H7N9 Project
Avian Influenza H7N9
Winnifred Brefo-kesse
Hlth 626
April 14, 2019,
Professor Hughes
Influenza H7N9 virus is a potentially pandemic subtype to which most people are immunologically naïve. To be better prepared for the potential occurrence of an H7N9 pandemic, in 2017 the World Health Organization recommended developing candidate vaccine viruses from two new H7N9 viruses, A/Guangdong/17SF003/2016 (A/GD) and A/Hong Kong/125/2017 (A/HK). This report describes the development of live attenuated influenza vaccine (LAIV) candidates against A/GD and A/HK viruses and study of their safety and immunogenicity in the ferret model in order to choose the most promising one for a phase I clinical trial. The A/HK-based vaccine candidate (A/17/HK) was developed by classical reassortment in eggs. The A/GD-based vaccine candidate (A/17/GD) was generated by reverse genetics. Ferrets were vaccinated with two doses of LAIV or phosphate-buffered saline. Both H7N9 LAIVs tested were safe for ferrets, as shown by absence of clinical signs, and by virologic and histological data; they were immunogenic after a single vaccination. These results provide a compelling argument for further testing of these vaccines in volunteers. Since the A/HK virus represents the cluster that has caused most human cases, and because the A/HK-based LAIV candidate was developed by classical reassortment, this is the preferred candidate for a phase I clinical trial. (1) Live attenuated influenza vaccines (LAIVs) are being developed to protect humans against future epidemics and pandemics. This study describes the results of a double–blinded randomized placebo–controlled phase I clinical trial of cold–adapted and temperature sensitive H7N3 live attenuated influenza vaccine candidate in healthy seronegative adults. IAVs are classified into subtypes based on different combinations of 16 hemagglutinin (HA: H1 – H16) and 9 neuraminidase (NA: N1 – N9) surface antigens, and two pathotypes (low and high pathogenicity) based on lethality for chicken. All highly pathogenic avian IAVs known to date belong to the H5 or H7 subtype. The H7N9 viruses, a subgroup of H7 viruses that normally spread among birds have currently been found to cause human infections in China, prompting intensive research to address the challenge of a potential epidemic/pandemic. Although H7N9 family clusters have been reported in Shanghai and Shandong Province, no evidence of human-to-human H7N9 virus transmission has been found to date. Presently, there is a general lack of information about H7N9 infections, e.g., the transmission mechanism and the number of mild infections in China are unknown. Unlike H5N1, which could wipe out a flock of poultry within days, H7N9 infections in poultry are usually asymptomatic or mild. Nonetheless, based on what has been learned from the H5N1 avian flu virus which has killed 371 people in 15 countries since 2003 and proved extremely difficult to control, the risk of an H7N9 epidemic/pandemic should not be underestimated, especially in China where poultries are reared with diverse methods without strict biosecurity measures . Studies on H7N9 transmission mechanisms and clinical features/outcomes are critical to prevent and control potential H7N9 epidemic/pandemic. (4) Two doses of H7N3 LAIV or placebo were administered to 40 randomly divided subjects (30 received vaccine and 10 placebo). The presence of influenza A virus RNA in nasal swabs was detected in 60.0% and 51.7% of subjects after the first and second vaccination, respectively. In addition, vaccine virus was not detected among placebo recipients demonstrating the absence of person–to–person transmission. The H7N3 live attenuated influenza vaccine demonstrated a good safety profile and was well tolerated. The two–dose immunization resulted in measurable serum and local antibody production and in generation of antigen–specific CD4+ and CD8+memory T cells. Composite analysis of the immune response which included hemagglutinin inhibition assay, microneutralization tests, and measures of IgG and IgA and virus–specific T cells showed that the majority (86.2%) of vaccine recipients developed serum and/or local antibodies responses and generated CD4+ and CD8+ memory T cells. (2)
Another Live attenuated H7N9 influenza vaccine viruses that possess the hemagglutinin (HA) and neuraminidase (NA) gene segments from the newly emerged wild-type A/Anhui/1/2013 (H7N9) and six internal protein gene segments from the cold-adapted influenza virus A/Ann Arbor/6/60 (AA ca) were generated by reverse genetics. The reassortant virus containing the original A/Anhui/1/2013 HA and NA sequences replicated poorly in eggs. Multiple variants with amino acid substitutions in the HA head domain that improved viral growth were identified by viral passage in eggs and MDCK cells. The selected vaccine virus containing two amino acid changes (N133D/G198E) in the HA improved viral titer by more than 10-fold (reached a titer of 10(8.6) fluorescent focus units/ml) without affecting viral antigenicity. Introduction of these amino acid changes into an H7N9 PR8 reassortant virus also significantly improved viral titers and HA protein yield in eggs. The H7N9 ca vaccine virus was immunogenic in ferrets. A single dose of vaccine conferred complete protection of ferrets from homologous A/Anhui/1/2013 (H7N9) and nearly complete protection from heterologous A/Netherlands/219/2003 (H7N7) challenge infection. Therefore, this H7N9 live attenuated influenza vaccine (LAIV) candidate has been selected for vaccine manufacture and clinical evaluation to protect humans from H7N9 virus infection(3) Overall, few cases of H7 virus transmission to mammals have ever been reported in Asia and N9 virus infections in human have never been documented anywhere in the world except H7N9 . The H7N9 variants currently in circulation most likely evolved through a combination of genes from viruses in Beijing bramblings, Zhejiang ducks, and Korean wild birds according to report by Chinese scientists. Human infections with highly pathogenic H7 viruses generally resulted in conjunctivitis or uncomplicated influenza. By April 30, 2013, confirmed cases of H7N9 infections had been reported in 11 provinces across the Yangtze Delta region of Eastern, Northern, and Southeast China. A total of 126 patients have been diagnosed with H7N9 infection and 24 patients have died since the first confirmed case was reported on April 24, 2013 in Taiwan. Among the 33 patients diagnosed in Shanghai, 21 have recovered while 12 died from complications caused by the infection, as confirmed by the Shanghai Municipal Health and Family Planning Commission. The clinical features, treatment, outcomes, and other factors associated with H7N9 infection have not been reported. From April 6 to April 20, 2013, 18 H7N9-infected patients were admitted into our hospital, which is one of the designated treatment centers for H7N9 infection in Shanghai. In the present article, we reported our observations of clinical features and clinical progress in H7N9-infected patients and interpreted factors related to treatment outcomes. The information provided herein could help early screening, diagnosis, and treatment of H7N9 infection and facilitate development of strategies to prevent death. (4) In china progress were made when it came to the treatment of the virus. there. All participating patients were treated by twice daily oral administration of 75 mg oseltamivir. Patients were also given antibiotics based on blood and/or throat-swab specimens/sputum tests for bacterial infections. If no specific bacterial pathogens were detected from the specimens, advanced treatment was considered. Antibiotics given to H7N9-infected patients if applicable included moxifloxacin, sulbactam and cefoperazone, levofloxacin, meropenem, piperacillin, imipenem, and cilastatin. Some patients also received glucocorticoid therapy, intravenous immunoglobulin therapy, and TCM therapy. Only Chinese herbs prescribed according to specific syndromes were considered TCM in this study. Proprietary Chinese medicines and injections of Chinese medicines were excluded because they could contain certain western drug ingredients. These herbal TCMs were prescribed following group discussions of TCM experts from Longhua Hospital, Shanghai University of TCM, Department of TCM of Zhongshan Hospital, Fudan University, and XR Chen in our hospital. Based on syndrome differentiation criteria from Wei-Qi-Ying-Xue and clinic programs of influenza A H7N9 implemented by the National Health and Family Planning Commission of P. R. China, Yinqiao Powder and Hoisting Powder were prescribed for patients with mild syndromes and Qingwen-Baidu-Decoction was prescribed for critically ill patients. TCMs were taken orally twice daily at 150 ml decoction per dose. The purchase, decoction, and administration of Chinese herbs were supervised by Pharmacy Department of TCM in Shanghai Public Health Clinical Center. (4) Influenza virus infections pose a significant threat to public health due to annual seasonal epidemics and occasional pandemics. Influenza is also associated with significant economic losses in animal production. The most effective way to prevent influenza infections is through vaccination. Current vaccine programs rely heavily on the vaccine's ability to stimulate neutralizing antibody responses to the hemagglutinin (HA) protein. One of the biggest challenges to an effective vaccination program lies on the fact that influenza viruses are ever-changing, leading to antigenic drift that results in escape from earlier immune responses. Efforts toward overcoming these challenges aim at improving the strength and/or breadth of the immune response. Novel vaccine technologies, the so-called universal vaccines, focus on stimulating better cross-protection against many or all influenza strains. However, vaccine platforms or manufacturing technologies being tested to improve vaccine efficacy are heterogeneous between different species and/or either tailored for epidemic or pandemic influenza. (5) Vaccination remains the most efficient and cost-effective means to prevent and control influenza in human and animal populations. Vaccines rely on the effective stimulation of the immune response against the virus, mostly against the surface glycoprotein hemagglutinin (HA), the primary immunogen of influenza viruses. Influenza vaccines were a high priority for the U.S. military since the Spanish influenza pandemic of 1918–1919 when 1 in every 67 soldiers died from influenza-related infections. However, it was not until 1946 that influenza vaccines became available for the general population. Despite many advances in terms of vaccine manufacturing and production, the technology available for influenza vaccines differs little from its origins and continue to face significant shortcomings about availability and/or efficacy. (5). As you can see from this research, they have been a lot of progress that has been done when it comes to the H7N9 Influenza Viruses. Vaccines have been created and they are working on preventing the spread of the disease. Hopefully one day this virus with be a thing of the past.
References
2. Rudenko L, Kiseleva I, Naykhin AN, et al. Assessment of human immune responses to H7 avian influenza virus of pandemic potential: results from a placebo-controlled, randomized double-blind phase I study of live attenuated H7N3 influenza vaccine. PLoS One. 2014;9(2): e87962. Published 2014 Feb 12. doi: 10.1371/journal.pone.0087962
3. Chen Z, Baz M, Lu J, et al. Development of a high-yield live attenuated H7N9 influenza virus vaccine that provides protection against homologous and heterologous H7 wild-type viruses in ferrets. J Virol. 2014;88(12):7016–7023. doi:10.1128/JVI.00100-14
4. Chen X, Yang Z, Lu Y, Xu Q, Wang Q, Chen L (2013) Clinical Features and Factors Associated with Outcomes of Patients Infected with a Novel Influenza A (H7N9) Virus: A Preliminary Study. PLoS ONE 8(9): e73362. https://doi.org/10.1371/journal.pone.007336
5. Rajão DS, Pérez DR. Universal Vaccines and Vaccine Platforms to Protect against Influenza Viruses in Humans and Agriculture. Front Microbiol. 2018; 9:123. Published 2018 Feb 6. doi:10.3389/fmicb.2018.00123