Inactivated H7 Influenza Virus Vaccines Protect Mice despite Inducing Only Low Levels of Neutralizing Antibodies.

Avian influenza viruses of the H7 hemagglutinin (HA) subtype present a significant public health threat, as evidenced by the ongoing outbreak of human A(H7N9) infections in China. When evaluated by hemagglutination inhibition (HI) and microneutralization (MN) assays, H7 viruses and vaccines are found to induce lower level of neutralizing antibodies (nAb) than do their seasonal counterparts, making it difficult to develop and evaluate prepandemic vaccines. We have previously shown that purified recombinant H7 HA appear to be poorly immunogenic in that they induce low levels of HI and MN antibodies. In this study, we immunized mice with whole inactivated reverse genetics reassortant (RG) viruses expressing HA and neuraminidase (NA) from 3 different H7 viruses [A/Shanghai/2/2013(H7N9), A/Netherlands/219/2003(H7N7), and A/New York/107/2003(H7N2)] or with human A(H1N1)pdm09 (A/California/07/2009-like) or A(H3N2) (A/Perth16/2009) viruses. Mice produced equivalent titers of antibodies to all viruses as measured by enzyme-linked immunosorbent assay (ELISA). However, the antibody titers induced by H7 viruses were significantly lower when measured by HI and MN assays. Despite inducing very low levels of nAb, H7 vaccines conferred complete protection against homologous virus challenge in mice, and the serum antibodies directed against the HA head region were capable of mediating protection. The apparently low immunogenicity associated with H7 viruses and vaccines may be at least partly related to measuring antibody titers with the traditional HI and MN assays, which may not provide a true measure of protective immunity associated with H7 immunization. This study underscores the need for development of additional correlates of protection for prepandemic vaccines.IMPORTANCE H7 avian influenza viruses present a serious risk to human health. Preparedness efforts include development of prepandemic vaccines. For seasonal influenza viruses, protection is correlated with antibody titers measured by hemagglutination inhibition (HI) and virus microneutralization (MN) assays. Since H7 vaccines typically induce low titers in HI and MN assays, they have been considered to be poorly immunogenic. We show that in mice H7 whole inactivated virus vaccines (WIVs) were as immunogenic as seasonal WIVs, as they induced similar levels of overall serum antibodies. However, a larger fraction of the antibodies induced by H7 WIV was nonneutralizing in vitro Nevertheless, the H7 WIV completely protected mice against homologous viral challenge, and antibodies directed against the HA head were the major contributor toward immune protection. Vaccines against H7 avian influenza viruses may be more effective than HI and virus neutralization assays suggest, and such vaccines may need other methods for evaluation.

An extended period of elevated influenza mortality risk follows the main waves of influenza pandemics.

Understanding the extent and evolution of pandemic-induced mortality risk is critical given its wide-ranging impacts on population health and socioeconomic outcomes. We examine empirically the persistence and scale of influenza mortality risk following the main waves of influenza pandemics, a quantitative analysis of which is required to understand the true scale of pandemic-induced risk. We provide evidence from municipal public health records that multiple recurrent outbreaks followed the main waves of the 1918-19 pandemic in eight large cities in the UK, a pattern we confirm using data for the same period in the US and data for multiple influenza pandemics during the period 1838-2000 in England and Wales. To estimate the persistence and scale of latent post-pandemic influenza mortality risk, we model the stochastic process of mortality rates as a sequence of bounded Pareto distributions whose tail indexes evolves over time. Consistently across pandemics and locations, we find that influenza mortality risk remains elevated for around two decades after the main pandemic waves before more rapid convergence to background influenza mortality, amplifying the impact of pandemics. Despite the commonality in duration, there is heterogeneity in the persistence and scale of risk across the cities, suggesting effects of both immunity and socioeconomic conditions.

Novel Influenza Vaccines: From Research and Development (R&D) Challenges to Regulatory Responses.

Influenza vaccines faced significant challenges in achieving sufficient protective efficacy and production efficiency in the past. In recent decades, novel influenza vaccines, characterized by efficient and scalable production, advanced platforms, and new adjuvant technologies, have overcome some of these weaknesses and have been widely licensed. Furthermore, researchers are actively pursuing the development of next-generation and universal influenza vaccines to provide comprehensive protection against potential pandemic subtypes or strains. However, new challenges have emerged as these novel vaccines undergo evaluation and authorization. In this review, we primarily outline the critical challenges and advancements in research and development (R&D) and highlight the improvements in regulatory responses for influenza vaccines.

Pandemics Throughout the History.

As we move amidst the coronavirus disease 2019 (COVID-19) pandemic, we have witnessed tremendous distress, death, and turmoil of everyday life for more than one year now. However, they are not modern phenomena; deadly pandemics have happened throughout recorded history. Pandemics such as the plague, Spanish Flu, HIV, and Ebola caused deaths, destruction of political regimes, as well as financial and psychosocial burdens. However, they sometimes resulted in scientific discoveries. Understanding the mechanism of the emergence of these pandemics is crucial to control any spreading pandemic and prevent the emergence of a potential new one. Public health agencies need to work on improving the countries' pandemic preparedness to prevent any future pandemics. The review article aims to shed light on some of the deadliest pandemics throughout history, information of critical importance for clinicians and researchers.

Identification of a novel antiviral micro-RNA targeting the NS1 protein of the H1N1 pandemic human influenza virus and a corresponding viral escape mutation.

The influenza A virus (IAV) NS1 protein is one of the major regulators of pathogenicity, being able to suppress innate immune response and host protein synthesis. In this study we identified the human micro RNA hsa-miR-1307-3p as a novel potent suppressor of NS1 expression and influenza virus replication. Transcriptomic analysis indicates that hsa-miR-1307-3p also negatively regulates apoptosis and promotes cell proliferation. In addition, we identified a novel mutation in the NS1 gene of A(H1N1)pdm09 strains circulating in Italy in the 2010-11 season, which enabled the virus to escape the hsa-miR-1307-3p inhibition, conferring replicative advantage to the virus in human cells. To the best of our knowledge, this is the first validation of suppression of IAV H1N1 NS1 by a human micro RNA and the first example of an escape mutation from micro RNA-mediated antiviral response for the A(H1N1)pdm09 virus.

Determinant of receptor-preference switch in influenza hemagglutinin.

Influenza pandemic occurs when a new strain from other animal species overcomes the inter-species barriers and supports rapid human-to-human transmission. A critical prerequisite to this process is that hemagglutinin (HA) acquires a few key mutations to switch from avian receptors to human receptors. Previous studies suggest that H1 and H2/H3 HAs use different sets of mutations for the switch. This report shows that HA from the 1918 H1N1 pandemic virus (1918H1 HA) adopts the set of mutations used by H2/H3 HAs in receptor-preference switch when its 130-loop is made similar to those of H2/H3 HAs. Thus, the 130-loop appears to be the key determinant for the different mutations employed by pandemic H1 or H2/H3 HA. The correlation of the mutational routes and the 130-loop as unraveled in this study opens the door for efficient investigation of mutations required by other HA subtypes for inter-human airborne transmission.

Detection of pandemic strain of influenza virus (A/H1N1/pdm09) in pigs, West Africa: implications and considerations for prevention of future influenza pandemics at the source.

BACKGROUND: Human and animal influenza are inextricably linked. In particular, the pig is uniquely important as a mixing vessel for genetic reassortment of influenza viruses, leading to emergence of novel strains which may cause human pandemics. Significant reduction in transmission of influenza viruses from humans, and other animals, to swine may therefore be crucial for preventing future influenza pandemics. This study investigated the presence of the 2009 pandemic influenza A/H1N1 virus, A(H1N1)pdm09, in Nigerian and Ghanaian pigs, and also determined levels of acceptance of preventive measures which could significantly reduce the transmission of this virus from humans to pigs. METHODS: Nasal swab specimens from 125 pigs in Ibadan, Nigeria, and Kumasi, Ghana, were tested for the presence of influenza A/California/04/2009 (H1N1) by quantitative antigen-detection ELISA. A semi-structured questionnaire was also administered to pig handlers in the two study areas and responses were analyzed to evaluate their compliance with seven measures for preventing human-to-swine transmission of influenza viruses. RESULTS: The virus was detected among pigs in the two cities, with prevalence of 8% in Ibadan and 10% in Kumasi. Levels of compliance of pig handlers with relevant preventive measures were also found to be mostly below 25 and 40% in Ibadan and Kumasi, respectively. CONCLUSION: Detection of influenza A(H1N1)pdm09 among pigs tested suggests the possibility of human-to-swine transmission, which may proceed even more rapidly, considering the very poor acceptance of basic preventive measures observed in this study. This is also the first report on detection of influenza A(H1N1)pdm09 in Ghanaian pigs. We recommend improvement on personal hygiene among pig handlers, enforcement of sick leave particularly during the first few days of influenza-like illnesses, and training of pig handlers on recognition of influenza-like signs in humans and pigs. These could be crucial for prevention of future influenza pandemics.

Principales pandemias en la historia de la humanidad / Major pandemics in the history of mankind

Introducción: Se describen las principales pandemias en la historia de la humanidad desde a.n.e. hasta la más reciente causada por el coronavirus SARS-CoV-2. Objetivo: Examinar las principales pandemias en la historia de la humanidad y su repercusión en la salud pública, ámbito social y perspectivas de la actual pandemia de la COVID-19 en el desarrollo de la sociedad. Métodos: Se revisaron las publicaciones sobre el tema en español e inglés en bases de datos de PubMed, Google Scholar, SciELO y Latindex desde el 2000 hasta al 25 de mayo 2020. Resultados: Se describen los aspectos más sobresalientes de las epidemias causadas por viruela, peste bubónica, cólera, VIH/sida. gripes y la actual producida por el coronavirus SARS-CoV-2, atendiendo a su aparición, duración en años, fallecidos, localización mundial, países más afectados e impacto en la sociedad y ámbito sanitario. Se exponen las perspectivas sociales determinadas por la pandemia de la COVID-19. Conclusiones: Se examinan los rasgos sobresalientes, en especial las pérdidas de vidas humanas en las principales pandemias que han azotado a la humanidad, desde a.n.e. hasta la más reciente causada por el coronavirus SARS-CoV-2. La sociedad en su momento actual se enfrenta a incertidumbres y retos sociales, económicos, culturales, éticos, sanitarios y existenciales, provenientes de las implicaciones que está teniendo la pandemia de la COVID-19, lo que determinará consecuencias para la salud y la vida humana. Esta pandemia es mucho más que una crisis sanitaria(AU)

Introduction: This work describes the major pandemics in the history of mankind from B.C. until the most recent caused by the coronavirus SARS-CoV-2. Objective: To examine the major pandemics in the history of mankind and their impact on public health, social scopes and prospects of the current pandemic of COVID-19 in the development of mankind. Methods: There were reviewed publications on the subject in Spanish and English in databases of PubMed, Google Scholar, SciELO and Latindex from 2000 to 25 May, 2020. Results: There is a description of the most important aspects of epidemics caused by smallpox, bubonic plague, cholera, HIV/AIDS, influenzas and the current one produced by the coronavirus SARS-CoV-2, on the basis of their onsets, duration in years, amount of deceased, world location, most affected countries and impact on society and the health field. The social perspectives determined by the pandemic of COVID-19 are presented. Conclusions: There was an study on the outstanding features, especially the loss of human lives in the major pandemics that have plagued mankind, from B.C. until the most recent caused by the coronavirus SARS-CoV-2. The global society at present time is facing uncertainties and challenges of social, economic, cultural, ethical, health and existential kind coming from the implications caused by the COVID-19 pandemic, which will determine consequences for human health and life. This pandemic is much more than a health crisis(AU)

Recombinant influenza H7 hemagglutinins induce lower neutralizing antibody titers in mice than do seasonal hemagglutinins.

BACKGROUND: Vaccines against avian influenza viruses often require high hemagglutinin (HA) doses or adjuvants to achieve serological titers associated with protection against disease. In particular, viruses of the H7 subtype frequently do not induce strong antibody responses following immunization. OBJECTIVES: To evaluate whether poor immunogenicity of H7 viruses is an intrinsic property of the H7 hemagglutinin. METHODS: We compared the immunogenicity, in naïve mice, of purified recombinant HA from two H7 viruses [A/Netherlands/219/2003(H7N7) and A/New York/107/2003(H7N2)] to that of HA from human pandemic [A/California/07/2009(H1N1pdm09)] and seasonal [A/Perth16/2009(H3N2)] viruses. RESULTS: After two intramuscular injections with purified hemagglutinin, mice produced antibodies to all HAs, but the response to the human virus HAs was greater than to H7 HAs. The difference was relatively minor when measured by ELISA, greater when measured by hemagglutination inhibition assays, and more marked still by microneutralization assays. H7 HAs induced little or no neutralizing antibody response in mice at either dose tested. Antibodies induced by H7 were of significantly lower avidity than for H3 or H1N1pdm09. CONCLUSIONS: We conclude that H7 HAs may be intrinsically less immunogenic than HA from seasonal human influenza viruses.