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Concern for a pandemic caused by a newly emerged avian influenza A virus has led to clinical trials with candidate vaccines as preparation for such an event. Most trials have involved vaccines for influenza A (H5N1), A (H7N7) or A (H9N2). To evaluate dosage-related safety and immunogenicity of an inactivated influenza A (H7N7) vaccine in humans. One hundred twenty-five healthy young adults were randomized to receive two doses intramuscularly of placebo or 7.5, 15, 45 or 90 µg of HA of an inactivated subunit influenza A (H7N7) vaccine (25 per group), four weeks apart. Reactogenicity was evaluated closely for one week and for any adverse effect for six months after each dose. Serum hemagglutination-inhibiting and neutralizing antibody responses were determined four weeks after each dose and at six months. Reactogenicity evaluations indicated the vaccinations were well tolerated. Only one subject developed a ≥4-fold serum hemagglutination-inhibition (HAI) antibody response and a final titer of ≥1:40 four weeks after dose two and only five subjects developed a neutralizing antibody rise and a final titer of ≥1:40 in tests performed at a central laboratory. Four of the five were given the 45 or 90 µg HA dosage. A more sensitive HAI assay at the study site revealed a dose-response with increasing HA dosage but only 36% in the 90 µg HA group developed a ≥4-fold rise in antibody in this test and only one of these achieved a titer of ≥1:32. This inactivated subunit influenza A (H7N7) vaccine was safe but poorly immunogenic in humans. ClinicalTrials.gov NCT00546585.

Influenza virus infection triggers host innate immune response by stimulating various pattern recognition receptors (PRRs). Activation of these PRRs leads to the activation of a plethora of signaling pathways, resulting in the production of interferon (IFN) and proinflammatory cytokines, followed by the expression of interferon-stimulated genes (ISGs), the recruitment of innate immune cells, or the activation of programmed cell death. All these antiviral approaches collectively restrict viral replication inside the host. However, influenza virus also engages in multiple mechanisms to subvert the innate immune responses. In this review, we discuss the role of PRRs such as Toll-like receptors (TLRs), Retinoic acid-inducible gene I (RIG-I), NOD-, LRR-, pyrin domain-containing protein 3 (NLRP3), and Z-DNA binding protein 1 (ZBP1) in sensing and restricting influenza viral infection. Further, we also discuss the mechanisms influenza virus utilizes, especially the role of viral non-structure proteins NS1, PB1-F2, and PA-X, to evade the host innate immune responses.

H5N1, a highly pathogenic avian influenza virus, presents pandemic risks due to its ability to adapt and spread among mammalian species. Vaccination may control its spread, but the effectiveness of existing H5N1 vaccines against circulating strains, especially clade 2.3.4.4b, remains uncertain. In this study, we assess neutralizing antibody responses to global circulating H5N1 strains, using sera from individuals vaccinated with an inactivated H5N1 vaccine (NCT00535665). Neutralization is measured against 17 pseudoviruses, representing circulating and vaccine H5 strains. Our results indicate that broad protective effects are observed only when high antibody titers are achieved by vaccination. Correlation analysis estimates that a pseudovirus-based neutralization titer of at least 1:980 is required to achieve a cross-protection rate above 60%. The findings suggest that the current H5N1 vaccine can elicit cross-neutralization of circulating H5N1 strains, if high antibody titers are achieved. Until updated H5N1 vaccines are developed, this vaccine may serve as a bridging measure. Effectiveness of existing H5N1 vaccines against circulating influenza strains remains largely unknow. Here, the authors test neutralization activity of sera from individuals vaccinated with an inactivated H5N1 vaccine against 17 pseudoviruses and suggest that high vaccine-induced antibody level likely provide cross-protection against circulating H5N1 strains.

Rapid and specific detection of avian influenza virus (AIV) is urgently needed due to the concerns over the potential outbreaks of highly pathogenic H5N1 influenza in animals and humans. Aptamers are artificial oligonucleic acids that can bind specific target molecules, and show comparable affinity for target viruses and better thermal stability than monoclonal antibodies. The objective of this research was to use a DNA-aptamer as the specific recognition element in a portable Surface Plasmon Resonance (SPR) biosensor for rapid detection of AIV H5N1 in poultry swab samples. A SPR biosensor was fabricated using selected aptamers that were biotinylated and then immobilized on the sensor gold surface coated with streptavidin via streptavidin-biotin binding. The immobilized aptamers captured AIV H5N1 in a sample solution, which caused an increase in the refraction index (RI). After optimizing the streptavidin and aptamer parameters, the results showed that the RI value was linearly related (R2 = 0.99) to the concentration of AIV in the range of 0.128 to 1.28 HAU. Negligible signal ( < 4% of H5N1) was observed from six non-target AIV subtypes. The AIV H5N1 in poultry swab samples with concentrations of 0.128 to 12.8 HAU could be detected using this aptasensor in 1.5 h.

Avian influenza continues to circulate and remains a global health threat not least because of the associated high mortality. In this study antibody persistence, booster vaccine response and cross-clade immune response between two influenza A(H5N1) vaccines were compared. Participants aged over 18-years who had previously been immunized with a clade 1, A/Vietnam vaccine were re-immunized at 6-months with 7.5 μg of the homologous strain or at 22-months with a clade 2, alum-adjuvanted, A/Indonesia vaccine. Blood sampled at 6, 15 and 22-months after the primary course was used to assess antibody persistence. Antibody concentrations 6-months after primary immunisation with either A/Vietnam vaccine 30 μg alum-adjuvanted vaccine or 7.5 μg dose vaccine were lower than 21-days after the primary course and waned further with time. Re-immunization with the clade 2, 30 μg alum-adjuvanted vaccine confirmed cross-clade reactogenicity. Antibody cross-reactivity between A(H5N1) clades suggests that in principle a prime-boost vaccination strategy may provide both early protection at the start of a pandemic and improved antibody responses to specific vaccination once available. ClinicalTrials.gov NCT00415129.

The widespread incidence of H5N1 influenza viruses in bird populations poses risks to human health. Although the virus has not yet adapted for facile transmission between humans, it can cause severe disease and often death. Here we report the generation of combinatorial antibody libraries from the bone marrow of five survivors of the recent H5N1 avian influenza outbreak in Turkey. To date, these libraries have yielded >300 unique antibodies against H5N1 viral antigens. Among these antibodies, we have identified several broadly reactive neutralizing antibodies that could be used for passive immunization against H5N1 virus or as guides for vaccine design. The large number of antibodies obtained from these survivors provide a detailed immunochemical analysis of individual human solutions to virus neutralization in the setting of an actual virulent influenza outbreak. Remarkably, three of these antibodies neutralized both H1 and H5 subtype influenza viruses.

Given the high mortality rate (>50%) and potential danger of intrapersonal transmission, highly pathogenic avian influenza (HPAI) H5N1 epidemics still pose a significant threat to humans. γδ T cells, which participate on the front line of the host immune defense, demonstrate both innate, and adaptive characteristics in their immune response and have potent antiviral activity against various viruses. However, the roles of γδ T cells in HPAI H5N1 viral infection remain unclear. In this study, we found that γδ T cells provided a crucial protective function in the defense against HPAI H5N1 viral infection. HPAI H5N1 viruses could directly activate γδ T cells, leading to enhanced CD69 expression and IFN-γ secretion. Importantly, we found that the trimer but not the monomer of HPAI H5N1 virus hemagglutinin (HA) proteins could directly activate γδ T cells. HA-induced γδ T cell activation was dependent on both sialic acid receptors and HA glycosylation, and this activation could be inhibited by the phosphatase calcineurin inhibitor cyclosporin A but not by the phosphatidylinositol 3-kinase (PI3-K) inhibitors wortmannin and LY294002. Our findings provide a further understanding the mechanism underlying γδ T cell-mediated innate and adoptive immune responses against HPAI H5N1 viral infection, which helps to develop novel therapeutic strategies for the treatment of H5N1 infection in the future.

Long-distance migratory birds are often considered extreme athletes, possessing a range of traits that approach the physiological limits of vertebrate design. In addition, their movements must be carefully timed to ensure that they obtain resources of sufficient quantity and quality to satisfy their high-energy needs. Migratory birds may therefore be particularly vulnerable to global change processes that are projected to alter the quality and quantity of resource availability. Because long-distance flight requires high and sustained aerobic capacity, even minor decreases in vitality can have large negative consequences for migrants. In the light of this, we assess how current global change processes may affect the ability of birds to meet the physiological demands of migration, and suggest areas where avian physiologists may help to identify potential hazards. Predicting the consequences of global change scenarios on migrant species requires (i) reconciliation of empirical and theoretical studies of avian flight physiology; (ii) an understanding of the effects of food quality, toxicants and disease on migrant performance; and (iii) mechanistic models that integrate abiotic and biotic factors to predict migratory behaviour. Critically, a multi-dimensional concept of vitality would greatly facilitate evaluation of the impact of various global change processes on the population dynamics of migratory birds.

All known subtypes of influenza A viruses are maintained in wild waterfowl, the natural reservoir of these viruses. Influenza A viruses are isolated from a variety of animal species with varying morbidity and mortality rates. More importantly, influenza A viruses cause respiratory disease in humans with potentially fatal outcome. Local or global outbreaks in humans are typically characterized by excess hospitalizations and deaths. In 1997, highly pathogenic avian influenza viruses of the H5N1 subtype emerged in Hong Kong that transmitted to humans, resulting in the first documented cases of human death by avian influenza virus infection. A new outbreak started in July 2003 in poultry in Vietnam, Indonesia, and Thailand, and highly pathogenic avian H5N1 influenza viruses have since spread throughout Asia and into Europe and Africa. These viruses continue to infect humans with a high mortality rate and cause worldwide concern of a looming pandemic. Moreover, H5N1 virus outbreaks have had devastating effects on the poultry industries throughout Asia. Since H5N1 virus outbreaks appear to originate from Southern China, we here examine H5N1 influenza viruses in China, with an emphasis on their biological properties.

In 1997, pathogenic avian influenza A/Hong Kong/97 (H5N1) viruses emerged as a pandemic threat to human beings. A non-pathogenic variant, influenza A/Duck/Singapore/97 (H5N3), was identified as a leading vaccine candidate. We did an observer-blind, phase I, randomised trial in healthy volunteers to assess safety, tolerability, and antigenicity of MF59-adjuvanted and non-adjuvanted vaccines. 32 participants were randomly assigned MF59, and 33 non-adjuvanted vaccine. Two doses were given 3 weeks apart, of 7·5, 15, or 30 μg haemagglutinin surface-antigen influenza A H5N3 vaccine. Antibody responses were measured by haemagglutination inhibition, micro-neutralisation, and single radial haemolysis (SRH). The primary outcome was geometric mean antibody titre 21 days after vaccination. The A/Duck/SIngapore vaccines were safe and well tolerated. Antibody response to non-adjuvanted vaccine was poor, the best response occurring after two 30 μg doses: one, four, four, and one person of eleven seroconverted by haemagglutination inhibition, microneutralisation, H5N3 SRH, and H5N1 SRH, respectively. The geometric mean titres of antibody, and seroconversion rates, were significantly higher after MF59 adjuvanted vaccine. Two 7·5 μg doses of MF59 adjuvanted vaccine gave the highest seroconversion rates: haemagglutination inhibition, six of ten; microneutralisation, eight often; H5N3 SRH, ten often; H5N1 SRH, nine of ten. Geometric mean titre of antibody to the pathogenic virus, A/Hong Kong/489/97 (H5N1), was about half that to A/Duck/Singapore virus. Non-adjuvanted A/Duck/Singapore/97 (H5N3) vaccines are poorly immunogenic and doses of 7·5–30 μg haemagglutinin alone are unlikely to give protection from A/Hong Kong/97 (H5N1) virus. Addition of MF59 to A/Duck/Singapore/97 vaccines boost the antibody response to protection levels. Our findings have implications for development and assessment of vaccines for future pandemics.