Influenza A viruses of avian origin represent an emerging threat to human health as the progenitors of the next influenza pandemic. In recent years, highly pathogenic avian influenza H5N1 viruses ...have caused unprecedented epizootics on three continents and rare but highly fatal disease among humans exposed to diseased birds. Avian viruses of the H7 and H9 subtypes have also infected humans but generally resulted in far milder disease, yet they too should be considered as possible pandemic threats. Influenza virus infection elicits a complex network of host immune responses that, in uncomplicated influenza, results in effective control of the virus and the development of long-term memory responses. However, fatal avian H5N1 virus infection in both humans and experimental mammalian models is characterized by a high viral load in the respiratory tract, peripheral leukopenia and lymphopenia, a massive infiltration of macrophages into the lung, and dysregulation of cytokine and chemokine responses. This review focuses on avian influenza viruses as a pandemic threat, their induction of host innate immune responses in mammalian species, and the contribution of these responses to the disease process.
...there should be enhanced international coordination in research and development to best use limited funding. ...a global clinical-trials network should be developed and maintained to ensure that ...diagnostics, therapeutics, and vaccines are evaluated in regions where they are likely to be used. ...a sustainable, regional manufacturing strategy could enable improved availability of diagnostics, therapeutics, and vaccines and equitable access in low-income and middle-income countries, as well as supporting local product confidence (ie, trust in these products). RAB is the former Director of the US Biomedical Advanced Research and Development Authority (BARDA), is on the Scientific Advisory Board for Qiagen, is on the Board of Directors for Foundation for Innovative New Diagnostics, and holds stock in Cue Health.
CONTEXT The adamantanes, amantadine and rimantadine, have been used as first-choice
antiviral drugs against community outbreaks of influenza A viruses for many
years. Rates of viruses resistant to ...these drugs have been increasing globally.
Rapid surveillance for the emergence and spread of resistant viruses has become
critical for appropriate treatment of patients. OBJECTIVE To investigate the frequency of adamantane-resistant influenza A viruses
circulating in the United States during the initial months of the 2005-2006
influenza season. DESIGN AND SETTING Influenza isolates collected from 26 states from October 1 through December
31, 2005, and submitted to the US Centers for Disease Control and Prevention
were tested for drug resistance as part of ongoing surveillance. Isolates
were submitted from World Health Organization collaborating laboratories and
National Respiratory and Enteric Virus Surveillance System laboratories. MAIN OUTCOME MEASURES Using pyrosequencing and confirmatory assays, we identified viruses
containing mutations within the M2 gene that are known to confer resistance
to both amantadine and rimantadine. RESULTS A total of 209 influenza A(H3N2) viruses isolated from patients in 26
states were screened, of which 193 (92.3%) contained a change at amino acid
31 (serine to asparagine S31N) in the M2 gene known to be correlated with
adamantane resistance. Two of 8 influenza A(H1N1) viruses contained the same
mutation. Drug-resistant viruses were distributed across the United States. CONCLUSIONS The high proportion of influenza A viruses currently circulating in
the United States demonstrating adamantane resistance highlights the clinical
importance of rapid surveillance for antiviral resistance. Our results indicate
that these drugs should not be used for the treatment or prophylaxis of influenza
in the United States until susceptibility to adamantanes has been reestablished
among circulating influenza A isolates.Published online February 2, 2006 (doi:10.1001/jama.295.8.joc60020).
OBJECTIVES:To distinguish characteristics of Medicare beneficiaries who will have an acute inpatient admission for sepsis from those who have an inpatient admission without sepsis, and to describe ...their further trajectories during and subsequent to those inpatient admissions.
DESIGN:Analysis of paid Medicare claims via the Centers for Medicare and Medicaid Services DataLink Project.
SETTING:All U.S. acute care hospitals, excepting federal hospitals (Veterans Administration and Defense Health Agency).
PATIENTS:Medicare beneficiaries, 2012–2018, with an inpatient hospital admission including one or more explicit sepsis codes.
INTERVENTIONS:None.
MEASUREMENTS AND MAIN RESULTS:Prevalent diagnoses in the year prior to the inpatient admission; healthcare contacts in the week prior to the inpatient admission; discharges, transfers, readmissions, and deaths (trajectories) for 6 months following discharge from the inpatient admission. Beneficiaries with no sepsis inpatient hospital admission for a year prior to an index hospital admission for sepsis were nearly indistinguishable by accumulated diagnostic codes from beneficiaries who had an index hospital admission without sepsis. Although the timing of healthcare services in the week prior to inpatient hospital admission was similar among beneficiaries who would be admitted for sepsis versus those whose inpatient admission did not include a sepsis code, the setting differedbeneficiaries destined for a sepsis admission were more likely to have received skilled nursing or unskilled nursing (e.g., nursing aide for activities of daily living) care. In contrast, comparing beneficiaries who had been free of any inpatient admission for an entire year and then required an inpatient admission, acute inpatient stays that included a sepsis code led to more than three times as many deaths within 1 week of discharge, with more admissions to skilled nursing facilities and fewer discharges to home. Comparing all beneficiaries who were admitted to a skilled nursing facility after an inpatient hospital admission, those who had sepsis coded during the index admission were more likely to die in the skilled nursing facility; more likely to be readmitted to an acute inpatient hospital and subsequently die in that setting; or if they survive to discharge from the skilled nursing facility, they are more likely to go next to a custodial nursing home.
CONCLUSIONS:Although Medicare beneficiaries destined for an inpatient hospital admission with a sepsis code are nearly indistinguishable by other diagnostic codes from those whose admissions will not have a sepsis code, their healthcare trajectories following the admission are worse. This suggests that an inpatient stay that included a sepsis code not only identifies beneficiaries who were less resilient to infection but also signals increased risk for worsening health, for mortality, and for increased use of advanced healthcare services during and postdischarge along with an increased likelihood of an inpatient hospital readmission.
OBJECTIVE:To evaluate the impact of sepsis, age, and comorbidities on death following an acute inpatient admission and to model and forecast inpatient and skilled nursing facility costs for Medicare ...beneficiaries during and subsequent to an acute inpatient sepsis admission.
DESIGN:Analysis of paid Medicare claims via the Centers for Medicare & Medicaid Services DataLink Project (CMS) and leveraging the CMS-Hierarchical Condition Category risk adjustment model.
SETTING:All U.S. acute care hospitals, excepting federal hospitals (Veterans Administration and Defense Health Agency).
PATIENTS:All Part A/B (fee-for-service) Medicare beneficiaries with an acute inpatient admission in 2017 and who had no inpatient sepsis admission in the prior year.
INTERVENTIONS:None.
MEASUREMENTS AND MAIN RESULTS:Logistic regression models to determine covariate risk contribution to death following an acute inpatient admission; conventional regression to predict Medicare beneficiary sepsis costs. Using the Hierarchical Condition Category risk adjustment model to illuminate influence of illness on outcome of inpatient admissions, representative odds ratios (with 95% CIs) for death within 6 months of an admission (referenced to beneficiaries admitted but without the characteristic) are as followsseptic shock, 7.27 (7.19–7.35); metastatic cancer and acute leukemia (Hierarchical Condition Category 8), 6.76 (6.71–6.82); all sepsis, 2.63 (2.62–2.65); respiratory arrest (Hierarchical Condition Category 83), 2.55 (2.35–2.77); end-stage liver disease (Hierarchical Condition Category 27), 2.53 (2.49–2.56); and severe sepsis without shock, 2.48 (2.45–2.51). Models of the cost of sepsis care for Medicare beneficiaries forecast arise approximately 13% over 2 years owing the rising enrollments in Medicare offset by the cost of care per admission.
CONCLUSIONS:A sepsis inpatient admission is associated with marked increase in risk of death that is comparable to the risks associated with inpatient admissions for other common and serious chronic illnesses. The aggregate costs of sepsis care for Medicare beneficiaries will continue to increase.
Transmission of Equine Influenza Virus to Dogs Crawford, P. C.; Dubovi, Edward J.; Castleman, William L. ...
Science (American Association for the Advancement of Science),
10/2005, Volume:
310, Issue:
5747
Journal Article
Peer reviewed
Molecular and antigenic analyses of three influenza viruses isolated from outbreaks of severe respiratory disease in racing greyhounds revealed that they are closely related to H3N8 equine influenza ...virus. Phylogenetic analysis indicated that the canine influenza virus genomes form a monophyletic group, consistent with a single interspecies virus transfer. Molecular changes in the hemagglutinin suggested adaptive evolution in the new host. The etiologic role of this virus in respiratory disease was supported by the temporal association of rising antibody titers with disease and by experimental inoculation studies. The geographic expansion of the infection and its persistence for several years indicate efficient transmission of canine influenza virus among greyhounds. Evidence of infection in pet dogs suggests that this infection may also become enzootic in this population.
There is need for improved human influenza vaccines, particularly for older adults who are at greatest risk for severe disease, as well as to address the continuous antigenic drift within circulating ...human subtypes of influenza virus. We have engineered an influenza virus-like particle (VLP) as a new generation vaccine candidate purified from the supernatants of Sf9 insect cells following infection by recombinant baculoviruses to express three influenza virus proteins, hemagglutinin (HA), neuraminidase (NA), and matrix 1 (M1). In this study, a seasonal trivalent VLP vaccine (TVV) formulation, composed of influenza A H1N1 and H3N2 and influenza B VLPs, was evaluated in mice and ferrets for the ability to elicit antigen-specific immune responses. Animals vaccinated with the TVV formulation had hemagglutination-inhibition (HAI) antibody titers against all three homologous influenza virus strains, as well as HAI antibodies against a panel of heterologous influenza viruses. HAI titers elicited by the TVV were statistically similar to HAI titers elicited in animals vaccinated with the corresponding monovalent VLP. Mice vaccinated with the TVV had higher level of influenza specific CD8+ T cell responses than a commercial trivalent inactivated vaccine (TIV). Ferrets vaccinated with the highest dose of the VLP vaccine and then challenged with the homologous H3N2 virus had the lowest titers of replicating virus in nasal washes and showed no signs of disease. Overall, a trivalent VLP vaccine elicits a broad array of immunity and can protect against influenza virus challenge.
Abstract Influenza virus is a highly infectious respiratory pathogen that results in severe morbidity and mortality. The current licensed trivalent vaccine formulations in the U.S. are made from ...virus grown in allantoic fluid from infected hen eggs that is then chemically inactivated and split into subunit components. These vaccines elicit antibodies, primarily to the viral hemagglutinin (HA), which are efficacious in healthy adults, but are limited in protecting high risk individuals, such as the elderly and immunocompromised. To address the need for improved influenza vaccines and the limitations of egg-based manufacturing, we have engineered an influenza virus-like particle (VLP) as a new generation of non-egg or non-mammalian cell culture-based candidate vaccine against influenza infection. VLPs, based on the A/Fujian/411/2002 (H3N2) isolate, were purified from the supernatants of Spodoptera frugiperda Sf9 insect cells following infection of baculovirus vectors encoding an expression cassette comprised of only three influenza virus structural proteins, hemagglutinin (HA), neuraminidase (NA), and matrix (M1). Mice or ferrets were vaccinated intramuscularly with VLPs in a dose sparing experiment, based on HA concentration (3 μg–24 ng), and the immune responses were compared to responses elicited in animals vaccinated with recombinant HA (rHA) or inactivated whole influenza virions (WIV). All vaccinated animals had high titer anti-HA antibodies regardless of the vaccine immunogen and animals vaccinated with the highest doses of VLPs (3 μg and 600 ng) also had antibodies against NA. Purified rHA elicited primarily IgG1 antibodies, which is indicative of a T helper (Th) type 2 response, whereas mice vaccinated with the VLPs or WIV were associated with a dominant Th1 immune response (IgG2a and IgG2b). Interestingly, VLPs elicited antibodies that recognized a broader panel of antigenically distinct H3N2 viral isolates compared to rHA or WIV in a hemagglutination-inhibition (HAI) assay.
Avian H5N1 influenza viruses currently circulating in southeast Asia could potentially cause the next pandemic. However, currently licensed human vaccines are subtype-specific and do not protect ...against these H5N1 viruses. We aimed to develop an influenza vaccine and assessed its immunogenicity and efficacy to confer protection in BALB/c mice.
We developed an egg-independent strategy to combat the avian influenza virus, because the virus is highly lethal to chickens and the maintenance of a constant supply of embryonated eggs would be difficult in a pandemic. We used a replication-incompetent, human adenoviral-vector-based, haemagglutinin subtype 5 influenza vaccine (HAd-H5HA), which induces both humoral and cell-mediated immune responses against avian H5N1 influenza viruses isolated from people.
Immunisation of mice with HAd-H5HA provided effective protection from H5N1 disease, death, and primary viral replication (p<0·0001) against antigenically distinct strains of H5N1 influenza viruses. Unlike the recombinant H5HA vaccine, which is based on a traditional subunit vaccine approach, HAd-H5HA vaccine induced a three-fold to eight-fold increase in HA-518-epitope-specific interferon-γ-secreting CD8 T cells (p=0·01).
Our findings highlight the potential of an Ad-vector-based delivery system, which is both egg-independent and adjuvant-independent and offers stockpiling options for the development of a pandemic influenza vaccine.
Virulence factors of influenza A (H5N1) viruses collected in 1997 from mammalian hosts were examined using a BALB/c mouse model. Fifteen amino acid (aa) residues in four influenza virus genes which ...correlated with high- and low-pathogenic phenotypes in mice were identified by analyzing sequence alignments. In addition to these specific residues, the effects of aa residue 627 of the PB2 gene, and the hemagglutinin (HA) and neuraminidase (NA) genes were also investigated using a reverse genetics system established with representative viruses of low (A/Hong Kong/486/97) and high (A/Hong Kong/483/97) pathogenicity for mice. None of 15 aa residues alone had any effect on virulence. The HA and NA genes had a synergistic effect on virulence and the absence of a glycosylation site at aa154 in the HA gene also increased virulence of virus. Multiple genes are involved in virulence of Hong Kong H5N1 influenza A viruses for mice with the presence of lysine at aa627 in the PB2 gene exhibiting a significantly larger effect than the HA and NA genes.
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