Influenza Vaccines: Successes and Continuing Challenges.

Influenza vaccines have been available for over 80 years. They have contributed to significant reductions in influenza morbidity and mortality. However, there have been limitations in their effectiveness, in part due to the continuous antigenic evolution of seasonal influenza viruses, but also due to the predominant use of embryonated chicken eggs for their production. The latter furthermore limits their worldwide production timelines and scale. Therefore today, alternative approaches for their design and production are increasingly pursued, with already licensed quadrivalent seasonal influenza vaccines produced in cell cultures, including based on a baculovirus expression system. Next-generation influenza vaccines aim at inducing broader and longer-lasting immune responses to overcome seasonal influenza virus antigenic drift and to timely address the emergence of a new pandemic influenza virus. Tailored approaches target mechanisms to improve vaccine-induced immune responses in individuals with a weakened immune system, in particular older adults.

The immune response and within-host emergence of pandemic influenza virus.

Zoonotic influenza viruses that are a few mutations away from pandemic viruses circulate in animals, and can evolve into airborne-transmissible viruses in human beings. Paradoxically, such viruses only occasionally emerge in people; the four influenza pandemics that occurred in the past 100 years were caused by zoonotic viruses that acquired efficient transmissibility. Emergence of a pandemic virus in people can happen when transmissible viruses evolve in individuals with zoonotic influenza and replicate to titres allowing transmission. We postulate that this step in the genesis of a pandemic virus only occasionally occurs in human beings, because the immune response triggered by zoonotic influenza virus also controls transmissible mutants that emerge during infection. Therefore, an impaired immune response might be needed for within-host emergence of a pandemic virus and replication to titres allowing transmission. Immunocompromised individuals--eg, those with comorbidities, of advanced age, or receiving immunosuppressive treatment--could be at increased risk of generating transmissible viruses and initiating chains of human-to-human infection.

The importance of understanding the human-animal interface : from early hominins to global citizens.

The complex relationships between the human and animal species have never ceased to evolve since the emergence of the human species and have resulted in a human-animal interface that has promoted the cross-species transmission, emergence and eventual evolution of a plethora of infectious pathogens. Remarkably, most of the characteristics of the human-animal interface-as we know it today-have been established long before the end of our species pre-historical development took place, to be relentlessly shaped throughout the history of our species. More recently, changes affecting the modern human population worldwide as well as their dramatic impact on the global environment have taken domestication, agriculture, urbanization, industrialization, and colonization to unprecedented levels. This has created a unique global multi-faceted human-animal interface, associated with a major epidemiological transition that is accompanied by an unexpected rise of new and emerging infectious diseases. Importantly, these developments are largely paralleled by medical, technological, and scientific progress, continuously spurred by our never-ending combat against pathogens. The human-animal interface has most likely contributed significantly to the evolutionary shaping and historical development of our species. Investment in a better understanding of this human-animal interface will offer humankind a future head-start in the never-ending battle against infectious diseases.

Marked endotheliotropism of highly pathogenic avian influenza virus H5N1 following intestinal inoculation in cats.

Highly pathogenic avian influenza virus (HPAIV) H5N1 can infect mammals via the intestine; this is unusual since influenza viruses typically infect mammals via the respiratory tract. The dissemination of HPAIV H5N1 following intestinal entry and associated pathogenesis are largely unknown. To assess the route of spread of HPAIV H5N1 to other organs and to determine its associated pathogenesis, we inoculated infected chicken liver homogenate directly into the intestine of cats by use of enteric-coated capsules. Intestinal inoculation of HPAIV H5N1 resulted in fatal systemic disease. The spread of HPAIV H5N1 from the lumen of the intestine to other organs took place via the blood and lymphatic vascular systems but not via neuronal transmission. Remarkably, the systemic spread of the virus via the vascular system was associated with massive infection of endothelial and lymphendothelial cells, resulting in widespread hemorrhages. This is unique for influenza in mammals and resembles the pathogenesis of HPAIV infection in terrestrial poultry. It contrasts with the pathogenesis of systemic disease from the same virus following entry via the respiratory tract, where lesions are characterized mainly by necrosis and inflammation and are associated with the presence of influenza virus antigen in parenchymal, not endothelial cells. The marked endotheliotropism of the virus following intestinal inoculation indicates that the pathogenesis of systemic influenza virus infection in mammals may differ according to the portal of entry.

Putative 14th Century Outbreak of Foodborne Chagas Disease, Mexico.

A severe epidemic erupted in Coyoacán at the southern end of Lake Texcoco, in Central Mexico, around 1330. Chroniclers of the 16th century reported that after disrupted fish supply, the inhabitants of Coyoacán had suffered high morbidity and mortality. They developed edema of their eyelids, face, and feet, and hemorrhagic diarrhea. Many died, mainly the young and the old. Pregnant women miscarried. The disease is classically considered an illness of nutritional origin. However, its clinical picture and the circumstances of its emergence are remarkably consistent with an outbreak of foodborne Chagas disease, possibly acquired upon the hunting and consumption of alternative food sources, such as infected opossums (Didelphis spp.), unique reservoirs of Trypanosoma cruzi.

Spatial and temporal association of outbreaks of H5N1 influenza virus infection in wild birds with the 0 degrees C isotherm.

Wild bird movements and aggregations following spells of cold weather may have resulted in the spread of highly pathogenic avian influenza virus (HPAIV) H5N1 in Europe during the winter of 2005-2006. Waterbirds are constrained in winter to areas where bodies of water remain unfrozen in order to feed. On the one hand, waterbirds may choose to winter as close as possible to their breeding grounds in order to conserve energy for subsequent reproduction, and may be displaced by cold fronts. On the other hand, waterbirds may choose to winter in regions where adverse weather conditions are rare, and may be slowed by cold fronts upon their journey back to the breeding grounds, which typically starts before the end of winter. Waterbirds will thus tend to aggregate along cold fronts close to the 0 degrees C isotherm during winter, creating conditions that favour HPAIV H5N1 transmission and spread. We determined that the occurrence of outbreaks of HPAIV H5N1 infection in waterbirds in Europe during the winter of 2005-2006 was associated with temperatures close to 0 degrees C. The analysis suggests a significant spatial and temporal association of outbreaks caused by HPAIV H5N1 in wild birds with maximum surface air temperatures of 0 degrees C-2 degrees C on the day of the outbreaks and the two preceding days. At locations where waterbird census data have been collected since 1990, maximum mallard counts occurred when average and maximum surface air temperatures were 0 degrees C and 3 degrees C, respectively. Overall, the abundance of mallards (Anas platyrhynchos) and common pochards (Aythya ferina) was highest when surface air temperatures were lower than the mean temperatures of the region investigated. The analysis implies that waterbird movements associated with cold weather, and congregation of waterbirds along the 0 degrees C isotherm likely contributed to the spread and geographical distribution of outbreaks of HPAIV H5N1 infection in wild birds in Europe during the winter of 2005-2006.

Association between vaccine adjuvant effect and pre-seasonal immunity. Systematic review and meta-analysis of randomised immunogenicity trials comparing squalene-adjuvanted and aqueous inactivated influenza vaccines.

The immunogenicity benefit of inactivated influenza vaccine (IIV) adjuvanted by squalene over non-adjuvanted aqueous IIV was explored in a meta-analysis involving 49 randomised trials published between 1999 and 2017, and 22,470 eligible persons of all age classes. Most vaccines contained 15 µg viral haemagglutinin per strain. Adjuvanted IIV mostly contained 9.75 mg squalene per dose. Homologous pre- and post-vaccination geometric mean titres (GMTs) of haemagglutination-inhibition (HI) antibody were recorded for 290 single influenza (sub-)type arms. The adjuvant effect was expressed as the ratio of post-vaccination GMTs between squalene-IIV and aqueous IIV (GMTR, 145 estimates). GMTRs > 1.0 favoured squalene-IIV over aqueous IIV. For all influenza (sub-)types, the adjuvant effect proved negatively associated with pre-vaccination GMT and mean age. The adjuvant effect appeared most pronounced in young children (mean age < 2.5 years) showing an average GMTR of 3.7 (95% CI: 2.5 to 5.5). With increasing age, GMTR values gradually decreased towards 1.4 (95% CI: 1.0 to 1.9) in older adults. Heterologous antibody titrations simulating mismatch between vaccine and circulating virus (30 GMTR estimates) again showed a larger adjuvant effect at young age. GMT values and their variances were converted to antibody-predicted protection rates using an evidence-based clinical protection curve. The adjuvant effect was expressed as the protection rate differences, which showed similar age patterns as corresponding GMTR values. However for influenza B, the adjuvant effect lasted longer than for influenza A, possibly due to a generally later influenza B virus exposure. Collectively, this meta-analysis indicates the highest benefit of squalene-IIV over aqueous IIV in young children and decreasing benefit with progressing age. This trend is similar for seasonal influenza (sub-)types and the 2009 pandemic strain, by both homologous and heterologous titration. The impact of pre-seasonal immunity on vaccine effectiveness, and its implications for age-specific vaccination recommendations, are discussed.

Highly pathogenic avian influenza virus (H5N1) infection in red foxes fed infected bird carcasses.

Eating infected wild birds may put wild carnivores at high risk for infection with highly pathogenic avian influenza (HPAI) virus (H5N1). To determine whether red foxes (Vulpes vulpes) are susceptible to infection with HPAI virus (H5N1), we infected 3 foxes intratracheally. They excreted virus pharyngeally for 3-7 days at peak titers of 103.5-105.2 median tissue culture infective dose (TCID50) per mL and had severe pneumonia, myocarditis, and encephalitis. To determine whether foxes can become infected by the presumed natural route, we fed infected bird carcasses to 3 other red foxes. These foxes excreted virus pharyngeally for 3-5 days at peak titers of 104.2-104.5 TCID50/mL, but only mild or no pneumonia developed. This study demonstrates that red foxes fed bird carcasses infected with HPAI virus (H5N1) can excrete virus while remaining free of severe disease, thereby potentially playing a role in virus dispersal.

AIDS, Avian flu, SARS, MERS, Ebola, Zika what next?

Emerging infections have threatened humanity since times immemorial. The dramatic anthropogenic, behavioral and social changes that have affected humanity and the environment in the past century have accelerated the intrusion of novel pathogens into the global human population, sometimes with devastating consequences. The AIDS and influenza pandemics have claimed and will continue to claim millions of lives. The recent SARS and Ebola epidemics have threatened populations across borders. The emergence of MERS may well be warning signals of a nascent pandemic threat, while the potential for geographical spread of vector-borne diseases, such as Zika, but also Dengue and Chikungunya is unprecedented. Novel technologies and innovative approaches have multiplied to address and improve response preparedness towards the increasing yet unpredictable threat posed by emerging pathogens.

Periodic global One Health threats update.

Emerging infectious diseases continue to impose unpredictable burdens on global health and economy. Infectious disease surveillance and pandemic preparedness are essential to mitigate the impact of future threats. Global surveillance networks provide unprecedented monitoring data on plant, animal and human infectious diseases. Using such sources, we report on current major One Health threats and update on their epidemiological status.

Influenza: from zoonosis to pandemic.

Global surveillance and advances in vaccine technology are essential to answer the threat of influenza pandemics http://ow.ly/Yt3e4.

Self-Centric and Altruistic Unmet Needs for Ebola: Barriers to International Preparedness.

OBJECTIVE: Barriers to international Ebola preparedness may be elucidated by identifying heterogeneities in arguments to invest in countermeasures during "peace time." METHODS: For each patent family (related patent documents that differed only by limited alterations to the same invention) concerning Ebola and published until the end of 2014 the oldest patent document was analyzed. Grounded theory coding identified 5 unmet needs for (1) vaccines and therapies, (2) control of outbreaks in endemic areas, (3) detection and control of outbreaks in nonendemic areas, (4) better understanding of filoviruses, and (5) protection against bioterrorism. Odds ratios for unmet needs by geographic regions and institution types were compared by using Pearson's chi-square test. RESULTS: Statistically significant heterogeneities in unmet need profiles were found. US applicants combined self-centric and altruistic arguments, focusing on medical unmet needs and bioterrorism protection. Russian and Asian applicants emphasized self-centric motives, specifically, detection and control of nonendemic outbreaks. A clear, statistically significant mismatch between industry and academia was found: whereas industrial applicants focused on bioterrorism and neglected detection and control of nonendemic outbreaks, academic applicants did the opposite. CONCLUSIONS: This research identified heterogeneities in articulated needs between geographic regions and stakeholder types. Structural articulation of unmet needs may form the basis for attuning stakeholder engagement strategies while progression across the demand-driven value chain might necessitate international concordance. (Disaster Med Public Health Preparedness. 2016;10:644-648).

Quantifying the risk of pandemic influenza virus evolution by mutation and re-assortment.

Large outbreaks of zoonotic influenza A virus (IAV) infections may presage an influenza pandemic. However, the likelihood that an airborne-transmissible variant evolves upon zoonotic infection or co-infection with zoonotic and seasonal IAVs remains poorly understood, as does the relative importance of accumulating mutations versus re-assortment in this process. Using discrete-time probabilistic models, we determined quantitative probability ranges that transmissible variants with 1-5 mutations and transmissible re-assortants evolve after a given number of zoonotic IAV infections. The systematic exploration of a large population of model parameter values was designed to account for uncertainty and variability in influenza virus infection, epidemiological and evolutionary processes. The models suggested that immunocompromised individuals are at high risk of generating IAV variants with pandemic potential by accumulation of mutations. Yet, both immunocompetent and immunocompromised individuals could generate high viral loads of single and double mutants, which may facilitate their onward transmission and the subsequent accumulation of additional 1-2 mutations in newly-infected individuals. This may result in the evolution of a full transmissible genotype along short chains of contact transmission. Although co-infection with zoonotic and seasonal IAVs was shown to be a rare event, it consistently resulted in high viral loads of re-assortants, which may facilitate their onward transmission among humans. The prevention or limitation of zoonotic IAV infection in immunocompromised and contact individuals, including health care workers, as well as vaccination against seasonal IAVs-limiting the risk of co-infection-should be considered fundamental tools to thwart the evolution of a novel pandemic IAV by accumulation of mutations and re-assortment.

Advances in influenza vaccination.

Influenza virus infections yearly cause high morbidity and mortality burdens in humans, and the development of a new influenza pandemic continues to threaten mankind as a Damoclean sword. Influenza vaccines have been produced by using egg-based virus growth and passaging techniques that were developed more than 60 years ago, following the identification of influenza A virus as an etiological agent of seasonal influenza. These vaccines aimed mainly at eliciting neutralizing antibodies targeting antigenically variable regions of the hemagglutinin (HA) protein, which requires regular updates to match circulating seasonal influenza A and B virus strains. Given the relatively limited protection induced by current seasonal influenza vaccines, a more universal influenza vaccine that would protect against more-if not all-influenza viruses is among the largest unmet medical needs of the 21st century. New insights into correlates of protection from influenza and into broad B- and T-cell protective anti-influenza immune responses offer promising avenues for innovative vaccine development as well as manufacturing strategies or platforms, leading to the development of a new generation of vaccines. These aim at the rapid and massive production of influenza vaccines that provide broad protective and long-lasting immunity. Recent advances in influenza vaccine research demonstrate the feasibility of a wide range of approaches and call for the initiation of preclinical proof-of-principle studies followed by clinical trials in humans.

Influenza virus and endothelial cells: a species specific relationship.

Influenza A virus (IAV) infection is an important cause of respiratory disease in humans. The original reservoirs of IAV are wild waterfowl and shorebirds, where virus infection causes limited, if any, disease. Both in humans and in wild waterbirds, epithelial cells are the main target of infection. However, influenza virus can spread from wild bird species to terrestrial poultry. Here, the virus can evolve into highly pathogenic avian influenza (HPAI). Part of this evolution involves increased viral tropism for endothelial cells. HPAI virus infections not only cause severe disease in chickens and other terrestrial poultry species but can also spread to humans and back to wild bird populations. Here, we review the role of the endothelium in the pathogenesis of influenza virus infection in wild birds, terrestrial poultry and humans with a particular focus on HPAI viruses. We demonstrate that whilst the endothelium is an important target of virus infection in terrestrial poultry and some wild bird species, in humans the endothelium is more important in controlling the local inflammatory milieu. Thus, the endothelium plays an important, but species-specific, role in the pathogenesis of influenza virus infection.

The Human-Animal Interface.

The human-animal interface is as ancient as the first bipedal steps taken by humans. Born with the human species, it has grown and expanded with the human species' prehistoric and historical development to reach the unprecedented scope of current times. Several facets define the human-animal interface, guiding the scope and range of human interactions with animal species. These facets have not ceased to evolve and expand since their emergence, all the more favoring disease emergence. Placing the human-animal interface in its historical perspective allows us to realize its versatile and dynamic nature. Changes in the scope and range of domestication, agriculture, urbanization, colonization, trade, and industrialization have been accompanied by evolving risks for cross-species transmission of pathogens. Because these risks are unlikely to decrease, improving our technologies to identify and monitor pathogenic threats lurking at the human-animal interface should be a priority.

Influenza viruses: from birds to humans.

Avian influenza viruses are the precursors of human influenza A viruses. They may be transmitted directly from avian reservoirs, or infect other mammalian species before subsequent transmission to their human host. So far, avian influenza viruses have caused sporadic-yet increasingly more frequently recognized-cases of infection in humans. They have to adapt to and circulate efficiently in human populations, before they may trigger a worldwide human influenza outbreak or pandemic. Cross-species transmission of avian influenza viruses from their reservoir hosts-wild waterbirds-to terrestrial poultry and to humans is based on different modes of transmission and results in distinctive pathogenetic manifestations, which are reviewed in this paper.