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Children who have undergone SOT mount a lower immune response after vaccination with TIV compared to healthy controls. HD or SD TIV in pediatric SOT was given to subjects 3-17 yr and at least six months post-transplant. Subjects were randomized 2:1 to receive either the HD (60 μg) or the SD (15 μg) TIV. Local and systemic reactions were solicited after each vaccination, and immune responses were measured before and after each vaccination. Thirty-eight subjects were enrolled. Mean age was 11.25 yr; 68% male, 45% renal, 26% heart, 21% liver, 5% lung, and 5% intestinal. Twenty-three subjects were given HD and 15 SD TIV. The median time since transplant receipt was 2.2 yr. No severe AEs or rejection was attributed to vaccination. The HD group reported more tenderness and local reactions, fatigue, and body ache when compared to the SD cohort, but these were considered mild and resolved within three days. Subjects in the HD group demonstrated a higher percentage of four-fold titer rise to H3N2 compared to the SD group. HD influenza vaccine was well tolerated and may have increased immunogenicity. A phase 2 trial is needed to confirm. [ABSTRACT FROM AUTHOR]

Secondary bacterial pneumonia is a significant cause of morbidity and mortality during influenza, despite routine use of standard antibiotics. Antibiotic-induced immunopathology associated with bacterial cell wall lysis has been suggested to contribute to these poor outcomes. Using Streptococcus pneumoniae in a well-established murine model of secondary bacterial pneumonia (SBP) following influenza, we stratified disease severity based on pneumococcal load in the lungs via in vivo bioluminescence imaging. Ampicillin treatment cured mice with mild pneumonia but was ineffective against severely pneumonic mice, despite effective bacterial killing. Adjunctive dexamethasone therapy improved ampicillin-induced immunopathology and improved outcomes in mice with severe SBP. However, early dexamethasone therapy during primary influenza infection impaired lung adaptive immunity as manifest by increased viral titers, with an associated loss of its protective functions in SBP. These data support adjunctive clinical use of corticosteroids in severe cases of community-acquired pneumonia. [ABSTRACT FROM PUBLISHER]

Concern that a highly pathogenic virus might cause the next influenza pandemic has spurred recent research into influenza and its complications. Bacterial superinfection in the lungs of people suffering from influenza is a key element that promotes severe disease and mortality. This co-pathogenesis is characterized by complex interactions between co-infecting pathogens and the host, leading to the disruption of physical barriers, dysregulation of immune responses and delays in a return to homeostasis. The net effect of this cascade can be the outgrowth of the pathogens, immune-mediated pathology and increased morbidity. In this Review, advances in our understanding of the underlying mechanisms are discussed, and the key questions that will drive the field forwards are articulated. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Wang et al. (2011) No evidence of a link between influenza vaccines and Guillain-Barre syndrome-associated antiganglioside antibodies. Influenza and Other Respiratory Viruses 6(3), 159-166. Background Guillain-Barre syndrome (GBS) is a rare autoimmune disease characterized by acute, progressive peripheral neuropathy and is commonly associated with the presence of antiganglioside antibodies. Previously, influenza vaccination was linked with the increased incidence of GBS; however, whether antiganglioside antibodies are subsequently induced remains unresolved. Methods Sera from human subjects vaccinated with seasonal influenza vaccines from the 2007-2008, 2008-2009, or 1976-1977 influenza seasons were screened for the induction of immunity to influenza and the presence of antiganglioside antibodies pre- and post-vaccination. Likewise, sera from mice vaccinated with seasonal influenza vaccines (1988-1989, 2007-2008) or 'swine flu' pandemic vaccines (1976, 2009) were assessed in the same manner. Viruses were also screened for cross-reacting ganglioside epitopes. Results Antiganglioside antibodies were found to recognize influenza viruses; this reactivity correlated with virus glycosylation. Antibodies to influenza viruses were detected in human and mouse sera, but the prevalence of antiganglioside antibodies was extremely low. Conclusions Although the correlation between antiganglioside antibody cross-reactivity and glycosylation of viruses suggests the role of shared carbohydrate epitopes, no correlation was observed between hemagglutinin-inhibition titers and the induction of antiganglioside antibodies after influenza vaccination. [ABSTRACT FROM AUTHOR]

Background: Pandemic influenza is said to 'shift mortality' to younger age groups; but also to spare a subpopulation of the elderly population. Does one of these effects dominate? Might this have important ramifications? Methods: We estimated age-specific excess mortality rates for all-years for which data were available in the 20th century for Australia, Canada, France, Japan, the UK, and the USA for people older than 44 years of age. We modeled variation with age, and standardized estimates to allow direct comparison across age groups and countries. Attack rate data for four pandemics were assembled. Results: For nearly all seasons, an exponential model characterized mortality data extremely well. For seasons of emergence and a variable number of seasons following, however, a subpopulation above a threshold age invariably enjoyed reduced mortality. 'Immune escape', a stepwise increase in mortality among the oldest elderly, was observed a number of seasons after both the A(H2N2) and A(H3N2) pandemics. The number of seasons from emergence to escape varied by country. For the latter pandemic, mortality rates in four countries increased for younger age groups but only in the season following that of emergence. Adaptation to both emergent viruses was apparent as a progressive decrease in mortality rates, which, with two exceptions, was seen only in younger age groups. Pandemic attack rate variation with age was estimated to be similar across four pandemics with very different mortality impact. Conclusions: In all influenza pandemics of the 20th century, emergent viruses resembled those that had circulated previously within the lifespan of then-living people. Such individuals were relatively immune to the emergent strain, but this immunity waned with mutation of the emergent virus. An immune subpopulation complicates and may invalidate vaccine trials. Pandemic influenza does not 'shift' mortality to younger age groups; rather, the mortality level is reset by the virulence of the emerging virus and is moderated by immunity of past experience. In this study, we found that after immune escape, older age groups showed no further mortality reduction, despite their being the principal target of conventional influenza vaccines. Vaccines incorporating variants of pandemic viruses seem to provide little benefit to those previously immune. If attack rates truly are similar across pandemics, it must be the case that immunity to the pandemic virus does not prevent infection, but only mitigates the consequences. [ABSTRACT FROM AUTHOR]

Relatively little is known about the viral factors contributing to the lethality of the 1918 pandemic, although its unparalleled virulence was likely due in part to the newly discovered PB1-F2 protein. This protein, while unnecessary for replication, increases apoptosis in monocytes, alters viral polymerase activity in vitro, enhances inflammation and increases secondary pneumonia in vivo. However, the effects the PB1-F2 protein have in vivo remain unclear. To address the mechanisms involved, we intranasally infected groups of mice with either influenza A virus PR8 or a genetically engineered virus that expresses the 1918 PB1-F2 protein on a PR8 background, PR8-PB1-F2(1918). Mice inoculated with PR8 had viral concentrations peaking at 72 hours, while those infected with PR8-PB1-F2(1918) reached peak concentrations earlier, 48 hours. Mice given PR8-PB1-F2(1918) also showed a faster decline in viral loads. We fit a mathematical model to these data to estimate parameter values. The model supports a higher viral production rate per cell and a higher infected cell death rate with the PR8-PB1-F2(1918) virus. We discuss the implications these mechanisms have during an infection with a virus expressing a virulent PB1-F2 on the possibility of a pandemic and on the importance of antiviral treatments. [ABSTRACT FROM AUTHOR]

With the recent emergence of a novel pandemic strain, there is presently intense interest in understanding the molecular signatures of virulence of influenza viruses. PB1-F2 proteins from epidemiologically important influenza A virus strains were studied to determine their function and contribution to virulence. Using 27-mer peptides derived from the C-terminal sequence of PB1-F2 and chimeric viruses engineered on a common background, we demonstrated that induction of cell death through PB1-F2 is dependent upon BAK/BAX mediated cytochrome c release from mitochondria. This function was specific for the PB1-F2 protein of A/Puerto Rico/8/34 and was not seen using PB1-F2 peptides derived from past pandemic strains. However, PB1-F2 proteins from the three pandemic strains of the 20th century and a highly pathogenic strain of the H5N1 subtype were shown to enhance the lung inflammatory response resulting in increased pathology. Recently circulating seasonal influenza A strains were not capable of this pro-inflammatory function, having lost the PB1-F2 protein's immunostimulatory activity through truncation or mutation during adaptation in humans. These data suggest that the PB1-F2 protein contributes to the virulence of pandemic strains when the PB1 gene segment is recently derived from the avian reservoir. [ABSTRACT FROM AUTHOR]

Pneumonia occurring as a secondary infection after influenza is a major cause of excess morbidity and mortality, despite the availability and use of antibiotics active against Streptococcus pneumoniae. We hypothesized that the use of a bacteriostatic protein synthesis inhibitor would improve outcomes by reducing the inflammatory response. BALB/cJ mice infected with influenza virus and superinfected with S. pneumoniae were treated with either the cell-wall-active antibiotic ampicillin or the protein synthesis inhibitor clindamycin or azithromycin. In the model, ampicillin therapy performed significantly worse (survival rate, 56%) than (1) clindamycin therapy used either alone (82%) or in combination with ampicillin (80%) and (2) azithromycin (92%). Improved survival appeared to be mediated by decreased inflammation manifested as lower levels of inflammatory cells and proinflammatory cytokines in the lungs and by observation of less-severe histopathologic findings. These data suggest that β-lactam therapy may not be optimal as a first-line treatment for community-acquired pneumonia when it follows influenza. [ABSTRACT FROM AUTHOR]

Summary: Secondary bacterial pneumonia frequently claimed the lives of victims during the devastating 1918 influenza A virus pandemic. Little is known about the viral factors contributing to the lethality of the 1918 pandemic. Here we show that expression of the viral accessory protein PB1-F2 enhances inflammation during primary viral infection of mice and increases both the frequency and severity of secondary bacterial pneumonia. The priming effect of PB1-F2 on bacterial pneumonia could be recapitulated in mice by intranasal delivery of a synthetic peptide derived from the C-terminal portion of the PB1-F2. Relative to its isogenic parent, an influenza virus engineered to express a PB1-F2 with coding changes matching the 1918 pandemic strain was more virulent in mice, induced more pulmonary immunopathology, and led to more severe secondary bacterial pneumonia. These findings help explain both the unparalleled virulence of the 1918 strain and the high incidence of fatal pneumonia during the pandemic. [Copyright &y& Elsevier]

Background Chloroquine is an inexpensive and widely available 9-aminoquinolone used in the management of malaria. Recently, in vitro assays suggest that chloroquine may have utility in the treatment of several viral infections including influenza. Objectives We sought to test whether chloroquine is effective against influenza in vivo in relevant animal models. Methods The effectiveness of chloroquine at preventing or ameliorating influenza following viral challenge was assessed in established mouse and ferret disease models. Results Although active against influenza viruses in vitro, chloroquine did not prevent the weight loss associated with influenza virus infection in mice after challenge with viruses expressing an H1 or H3 hemagglutinin protein. Similarly, clinical signs and viral replication in the nose of ferrets were not altered by treatment. Conclusions Although in vitro results were promising, chloroquine was not effective as preventive therapy in vivo in standard mouse and ferret models of influenza virus infection. This dampens enthusiasm for the potential utility of the drug for humans with influenza. [ABSTRACT FROM AUTHOR]

The segmented genome of influenza B virus allows exchange of gene segments between cocirculating strains. Through this process of reassortment, diversity is generated by the mixing of genes between viruses that differ in one or more gene segments. Phylogenetic and evolutionary analyses of all 11 genes of 31 influenza B viruses isolated from 1979 to 2003 were used to study the evolution of whole genomes. All 11 genes diverged into two new lineages prior to 1987. All genes except the NS1 gene were undergoing linear evolution, although the rate of evolution and the degree to which nucleotide changes translated into amino acid changes varied between lineages and by gene. Frequent reassortment generated 14 different genotypes distinct from the gene constellation of viruses circulating prior to 1979. Multiple genotypes cocirculated in some locations, and a sequence of reassortment events over time could not be established. The surprising diversity of the viruses, unrestricted mixing of lineages, and lack of evidence for coevolution of gene segments do not support the hypothesis that the reassortment process is driven by selection for functional differences. [ABSTRACT FROM AUTHOR]

Secondary bacterial pneumonia is an important cause of influenza-associated death. Although antibacterial therapy is standard, antiviral therapy has been ignored because viral infections usually resolve by the time bacterial pneumonia presents. In the present study, antiviral compounds were tested in a mouse model of secondary pneumococcal pneumonia after influenza. Treatment with oseltamivir improved survival in mice from 0% to 75%, even when therapy was delayed for up to 5 days after infection with influenza virus. In mice, treatment with rimantadine had no effect on survival. Treatment with ampicillin cleared infection but, in the absence of treatment with oseltamivir, did not improve survival. Pneumonia developed in only 7 of the 22 mice receiving oseltamivir, and subsequent treatment with ampicillin resulted in cure (100% survival). Treatment of the predisposing influenza-virus infection with inhibitors specific for the viral neuraminidase may improve the efficacy of antibiotics and increase survival in persons who are at high risk for complications and mortality during influenza. [ABSTRACT FROM AUTHOR]

Viruses such as influenza suppress host immune function by a variety of methods. This may result in significant morbidity through several pathways, including facilitation of secondary bacterial pneumonia from pathogens such as Streptococcus pneumoniae. PKH26-phagocytic cell labeling dye was administered intranasally to label resident alveolar macrophages (AMs) in a well-established murine model before influenza infection to determine turnover kinetics during the course of infection. More than 90% of resident AMs were lost in the first week after influenza, whereas the remaining cells had a necrotic phenotype. To establish the impact of this innate immune defect, influenza-infected mice were challenged with S. pneumoniae. Early AM-mediated bacterial clearance was significantly impaired in influenza-infected mice: ~50% of the initial bacterial inoculum could be harvested from the alveolar airspace 3 h later. In mock-infected mice, by contrast, >95% of inocula up to 50-fold higher was efficiently cleared. Coinfection during the AM depletion phase caused significant body weight loss and mortality. Two weeks after influenza, the AM population was fully replenished with successful re-establishment of early innate host protection. Local GM-CSF treatment partially restored the impaired early bacterial clearance with efficient protection against secondary pneumococcal pneumonia. We conclude that resident AM depletion occurs during influenza infection. Among other potential effects, this establishes a niche for secondary pneumococcal infection by altering early cellular innate immunity in the lungs, resulting in pneumococcal outgrowth and lethal pneumonia. This novel mechanism will inform development of novel therapeutic approaches to restore lung innate immunity against bacterial superinfections. [ABSTRACT FROM AUTHOR]

Abstract: Background: Recent guidance from related regulatory agencies and medical societies supports mandatory vaccination of healthcare workers (HCW) against influenza. At St. Jude Children''s Research Hospital, a pediatric oncology referral center, more than 90% of HCWs receive vaccine each year without a policy mandating immunization. Factors associated with HCW uptake of influenza vaccines have not previously been evaluated in a high compliance rate setting. Methods: A structured, anonymous, electronic questionnaire was distributed in August 2010 to employees (HCW and non-HCW). Demographics, prior receipt of influenza vaccines, reasons for acceptance or refusal of seasonal and 2009 H1N1 pandemic vaccine, and attitudes on mandatory vaccination were assessed. Results: 95.0% of 925 HCWs and 63.1% of all 3227 qualifying employees responded to the survey. 93.8% and 75.2% of HCW reported receiving seasonal and 2009 H1N1 influenza vaccines, respectively, in the 2009–2010 season. Benefits to self and/or patients were cited as the most frequent reasons for accepting seasonal (83.5% and 78.3%, respectively) and 2009 H1N1 (85.9% and 81.1%, respectively) vaccination. 36.6% of HCWs opposed mandating influenza vaccination; 88.2% and 59.9% of whom reported receiving the seasonal and 2009 H1N1 influenza vaccines, respectively. Violation of freedom of choice and personal autonomy were the most frequently reported reasons for opposition. Conclusion: In this cohort of HCWs with a high influenza vaccination rate, realistic assessments of the potential benefits of vaccination appear to have driven the choice to accept immunization. Despite this, mandating vaccination was viewed unfavorably by a significant minority of vaccinated individuals. Employee concerns over autonomy should be addressed as institutions transition to mandatory vaccination policies. [Copyright &y& Elsevier]

Abstract: Vaccines directed toward individual strains of highly variable viruses like influenza lose efficacy when the circulating viruses no longer resemble the vaccine isolate. Historically, inclusion of more than one isolate per subtype of influenza has been limited by the need to include large doses of antigen with typical protein-based vaccine approaches and by concerns that an immunodominant response to one antigen will limit the response to closely related antigens. Here we provide proof of principle demonstrating that a multi-valent vaccine directed against multiple influenza A virus hemagglutinins (HAs) can elicit broad, neutralizing immunity against multiple strains within a single influenza subtype (H3). We employed a DNA vaccine to direct immunity toward the HA component alone, and a live attenuated influenza virus (LAIV) to assess immunity against the whole virus. Delivery of either HA-DNA or LAIV yielded broad protective immunity across multiple antigenic clusters, including heterologous strains, that was similar to the combined immunity of each antigen assessed separately. Priming with HA-DNA followed by an LAIV boost strengthened and broadened the antibody response toward all three H3 HAs. This prime:boost multi-valent approach was thus able to elicit immunity against multiple strains within the H3 subtype without evidence of immune interference between closely related antigens. Although the trivalent vaccine described here is not a universal vaccine, since protection was limited to circulating viruses from about a two-decade period, these data suggest that full protection within a subtype is possible using this approach with multiple antigens from current and predicted future influenza strains. [Copyright &y& Elsevier]

Abstract: Historically, vaccines developed toward influenza viruses of the B type using methodologies developed for influenza A viruses as a blueprint have not been equally efficacious or effective. Because most influenza research and public attention concerns influenza A viruses, these shortcomings have not been adequately addressed. In this manuscript, we utilized different influenza vaccine vehicles to compare immunogenicity and protection in mice and ferrets after vaccination against an influenza B virus. We report that plasmid DNA vaccines demonstrate low immunogenicity profiles and poor protection compared to either whole, inactivated influenza virus (IIV) or, live, attenuated influenza virus (LAIV) vaccines. When mixed prime:boost regimens using LAIV and IIV were studied, we observed a boosting effect in mice after priming with LAIV that was not seen when IIV was used as the prime. In ferrets LAIV induced high antibody titers after a single dose and provided a boost in IIV-primed animals. Regimens including LAIV as a prime demonstrated enhanced protection, and adjuvantation was required for efficacy using the IIV preparation. Our results differ from generally accepted influenza A virus vaccine models, and argue that strategies for control of influenza B virus should be considered separately from those for influenza A virus. [Copyright &y& Elsevier]

Background: Mouse-adapted laboratory strains of influenza virus have to be used in mouse models of synergism between influenza virus and Streptococcus pneumoniae. Since ferrets support human influenza viruses without adaptation, we sought to characterize a ferret model of synergism between influenza and pneumococcus. Methods: Pairs of ferrets were infected with either influenza virus A/Sydney/5/97 or PBS then challenged 5 days later with either pneumococcus strain D39 or PBS. Clinical and laboratory parameters were monitored during a 48-h follow-up period after the challenge. Results: Ferrets receiving influenza then pneumococcus exhibited more severe clinical signs of illness and larger increases in WBC and segmental cell counts than did ferrets receiving influenza virus or pneumococcus alone. Pneumococcal nasal wash titers were higher in ferrets infected with influenza virus followed by pneumococcus than in those infected with pneumococcus alone. Histopathologic abnormalities in lungs were mild, but differences between sequentially infected and singly infected ferrets were observed. Conclusion: A sequential infection with influenza virus and pneumococcus causes a synergistic increase in morbidity in ferrets. This ferret model will be useful for study of the interactions between non-adapted human influenza viruses and S. pneumoniae. [Copyright &y& Elsevier]

Abstract: Background: Influenza vaccination is recommended for immunocompromised patients. Methods: Children (6 months to 21 years) with cancer, HIV infection, or sickle cell disease (SCD) received 1 or 2 doses of pandemic 2009 H1N1 monovalent influenza vaccine (H1N1 MIV). Safety and tolerability, hemagglutination inhibition (HI) and microneutralization (MN) antibody titers were measured against 2009 H1N1 influenza A virus after each dose. Seroprotection (SP) and seroconversion (SC) rates were determined. Results: 103 participants were enrolled and 99 were evaluable (39 with HIV, 37 with cancer and 23 with SCD). Mean age (±SD) was 7.9 (±5.4) years for cancer participants, 18.0 (±3.5) for HIV, and 13.3 (±4.2) for SCD. 54% were males; 65% black; and 96% had received seasonal influenza vaccine. HIV-infected participants had a median CD4 count of 625cells/mm3 (range, 140–1260). 46% had an undetectable HIV viral load and 41% were perinatally infected. No participant had vaccine-related serious adverse events. None developed influenza A proven illness during the 6 months after the vaccine. Local injection reactions were reported in 29% and systemic reactions in 42% after the first dose of vaccine. SC and SP were achieved after the last dose in 48% and 52%, respectively, of participants with leukemia or lymphoma, 50% and 75% of participants with solid tumors, 63% and 92% of HIV-infected participants, and 74% and 100% of participants with SCD. Conclusion: H1N1 MIV was safe and well tolerated. H1N1 MIV resulted in an adequate immune response in children with SCD. It was only modestly immunogenic in cancer or HIV participants. [Copyright &y& Elsevier]

Abstract: Background: The safety of intranasal live-attenuated influenza vaccine (LAIV) in immunocompromised children with cancer is unknown. The objective of this study was to describe the safety and immunogenicity of LAIV in mild to moderately immunocompromised children with cancer. Methods: We conducted a multicenter, randomized, double-blind study of LAIV versus placebo in children aged 5–17 years with cancer. LAIV (frozen formulation) or allantoic fluid/buffer was administered intranasally. Reactogenicity, adverse events, blood for immune assays, and nasal swabs for viral shedding were obtained during 5 visits over the first 42 days postvaccination; information concerning serious adverse events (SAEs) was collected for 180 days. Results: 20 subjects were enrolled (LAIV, n =10; placebo, n =10) with a mean age of 12.2 years. Ten subjects had hematologic malignancy (LAIV, n =4; placebo, n =6); 10 subjects had solid tumors (LAIV, n =6; placebo, n =4). One subject was excluded from immunogenicity analysis for not receiving a full dose of LAIV. LAIV resulted in an increased incidence of runny nose/nasal congestion occurring in all LAIV recipients; no related SAEs were observed. Four of 10 LAIV recipients shed vaccine virus, with none exceeding 7–10 days duration. LAIV demonstrated modest immunogenicity by hemagglutination inhibition (≥4 fold rise for any strain, 33%) and microneutralization assays (≥4 fold rise for any strain, 44%). Conclusion: In this small pilot study conducted in mild to moderately immunocompromised children with cancer, runny nose/nasal congestion was increased in LAIV recipients, no related SAEs occurred, and prolonged viral shedding was not detected. Moderate immunogenicity was demonstrated in this small group of individuals. (ClinTrials.gov: NCT00112112). [Copyright &y& Elsevier]