly, we found that, unlike most sites in the ferret respiratory tract, ferret ethmoid turbinate lined with olfactory epithelium favors replication of the AL/39-HA1-L226Q virus, suggesting that this site may serve as a unique niche for IAV with avian-like receptor binding specificity to potentially allow the virus to spread to extrapulmonary tissues and to facilitate adaptation of the virus to human hosts. |
Transmission of a human isolate of clade 2.3.4.4b A(H5N1) virus in ferrets
Pulit-Penaloza JA , Belser JA , Brock N , Kieran TJ , Sun X , Pappas C , Zeng H , Carney P , Chang J , Bradley-Ferrell B , Stevens J , De La Cruz JA , Hatta Y , Di H , Davis CT , Tumpey TM , Maines TR . Nature 2024 Since 2020, there has been unprecedented global spread of highly pathogenic avian influenza A(H5N1) in wild bird populations with spillover into a variety of mammalian species and sporadically humans(1). In March 2024, clade 2.3.4.4b A(H5N1) virus was first detected in dairy cattle in the U.S., with subsequent detection in numerous states(2), leading to over a dozen confirmed human cases(3,4). In this study, we employed the ferret model, a well-characterized species that permits concurrent investigation of viral pathogenicity and transmissibility(5) in the evaluation of A/Texas/37/2024 (TX/37) A(H5N1) virus isolated from a dairy farm worker in Texas(6). Here, we show that the virus has a remarkable ability for robust systemic infection in ferrets, leading to high levels of virus shedding and spread to naïve contacts. Ferrets inoculated with TX/37 rapidly exhibited a severe and fatal infection, characterized by viremia and extrapulmonary spread. The virus efficiently transmitted in a direct contact setting and was capable of indirect transmission via fomites. Airborne transmission was corroborated by the detection of infectious virus shed into the air by infected animals, albeit at lower levels compared to the highly transmissible human seasonal and swine-origin H1 subtype strains. Our results show that despite maintaining an avian-like receptor binding specificity, TX/37 displays heightened virulence, transmissibility, and airborne shedding relative to other clade 2.3.4.4b virus isolated prior to the 2024 cattle outbreaks(7), underscoring the need for continued public health vigilance. |
Pathogenesis and transmission assessment of three swine-origin influenza A(H3N2) viruses with zoonotic risk to humans isolated in the U.S from 2017-2020
Sun X , Belser JA , Pulit-Penaloza JA , Brock N , Pappas C , Zanders N , Jang Y , Jones J , Tumpey TM , Davis CT , Maines TR . J Infect Dis 2024 229 (4) 1107-1111 ![]() ![]() The sporadic occurrence of human infections with swine-origin influenza A(H3N2) viruses and the continual emergence of novel A(H3N2) viruses in swine herds underscore the necessity for ongoing assessment of the pandemic risk posed by these viruses. Here, we selected 3 recent novel swine-origin A(H3N2) viruses isolated between 2017 to 2020, bearing hemagglutinins from the 1990.1, 2010.1, or 2010.2 clades, and evaluated their ability to cause disease and transmit in a ferret model. We conclude that despite considerable genetic variances, all 3 contemporary swine-origin A(H3N2) viruses displayed a capacity for robust replication in the ferret respiratory tract and were also capable of limited airborne transmission. These findings highlight the continued public health risk of swine-origin A(H3N2) strains, especially in human populations with low cross-reactive immunity. |
Highly pathogenic avian influenza A(H5N1) virus of clade 2.3.4.4b isolated from a human case in Chile causes fatal disease and transmits between co-housed ferrets
Pulit-Penaloza JA , Brock N , Belser JA , Sun X , Pappas C , Kieran TJ , Thakur PB , Zeng H , Cui D , Frederick J , Fasce R , Tumpey TM , Maines TR . Emerg Microbes Infect 2024 2332667 ![]() Clade 2.3.4.4b highly pathogenic avian influenza A(H5N1) viruses have caused large outbreaks within avian populations on five continents, with concurrent spillover into a variety of mammalian species. Mutations associated with mammalian adaptation have been sporadically identified in avian isolates, and more frequently among mammalian isolates following infection. Reports of human infection with A(H5N1) viruses following contact with infected wildlife have been reported on multiple continents, highlighting the need for pandemic risk assessment of these viruses. In this study, the pathogenicity and transmissibility of A/Chile/25945/2023 HPAI A(H5N1) virus, a novel reassortment with four gene segments (PB1, PB2, NP, MP) from North America lineage, isolated from a severe human case in Chile, was evaluated in vitro and using the ferret model. This virus possessed a high capacity to cause fatal disease, characterized by high morbidity and extrapulmonary spread in virus-inoculated ferrets. The virus was capable of transmission to naïve contacts in a direct contact setting, with contact animals similarly exhibiting severe disease, but did not exhibit productive transmission in respiratory droplet or fomite transmission models. Our results indicate that the virus would need to acquire an airborne transmissible phenotype in mammals to potentially cause a pandemic. Nonetheless, this work warrants continuous monitoring of mammalian adaptations in avian viruses, especially in strains isolated from humans, to aid pandemic preparedness efforts. |
A naturally occurring HA-stabilizing amino acid (HA1-Y17) in an A(H9N2) low-pathogenic influenza virus contributes to airborne transmission
Sun X , Belser JA , Pulit-Penaloza JA , Brock N , Kieran TJ , Zeng H , Pappas C , Tumpey TM , Maines TR . mBio 2023 e0295723 ![]() Despite the accumulation of evidence showing that airborne transmissible influenza A virus (IAV) typically has a lower pH threshold for hemagglutinin (HA) fusion activation, the underlying mechanism for such a link remains unclear. In our study, by using a pair of isogenic recombinant A(H9N2) viruses with a phenotypical difference in virus airborne transmission in a ferret model due to an acid-destabilizing mutation (HA1-Y17H) in the HA, we demonstrate that an acid-stable A(H9N2) virus possesses a multitude of advantages over its less stable counterpart, including better fitness in the ferret respiratory tract, more effective aerosol emission from infected animals, and improved host susceptibility. Our study provides supporting evidence for the requirement of acid stability in efficient airborne transmission of IAV and sheds light on fundamental mechanisms for virus airborne transmission. |
Enhanced fitness of SARS-CoV-2 B.1.617.2 Delta variant in ferrets.
Sun X , Belser JA , Kieran TJ , Brock N , Pulit-Penaloza JA , Pappas C , Basu Thakur P , Jones J , Wentworth DE , Zhou B , Tumpey TM , Maines TR . Virology 2023 582 57-61 ![]() Competition assays were conducted in vitro and in vivo to examine how the Delta (B.1.617.2) variant displaced the prototype Washington/1/2020 (WA/1) strain. While WA/1 virus exhibited a moderately increased proportion compared to that in the inoculum following co-infection in human respiratory cells, Delta variant possessed a substantial in vivo fitness advantage as this virus becoming predominant in both inoculated and contact animals. This work identifies critical traits of the Delta variant that likely played a role in it becoming a dominant variant and highlights the necessities of employing multiple model systems to assess the fitness of newly emerged SARS-CoV-2 variants. |
Kinetics and magnitude of viral RNA shedding as indicators for Influenza A virus transmissibility in ferrets
Pulit-Penaloza JA , Brock N , Belser JA , Sun X , Pappas C , Tumpey TM , Maines TR . Commun Biol 2023 6 (1) 90 The ferret transmission model is routinely used to evaluate the pandemic potential of newly emerging influenza A viruses. However, concurrent measurement of viral load in the air is typically not a component of such studies. To address this knowledge gap, we measured the levels of virus in ferret nasal washes as well as viral RNA emitted into the air for 14 diverse influenza viruses, encompassing human-, swine-, and avian-origin strains. Here we show that transmissible viruses display robust replication and fast release into the air. In contrast, poorly- and non-transmissible viruses show significantly reduced or delayed replication along with lower detection of airborne viral RNA at early time points post inoculation. These findings indicate that efficient ferret-to-ferret transmission via the air is directly associated with fast emission of virus-laden particles; as such, quantification of viral RNA in the air represents a useful addition to established assessments of new influenza virus strains. |
Detection of Airborne Influenza A and SARS-CoV-2 Virus Shedding following Ocular Inoculation of Ferrets.
Belser JA , Sun X , Kieran TJ , Brock N , Pulit-Penaloza JA , Pappas C , BasuThakur P , Jones J , Wentworth DE , Zhou B , Tumpey TM , Maines TR . J Virol 2022 96 (24) e0140322 ![]() Despite reports of confirmed human infection following ocular exposure with both influenza A virus (IAV) and SARS-CoV-2, the dynamics of virus spread throughout oculonasal tissues and the relative capacity of virus transmission following ocular inoculation remain poorly understood. Furthermore, the impact of exposure route on subsequent release of airborne viral particles into the air has not been examined previously. To assess this, ferrets were inoculated by the ocular route with A(H1N1)pdm09 and A(H7N9) IAVs and two SARS-CoV-2 (early pandemic Washington/1 and Delta variant) viruses. Virus replication was assessed in both respiratory and ocular specimens, and transmission was evaluated in direct contact or respiratory droplet settings. Viral RNA in aerosols shed by inoculated ferrets was quantified with a two-stage cyclone aerosol sampler (National Institute for Occupational Safety and Health [NIOSH]). All IAV and SARS-CoV-2 viruses mounted a productive and transmissible infection in ferrets following ocular inoculation, with peak viral titers and release of virus-laden aerosols from ferrets indistinguishable from those from ferrets inoculated by previously characterized intranasal inoculation methods. Viral RNA was detected in ferret conjunctival washes from all viruses examined, though infectious virus in this specimen was recovered only following IAV inoculation. Low-dose ocular-only aerosol exposure or inhalation aerosol exposure of ferrets to IAV similarly led to productive infection of ferrets and shedding of aerosolized virus. Viral evolution during infection was comparable between all inoculation routes examined. These data support that both IAV and SARS-CoV-2 can establish a high-titer mammalian infection following ocular exposure that is associated with rapid detection of virus-laden aerosols shed by inoculated animals. IMPORTANCE Documented human infection with influenza viruses and SARS-CoV-2 has been reported among individuals wearing respiratory protection in the absence of eye protection, highlighting the capacity of these respiratory tract-tropic viruses to exploit nonrespiratory routes of exposure to initiate productive infection. However, comprehensive evaluations of how ocular exposure may modulate virus pathogenicity and transmissibility in mammals relative to respiratory exposure are limited and have not investigated multiple virus families side by side. Using the ferret model, we show that ocular exposure with multiple strains of either coronaviruses or influenza A viruses leads to an infection that results in shedding of detectable aerosolized virus from inoculated animals, contributing toward onward transmission of both viruses to susceptible contacts. Collectively, these studies support that the ocular surface represents a susceptible mucosal surface that, if exposed to a sufficient quantity of either virus, permits establishment of an infection which is similarly transmissible as that following respiratory exposure. |
Comparative Assessment of Severe Acute Respiratory Syndrome Coronavirus 2 Variants in the Ferret Model.
Pulit-Penaloza JA , Belser JA , Sun X , Pappas C , Brock N , Kieran TJ , Ritter JM , Seixas JN , Jones J , BasuThakur P , Pusch E , Wang L , Tumpey TM , Wentworth DE , Zhou B , Maines TR . mBio 2022 13 (5) e0242122 ![]() The continued spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in humans necessitates evaluation of variants for enhanced virulence and transmission. We used the ferret model to perform a comparative analysis of four SARS-CoV-2 strains, including an early pandemic isolate from the United States (WA1), and representatives of the Alpha, Beta, and Delta lineages. While Beta virus was not capable of pronounced replication in ferrets, WA1, Alpha, and Delta viruses productively replicated in the ferret upper respiratory tract, despite causing only mild disease with no overt histopathological changes. Strain-specific transmissibility was observed; WA1 and Delta viruses transmitted in a direct contact setting, whereas Delta virus was also capable of limited airborne transmission. Viral RNA was shed in exhaled air particles from all inoculated animals but was highest for Delta virus. Prior infection with SARS-CoV-2 offered varied protection against reinfection with either homologous or heterologous variants. Notable genomic variants in the spike protein were most frequently detected following WA1 and Delta virus infection. IMPORTANCE Continued surveillance and risk assessment of emerging SARS-CoV-2 variants are critical for pandemic response and preparedness. As such, in vivo evaluations are indispensable for early detection of variants with enhanced virulence and transmission. Here, we used the ferret model to compare the pathogenicity and transmissibility of an original SARS-CoV-2 isolate (USA-WA1/2020 [WA1]) to those of a panel of Alpha, Beta, and Delta variants, as well as to evaluate protection from homologous and heterologous reinfection. We observed strain-specific differences in replication kinetics in the ferret respiratory tract and virus load emitted into the air, revealing enhanced transmissibility of the Delta virus relative to previously detected strains. Prior infection with SARS-CoV-2 provided varied levels of protection from reinfection, with the Beta strain eliciting the lowest level of protection. Overall, we found that ferrets represent a useful model for comparative assessments of SARS-CoV-2 infection, transmission, and reinfection. |
Pathogenesis and transmissibility of North American highly pathogenic avian influenza a(H5N1) virus in ferrets
Pulit-Penaloza JA , Belser JA , Brock N , Thakur PB , Tumpey TM , Maines TR . Emerg Infect Dis 2022 28 (9) 1913-1915 Highly pathogenic avian influenza A(H5N1) viruses have spread rapidly throughout North American flyways in recent months, affecting wild birds in over 40 states. We evaluated the pathogenicity and transmissibility of a representative virus using a ferret model and examined replication kinetics of this virus in human respiratory tract cells. |
Pathogenesis and Transmission of Human Seasonal and Swine-origin A(H1) Influenza Viruses in the Ferret Model.
Pulit-Penaloza JA , Brock N , Jones J , Belser JA , Jang Y , Sun X , Thor S , Pappas C , Zanders N , Tumpey TM , Todd Davis C , Maines TR . Emerg Microbes Infect 2022 11 (1) 1-20 ![]() Influenza A viruses (IAVs) in the swine reservoir constantly evolve, resulting in expanding genetic and antigenic diversity of strains that occasionally cause infections in humans and pose threat of emerging as a strain capable of human-to-human transmission. For these reasons, there is an ongoing need for surveillance and characterization of newly emerging strains to aid pandemic preparedness efforts, particularly for the selection of candidate vaccine viruses and conducting risk assessments. Here, we performed a parallel comparison of the pathogenesis and transmission of genetically and antigenically diverse swine-origin A(H1N1) variant (v) and A(H1N2)v, and human seasonal A(H1N1)pdm09 IAVs using the ferret model. Both groups of viruses were capable of replication in the ferret upper respiratory tract; however, variant viruses were more frequently isolated from the lower respiratory tract as compared to the human-adapted viruses. Regardless of virus origin, observed clinical signs of infection differed greatly between strains, with some viruses causing nasal discharge, sneezing and, in some instances, diarrhea in ferrets. The most striking difference between the viruses was the ability to transmit through the air. Human-adapted viruses were capable of airborne transmission between all ferret pairs. In contrast, only one out of the four tested variant viruses was able to transmit via the air as efficiently as the human-adapted viruses. Overall, this work highlights the need for sustained monitoring of emerging swine IAVs to identify strains of concern such as those that are antigenically different from vaccine strains and that possess adaptations required for efficient respiratory droplet transmission in mammals. |
Inherent heterogeneity of influenza A virus stability following aerosolization
Belser JA , Pulit-Penaloza JA , Brock N , Creager HM , Gustin KM , Tumpey TM , Maines TR . Appl Environ Microbiol 2022 88 (4) aem0227121 Efficient human-to-human transmission represents a necessary adaptation for a zoonotic influenza A virus (IAV) to cause a pandemic. As such, many emerging IAVs are characterized for transmissibility phenotypes in mammalian models, with an emphasis on elucidating viral determinants of transmission and the role host immune responses contribute to mammalian adaptation. Investigations of virus infectivity and stability in aerosols concurrent with transmission assessments have increased in recent years, enhancing our understanding of this dynamic process. Here, we employ a diverse panel of 17 human and zoonotic IAVs, inclusive of seasonally circulating H1N1 and H3N2 viruses, and avian and swine viruses associated with human infection, to evaluate differences in spray factor (a value that assesses efficiency of the aerosolization process), stability, and infectivity following aerosolization. While most seasonal influenza viruses did not exhibit substantial variability within these parameters, there was more heterogeneity among zoonotic influenza viruses, which possess a diverse range of transmission phenotypes. Aging of aerosols at different relative humidities identified strain-specific levels of stability with different profiles identified between zoonotic H3, H5, and H7 subtype viruses associated with human infection. As studies continue to elucidate the complex components governing virus transmissibility, notably aerosol matrices and environmental parameters, considering the relative role of subtype- and strain-specific factors to modulate these parameters will improve our understanding of the pandemic potential of zoonotic influenza A viruses. Importance Transmission of respiratory pathogens through the air can facilitate the rapid and expansive spread of infection and disease through a susceptible population. While seasonal influenza viruses are quite capable of airborne spread, there is a lack of knowledge regarding how well influenza viruses remain viable after aerosolization, and if influenza viruses capable of jumping species barriers to cause human infection differ in this property from seasonal strains. We evaluated a diverse panel of influenza viruses associated with human infection (originating from human, avian, and swine reservoirs) for their ability to remain viable after aerosolization in the laboratory under a range of conditions. We found greater diversity among avian and swine-origin viruses compared with seasonal influenza viruses; strain-specific stability was also noted. Although influenza virus stability in aerosols is an underreported property, if molecular markers associated with enhanced stability are identified, we will be able to quickly recognize emerging strains of influenza that present the greatest pandemic threat. |
Outbreak of SARS-CoV-2 Infections, Including COVID-19 Vaccine Breakthrough Infections, Associated with Large Public Gatherings - Barnstable County, Massachusetts, July 2021.
Brown CM , Vostok J , Johnson H , Burns M , Gharpure R , Sami S , Sabo RT , Hall N , Foreman A , Schubert PL , Gallagher GR , Fink T , Madoff LC , Gabriel SB , MacInnis B , Park DJ , Siddle KJ , Harik V , Arvidson D , Brock-Fisher T , Dunn M , Kearns A , Laney AS . MMWR Morb Mortal Wkly Rep 2021 70 (31) 1059-1062 ![]() During July 2021, 469 cases of COVID-19 associated with multiple summer events and large public gatherings in a town in Barnstable County, Massachusetts, were identified among Massachusetts residents; vaccination coverage among eligible Massachusetts residents was 69%. Approximately three quarters (346; 74%) of cases occurred in fully vaccinated persons (those who had completed a 2-dose course of mRNA vaccine [Pfizer-BioNTech or Moderna] or had received a single dose of Janssen [Johnson & Johnson] vaccine ≥14 days before exposure). Genomic sequencing of specimens from 133 patients identified the B.1.617.2 (Delta) variant of SARS-CoV-2, the virus that causes COVID-19, in 119 (89%) and the Delta AY.3 sublineage in one (1%). Overall, 274 (79%) vaccinated patients with breakthrough infection were symptomatic. Among five COVID-19 patients who were hospitalized, four were fully vaccinated; no deaths were reported. Real-time reverse transcription-polymerase chain reaction (RT-PCR) cycle threshold (Ct) values in specimens from 127 vaccinated persons with breakthrough cases were similar to those from 84 persons who were unvaccinated, not fully vaccinated, or whose vaccination status was unknown (median = 22.77 and 21.54, respectively). The Delta variant of SARS-CoV-2 is highly transmissible (1); vaccination is the most important strategy to prevent severe illness and death. On July 27, CDC recommended that all persons, including those who are fully vaccinated, should wear masks in indoor public settings in areas where COVID-19 transmission is high or substantial.* Findings from this investigation suggest that even jurisdictions without substantial or high COVID-19 transmission might consider expanding prevention strategies, including masking in indoor public settings regardless of vaccination status, given the potential risk of infection during attendance at large public gatherings that include travelers from many areas with differing levels of transmission. |
Characterization of highly pathogenic avian influenza H5Nx viruses in the ferret model.
Pulit-Penaloza JA , Brock N , Pappas C , Sun X , Belser JA , Zeng H , Tumpey TM , Maines TR . Sci Rep 2020 10 (1) 12700 ![]() Highly pathogenic avian influenza (HPAI) H5 viruses, of the A/goose/Guangdong/1/1996 lineage, have exhibited substantial geographic spread worldwide since the first detection of H5N1 virus in 1996. Accumulation of mutations in the HA gene has resulted in several phylogenetic clades, while reassortment with other avian influenza viruses has led to the emergence of new virus subtypes (H5Nx), notably H5N2, H5N6, and H5N8. H5Nx viruses represent a threat to both the poultry industry and human health and can cause lethal human disease following virus exposure. Here, HPAI H5N6 and H5N2 viruses (isolated between 2014 and 2017) of the 2.3.4.4 clade were assessed for their capacity to replicate in human respiratory tract cells, and to cause disease and transmit in the ferret model. All H5N6 viruses possessed increased virulence in ferrets compared to the H5N2 virus; however, pathogenicity profiles varied among the H5N6 viruses tested, from mild infection with sporadic virus dissemination beyond the respiratory tract, to severe disease with fatal outcome. Limited transmission between co-housed ferrets was observed with the H5N6 viruses but not with the H5N2 virus. In vitro evaluation of H5Nx virus replication in Calu-3 cells and the identification of mammalian adaptation markers in key genes associated with pathogenesis supports these findings. |
Provision of Pediatric Immunization Services During the COVID-19 Pandemic: an Assessment of Capacity Among Pediatric Immunization Providers Participating in the Vaccines for Children Program - United States, May 2020.
Vogt TM , Zhang F , Banks M , Black C , Arthur B , Kang Y , Lucas P , Lamont B . MMWR Morb Mortal Wkly Rep 2020 69 (27) 859-863 Recent reports suggest that routine childhood immunization coverage might have decreased during the coronavirus disease 2019 (COVID-19) pandemic (1,2). To assess the capacity of pediatric health care practices to provide immunization services to children during the pandemic, a survey of practices participating in the Vaccines for Children (VFC) program was conducted during May 12-20, 2020. Data were weighted to account for the sampling design; thus, all percentages reported are weighted. Among 1,933 responding practices, 1,727 (89.8%) were currently open; 1,397 (81.1%) of these reported offering immunization services to all of their patients. When asked whether the practice would likely be able to accommodate new patients to assist with provision of immunization services through August, 1,135 (59.1%) respondents answered affirmatively. These results suggest that health care providers appear to have the capacity to deliver routinely recommended childhood vaccines, allowing children to catch up on vaccines that might have been delayed as a result of COVID-19-related effects on the provision of or demand for routine well child care. Health care providers and immunization programs should educate parents on the need to return for well-child and immunization visits or refer patients to other practices, if they are unable to provide services (3). |
Genetically and antigenically divergent influenza A(H9N2) viruses exhibit differential replication and transmission phenotypes in mammalian models.
Belser JA , Sun X , Brock N , Pappas C , Pulit-Penaloza JA , Zeng H , Jang Y , Jones J , Carney PJ , Chang J , Van Long N , Diep NT , Thor S , Di H , Yang G , Cook PW , Creager HM , Wang D , McFarland J , Van Dong P , Wentworth DE , Tumpey TM , Barnes JR , Stevens J , Davis CT , Maines TR . J Virol 2020 94 (17) ![]() Low pathogenicity avian influenza A(H9N2) viruses, enzootic in poultry populations in Asia, are associated with fewer confirmed human infections but higher rates of seropositivity compared to A(H5) or A(H7) subtype viruses. Co-circulation of A(H5) and A(H7) viruses leads to the generation of reassortant viruses bearing A(H9N2) internal genes with markers of mammalian adaptation, warranting continued surveillance in both avian and human populations. Here, we describe active surveillance efforts in live poultry markets in Vietnam in 2018 and compare representative viruses to G1 and Y280 lineage viruses that have infected humans. Receptor binding properties, pH thresholds for HA activation, in vitro replication in human respiratory tract cells, and in vivo mammalian pathogenicity and transmissibility were investigated. While A(H9N2) viruses from both poultry and humans exhibited features associated with mammalian adaptation, one human isolate from 2018, A/Anhui-Lujiang/39/2018, exhibited increased capacity for replication and transmission, demonstrating the pandemic potential of A(H9N2) viruses.IMPORTANCE A(H9N2) influenza viruses are widespread in poultry in many parts of the world, and for over twenty years, have sporadically jumped species barriers to cause human infection. As these viruses continue to diversify genetically and antigenically, it is critical to closely monitor viruses responsible for human infections, to ascertain if A(H9N2) viruses are acquiring properties that make them better suited to infect and spread among humans. In this study, we describe an active poultry surveillance system established in Vietnam to identify the scope of influenza viruses present in live bird markets and the threat they pose to human health. Assessment of a recent A(H9N2) virus isolated from an individual in China in 2018 is also reported and was found to exhibit properties of adaptation to humans and, importantly, show similarities to strains isolated from the live bird markets of Vietnam. |
Mammalian pathogenicity and transmissibility of low pathogenic avian influenza H7N1 and H7N3 viruses isolated from North America in 2018
Belser JA , Sun X , Brock N , Pulit-Penaloza JA , Jones J , Zanders N , Davis CT , Tumpey TM , Maines TR . Emerg Microbes Infect 2020 9 (1) 1037-1045 ABSTRACTLow pathogenic avian influenza (LPAI) H7 subtype viruses are infrequently, but persistently, associated with outbreaks in poultry in North America. These LPAI outbreaks provide opportunities for the virus to develop enhanced virulence and transmissibility in mammals and have previously resulted in both occasional acquisition of a highly pathogenic avian influenza (HPAI) phenotype in birds and sporadic cases of human infection. Two notable LPAI H7 subtype viruses caused outbreaks in 2018 in North America: LPAI H7N1 virus in chickens and turkeys, representing the first confirmed H7N1 infection in poultry farms in the United States, and LPAI H7N3 virus in turkeys, a virus subtype often associated with LPAI-to-HPAI phenotypes. Here, we investigated the replication capacity of representative viruses from these outbreaks in human respiratory tract cells and mammalian pathogenicity and transmissibility in the mouse and ferret models. We found that the LPAI H7 viruses replicated to high titre in human cells, reaching mean peak titres generally comparable to HPAI H7 viruses. Replication was efficient in both mammalian species, causing mild infection, with virus primarily limited to respiratory tract tissues. The H7 viruses demonstrated a capacity to transmit to naive ferrets in a direct contact setting. These data support the need to perform routine risk assessments of LPAI H7 subtype viruses, even in the absence of confirmed human infection. |
Identification of key hemagglutinin residues responsible for cleavage, acid stability, and virulence of fifth-wave highly pathogenic avian influenza A(H7N9) viruses.
Sun X , Belser JA , Yang H , Pulit-Penaloza JA , Pappas C , Brock N , Zeng H , Creager HM , Stevens J , Maines TR . Virology 2019 535 232-240 ![]() We previously demonstrated that despite no airborne transmissibility increase compared to low pathogenic avian influenza viruses, select human isolates of highly pathogenic avian influenza A(H7N9) virus exhibit greater virulence in animal models and a lower threshold pH for fusion. In the current study, we utilized both in vitro and in vivo approaches to identify key residues responsible for hemagglutinin (HA) intracellular cleavage, acid stability, and virulence in mice. We found that the four amino acid insertion (-KRTA-) at the HA cleavage site of A/Taiwan/1/2017 virus is essential for HA intracellular cleavage and contributes to disease in mice. Furthermore, a lysine to glutamic acid mutation at position HA2-64 increased the threshold pH for HA activation, reduced virus stability, and replication in mice. Identification of a key residue responsible for enhanced acid stability of A(H7N9) viruses is of great significance for future surveillance activities and improvements in vaccine stability. |
Tropism and infectivity of a seasonal A(H1N1) and a highly pathogenic avian A(H5N1) influenza virus in primary differentiated ferret nasal epithelial cell cultures
Zeng H , Goldsmith CS , Kumar A , Belser JA , Sun X , Pappas C , Brock N , Bai Y , Levine M , Tumpey TM , Maines TR . J Virol 2019 93 (10) Ferrets represent an invaluable animal model to study influenza virus pathogenesis and transmission. To further characterize this model, we developed a differentiated primary ferret nasal epithelial cell (FNEC) culture model for investigation of influenza A virus infection and virus-host interactions. This well-differentiated culture consists of various cell types, a mucociliary clearance system, and tight junctions, representing the nasal ciliated pseudostratified respiratory epithelium. Both alpha2,6-linked and alpha2,3-linked sialic acid (SA) receptors, which preferentially bind the HA of human and avian influenza viruses, respectively, were detected on the apical surface of the culture with different cellular tropism. In accordance with distribution of SA receptors, we observed that a pre-2009 seasonal A(H1N1) virus infected both ciliated and non-ciliated cells, whereas a highly pathogenic avian influenza (HPAI) A(H5N1) virus primarily infected non-ciliated cells. Transmission electron microscopy revealed that virions were released from or associated with the apical membranes of ciliated, non-ciliated, and mucin-secretory goblet cells. Upon infection, the HPAI A(H5N1) virus replicated to titers higher than those of the human A(H1N1) virus at 37 degrees C, however, replication of the A(H5N1) virus was significantly attenuated at 33 degrees C. Furthermore, we found that infection with the A(H5N1) virus induced higher expression of immune mediator genes and resulted in more cell damage/loss when compared with the human A(H1N1) virus. This primary differentiated FNEC culture model, recapitulating the structure of the nasal epithelium, provides a useful model to bridge in vivo and in vitro studies of cellular tropism, infectivity, and pathogenesis of influenza viruses during the initial stages of infection.IMPORTANCE: Although ferrets serve as an important model of influenza virus infection, much remains unknown about virus-host interactions in this species at the cellular level. The development of differentiated primary cultures of ferret nasal epithelial cells is an important step toward understanding cellular tropism and the mechanisms of influenza virus infection and replication in the airway milieu of this model. Using lectin staining and microscopy techniques, we characterized sialic acid receptor distribution and the cellular composition of the culture model. We then evaluated the replication of and immune response to human and avian influenza viruses at relevant physiological temperatures. Our findings offer significant insight into this first line defense against influenza virus infection and provide a model for the evaluation of emerging influenza viruses in a well-controlled in vitro environmental setting. |
Risk assessment of fifth-wave H7N9 influenza A viruses in mammalian models
Sun X , Belser JA , Pappas C , Pulit-Penaloza JA , Brock N , Zeng H , Creager HM , Le S , Wilson M , Lewis A , Stark TJ , Shieh WJ , Barnes J , Tumpey TM , Maines TR . J Virol 2018 93 (1) 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 HA cleavability. Here, several low pathogenic avian influenza (LPAI) and HPAI H7N9 human 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 a 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 compared with 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.ImportanceThe potential pandemic risk posed by avian influenza H7N9 viruses was heightened during the fifth epidemic wave in China due to the sudden increased 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 were evaluated for their 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 compared to LPAI H7N9 viruses suggest 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. |
Safety of bivalent human papillomavirus vaccine in the US vaccine adverse event reporting system (VAERS), 2009-2017.
Suragh TA , Lewis P , Arana J , Mba-Jonas A , Li R , Stewart B , Shimabukuro TT , Cano M . Br J Clin Pharmacol 2018 84 (12) 2928-2932 ![]() ![]() BACKGROUND: Human papillomavirus (HPV) vaccines prevent infection with oncogenic virus types. We analyzed reports to the U.S. Vaccine Adverse Event Reporting System (VAERS) of adverse events (AE) following bivalent HPV vaccine (2vHPV). METHODS: We conducted descriptive analysis of 2vHPV reports, reviewed individual reports, calculated crude AE reporting rates, and conducted empirical Bayesian data mining. RESULTS: Of 241 2vHPV reports, 158 were in females, 64 in males (2vHPV is approved for females only), and 19 with unknown sex; 95.8% were classified as non-serious. Dizziness, headache, nausea and injection site reactions were the most common symptoms. Crude AE reporting rates were 33.3 reports per 100,000 doses distributed overall, and 1.4 per 100,000 for serious reports. Empirical Bayesian data mining identified disproportional reporting for three types of medical errors; assessment indicated findings were likely driven by inadvertent 2vHPV use in males. CONCLUSIONS: We did not identify any new or unexpected safety concerns in our review of 2vHPV reports to VAERS. |
Comparative in vitro and in vivo analysis of H1N1 and H1N2 variant influenza viruses isolated from humans between 2011 and 2016.
Pulit-Penaloza JA , Pappas C , Belser JA , Sun X , Brock N , Zeng H , Tumpey TM , Maines TR . J Virol 2018 92 (22) ![]() Influenza A virus pandemics are rare events caused by novel viruses which have the ability to spread in susceptible human populations. With respect to H1 subtype viruses, swine H1N1 and H1N2 viruses occasionally cross the species barrier to cause human infection. Recently isolated from humans (termed variants), swine viruses were shown to display great genetic and antigenic diversity, hence posing considerable public health risk. Here, we utilized in vitro and in vivo approaches to provide characterization of H1 subtype variant viruses isolated since the 2009 pandemic and discuss the findings in context with previously studied H1 subtype human isolates. The variant viruses were well adapted to replicate in human respiratory cell line, Calu-3, and the respiratory tracts of mice and ferrets. However, with respect to HA activation pH, the variant viruses had fusion pH thresholds closer to that of most classical swine and triple reassortant H1 isolates rather than viruses that had adapted to humans. Consistent with previous observations for swine isolates, the tested variant viruses were capable of efficient transmission between co-housed ferrets but could transmit via respiratory droplets to differing degrees. Overall, this investigation demonstrates that swine H1 viruses that infected humans possess adaptations required for robust replication and, in some cases, efficient respiratory droplet transmission in a mammalian model, and therefore, need to be closely monitored for additional molecular changes that could facilitate transmission among humans. This work highlights the need for risk assessments of emerging H1 viruses as they continue to evolve and cause human infections.IMPORTANCE Influenza A virus is a continuously evolving respiratory pathogen. Endemic in swine, H1 and H3 subtype viruses sporadically cause human infections. As each zoonotic infection represents an opportunity for human adaptation, the emergence of a transmissible influenza virus to which there is little or no pre-existing immunity is an ongoing threat to public health. Recently isolated variant H1 subtype viruses were shown to display extensive genetic diversity and in many instances were antigenically distinct from seasonal vaccine strains. In this study, we provide characterization of representative H1N1v and H1N2v viruses isolated since the 2009 pandemic. Our results show that, although recent variant H1 viruses possess some adaptation markers of concern, these viruses have not fully adapted to humans and require further adaptation to present a pandemic threat. This investigation highlights the need for close monitoring of emerging variant influenza viruses for molecular changes that could facilitate efficient transmission among humans. |
Pathogenesis and transmission of genetically diverse swine-origin H3N2v influenza A viruses from multiple lineages isolated in the United States, 2011-2016.
Sun X , Pulit-Penaloza JA , Belser JA , Pappas C , Pearce MB , Brock N , Zeng H , Creager HM , Zanders N , Jang Y , Tumpey TM , Davis T , Maines TR . J Virol 2018 92 (16) ![]() While several swine-origin influenza A H3N2 variant (H3N2v) viruses isolated from humans prior to 2011 have been previously characterized for their virulence and transmissibility in ferrets, recent genetic and antigenic divergence of H3N2v viruses warrants an updated assessment of their pandemic potential. Here, four contemporary H3N2v viruses isolated during 2011-2016 were evaluated for their replicative ability in both in vitro and in vivo mammalian models, as well as their transmissibility among ferrets. We found that all four H3N2v viruses possessed similar or enhanced replication capacity in a human bronchial epithelium cell line (Calu-3) compared to a human seasonal influenza virus, suggestive of strong fitness in human respiratory tract cells. The majority of H3N2v viruses examined in our study were mildly virulent in mice and capable of replicating in mouse lungs with different degrees of efficiency. In ferrets, all four H3N2v viruses caused moderate morbidity and exhibited comparable titers in the upper respiratory tract, but only 2 of the 4 viruses replicated in the lower respiratory tract in this model. Furthermore, despite efficient transmission among cohoused ferrets, recently isolated H3N2v viruses displayed considerable variance in their ability to transmit by respiratory droplets. The lack of a full understanding of the molecular correlates of virulence and transmission underscores the need for close genotypic and phenotypic monitoring of H3N2v viruses and the importance of continued surveillance to improve pandemic preparedness.Importance: Swine-origin influenza viruses of the H3N2 subtype, with the HA and NA derived from historic human seasonal influenza viruses, continue to cross species barriers and cause human infections, posing an indelible threat to public health. To help us better understand the potential risk associated with swine-origin H3N2v viruses that emerged in the U.S between 2011-2016 influenza seasons, we use both in vitro and in vivo models to characterize the ability of these viruses to replicate, caused disease, and transmit in mammalian hosts. The efficient respiratory droplet transmission exhibited by some of the H3N2v viruses in the ferret model combined with the existing evidence of low immunity against such viruses in young children and older adults highlights their pandemic potential. Extensive surveillance and risk assessment of H3N2v viruses should continue to be an essential component of our pandemic preparedness strategy. |
Liver Disease in a Residential Cohort With Elevated Polychlorinated Biphenyl Exposures.
Clair HB , Pinkston CM , Rai SN , Pavuk M , Dutton ND , Brock G , Prough RA , Falkner KC , McClain CJ , Cave MC . Toxicol Sci 2018 164 (1) 39-49 ![]() Endocrine and metabolism disrupting chemicals (EDCs/MDCs) have been associated with environmental liver diseases including toxicant-associated steatohepatitis (TASH). TASH has previously been characterized by hepatocellular necrosis, disrupted intermediary metabolism, and liver inflammation. Polychlorinated biphenyls (PCBs) are environmental EDCs/MDCs associated with the genesis and progression of steatohepatitis in animal models and human liver injury in epidemiology studies. The cross-sectional Anniston Community Health Survey (ACHS) investigates ortho-substituted PCB exposures and health effects near a former PCB manufacturing complex. The rates of obesity, diabetes, and dyslipidemia were previously determined to be high in ACHS. In this study, 738 ACHS participants were categorized by liver disease status using the serum cytokeratin 18 biomarker. Associations between PCB exposures and mechanistic biomarkers of intermediary metabolism, inflammation, and hepatocyte death were determined. The liver disease prevalence was high (60.2%), and 80.7% of these individuals were categorized as having TASH. Sex and race/ethnicity differences were noted. TASH was associated with increased exposures to specific PCB congeners, insulin resistance, dyslipidemia, pro-inflammatory cytokines, and liver necrosis. These findings are consistent with PCB-related steatohepatitis. SigmaPCBs was inversely associated with insulin resistance/production, leptin, and hepatocyte apoptosis, while other adipocytokines were increased. This is possibly the largest environmental liver disease study applying mechanistic biomarkers ever performed and the most comprehensive analysis of PCBs and adipocytokines. It provides insight into the mechanisms of PCB-related endocrine and metabolic disruption in liver disease and diabetes. In the future, associations between additional exposures and liver disease biomarkers will be evaluated in the ACHS and follow-up ACHS-II studies. |
Post-licensure safety monitoring of quadrivalent human papillomavirus vaccine in the Vaccine Adverse Event Reporting System (VAERS), 2009-2015.
Arana JE , Harrington T , Cano M , Lewis P , Mba-Jonas A , Rongxia L , Stewart B , Markowitz LE , Shimabukuro TT . Vaccine 2018 36 (13) 1781-1788 ![]() ![]() BACKGROUND: The Food and Drug Administration (FDA) approved quadrivalent human papillomavirus vaccine (4vHPV) for use in females and males aged 9-26years, since 2006 and 2009 respectively. We characterized reports to the Vaccine Adverse Event Reporting System (VAERS), a US spontaneous reporting system, in females and males who received 4vHPV vaccination. METHODS: We searched VAERS for US reports of adverse events (AEs) following 4vHPV from January 2009 through December 2015. Signs and symptoms were coded using Medical Dictionary for Regulatory Activities (MedDRA). We calculated reporting rates and conducted empirical Bayesian data mining to identify disproportional reports. Clinicians reviewed available information, including medical records, and reports of selected pre-specified conditions. FINDINGS: VAERS received 19,760 reports following 4vHPV; 60.2% in females, 17.2% in males, and in 22.6% sex was missing. Overall, 94.2% of reports were non-serious; dizziness, syncope and injection site reactions were commonly reported in both males and females. Headache, fatigue and nausea were commonly reported serious AEs. More than 60 million 4vHPV doses were distributed during the study period. Crude AE reporting rates were 327 reports per million 4vHPV doses distributed for all reports, and 19 per million for serious reports. Among 29 verified reports of death, there was no pattern of clustering of deaths by diagnosis, co-morbidities, age, or interval from vaccination to death. INTERPRETATION: No new or unexpected safety concerns or reporting patterns of 4vHPV with clinically important AEs were detected. Safety profile of 4vHPV is consistent with data from pre-licensure trials and postmarketing safety data. |
Mammalian pathogenesis and transmission of avian influenza A(H7N9) viruses, Tennessee, USA, 2017
Belser JA , Brock N , Sun X , Jones J , Zanders N , Hodges E , Pulit-Penaloza JA , Wentworth D , Tumpey TM , Davis T , Maines TR . Emerg Infect Dis 2018 24 (1) 149-152 Infections with low pathogenicity and highly pathogenic avian influenza A(H7N9) viruses affected poultry in 4 states in the southeastern United States in 2017. We evaluated pathogenicity and transmission of representative viruses in mouse and ferret models and examined replication kinetics in human respiratory tract cells. These viruses can cause respiratory infections in mammalian models. |
Safety of currently licensed hepatitis B surface antigen vaccines in the United States, Vaccine Adverse Event Reporting System (VAERS), 2005-2015.
Haber P , Moro PL , Ng C , Lewis PW , Hibbs B , Schillie SF , Nelson NP , Li R , Stewart B , Cano MV . Vaccine 2017 36 (4) 559-564 ![]() ![]() INTRODUCTION: Currently four recombinant hepatitis B (HepB) vaccines are in use in the United States. HepB vaccines are recommended for infants, children and adults. We assessed adverse events (AEs) following HepB vaccines reported to the Vaccine Adverse Event Reporting System (VAERS), a national spontaneous reporting system. METHODS: We searched VAERS for reports of AEs following single antigen HepB vaccine and HepB-containing vaccines (either given alone or with other vaccines), from January 2005 - December 2015. We conducted descriptive analyses and performed empirical Bayesian data mining to assess disproportionate reporting. We reviewed serious reports including reports of special interest. RESULTS: VAERS received 20,231 reports following HepB or HepB-containing vaccines: 10,291 (51%) in persons <2years of age; 2588 (13%) in persons 2-18years and 5867 (29%) in persons >18years; for 1485 (7.3%) age was missing. Dizziness and nausea (8.4% each) were the most frequently reported AEs following a single antigen HepB vaccine: fever (23%) and injection site erythema (11%) were most frequent following Hep-containing vaccines. Of the 4444 (22%) reports after single antigen HepB vaccine, 303 (6.8%) were serious, including 45 deaths. Most commonly reported cause of death was Sudden Infant Death Syndrome (197). Most common non-death serious reports following single antigen HepB vaccines among infants aged <1month, were nervous system disorders (15) among children aged 1-23months; infections and infestation (8) among persons age 2-18years blood and lymphatic systemic disorders; and general disorders and administration site conditions among persons age >18years. Most common vaccination error following single antigen HepB was incorrect product storage. CONCLUSIONS: Review current U.S.-licensed HepB vaccines administered alone or in combination with other vaccines did not reveal new or unexpected safety concerns. Vaccination errors were identified which indicate the need for training and education of providers on HepB vaccine indications and recommendations. |
A novel A(H7N2) influenza virus isolated from a veterinarian caring for cats in a New York City animal shelter causes mild disease and transmits poorly in the ferret model
Belser JA , Pulit-Penaloza JA , Sun X , Brock N , Pappas C , Creager HM , Zeng H , Tumpey TM , Maines TR . J Virol 2017 91 (15) In December 2016, a low pathogenic avian influenza (LPAI) A(H7N2) virus was identified as the causative source of an outbreak in a cat shelter in New York City, which subsequently spread to multiple shelters in New York and Pennsylvania. One person with occupational exposure to infected cats became infected with the virus, representing the first LPAI H7N2 human infection in North America since 2003. Considering the close contact that frequently occurs between companion animals and humans, it was critical to assess the relative risk of this novel virus to public health. Virus isolated from the human case, A/New York/108/2016 (NY/108), caused mild and transient illness in ferrets and mice, but did not transmit to naive co-housed ferrets following traditional or aerosol-based inoculation methods. Environmental persistence of NY/108 virus was generally comparable to other LPAI H7N2 viruses. However, NY/108 virus replicated with increased efficiency in human bronchial epithelial cells compared with previously isolated H7N2 viruses. Furthermore, the novel H7N2 virus was found to utilize a relatively lower pH for HA activation, similar to human influenza viruses. Our data suggest that the LPAI H7N2 virus requires further adaptation before representing a substantial threat to public health. However, the reemergence of a LPAI H7N2 virus in the Northeastern United States underscores the need for continuous surveillance of emerging zoonotic influenza viruses, inclusive of mammalian species such as domestic felines that are not commonly considered intermediate hosts for avian influenza viruses.IMPORTANCE Avian influenza viruses are capable of crossing the species barrier to infect mammals, an event of public health concern due to the potential acquisition of a pandemic phenotype. In December 2016, an H7N2 virus caused an outbreak in cats in multiple New York animal shelters, which was the first detection of this virus in the Northeastern U.S. in over a decade and the first documented infection of H7N2 virus in a felid. A veterinarian became infected following occupational exposure to H7N2 virus-infected cats, necessitating the evaluation of this virus for its capacity to cause mammalian disease. While the H7N2 virus was associated with mild illness in mice and ferrets, and did not spread well between ferrets, it nonetheless possessed several markers of mammalian virulence. These data highlight the promiscuity of influenza viruses and the need for diligent surveillance across multiple species to quickly identify an emerging strain with pandemic potential. |
Safe recombinant outer membrane vesicles that display M2e elicit heterologous influenza protection
Watkins HC , Rappazzo CG , Higgins JS , Sun X , Brock N , Chau A , Misra A , Cannizzo JP , King MR , Maines TR , Leifer CA , Whittaker GR , DeLisa MP , Putnam D . Mol Ther 2017 25 (4) 989-1002 Recombinant, Escherichia coli-derived outer membrane vesicles (rOMVs), which display heterologous protein subunits, have potential as a vaccine adjuvant platform. One drawback to rOMVs is their lipopolysaccharide (LPS) content, limiting their translatability to the clinic due to potential adverse effects. Here, we explore a unique rOMV construct with structurally remodeled lipids containing only the lipid IVa portion of LPS, which does not stimulate human TLR4. The rOMVs are derived from a genetically engineered B strain of E. coli, ClearColi, which produces lipid IVa, and which was further engineered in our laboratory to hypervesiculate and make rOMVs. We report that rOMVs derived from this lipid IVa strain have substantially attenuated pyrogenicity yet retain high levels of immunogenicity, promote dendritic cell maturation, and generate a balanced Th1/Th2 humoral response. Additionally, an influenza A virus matrix 2 protein-based antigen displayed on these rOMVs resulted in 100% survival against a lethal challenge with two influenza A virus strains (H1N1 and H3N2) in mice with different genetic backgrounds (BALB/c, C57BL/6, and DBA/2J). Additionally, a two-log reduction of lung viral titer was achieved in a ferret model of influenza infection with human pandemic H1N1. The rOMVs reported herein represent a potentially safe and simple subunit vaccine delivery platform. |
Spatial variation in hyperthermia emergency department visits among those with employer-based insurance in the United States - a case-crossover analysis
Saha S , Brock JW , Vaidyanathan A , Easterling DR , Luber G . Environ Health 2015 14 (20) 20 BACKGROUND: Predictions of intense heat waves across the United States will lead to localized health impacts, most of which are preventable. There is a need to better understand the spatial variation in the morbidity impacts associated with extreme heat across the country to prevent such adverse health outcomes. METHODS: Hyperthermia-related emergency department (ED) visits were obtained from the Truven Health MarketScan research dataset for 2000-2010. Three measures of daily ambient heat were constructed using meteorological observations from the National Climatic Data Center (maximum temperature, heat index) and the Spatial Synoptic Classification. Using a time-stratified case crossover approach, odds ratio of hyperthermia-related ED visit were estimated for the three different heat measures. Random effects meta-analysis was used to combine the odds ratios for 94 Metropolitan Statistical Areas (MSA) to examine the spatial variation by eight latitude categories and nine U.S. climate regions. RESULTS: Examination of lags for all three temperature measures showed that the odds ratio of ED visit was statistically significant and highest on the day of the ED visit. For heat waves lasting two or more days, additional statistically significant association was observed when heat index and synoptic classification was used as the temperature measure. These results were insensitive to the inclusion of air pollution measures. On average, the maximum temperature on the day of an ED visit was 93.4 degrees F in 'South' and 81.9 degrees F in the 'Northwest' climatic regions of United States. The meta-analysis showed higher odds ratios of hyperthermia ED visit in the central and the northern parts of the country compared to the south and southwest. CONCLUSION: The results showed spatial variation in average temperature on days of ED visit and odds ratio for hyperthermia ED visits associated with extreme heat across United States. This suggests that heat response plans need to be customized for different regions and the potential role of hyperthermia ED visits in syndromic surveillance for extreme heat. |
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