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A brief review of influenza virus infection

Affiliations.

1 Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
2 Student Research Committee, Babol University of Medical Sciences, Babol, Iran.
3 Cheshire and Merseyside Health Protection Team, Public Health England North West, Liverpool, UK.
4 Scientist, Department of Analytical Biotechnology, MedImmune/AstraZeneca, Gaithersburg, Maryland, 20878, USA.
5 Department of General Medicine, Rangaraya Medical College, NTR University of Health Sciences, Vijayawada, Andhra Pradesh, India.
PMID: 33792930
DOI: 10.1002/jmv.26990

Influenza is an acute viral respiratory infection that affects all age groups and is associated with high mortality during pandemics, epidemics, and sporadic outbreaks. Nearly 10% of the world's population is affected by influenza annually, with about half a million deaths each year. Influenza vaccination is the most effective method for preventing influenza infection and its complications. The influenza vaccine's efficacy varies each season based on the circulating influenza strains and vaccine uptake rates. Currently, three antiviral drugs targeting the influenza virus surface glycoprotein neuraminidase are available for treatment and prophylaxis of disease. Given the significant burden of influenza infection globally, this review is focused on the latest findings in the etiology, epidemiology, transmission, clinical manifestation, diagnosis, prevention, and treatment of influenza.

Keywords: antiviral agents; epidemiology; influenza virus, treatment.

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Influenza viruses and coronaviruses: Knowns, unknowns, and common research challenges

Affiliations CNRS GDR2073 ResaFlu, Groupement de Recherche sur les Virus Influenza, France, CIRI, Centre International de Recherche en Infectiologie (Team VirPath), Inserm U1111, Université Claude Bernard Lyon 1, CNRS UMR5308, ENS de Lyon, Lyon, France

Affiliations CNRS GDR2073 ResaFlu, Groupement de Recherche sur les Virus Influenza, France, Inserm U1100, Research Center for Respiratory Diseases (CEPR), Université de Tours, Tours, France

Affiliations CNRS GDR2073 ResaFlu, Groupement de Recherche sur les Virus Influenza, France, IHAP, UMR1225, Université de Toulouse, ENVT, INRAE, Toulouse, France

Affiliations CNRS GDR2073 ResaFlu, Groupement de Recherche sur les Virus Influenza, France, Université Paris-Saclay, UVSQ, INRAE, VIM, Equipe Virus Influenza, Jouy-en-Josas, France

Affiliations CNRS GDR2073 ResaFlu, Groupement de Recherche sur les Virus Influenza, France, Institut de Biologie Structurale (IBS), Université Grenoble Alpes, CEA, CNRS, Grenoble, France

Affiliations CNRS GDR2073 ResaFlu, Groupement de Recherche sur les Virus Influenza, France, Swine Virology Immunology Unit, Ploufragan-Plouzané-Niort Laboratory, ANSES, Ploufragan, France

* E-mail: [email protected]

Affiliations CNRS GDR2073 ResaFlu, Groupement de Recherche sur les Virus Influenza, France, RNA Biology and Influenza Virus Unit, Institut Pasteur, CNRS UMR3569, Université de Paris, Paris, France

Olivier Terrier,
Mustapha Si-Tahar,
Mariette Ducatez,
Christophe Chevalier,
Andrés Pizzorno,
Ronan Le Goffic,
Thibaut Crépin,
Gaëlle Simon,
Nadia Naffakh

Published: December 30, 2021

https://doi.org/10.1371/journal.ppat.1010106
Reader Comments

The development of safe and effective vaccines in a record time after the emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a remarkable achievement, partly based on the experience gained from multiple viral outbreaks in the past decades. However, the Coronavirus Disease 2019 (COVID-19) crisis also revealed weaknesses in the global pandemic response and large gaps that remain in our knowledge of the biology of coronaviruses (CoVs) and influenza viruses, the 2 major respiratory viruses with pandemic potential. Here, we review current knowns and unknowns of influenza viruses and CoVs, and we highlight common research challenges they pose in 3 areas: the mechanisms of viral emergence and adaptation to humans, the physiological and molecular determinants of disease severity, and the development of control strategies. We outline multidisciplinary approaches and technological innovations that need to be harnessed in order to improve preparedeness to the next pandemic.

Citation: Terrier O, Si-Tahar M, Ducatez M, Chevalier C, Pizzorno A, Le Goffic R, et al. (2021) Influenza viruses and coronaviruses: Knowns, unknowns, and common research challenges. PLoS Pathog 17(12): e1010106. https://doi.org/10.1371/journal.ppat.1010106

Editor: Seema Lakdawala, University of Pittsburgh, UNITED STATES

Copyright: © 2021 Terrier et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The french influenza research network ResaFlu coordinated by NN is funded by the Centre National de la Recherche Scientifique (CNRS GDR 2073). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

The years 2020 to 2021 are characterized by an outstanding and worldwide research effort aimed at mitigating the Coronavirus Disease 2019 (COVID-19) pandemic, leading to >145,000 published articles and >2,900 completed or underway clinical trials ( https://www.covid-trials.org ). Experience and research work related to previous outbreaks, including the emergence of the H1N1pdm09 influenza virus in 2009, was also leveraged. As a result, safe and effective vaccines [ 1 ] as well as monoclonal antibody–based treatments [ 2 ] have been developed in less than 1 year. At the same time, the COVID-19 crisis exposed the weaknesses of our preparedness and response to pandemics and highlighted large gaps that remain in our knowledge of the biology of coronaviruses (CoVs) and influenza A viruses (IAVs), the 2 major zoonotic respiratory viruses with pandemic potential. Here, we sought to identify common challenges of influenza virus and CoV research that should be addressed in order to become better prepared for upcoming pandemics.

1. Emergence, transmission, and adaptation to humans

1.1. mapping of animal reservoirs and intermediate hosts.

Wild waterfowl are the main reservoir for IAVs, with poultry and swine being evolutionary intermediaries and possibly “mixing vessels” for the transmission to humans [ 3 ]. Human CoVs come from wild animal reservoirs as well, especially bats as in the case of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) or rodents [ 4 , 5 ]. They are thought to emerge in humans through an intermediate mammalian host, possibly domesticated or tamed or hunted, e.g., dromedary camels for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and civets for Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) [ 4 ]. However, the direct animal progenitor of SARS-CoV-2 remains elusive to date [ 6 ].

Neither the emergence of H1N1pdm09 virus nor that of SARS-CoV-2, the viruses responsible for the 2 last pandemics ( Table 1 ), were preceded by a disease outbreak in an animal population. This fits with phylogenetic data suggesting that viruses potentially “preadapted” to humans could have evolved and circulated undetected in wild or domesticated animals for years [ 7 , 8 ]. This situation, along with the genetic plasticity of IAVs and CoVs, as well as the diversity of animal species that could potentially represent prepandemic reservoirs, makes it an unrealistic goal to identify all viruses with pandemic potential before they emerge in humans.

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However, once a cluster of human zoonotic cases has been detected, the capacity to rapidly characterize the animal origin, route of transmission, and site of emergence of the pathogen is essential for informed public health decisions and early control of the outbreak. Such a capacity requires extensive and long-term surveillance data sets on the spatial and temporal dynamics of viruses in their reservoir and intermediate host species. With regard to IAVs, major progress has been achieved in recent years. Tracking of the epidemiology and evolution of highy pathogenic avian IAVs has improved due to the rise in whole genome sequencing [ 9 ] and initiatives on sharing sequencing data such as the GISAID database [ 10 ]. Genomic surveillance was integrated with the collaborative expertise of virologists, ornithologists, ecologists, and mathematical modelers to identify bird species, time periods, habitats, and geographies that are associated with increased risks of transmission to humans and therefore require an active surveillance of wild and domestic animals [ 11 , 12 ]. This approach should be further developed and extended to CoVs. Zooanthroponosis, as exemplified by the transmission of the H1N1pdm09 and SARS-CoV-2 human viruses back to animal species [ 13 , 14 ], should be closely monitored. Indeed, such spillover events can lead to the selection of variants at the time of cross-species transmission, such as SARS-CoV-2 variants isolated in mink farms from the Netherlands and Denmark, which showed amino acid substitutions in the spike protein possibly increasing its affinity for the mink angiotensin converting enzyme 2 (ACE2) receptor [ 15 ], or to the accumulation and fixation of mutations over time, as observed upon introduction of the human H1N1pdm09 virus in swine [ 16 ]. Ultimately, these events can lead to the establishment of novel animal virus lineages with subsequent risks for animal and human health [ 17 ]. To this end, taking advantage of recent developments in next generation sequencing technologies, such as the Oxford Nanopore MinION, in-field collection of genomic and metagenomic data should be intensified and combined with complementary approaches such as syndromic surveillance and serological surveys in farmed species [ 18 – 20 ].

Finally, research aiming at further understanding the molecular determinants for the host range and host switching potential of IAVs and CoVs will help identify high-risk viruses. This knowledge, together with surveillance data, should ultimately serve to feed and refine the risk assessment tools that have already been implemented for IAVs, such as the World Health Organization’s (WHO) Tool for Influenza Pandemic Risk Assessment (TIPRA) and the Centers for Disease Control and Prevention’s (CDC) Influenza Risk Assessment Tool (IRAT) [ 21 ], and adapt them to CoVs.

1.2. Understanding how selective pressures are shaping viral evolution

IAVs and CoVs harbor single-stranded RNA genomes (negative or positive sense, respectively). High mutation rates occur during replication, which allows them to evolve rapidly [ 22 , 23 ]. There is much evidence that CoVs can limit their mutation rates due to a proofreading mechanism of their polymerase [ 24 , 25 ]. However, it is unclear to what extent this proofreading mechanism is limiting CoVs diversification in an epidemiological context [ 23 , 26 ]. Both viral families also undergo evolutionary shortcuts (reassortment of genomic segments for IAVs and homologous recombination for CoVs), which may favor the emergence of pandemic viruses. For instance, the H1N1pdm09 virus was a complex reassortant harboring genomic segments of swine, avian, and human IAVs origin [ 7 ]. SARS-CoV-2 is characterized by a polybasic cleavage site in the spike glycoprotein that was possibly acquired from another bat CoV through recombination [ 27 ]. Interestingly, recurrent occurrence of short deletions are currently being observed in the spike glycoprotein of SARS-CoV-2 [ 28 , 29 ] and in the hemagglutinin glycoprotein of H1N2 swine IAVs [ 30 , 31 ].

Depending on the nature of the host barrier and the level of preexisting immunity in the human population, CoVs or IAVs transmitted from animals to humans can show different patterns of pathogenicity and human-to-human transmissibility, which will result in different evolutionary pressures acting on the viruses. For instance, the emerging SARS-CoV-2 and H1N1pdm09 IAV were both less deadly and more transmissible among humans than the SARS-CoV, MERS-CoV, and zoonotic H5N1/H7N9 IAVs, but SARS-CoV-2 and the 2009 influenza pandemic virus differed in that the mortality was the highest in people older than 70 years for the former but not the latter [ 32 ]. Improving the accuracy of phylogenetic methods that infer the evolutionary history of the emerging viruses by sequence comparison with samples derived from the reservoir and intermediate hosts (see Section 1.1) will help characterize the pattern of host species jump. For the H1N1pdm09 as well as the SARS-CoV-2 viruses, real-time monitoring of the emerging virus evolution has been a key component of the pandemic response, not only to track transmission chains and evaluate the reproductive number [ 33 , 34 ] but also to infer the spatiotemporal spread of the virus country-wide or worldwide and evaluate the efficacy of mitigation measures [ 35 , 36 ]. A major challenge is to ensure the representativeness of sequences and to improve the predictive value of data-driven mathematical models so that they accurately anticipate how the course of the pandemic will be affected by the rise of new viral variants and by the implementation of mitigation measures [ 37 , 38 ]. Another challenge in the field is to combine phylogenetic and phenotypic data (e.g., virulence, transmissibility, escape from the antibody or T-cell response), in order to better understand how selective pressures and trade-offs are shaping viral evolution at both the intra- and interhost levels. For instance, the often mentioned hypothesis that virulence and transmissibility are inversely correlated and that this trade-off determines evolutionary trajectories remain to be verified for emerging IAVs and CoVs [ 39 ]. While the H1N1pmd09 remained genetically stable several years after its emergence, it has taken less than 1 year to see SARS-CoV-2 variants with distinct phenotypes from the progeny virus emerge, possibly due to differences in the nature and effects of cross-immunity. An hypothesis is that some early SARS-CoV-2 variants may have emerged from immunocompromised patients with long-lasting infection and, possibly, treatment with plasma from convalescent patients or recombinant antibodies [ 40 ]. Which mutations are evolutionary neutral or are associated with immune escape, increased replication, or increased transmissibility remains to be fully evaluated. Mutations on the viral spike protein are best characterized so far. Notably, the N501Y mutation, shared by the 4 main variants of concern (B.1.1.7, P.1, B.1.351 and B.1.1.529), increases the spike’s affinity of the ACE2 receptor and could thereby increase transmissibility, whereas the E484K mutation, found in the P.1 and B.1.351 variants, decreases binding of neutralizing antibodies and could thereby favor immune escape (for a review, see [ 41 , 42 ]). Unraveling the evolutionary drivers of IAVs and CoVs genetic diversity will help improve policy responses as well as the design of vaccines and antiviral therapies in the future.

1.3. Investigating the mechanisms of transmission through aerosols

There is now much evidence for mid- to long-range (>2 m) airborne and direct contact transmission of IAVs and CoVs [ 43 , 44 ]. Indirect contact transmission via contaminated surfaces or objects, also called fomites, can occur according to environmental sampling data [ 43 ]. However, it remains unclear how efficiently it does occur in real-life situations [ 45 , 46 ]. By contrast, the contribution of virus aerosolization to viral dissemination in the human population has been largely documented mostly in indoor environments (e.g., [ 47 , 48 ]) and is considered less likely in outdoor conditions [ 49 ]. The contribution of aerosols to the bird-to-bird spread of highly pathogenic avian IAVs in poultry farms, with serious consequences for the poultry industry, is also of great concern [ 50 , 51 ].

Transmission via aerosols remains poorly understood and largely understudied. A traditional distinction is made between large respiratory virus-containing droplets (>5 μm) that usually fall to the ground within 2 meters and viral aerosols formed of droplets <5 μm in size, which can be transported in the air up to 70 meters [ 43 ]. This distinction has been recently challenged, as (i) droplets generated upon coughing, sneezing, talking, and breathing span a continuous range of size from 0.01 to hundreds of microns [ 52 ]; and (ii) their size can vary over time through evaporation, along with their composition and morphology [ 53 ]. There is an urgent need to investigate the processes of aerosols production, dispersion in the air, deposition on surfaces and decay, and to understand how the production, fate, and infectivity of aerosols are affected by environmental, biological, and behavioral parameters ( Fig 1 ). Studies on the effect of temperature and relative humidity [ 54 , 55 ] should be pursued and extended to other environmental parameters such as exposure to UV, chemical pollution, and ventilation. In addition, methodological advances are needed regarding aerosol sampling and monitoring [ 56 , 57 ], as well as aerosol reduction and inactivation. Finally, understanding what determines the extent to which asymptomatic individuals can transmit respiratory viruses will be essential to guide nonpharmaceutical interventions and vaccination strategies. It was established as of spring 2020 that asymptomatic SARS-CoV-2 carriers could transmit the virus [ 58 , 59 ]. This question has long been understudied for influenza viruses; however, there is a recent report that asymptomatic individuals can transmit seasonal influenza viruses to approximately 6% of household contacts [ 60 ].

Only few (mostly environmental and viral factors) have been documented so far. Multidisciplinary progress in this research field will help improve mitigation measures when a new pandemic respiratory virus emerges. Created with BioRender.com . LRT, lower respiratory tract; URT, upper respiratory tract; UV, ultraviolet.

https://doi.org/10.1371/journal.ppat.1010106.g001

The environmental persistence and dissemination of IAVs have been shown to also depend upon viral and host determinants [ 43 , 61 ]. Traits of the hemagglutinin surface protein that increase receptor binding were found to increase the efficiency of IAV transmission between mammals [ 62 , 63 ]. Similarly, changes in the spike surface protein of the SARS-CoV-2 that increase receptor binding confer a higher human-to-human transmissiblity [ 64 ]. Mutations resulting in an increased stability of the hemagglutinin were also found to increase the infectivity of viruses isolated from air exhaled by infected ferrets [ 65 ] and to increase ferret-to-ferret transmission via the aerosol route [ 62 ]. The impact of other viral features, such as the morphology of IAV and CoV particles, on aerosol transmission remains to be documented. Regarding host factors, basic questions remain unanswered such as the impact of age (children versus adults) and site of infection (upper or lower respiratory tract) on the characteristics of aerosols in terms of size distribution, chemical composition, mucus/saliva/cell content, and infectivity of the droplets. Investigations of superspreading events suggested that the nasal microbiome and respiratory coinfections could influence the airborne transmission of IAVs and SARS-CoV-2, which deserves further studies [ 66 , 67 ]. Age and obesity were found to be associated with an increased release of SARS-CoV-2–laden aerosols [ 68 ] and could possibly contribute to superspreading events along with other host and environmental conditions [ 66 ]. Epidemiological and viral shedding data suggest that obesity may play a role in influenza transmission [ 69 ], a question that could be investigated further using the recently developed obese ferret model [ 70 ]. There is evidence that host genetics can determine the susceptibility to severe influenza [ 71 ] and COVID-19 [ 72 , 73 ]. However, evidence is so far lacking for a role of host genetics in determining the route and propensity of transmission of respiratory viruses.

2. Determinants of viral load dynamics and disease severity

2.1. deciphering how the immune and inflammatory responses contribute to severe pathogenesis.

In severe influenza and COVID-19 cases, elevated systemic levels of interferons, cytokines, chemokines, and other inflammatory mediators are a major cause for fatal outcome [ 1 , 74 , 75 ]. They are usually associated with acute mononuclear/neutrophilic inflammatory infiltration in the lower respiratory tract and with diffuse alveolar damage, which impair gas exchange and blood oxygenation. In addition, patients with severe COVID-19 show vascular damage and thrombosis according to autopsy findings [ 76 ] and dysregulated function of T cells [ 77 , 78 ]. Uncovering the multiple and complex mechanisms that control the innate and adaptative responses to viral infection is paramount for the design of effective and safe immunomodulatory therapies (see Section 3.1). The hyperinflammatory profiles of influenza and COVID-19 patients show similarities, e.g., high serum levels of interleukin (IL)-6 and tumor necrosis factor (TNF) alpha, and also exhibit distinct features. Elevated levels of IL-18 or IFN-gamma are specifically and most prominently observed in COVID-19 or influenza patients, respectively [ 79 , 80 ]. Findings in COVID-19 patients still need to be consolidated. However, there is strong evidence that a hallmark of severe COVID-19 infection is a delayed type I/III interferon response [ 81 ]. It remains to be fully understood which molecules play a critical role in disrupting the balance between viral clearance and collateral lung damage and are good correlates of disease severity. Serum levels may not accurately reflect the production of inflammatory molecules in the lower respiratory tract. Therefore, it is important to study the viral-induced immunopathology in the lung-specific microenvironment. COVID-19 has highlighted the major contribution of lung endothelial cells to pathogenesis [ 82 ]. There is growing evidence that lung epithelial and mesenchymal cells are also playing a regulatory role in the response to viral infections (reviewed in [ 83 ]). A challenge will be to further define the role of cell-to-cell heterogeneity within each cell type through single-cell studies [ 84 , 85 ]. Another challenge will be to identify and integrate the multiple cellular pathways that control the cellular response to viral infection. Interestingly, there is increasing evidence for a cross-talk between metabolism and hyperinflammation [ 86 , 87 ]. In line with these observations, obesity and diabetes are associated with a higher risk of developing a severe form of COVID-19 and influenza pneumonia [ 88 – 90 ].

Viral and host genetic determinants of the immune response remain largely unknown. Specific mechanisms evolved by highly pathogenic IAVs and CoVs to counteract the type I interferon response have been described [ 91 , 92 ]. Loss-of-function mutations in interferon induction or signaling genes, or the presence of autoantibodies with interferon neutralizing activity, predispose patients to severe COVID-19 [ 93 , 94 ] or severe influenza [ 95 ]. An initiative for genome-wide mapping of host genetic factors associated with COVID-19 was launched recently [ 96 ] and would deserve to be extended to influenza disease.

2.2. Elucidating the mechanisms for extrapulmonary tropism and/or complications

Although SARS-CoV-2 infection affects primarily the respiratory tract, many extrapulmonary dysfunctions have been reported in severe COVID-19 patients, especially in the central nervous system (CNS), kidney, liver, gastrointestinal tract, and cardiovascular system [ 97 , 98 ]. The most commonly reported extrapulmonary dysfunctions in influenza patients affect the CNS and the cardiovascular system [ 99 ]. A vast majority of published observations focus on emerging zoonotic (SARS-CoV, MERS-CoV, and highly pathogenic IAVs of the H5 or H7 subtypes) and pandemic (SARS-CoV-2 and H1N1pdm09) viruses. The extent to which infections with seasonal viruses can lead to extrapulmonary complications might be underappreciated. One of the most prominent extrapulmonary symptoms associated with SARS-CoV-2 is anosmia [ 100 ], a feature also observed during influenza virus infections, but to a lesser extent [ 101 ]. Olfactory dysfunctions are related to the tropism of both viruses for the olfactory epithelium. Infection of the olfactory epithelium induces direct (replication) or indirect (inflammation) damage to olfactory neurons, leading to anosmia [ 102 , 103 ]. In the case of long-term persistence of anosmia post-COVID-19, an anterograde propagation of the virus to the olfactory bulb and CNS is suspected [ 104 ]. Influenza-associated encephalopathies are reported with a relatively high incidence in Japan, which could be due to more reporting and/or to a genetic predisposition [ 99 , 105 ].

The mechanisms underlying extrapulmonary manifestations remain largely unknown. One of the proposed mechanisms is direct tissue damage caused by IAV or CoV infection as there is evidence that the viral receptors (sialic acids and ACE2, respectively) and transmembrane protease serine 2 (TMPRSS2) protease, which cleaves the surface glycoproteins (hemagglutinin and Spike, respectively), both required for viral entry, are expressed at extrapulmonary sites [ 106 , 107 ]. Immunohistochemistry detection of viral nucleic acids or antigens in extrapulmonary tissues has been reported on autopsy samples and in animal models [ 99 , 108 , 109 ]. However, the robustness and clinical relevance of these findings remains debatable. Moreover, there is no strong evidence for viremia in COVID-19 or influenza patients, so the mechanisms for extrapulmonary spread of infectious viruses, if any occurs, remain unclear. There is evidence for influenza virus CNS invasion via retrograde axonal transport in the olfactory nerve in an immunocompromised child [ 110 ] and in animal models [ 108 ]. Whether CoVs and in particular SARS-CoV-2 could use this route of neuroinvasion remains unclear [ 102 , 103 , 111 ].

Beyond direct viral toxicity, other proposed mechanisms for extrapulmonary pathology include dysregulation of the immune response and endothelium inflammation and damage [ 97 , 99 , 112 ]. It is important to determine to what extent viral replication, and possibly viral persistence, can occur outside the lung, to understand organ-specific pathophysiologies and to identify the viral and host (e.g., age, sex, comorbidities, and genetic traits) determinants involved. This knowledge is needed to improve therapeutic interventions not only during the acute phase of disease, but also in the longer term in patients that experience post-acute syndromes [ 113 ].

2.3. Tackling the burden of bacterial coinfections and rethinking antimicrobial stewardship

Bacterial coinfections and secondary infections are detected in severe influenza patients with a high frequency (11 to 35% in most studies) and are a major cause of morbidity and mortality [ 114 ]. Most reports indicate they are detected only in low proportions in severe COVID-19 patients [ 115 – 117 ], although there are contradictory observations [ 118 ]. For instance, the proportion was 2.3% in a large multicentre prospective cohort of patients hospitalized during the first wave of the pandemic in the United Kingdom [ 117 ]. Different biases may have led to underestimation of bacterial coinfections in COVID-19 patients, including the accelerated patient flow, lack of microbiological diagnosis, effect of barrier measures, and, possibly, high antibiotic use. Whether and how bacterial infections affect the outcome of COVID-19 remains unclear so far [ 117 , 119 ]. It is essential to extend the clinical and basic knowledge in this field, especially as there is evidence that treatments targeting immune and inflammatory responses (e.g., corticosteroids and IL-6 inhibitors) could increase the risk of bacterial superinfections [ 120 , 121 ].

The mechanistic understanding of how respiratory virus infections can favor bacterial superinfection needs to be improved. Multiple mechanisms have been described in the case of influenza infections, including facilitation of the attachment of bacteria to the bronchopulmonary epithelium, impairment of the respiratory ciliary function, and alterations of the innate immune responses (reviewed in [ 122 , 123 ]). Bacteria recovered in influenza and COVID-19 patients are mostly gram-positive and gram-negative, respectively, suggesting that distinct mechanisms could be involved. However, the lung barrier damage resulting from interferon-λ signaling upon viral infection was recently proposed to cause increased susceptibility to bacterial superinfections in both influenza virus and SARS-CoV-2-infected mice [ 124 , 125 ]. There is growing evidence for bidirectional interactions between respiratory viruses and bacteria and for a complex interplay with the microbiome and the immune system [ 122 , 126 ]. So far, the mechanisms of copathogenesis have been investigated mostly in animal models. They remain to be explored in humans and to be taken into consideration in the development of clinical practices.

A shared concern regarding management of influenza and COVID-19 infections is the overuse of antibiotics (e.g., [ 127 , 128 ]), which might contribute to the emergence of multiantibiotic-resistant strains. An important challenge is therefore to rethink antibiotic stewardship and guidelines, to promote more systematic, early and rapid microbiological diagnostic approaches on admission to hospital, and to consider less empirical and more tailored treatments for each patient presentation.

3. Virus- and host-targeted therapies, vaccine development

3.1. developing novel host-directed therapies.

De novo drug development is notoriously a slow, expensive, and uncertain process. Drug repurposing, i.e., using a drug that has been validated as toxicologically safe and approved for another indication, represents a potentially time- and cost-effective strategy, especially in the context of pandemic response. However, this strategy has so far not led to the identification of any effective prophylactic or therapeutic treatment upon emergence of SARS-CoV-2 [ 129 ], with the exception of dexamethasone [ 130 ] and IL6 receptor blockers [ 131 ]. Successful drug repurposing against emerging respiratory viruses will require a better exploration of the drugs’ pharmacological and biodistribution properties and their suitability for lung delivery [ 132 ]. Being able to reliably evaluate which molecules are likely or unlikely to treat respiratory infections within approved therapeutic windows would allow to screen more effectively a larger proportion of the pharmacopeia. Developing formulations and/or delivery procedures distinct from the approved ones would minimize but not totally abrogate the benefits of repurposing over de novo drug design.

Host-directed therapies, which target host proteins essential for the viral life cycle and/or pathogenesis instead of viral proteins, can in principle provide the advantage of broad-spectrum efficacy and reduced antiviral resistance and can rely on the repurposing of approved drugs [ 133 ]. Immunomodulatory therapies hold particular promises for treating severe cases of influenza disease or COVID-19, which are frequently associated with an excessive and/or imbalanced release of pro-inflammatory cytokines and chemokines [ 1 , 81 , 134 ]. Regarding immunomodulatory treatment of the cytokine storm in severe influenza, published data based on randomized controlled trials are limited, and the efficiency of immunomodulatory therapy is still under debate [ 134 ]. Various immunomodulatory treatments, including corticosteroids, interferons, antagonists of the IL-1 or -6 receptors, or Janus kinase inhibitors, have been assessed clinically in severe COVID-19 patients with contrasting results (reviewed in [ 135 ]). Immunomodulatory drugs can delay viral clearance if administered prematurely and can also affect the course of tissue repair [ 83 ]. Therefore, a major challenge is not only to identify the most relevant immunomodulatory pathways but also to establish the optimal timing of intervention during the course of the disease. Drugs having immunoregulatory as well as antiviral activities might show the strongest benefits.

The combination of host-directed and/or conventional antivirals is an additional avenue of research, as it can potentially result in synergistic effects and prevent antiviral resistance [ 136 – 138 ]. In a randomized clinical trial on hospitalized adults with COVID-19, the combination of baricitinib and remdesivir was found to reduce the recovery time and to limit serious adverse events [ 139 ]. However, drug combination therapy remains a challenging approach, as not only the drugs biological activity but also their pharmacokinetics, biodisponibility, and mode of delivery have to be addressed in order to optimize synergistic effects.

3.2. Leveraging cutting-edge technologies in structural biology and computational tools to develop highly potent antivirals

Structural biology plays a major role in drug development. Knowledge of the tridimensional (3D) structure of a target protein bound with a first ligand provides information that allows to design chemical modifications in order to improve the affinity of the ligand for the target and its biological activity, through iterative cycles of costructure determination/chemical optimization. Influenza was one of the first infectious diseases for which a rationale structure-based design of inhibitors led to the marketing of a drug [ 140 ]. More than 15 years of development were required between determination of the viral neuraminidase X-ray structures of IAV in 1983 and influenza B virus in 1992 [ 141 , 142 ] and the Food and Drug Administration (FDA) approval of the first neuraminidase inhibitors Relenza and Tamiflu in 1999 [ 143 ] ( Fig 2 ). Almost 10 years separate the X-ray structure of the influenza polymerase endonuclease domain [ 144 ] and FDA approval of the endonuclease inhibitor Xofluza in 2018 [ 145 ]. A significant breakthrough occurred in the mid-2010s when new generation detectors enabled a tremendous expansion of the electron microscopy (EM) techniques. Cryo-EM does not depend on protein crystal formation and can unveil the flexibility inherent to the different conformational states of large complexes in the sample. As a result, the number of available 3D structures has been growing explosively, even for large or difficult-to-crystallize proteins such as membrane proteins: >600 structures of influenza virus proteins have been deposited in the Protein Data Bank between 2015 and mid-2021 and >1,200 structures of SARS-CoV-2 proteins in only 1.5 year ( Fig 2 ). For instance, cryo-EM has allowed to visualize the conformational dynamics of IAV polymerase during the complete transcription cycle [ 146 ], IAV hemagglutinin along the process of membrane fusion [ 147 ], and SARS-CoV-2 spike protein at the surface of virions [ 148 ], thus increasing the mechanistic understanding of these proteins and opening new avenues for antiviral strategies. Cryo-EM was used to solve the structure of several SARS-CoV-2 proteins complexed with ligands (e.g., [ 149 , 150 ]). To date, X-ray crystallography and NMR still remain more suitable than cryo-EM for the high-throughput screening of small molecules libraries, an approach that was recently undertaken to identify inhibitors of SARS-CoV-2 main protease [ 151 ]. The field will benefit from further improvements of cryo-EM in terms of resolution and speed of data acquisition/processing and from the development of emerging structural biology and microscopy methods that allow to capture dynamic processes at the sub-nanoscale resolution and, for some, in native conditions [ 152 , 153 ].

The number of 3D structures available in the Protein Data Bank ( https://www.rcsb.org , 17 October 2021) for each of the indicated category of viral proteins has been recorded separately for the 1981 to 2014 and the 2015 to 2021 period (the latter corresponding to an extended use of new generation detectors and cryo-EM, gray background). SARS-CoV-2 protein structures were counted separately (inset on the right). The years when the Relenza, Tamiflu and Xofluza inhibitors were approved by the FDA are indicated. RdRp, RNA-dependent RNA polymerase: PB1, PB2, and PA proteins of influenza viruses; nsp7, nsp8, nsp10, nsp12, and nsp14 proteins of corona viruses. Proteases: nsp3 and nsp5. * corresponds to the publication years of the first HA and NA X-ray structure, which preceded by several years their deposition in the PDB. HA, hemagglutinin; NA, neuraminidase; S, Spike; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2.

https://doi.org/10.1371/journal.ppat.1010106.g002

Efforts to push further the current limits of structural biology techniques need to be backed up by advances in other disciplines, e.g., protein chemistry expertise for sample preparation, protein-structure prediction tools, and computational chemistry tools. The artificial intelligence program named AlphaFold represents a considerable leap in accurately predicting the 3D structure of proteins from their amino acid sequence [ 154 ]. Combined with extensive next generation sequencing, it will guide drug discovery and help understand the biological significance of amino acid variations, in particular in the context of a viral pandemic. Advanced computational and machine learning methods should also help improve the performance of in silico docking programs, whose limitations have been highlighted by the COVID-19 pandemic [ 155 ].

3.3. Developing improved vaccines with well-defined correlates of protection

Influenza vaccines have been administered each year since the 1940s to protect against seasonal influenza epidemics. Despite recent advances such as the development of live attenuated vaccines, current vaccines still show major limitations [ 156 ]. It has become a public health priority to develop next generation universal influenza vaccines capable to provide a more durable and broader protection, ideally against drifted seasonal viruses as well as against zoonotic or pandemic viruses of any subtype. Several approaches that target conserved regions of the virus such as the hemagglutinin stalk, or stimulate T cell–mediated immune responses, are currently in preclinical development [ 157 , 158 ]. Other strategies to improve vaccine effectiveness include a better understanding and forecasting of viral evolution, the optimization of neuraminidase content, the use of novel adjuvants, and the development of more efficient, nucleic acid–based, vector-based, or recombinant protein–based production platforms [ 158 , 159 ]. Computation- or structure-based design of the hemagglutinin antigens and nanoparticle display are being used to enchance vaccine immunogenicity [ 160 , 161 ]. The first Phase I clinical trial of a quadrivalent influenza nanoparticle vaccine candidate was launched by the National Institute of Health in June 2021 ( https://bit.ly/2Ua0Lw3 ).

In contrast to influenza, no vaccine has ever been approved for the prevention of seasonal human CoV infection. However, vaccines are widely used to prevent CoV infections in domestic animal species such as cats, swine, cattle, and poultry, although their effectiveness is limited by a short duration of vaccine-induced immunity and by genetic drifting of the circulating viral strains [ 162 ]. Knowledge gained from CoV veterinary vaccines and the initial development of vaccines for SARS-CoV and MERS-CoV, combined with tremendous research efforts, led to the development, trial, and approval of several safe and effective vaccines against SARS-CoV-2 within 12 months [ 1 , 163 ]. Along with more traditional vaccine platforms, the mRNA vaccine platforms from BioNtech/Pfizer and Moderna, previously developed for cancer treatment and viral vaccines (e.g., Zika vaccine), were among the first to reach Phase I clinical trial and to be approved. mRNA vaccines now appear as a technology of choice in the context of pandemic response, owing to its simple and flexible manufacturing process and its safety profile [ 164 ]. Multiplexed chimeric spike mRNA vaccines could possibly offer broad-range protection against SARS-like CoV infection [ 165 ]. Several companies have started to develop an mRNA-based influenza vaccine. However, a number of challenges remain to be addressed. The determinants of mRNA vaccine efficacy and tolerability need to be better understood [ 166 ], while the cost-effectiveness of the manufacturing process and long-term storage stability still need to be improved [ 167 ].

For the ongoing development of universal influenza vaccines and improved COVID-19 vaccines, a key research area is the identification of good immune correlates of protection (CoP), which might then be used as a proxy of vaccine efficacy. The serum hemagglutination inhibition (HAI) antibody titer has been largely used as a CoP for influenza vaccines. However, its relevance and robustness to predict vaccine performance, especially for new universal vaccines, are subject to debate. Other potential immune CoP, such as CD8 + and CD4 + T-cell counts, interferon gamma-secreting cells counts, neuraminidase inhibition titers, nasal IgA or hemagglutinin-stalk antibodies titers, are currently under investigation [ 168 , 169 ]. In the case of SARS-CoV-2, epidemiological studies and studies of vaccine-induced immunity in nonhuman primates identified neutralizing antibodies as a CoP (e.g., [ 170 , 171 ]). The ongoing large-scale vaccination campaigns should allow the monitoring of multiple immune readouts and their analysis for CoP, which hopefully will facilitate the optimization of vaccine dose and schedule in the future. As with influenza viruses, a global monitoring of genetic and antigenic changes that occur in circulating SARS-CoV-2 viruses will be required to inform whether updating of the vaccine is required [ 172 ]. Finally, a number of important social issues, including vaccine hesitancy, vaccine equity, and access to vaccination in low-to-middle income countries, still remain to be tackled.

Conclusions

Although influenza viruses and CoVs differ in many ways, several challenging research issues are common to both. It is very likely that synergies and cross-fertilizing ideas between influenza and CoV research will occur in the coming years. There is a “challenge in the challenge” for most of the topics addressed above: the development of physiologically relevant cellular and animal models ( Fig 3 ). The cell lines that are widely used in influenza and CoV research (e.g., MDCK, Vero-E6, and A549) bear very little resemblance to the human respiratory epithelium, which can compromise the relevance and applicability of the findings. The use of primary cells, induced human pluripotent stem cells, and 3D lung-on-a-chip or organoid cultures should be facilitated and developed, to provide more accurate models for the differentiated respiratory epithelium or the microanatomy of the lung [ 173 ]. Likewise, it is crucial to set up animal models that mimic more closely the physiopathology in human patients and can provide reliable information for fundamental research as well as preclinical testing of therapeutic and vaccine candidates [ 106 , 174 ].

An estimation of the performance to the criteria indicated on the left is provided with the following color code: dark blue (very good), light blue (good), orange (poor), red (very poor), gray (not documented), no color (irrelevant). a All transmission routes including aerosol and direct contact routes. b NHP have been very rarely used in transmission studies; however, it was reported that H1N1pdm09 influenza viruses can efficiently transmit between marmosets [ 177 ]. 2D/3D, two- or three-dimensional; HAE, human airway epithelium; Hu mice, humanized mice (refers to mice grafted with human immune cells in the case of IAV and to mice grafted with human lung tissue in the case of SARS-CoV-2); IAV, influenza A virus; NHP, nonhuman primate; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; Tg mice, transgenic mice.

https://doi.org/10.1371/journal.ppat.1010106.g003

Each of the research topics mentioned above presents a breadth and level of complexity that call for synergies and multidisciplinary approaches. For instance, progress in understanding the complexity of airborne transmission will require a multidisciplinary approach that combines virology and clinical medicine with aerobiology, biophysics, chemistry, mathematical modeling, and engineering. Cooperation will also be required outside the field of life sciences, e.g., with regulators and manufacturers for the development of novel vaccines and with the socioeconomics and humanities fields when it comes to vaccine acceptance or to the impact of human behavior (such as deforestation, intensive farming, consumption and trade of wild animals, or global traveling) on the risk of zoonotic viral emergences.

Finally, the global research ecosystem needs to be strengthened by consolidating and connecting to each other existing networks of expertise and by promoting rapid and effective data sharing through the establishment of flexible platforms and rigorous guidelines.

Acknowledgments

We thank Hubert Laude (INRAE, Jouy-en-Josas), Rob Ruigrok (IBS, Grenoble), Sylvie van der Werf, Etienne Simon-Lorière, Hélène Strick-Marchand and Catherine Isel (Institut Pasteur, Paris), and François Ferron (AFMB, Université Aix-Marseille) for discussions and insightful comments on the manuscript. We apologize for not being able to cite all available literature owing to space limitations.

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Influenza Basic Research

NIAID has a longstanding commitment to conducting and supporting the basic research necessary to understand how influenza strains emerge, evolve, infect and cause disease (called pathogenesis) in animals and humans. Results from this research are used to inform the design of new and improved influenza vaccines, diagnostics and antiviral drugs to treat flu infection.

Influenza is challenging for scientists to study because there are hundreds of strains that are classified into four main categories: A through D, though D is not known to infect people. Influenza A virus is the group that most commonly causes illness in humans and is the source of all of the major influenza pandemics in modern history. This type can drift and shift through birds and animals, meaning it emerges with rearranged surface proteins that create different strains of the virus.

The surface proteins that combine in different ways to create an assortment of influenza virus type A strains are called hemagglutinin (HA) and neuraminidase (NA). Hemagglutinin enables the flu virus to enter a human cell and initiate infection; neuraminidase allows newly formed flu viruses to exit the host cell and multiply throughout the body. There are 18 types of HA and 11 types of NA, leaving the possibility for dozens of different subtypes of influenza A viruses (such as H1N1, H3N2, H5N8, and H7N9) and strains (such as 1918 H1N1 influenza and 2009 H1N1 flu).

Some of the specific questions about influenza that basic science researchers explore include how strains of viruses differ from each other by gene structure; how viruses can defeat the immune system to cause disease; how some viruses can transmit from person to person; and how some treatments and vaccines effectively prevent or minimize infection.

Specific examples of NIAID influenza basic research include:

Trying to determine if hyperimmune plasma – the liquid component of blood that contains antibodies to help to clear the virus from the body – is an effective treatment against influenza, specifically for patients at high risk for developing severe disease. Similar work is exploring the use of hyperimmune immunoglobulin (purified antibodies).
Developing human and animal models to observe how influenza virus enters a host – and documenting the specific processes that occur and the structures within the virus and the host that contribute to infection. Then, similar to reading a road map, scientists try and introduce biological “detours” to both avoid a route to infection (preventive vaccination) and improve recovery time from infection (therapeutic treatment).
Studying the relationship between influenza and co-infection with bacteria, such as Staphylococcus aureus or Streptococcus pneumoniae . Influenza can lead to viral and bacterial pneumonia (most deaths attributed to influenza virus are caused by pneumonia). The studies use an animal model to assess damage to the lungs and the amount of oxygen reaching the bloodstream. This approach will help researchers assess the effectiveness of new vaccines and therapeutics at stopping disease.
Exposing healthy volunteers under carefully controlled and monitored conditions to influenza A viruses. These types of challenge studies provide critical information as to how the flu develops and persists and how humans fight infection. This information is key to establishing more rapid, cost-effective clinical trials for new influenza medicines or for determining the efficacy of candidate vaccines for preventing seasonal or pandemic influenza.
Characterizing historic influenza A viruses to compare and understand their genetic traits to learn why some influenza virus strains of the same subtype are more severe than others. For example, 1918 H1N1 flu killed an estimated 675,000 people in the United States and was much more severe than the 2009 H1N1 influenza. Both of these virus strains are considered pandemic because they circulated around the world. After successfully sequencing the 1918 H1N1 virus in 2005, scientists are now working on the same project for influenza A viruses that circulated in the decade before and after 1918. They are hoping the comparisons will help them understand the biological scenario that allowed the deadly 1918 strain to emerge and what has happened to that virus since 1918. One goal is to help global leaders plan for the next H1N1 subtype that could cause severe disease in people and become a pandemic.
Examining common influenza vaccination practices in an effort to develop more effective vaccines. For example, one study is exploring whether suppressing neuraminidase could have a more significant role in establishing immunity; most influenza vaccines focus on limiting concentrations of hemagglutinin. Another study is examining influenza virus epitopes – the precise locations on the HA protein where antibodies bind to prevent infection. Little is known about relationships between epitope display and vaccine effectiveness, though researchers are using specialized electron microscopy and computational analyses to build three-dimensional models to predict how and where antibodies bind to epitopes. Scientists believe that a better understanding of the molecular architecture of epitopes will help them develop more effective vaccines.
Understanding why influenza replication is higher in some people to develop strategies to prevent disease and viral spread. A March 2016 study found that estrogen provides women, but not men, extra protection from influenza. Researchers showed how estrogen affects the ability of the influenza virus to replicate in nasal cells and why the antiviral effect is more robust in women. The results suggest that pre-menopausal or post-menopausal women who do not produce estrogen could benefit from hormone replacement during influenza season.

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New Hampshire resident dies after infection by mosquito-borne encephalitis virus

FILE — A Cattail mosquito is held up for inspection Wednesday, Sept. 8, 2010, at the Maine Medical Center Research Institute, in South Portland, Maine. (AP Photo/Pat Wellenbach, File)

A New Hampshire resident infected with the mosquito-borne eastern equine encephalitis virus has died, state health authorities said.

The Hampstead resident’s infection was the first in the state in a decade, the New Hampshire Department of Health and Human Services said Tuesday. The resident, whom the department only identified as an adult, had been hospitalized due to severe central nervous system symptoms, the department said.

About a third of people who develop encephalitis from the virus die from the infections, and survivors can suffer lifelong mental and physical disabilities. There is no vaccine or antiviral treatment available for infections, which can cause flu-like symptoms and lead to severe neurological disease along with inflammation of the brain and membranes around the spinal cord.

“When it does cause an infection, it is very, very severe. Although it’s a very rare infection, we have no treatment for it,” said Dr. Richard Ellison, immunologist and infectious disease specialist at University of Massachusetts Memorial Medical Center. “Once someone gets it, it’s just — all we can do is provide supportive care, and it can kill people.”

There are typically about 11 human cases of eastern equine encephalitis in the U.S. per year, according to the U.S. Centers for Disease Control and Prevention. Two of the three people infected in New Hampshire in 2014 died.

The health department said the virus has also been detected in one horse and several mosquito batches in New Hampshire this summer, and people in Massachusetts and Vermont also have been infected. Mosquitoes that carry the virus can sometimes be found in areas that used to be swamp land that has been converted but where they can still find habitat, Ellison said.

Public health authorities in states where mosquito-borne infections happen encourage people to take precautions, preventing mosquito bites by using repellent, wearing long sleeves and pants and avoiding outdoor activity in the early morning and evening when mosquitoes are most active. Removing any standing water where mosquitoes breed also is important.

A passer-by walks a dog, Monday, Aug. 26, 2024, along a walkway, in Plymouth, Mass., near a sign that advises people of a ban in effect for outdoor activity between dusk and dawn due to the risk of exposure to mosquito-borne diseases. (AP Photo/Steven Senne)

“We believe there is an elevated risk for EEEV infections this year in New England given the positive mosquito samples identified. The risk will continue into the fall until there is a hard frost that kills the mosquitos. Everybody should take steps to prevent mosquito bites when they are outdoors,” said New Hampshire epidemiologist Dr. Benjamin Chan.

In Massachusetts, several towns have urged people to avoid going outdoors at night this summer because of concerns over this virus, one of several diseases mosquitoes can spread to humans. Massachusetts authorities planned to begin spraying Tuesday in some communities to prevent the spread.

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Fda approves two updated covid vaccines.

Rob Stein, photographed for NPR, 22 January 2020, in Washington DC.

New COVID Vaccines

A pharmacist administers a COVID-19 vaccine.

A new round of COVID-19 vaccines will be rolled out soon. Scott Olson/Getty Images hide caption

The Food and Drug Administration Thursday gave the green light to two updated COVID-19 vaccines to help people protect themselves from the latest strains of the virus.

The new COVID vaccines are designed to keep the shots up to date with the virus, which keeps evolving to evade our immune systems.

Olympic sprinter Noah Lyles wears a black KN95 mask and a blue t-shirt with an American flag on it.

Is COVID endemic yet? Yep, says the CDC. Here's what that means

"Vaccination continues to be the cornerstone of COVID-19 prevention," said Dr. Peter Marks , director of the FDA's Center for Biologics Evaluation and Research in a statement announcing the decision. "These updated vaccines meet the agency's rigorous, scientific standards for safety, effectiveness, and manufacturing quality. Given waning immunity of the population from previous exposure to the virus and from prior vaccination, we strongly encourage those who are eligible to consider receiving an updated COVID-19 vaccine to provide better protection against currently circulating variants."

The Pfizer-BioNTech and Moderna mRNA vaccines that got the go-ahead on Thursday target the KP.2 variant . The Novavax vaccine, which is based on an older technology, targets an earlier strain called JN.1 and is expected to get the FDA's stamp of approval soon too.

An imperfect vaccine can still provide protection

Both target strains have already been overtaken by even newer variants, but they’re all still part of the omicron group. The hope is the vaccines are close enough to boost immunity and protect people through the rest of the surprisingly big summer wave and the surge expected this winter.

“The vaccine is not intended to be perfect. It’s not going to absolutely prevent COVID-19," Marks told NPR in an interview. "But if we can prevent people from getting serious cases that end them up in emergency rooms, hospitals or worse — dead — that’s what we’re trying to do with these vaccines.”

The new vaccines should cut the risk of getting COVID by 60% to 70% and reduce the risk of getting seriously ill by 80% to 90%, Marks says. The shots are expected to become available as soon as this weekend to anyone age 6 months and older.

Vaccination timing could be a personal decision

“Right now we’re in a wave, so you’d like to get protection against what’s going on right now,” Marks says. “So I would probably get vaccinated in as timely a manner as possible. Because right now the match is reasonably close. You’re probably going to get the most benefit you’re going to get from this vaccine against what’s currently circulating. So when this gets into pharmacies I will probably be on line as soon as it gets rolled out.”

To maximize the chances of getting the best protection, people should wait at least two or three months since their last bout of COVID or their last shot to get one of the new vaccines, Marks says.

Some people could consider waiting until September or October if they’re especially concerned about maximizing protection through the winter surge and over the holidays.

“Getting vaccinated sometime in the September to early October time frame seems like a pretty reasonable thing to do to help bring you protection through the December/January time frame,” says Marks. “It doesn’t, like, suddenly stop. This is not like something that suddenly cuts off at three or four months. It’s just that the immunity will decrease with time.”

Vaccination can help slow COVID's spread

“In my opinion, everyone should get one of the new vaccines,” says Dr. George Diaz , chief of medicine at Providence Regional Medical Center Everett in Everett, Wash., and a spokesperson for the Infectious Disease Society of America. “Being vaccinated yourself will prevent transmission to other people. So that will help reduce the spread of the disease in the community, especially to the most vulnerable people. So you’re not just helping yourself but also helping others.”

In addition, getting vaccinated reduces the risk for long COVID, Diaz adds.

Others question whether everyone necessarily needs another shot, arguing most younger healthy people still probably have enough immunity from all the shots and infections they’ve already gotten to protect them from getting really sick.

“Anyone who wants to get this vaccine should get it,” says Dr. Paul Offit , a vaccine expert at the University of Pennsylvania who advises the FDA. “It certainly makes sense why someone would want to get it because it lessens your chance of getting a mild or moderate infection for about four to six months and to some extent lessens your chances of spreading the virus.” But the calculation could be different for younger people. “Were I a 35-year-old healthy adult who’d already had several doses of vaccine and one or two natural infections I wouldn’t feel compelled to get it,” Offit says.

And regardless of the public health advice, it’s far from clear how many people will want one of the new shots. Only about 22% of eligible adults got one of the last ones.

But for anyone who does want the COVID vaccine, they can get the flu shot at the same time . In addition, federal officials are recommending anyone age 75 and older also get one of the new vaccines to protect against the respiratory syncytial virus , or RSV. Same goes for pregnant people and those ages 60 to 74 who are at high risk of getting seriously ill from RSV.

Older at-risk people will probably be able to get a second shot with the new COVID vaccines in the spring or early summer to help protect them against another wave next summer.

Insured people can get all three vaccines for free if they get their shot from an in-network provider. But a federal program that paid for the vaccines for uninsured adults expired.

“In the public health community we’re very concerned about how they will access protection and looking for ways for how we’re going to solve that problem,” says Dr. Kelly Moore , who runs Immunize.org , an advocacy group. “We know that the people who are uninsured are the least likely to be able to afford becoming ill – missing work, staying home from school.”

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Review Article
Published: 28 January 2019

Current and future influenza vaccines

Seiya Yamayoshi 1 &
Yoshihiro Kawaoka 1 , 2 , 3

Nature Medicine volume 25 , pages 212–220 ( 2019 ) Cite this article

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Influenza virus
Viral evolution

Although antiviral drugs and vaccines have reduced the economic and healthcare burdens of influenza, influenza epidemics continue to take a toll. Over the past decade, research on influenza viruses has revealed a potential path to improvement. The clues have come from accumulated discoveries from basic and clinical studies. Now, virus surveillance allows researchers to monitor influenza virus epidemic trends and to accumulate virus sequences in public databases, which leads to better selection of candidate viruses for vaccines and early detection of drug-resistant viruses. Here we provide an overview of current vaccine options and describe efforts directed toward the development of next-generation vaccines. Finally, we propose a plan for the development of an optimal influenza vaccine.

Next-generation influenza vaccines: opportunities and challenges

Seasonal and pandemic influenza: 100 years of progress, still much to learn

Defining the balance between optimal immunity and immunopathology in influenza virus infection

One hundred years have passed since the first recorded influenza pandemic was caused by an influenza A(H1N1) virus—the 1918 Spanish flu (Boxes 1 and 2 ). Since then, there have been three other pandemics caused by A(H2N2), A(H3N2), and A(H1N1)pdm09 viruses—the 1957 Asian flu, the 1968 Hong Kong flu, and the 2009 swine-origin flu, respectively 1 . Currently, A(H1N1)pdm09 and A(H3N2) viruses together with influenza B virus (Yamagata and Victorian lineages) cause epidemics as seasonal influenza, but A(H1N1) and A(H2N2) viruses have disappeared 1 .

To understand and contend with influenza virus, a considerable amount of research has been conducted, and this effort has yielded a vast amount of information. For example, functional analysis of influenza virus proteins in vitro has revealed fundamental virological properties of influenza, resulting in the establishment of a method to generate influenza viruses entirely from plasmids 2 . This method has been and continues to be used to understand the biology of influenza viruses and to improve influenza countermeasures. Many host proteins have now been shown to contribute to virus propagation, revealing part of the complicated virus–host interaction 3 , 4 . Viral proteins and amino acid residues involved in the pathogenicity of influenza virus have also been identified, and the experimental procedures used to assess them are now well-established, leading to rapid risk assessment of newly emerged influenza viruses 5 , 6 , 7 . Several neuraminidase (NA) and polymerase inhibitors, which target virus proteins, have been developed and are efficacious when used early after onset, and rapid influenza diagnostic kits, which can provide results in 5–20 minutes, are now also available 8 , 9 , 10 , 11 . Seasonal influenza vaccines are available prior to every influenza season, and prepandemic vaccines against particular virus subtypes with pandemic potential have also been prepared 12 . Nevertheless, the control of seasonal influenza remains suboptimal, and there is always the risk of a pandemic caused by a virus to which the majority of human populations have no immunity.

To understand virus properties, viral genomic sequences have been analyzed since the late 1970s using the Sanger sequencing method, also known as the dideoxy chain termination method 13 . Recently, deep-sequencing technology has allowed us to determine the whole genomic sequence of many isolates, resulting in the accumulation of a large number of virus sequences in public databases. This wealth of information now makes it possible to monitor viruses circulating worldwide 14 , 15 , to predict virus fitness in silico 16 , and to assess the pandemic risk of virus isolates 17 .

Here, we review the understanding of viral evolution and spread and the current vaccine situation, and we describe future prospects for the development of next-generation vaccines.

Box 1 Types of influenza

There are four types of influenza virus: types A, B, C, and D. Influenza A and B viruses cause seasonal epidemics in humans. While influenza A virus circulates in humans and a variety of animals in addition, such as birds, pigs, dogs, and horses, influenza B virus infection is limited to humans and seals 120 . Influenza C virus causes a mild respiratory illness only in humans. Influenza D virus has not been shown to cause illness in humans.

The four types of influenza virus belong to the family Orthomyxoviridae, in which viruses possess negative-sense, single-stranded, segmented RNAs as their genome. All influenza A viruses encode at least ten major viral proteins (PB2, PB1, PA, HA, NP, NA, M1, M2, NS1, and NS2), and some isolates express several additional proteins, including PB1-F2, PA-X, M42, NS3, PB2-S1, PB1-N40, PA-N155, and PA-N182 (ref. 121 ). On the basis of the similarity of the major antigenic hemagglutinin (HA) and neuraminidase (NA) sequences, influenza A viruses are classified into 18 HA subtypes (H1 through H18) and 11 NA subtypes (N1 through N11) in various combinations 122 . These subtypes are further divided into two or three groups: group 1 HA (H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17, and H18) and group 2 HA (H3, H4, H7, H10, H14, and H15), or group 1 NA (N1, N4, N5, and N8), group 2 NA (N2, N3, N6, N7, and N9) and group 3 NA (N10 and N11) 122 . The trimeric type I transmembrane glycoprotein HA is produced as HA0, which is proteolytically split into HA1 and HA2. The HA1–HA2 monomer assembles as trimers consisting of a cytoplasmic domain, a transmembrane domain, an apical globular head region, which contains the receptor-binding site (RBS), and a stem region, which possesses a fusion peptide 123 . HA is essential for virus entry into host cells because its globular head and stem regions are involved in binding to the cellular receptor sialyloligosaccharides and in membrane fusion, respectively. The tetrameric type II transmembrane glycoprotein NA comprises several domains: a cytoplasmic domain, a transmembrane domain, a catalytic head domain, which is formed by six antiparallel β-sheets in a propeller-like arrangement and possesses the sialidase active site, and a stalk domain that connects the head and transmembrane domains 124 . The sialidase activity of NA cleaves off the sialic acid, allowing release of the progeny virions from the cell surface 125 . The enzymatic activity of NA also contributes to virus entry by removing receptor decoys within the airways 126 .

Box 2 Historic pandemics

The first recorded pandemic, which began in 1918, was caused by the Spanish influenza virus A(H1N1), which killed 50‒100 million people worldwide in 1918‒1919. Nucleotide sequence analysis suggested a ‘considerable evolutionary distance between the source of the 1918 NP and the currently sequenced virus strains in wild birds’ 127 . However, avian viruses whose proteins (with the exception of HA and NA) differ by less than 10 amino acids from those of the 1918 virus are still circulating in nature 128 .

The second recorded pandemic began in 1957 and was caused by the Asian influenza virus A(H2N2); this pandemic caused 1.1 million deaths globally from 1957‒1959 129 . The Asian influenza virus was a human–avian reassortant that possessed H2 HA, N2 NA, and PB1 segments derived from an avian virus and its other five segments from the Spanish A(H1N1) virus.

In 1968, the third recorded pandemic was caused by the Hong Kong influenza virus A(H3N2), which was a human–avian reassortant that possessed H3 HA and PB1 segments of an avian virus and its other six segments from the Asian A(H2N2) virus.

The latest pandemic, caused by the swine-origin influenza virus A(H1N1)pdm09, was first identified in Mexico in 2009 130 . More than 18,000 deaths among the laboratory-confirmed cases were reported to the World Health Organization ( http://www.who.int/csr/don/2010_08_06/en/ ). Genomic composition analysis revealed that this swine-origin virus resulted from the reassortment of North American triple-reassortant swine viruses (PB2, PB1, PA, H1 HA, NP, and NS segments) with Eurasian avian-like swine viruses (N1 NA and M segments) 131 .

Influenza virus and current epidemics

Influenza viruses cause a respiratory illness with symptoms such as fever, cough, sore throat, runny nose, muscle or body aches, headaches, and/or gastrointestinal symptoms (vomiting and diarrhea). The virus annually causes 3‒5 million severe cases, 0.3‒0.6 million deaths, and subsequent economic losses 18 . Currently, the influenza A virus subtypes H1N1pdm09 and H3N2, as well as influenza B viruses of the Yamagata and Victoria lineages, are as globally prevalent among humans as seasonal influenza viruses (Box 1 ). Global year-round surveillance is conducted by the World Health Organization (WHO) Global Influenza Surveillance and Response System (GISRS), which includes the National Influenza Centres, the WHO Collaborating Centres for Reference and Research on Influenza, and the Essential Regulatory Laboratories, to monitor changes in the virus genome, especially in hemagglutinin (HA) and NA ( http://www.who.int/influenza/gisrs_laboratory/flunet/en/ ). On the basis of the phylogenetic similarity of the nucleotide sequence of HA, epidemic viruses are classified into a ‘clade’ or ‘subclade.’ A real-time snapshot of the current populations of these viruses is available at the website nextstrain.org 15 .

Emergence and subsequent evolution of pandemic viruses in humans

Pandemic influenza is caused by the emergence of a virus with an HA protein to which the majority of human populations do not have immunity 19 . Previously, it was thought that a pandemic occurs when a virus whose HA subtype is different from that of viruses circulating in humans emerges; however, this concept was challenged when the A(H1N1)pdm09 virus caused a pandemic in 2009 even though A(H1N1) and A(H3N2) viruses were cocirculating. Influenza A viruses of a variety of subtypes are naturally maintained in avian species, especially aquatic birds, and are the typical source of the current HA. In contrast, influenza B viruses are unlikely to cause a pandemic because their antigenic diversity is limited. Reassortment (i.e., the exchange of genes between two or more influenza viruses upon co-infection of cells) between human, swine, and/or avian viruses in pigs and the direct interspecies transmission of an avian virus to humans led to the latest four pandemics 1 (Box 2 ). One of the most important facts that we have learned from these past pandemics is that no one knows when, where, or which subtype of influenza virus will cause the next pandemic.

After each pandemic, all four pandemic viruses continued to circulate in humans as a seasonal influenza virus after competing out previous seasonal viruses. Since inhibitory antibodies against HA and NA are usually elicited upon influenza virus infection in infected individuals 20 , 21 , 22 , it is viruses with amino acid mutations in HA and NA that are responsible for antigenic changes for evasion from such antibodies, so-called ‘antigenic drift' (Fig. 1 ). The mutations in HA mostly accumulate around the receptor-binding site (RBS) because antibodies that recognize the area around the RBS efficiently inhibit the binding of HA to its receptor, resulting in the neutralization of virus infectivity 23 , 24 . The five major antigenic sites, Ca1, Ca2, Cb, Sa, and Sb for H1 HA and A through E for H3 HA, have been mapped by X-ray crystallography, comparative sequence analysis, and characterization of mutant viruses that escaped from neutralizing mouse monoclonal antibodies 25 , 26 , 27 , 28 . Antigenic cartography suggests that antigenic drift of human influenza viruses occurs in clusters; while nucleotide changes continue to occur, clusters of antigenically similar variants exist for several years until they are replaced by viruses that form a novel cluster 29 , 30 , meaning that the genetic evolution is continuous, whereas antigenic evolution is punctuated. The ‘cluster-transitions’ of A(H3N2) virus over a 35-year period were predominantly caused by single amino acid substitutions that occurred at only seven positions (position 145 at antigenic site A and positions 155, 156, 158, 159, 189, and 193 at antigenic site B) adjacent to the RBS 31 . Similarly, mutations in NA are frequently identified around the enzymatic active center 32 , 33 . Antibodies that recognize these epitopes interfere with the sialidase activity of NA, resulting in the suppression of virus release from infected cells 34 . Studies with monoclonal antibodies and amino acid sequence analysis have revealed two to three antigenic sites in the NA protein 35 .

Debbie Maizels/Springer Nature

Immunologically naive human populations are infected with an influenza virus (i). Infected individuals acquire immunity against influenza virus (yellow) (ii). Viruses accumulate amino acid mutations in their antigenic HA during replication (iii). Some individuals who do not possess immunity against the initial virus are infected by the mutated virus (iv). Infected individuals acquire immunity against this virus (purple) (v). The virus further accumulates amino acid mutations in its HA (vi). The remaining naive individuals are attacked by this further mutated virus (vii). The majority of the individuals in human populations eventually acquire immunity against these viruses (yellow, purple, orange). They are then protected from influenza viruses with similar antigenicity (viii). The virus obtains one or two mutations in its HA that substantially alter antigenicity (i.e., antigenic drift) (xi). The antigenically drifted virus can infect individuals who possessed immunity against the previously circulating viruses (x). The individuals infected with the antigenically drifted virus mount immunity to this virus (blue). The cycle continues (xi). b , Real-world tracking of influencza viral epidemics allows the development of appropriate vaccines. Note that the virus evoles gradually, whereas antigenic shift occurs in steps. This is a screenshot of a phylogenic tree based on the HA sequences of human A(H3N2) viruses isolated between 2006 and 2018 from next strain ( https://nextstrain.org/ ). Subclades (3b, 3c, 3c2, 3c3, and 3c2A, etc.) are indicated by grey letters, and antigenic advance of isolates is indicated by each color. Vaccine seed A(H3N2) viruses indicated in the tree were changed in response to antigenic advance of circulating virusese. The labels are the names of virus isolates. For example, in A/Texas/50/2012, ‘A’ means influenza A virus, ‘50’ is sample number, and ‘2012’ is collection year.

Current influenza vaccines

To reduce the burden attributed to seasonal and pandemic influenza, multiple approaches, including vaccines and antiviral drugs, have been developed. Since a fully effective vaccine, if available, would be able to prevent influenza completely, vaccination is an appropriate option to combat influenza virus. Currently, three kinds of vaccines (inactivated, live attenuated, and recombinant HA vaccines) are licensed in various countries, and each type of vaccine has advantages and drawbacks 36 . For all of these vaccines, the vaccine seed viruses must be replaced periodically to match their antigenicity to that of the circulating viruses. Since antigenic mismatch causes low vaccine efficacy, the WHO biannual influenza vaccine composition meetings (one for the Northern hemisphere and the other for the Southern hemisphere) try to select the correct ones on the basis of the genetic and antigenic characteristics of the circulating viruses and epidemiologic information from individual countries. Since the vaccine seed viruses are determined more than 6 months before each epidemic season ( http://www.who.int/influenza/vaccines/virus/recommendations/consultation201802/en/ ), antigenic mismatch between vaccine candidates and circulating strains occurs occasionally 37 .

Inactivated vaccines

Inactivated vaccine, produced by growing the vaccine seed virus in chicken embryonated eggs, is the most popular approach in the world because of relatively low production costs and high safety. Vaccinations with inactivated vaccines begin at 6‒12 months of age, and annual vaccinations are needed because the immunity conferred by the vaccine does not last long 38 . There are three types of inactivated vaccines: whole-virion vaccines, split-virion vaccines, and subunit vaccines. Whole-virion vaccine is prepared by purification of virions that have been chemically inactivated with formaldehyde or β-propiolactone. In the split-virion vaccine, the virus envelope of the whole virion is disrupted by diethyl ether or detergent treatment. Subunit vaccines contain HA and NA that are further purified by exclusion of the viral ribonucleoprotein (vRNP), M1, and viral envelope (lipid). Despite low immunogenicity and a narrow range of protection, split-virion and subunit vaccines are used more commonly than whole-virion vaccines to vaccinate humans against seasonal influenza. Another key issue for inactivated vaccines is that influenza A virus, especially the recent A(H3N2) virus, requires many passages in eggs to achieve high titers because the initial isolates replicate poorly in eggs. Excessive passages in eggs can change the antigenicity of HA, resulting in an antigenic mismatch with the epidemic isolates 39 , 40 , 41 .

To avoid egg-adaptive mutations in HA, cultured cell lines (such as Madin-Darby canine kidney (MDCK) and Vero cells) can be used for virus propagation 42 . However, the titers of vaccine seed viruses in such cell lines grown under serum- and animal-component-free conditions and in suspension or a bioreactor are lower than those in eggs, resulting in high cost and low productivity 43 . Therefore, the use of cell-culture-based inactivated seasonal vaccines has been limited.

Live attenuated vaccines

Live attenuated vaccines are available in the United States, Canada, and several European countries. Vaccines derived from cold-adapted and temperature-sensitive master donor viruses 44 , 45 , 46 are propagated in eggs, causing egg-adaptive mutations in HA. Because live attenuated vaccines mimic a natural infection without causing major adverse reactions, they can elicit both IgA, which is the principal isotype in secretions at the mucous membrane and which operates mainly on epithelial surfaces, in the upper respiratory tract as well as IgG, which is the principal isotype in blood and extracellular fluid and which operates mainly in body tissues, in serum, providing cross-reactive immune responses at the initial replication site 47 , 48 . However, the live attenuated vaccine is not recommended for use in children younger than 2 years of age, pregnant women, and people with certain underlying illnesses or a compromised immune system because the vaccine viruses may replicate to higher titers in these individuals, leading to some side effects.

Recombinant HA vaccines

The recombinant HA vaccine is produced by a recombinant-protein-expressing system using insect cells and baculovirus 49 and is approved by the Food and Drug Administration (FDA) for use in the United States. Since this system does not use live influenza viruses, HA protein is obtained that lacks the unwanted mutations that can be introduced during egg adaptation. Furthermore, recombinant HA vaccine can be manufactured within 2 months, indicating that this vaccine would be suitable for the prevention of pandemic influenza viruses. Although the mechanism of action of this vaccine is similar to that of inactivated vaccines, the commercial formulation of the recombinant HA vaccine contains three times the amount of HA as the inactivated influenza vaccines to induce antibody titers equivalent to those obtained with conventional inactivated vaccines 50 . Since the elicited immunity is HA- and strain-specific, the HA must be updated frequently to match the antigenicity of the epidemic strains. The recombinant HA vaccine is limited to use in individuals 18‒49 years of age because of its low immunogenicity, especially in children.

Development of next-generation vaccines

Although vaccines are used in many countries, seasonal influenza epidemics have not been controlled. To improve the effectiveness of vaccines, advances must be made in five major areas: selection of the vaccine seed virus, targeting the vaccine, use of cultured cells instead of eggs for vaccine virus preparation, increasing the NA content of vaccines, and development of novel classes of adjuvants.

Selection of vaccine seed virus

To improve vaccine selection, in silico and in vitro studies have been conducted. Current epidemics can be visualized by integrating sequence data with epidemiologic information 14 or by the continuous updating of databases to monitor the rise and decline of virus clades 15 , 51 (Fig. 2 ). In silico modelling using past epidemic patterns together with information on viral fitness 16 or the relative distances of amino acid sequences in the multidimensional scaling-constructed 3D space 52 are used to predict the future direction of influenza virus evolution. To model which viruses may circulate in the future, viruses possessing random mutations in the HA head are first generated by reverse genetics. Of these, the viruses that could escape from neutralizing antibodies against HA are identified by using antisera obtained from ferrets that are experimentally infected with the parental virus, or sera obtained from humans who were exposed to influenza virus infection or vaccination 53 . These approaches allow the antigenicity of future epidemic strains to be determined and, in some cases, the exact amino acid changes that may occur can be predicted. Therefore, scientists are getting closer to identifying viruses that are antigenically similar to those that may circulate in nature before they emerge.

Real-time tracking of influenza A is now possible, which allows tracking of strains across the globe. This is a screen shot of a phylogenic tree based on the HA sequences of human A(H3N2) viruses isolated between 2016 and 2018 generated at https://nextstrain.org/ . Subclades (3c2, A1, A1b, and A1a, etc.) are indicated by grey letters, and different colors indicate where the isolate was isolated.

The next challenge for the selection of better vaccine components is to identify emerging viruses with antigenic drift. Antigenically similar viruses circulate in humans for several years without antigenic change 31 . During this period, the viruses first accumulate amino acid mutations in their HA that do not affect antigenicity and then acquire mutations that do affect the antigenicity of the virus, resulting in the emergence of antigenically drifted viruses (Fig. 1 ). Therefore, we need to learn what triggers the emergence of the latter amino acid changes. Studies on the antibody landscape (i.e., population dynamics of the levels of antibodies against the circulating strains) may help to solve this problem.

Vaccine targeting

The Center for Disease Control (CDC) recommends influenza vaccinations for all age groups ( https://www.cdc.gov/flu/protect/whoshouldvax.htm ). Individuals with a relatively higher risk for influenza, such as young children, the elderly, pregnant women, and people with chronic medical conditions, are highly encouraged to get vaccinated 54 , 55 , 56 . For these high-risk groups, vaccination tailored to specific targets may improve protection. For young children, the inactivated vaccine and live attenuated vaccine are available for individuals >6 months of age and >2 years of age, respectively (see above). Although annual vaccination for those who are 6 months of age and older is recommended to reduce the risk of influenza, it is unclear how best to induce ‘good’ immunologic imprinting in these individuals (see below). For pregnant women, vaccination benefits both the pregnant woman and her unborn baby 54 .

Improvement of cell-based vaccine productivity

To address problems with low productivity, efforts have been made in two distinct areas: modification of the virus and amelioration of the cells in which it is produced. For virus modification, several sets of a vaccine backbone are prepared by optimizing the polymerase activity and efficiency of genome packaging and virion release of the influenza A or B vaccine viruses to achieve a high virus titer in MDCK and/or Vero cells 57 , 58 , 59 , 60 . A mutation that increases the fidelity of the virus polymerase may be useful for genetic stability of the virus for vaccine production 61 , 62 . Such backbones, together with HA and NA segments derived from circulating isolates, can be utilized for virus candidate production by using plasmid-driven reverse genetics 2 . For cell amelioration, researchers pick up high-virus-producing clones from parental cells 63 , downregulate host protein expression that suppresses virus growth 64 , and upregulate expression of human-type virus receptor 65 , 66 . Although these improvements show promise, they have not yet been incorporated into actual vaccine production.

The protection afforded by current inactivated vaccines is thought to be primarily mediated by HA because HA is a major target for protective antibodies. Therefore, the HA content of inactivated vaccines is standardized and measured. Despite the fact that antibody responses to NA have been shown to be the only independent immune correlate of all assessed measures of protection in human challenge models 67 , the NA content of inactivated vaccines is not quantified and is suboptimal, resulting in a lack of immune response against NA in vaccinees 68 . In infected patients, NA can elicit protective antibodies, most of which possess neuraminidase inhibition (NI) activity 68 ; some antibodies without NI activity also protect against influenza infection via Fc-mediated effector cell activation 69 . Although antigenic drift and immunologic imprinting of NA have been reported 70 , 71 , only NA antibodies that recognize the epitopes around the enzymatic active site and inhibit sialidase activity have been studied. Therefore, there is a need for analyses of antibodies against the NA head that lack sialidase inhibitory activity and of anti-NA stalk antibodies to fully understand the importance of NA as a vaccine antigen. In addition, a cross-reactive anti-NA antibody that binds and inhibits N1 through N9 NA activity was shown to be partially protective against H1N1 and H3N2 virus infection in mice 72 , suggesting that an NA-targeted vaccine may have the potential to induce cross-protective antibodies and that the NA content in inactivated vaccines should be increased and standardized.

Another improvement in vaccine efficacy may come from novel classes of adjuvant. An adjuvant is a substance that is formulated as part of a vaccine to enhance its ability to induce protection via activation of the immune system, allowing the antigens in vaccines to induce long-term protective immunity. The current adjuvanted vaccines normally cause local and general side effects, including pain, fatigue, headache, and myalgia, more frequently than nonadjuvanted vaccines because the adjuvant fundamentally promotes immune responses by mimicking the infection and causing inflammation. Mild adverse effects are acceptable, but severe adverse effects should be avoided. The severe adverse reaction of an increased risk of narcolepsy has been reported to be associated with the currently licensed adjuvant AS03 (refs. 73 , 74 ).

To reduce the possibility of the occurrence of serious adverse effects, researchers have developed novel classes of adjuvant with a clear mechanism of action. Toll-like receptor (TLR) ligands are the best understood of these adjuvants. TLRs are members of a family of pattern recognition receptors that recognize common motifs of pathogens. TLR4 agonists MPLA (monophosphoryl lipid A) and GLA (glucopyranosyl lipid adjuvant), a TLR7/8 agonist (imiquimod), a TLR3 agonist (rintatolimod), a TLR9 agonist (CpG ODN (CpG oligodeoxynucleotide)), and a TLR5 agonist (flagellin) have been evaluated as influenza vaccine adjuvants 75 . Cytokines are well-characterized cell signaling molecules. Since cytokine induction is an essential action for most adjuvants, representative cytokines involved in immune responses, such as the T cell activator IL-2, the dendritic cell activator granulocyte-macrophage colony-stimulating factor (GM-CSF), and type I interferon, have been incorporated as adjuvants into vaccines that are currently being developed 12 .

Other formulations and immunostimulators have been developed as adjuvants, but their mechanisms of action have not yet been characterized; the simplest approach to improving the host immune response via an adjuvant could be usage of the whole virion as the vaccine antigen. Whole-virion vaccines, but not split vaccines, elicit high neutralizing antibodies in the early T-cell-independent response, which requires B-cell–intrinsic TLR7 signaling activated by viral RNAs within the whole-virion vaccine 76 .

Evaluation of host immune responses to vaccines

Vaccine efficacy is assessed according to the level of protection from infection the vaccine provides. However, surrogates, such as hemagglutinin-inhibition (HI) antibody titers in sera and virus-specific cytotoxic T lymphocyte (CTL) levels have been used to evaluate vaccine immunogenicity. Since a serum HI antibody titer of ≥ 1:40 is associated with a significant reduction in influenza incidence, serum HI antibody titer induction is used as a measure of vaccine efficacy in clinical trials 77 . The inactivated vaccine elicits HI antibodies against viruses that vaccinees have encountered over their lifetime, not just the antigens in the vaccines, an effect known as the ‘back-boost’ 78 . Such serologic evaluation can measure the quantity of HI antibodies, especially the most potent neutralizing antibodies that recognize the epitopes around the HA RBS.

Recent studies have revealed that infection- and vaccine-induced human in vitro neutralizing and non-neutralizing antibodies against the HA stem, which mostly recognize heterosubtypic HA 79 , 80 , 81 , show in vivo protective efficacy via Fcγ-receptor-medicated activation of natural killer (NK) cells (antibody-dependent cellular cytotoxicity; ADCC), macrophages (antibody-dependent cellular phagocytosis; ADCP), and neutrophils (antibody-dependent neutrophil-mediated phagocytosis; ADNP) 69 , 82 , 83 . Antibodies against the HA head or stem also inhibit virus particle release from infected cells 81 , 84 . Thus, antibodies other than HI antibodies should be measured to evaluate vaccine immunogenicity in future trials. Accordingly, it is important to develop methods to evaluate different types of immunity that can serve as immune correlates for protection.

Since vaccination induces antibodies that protect vaccinees by different mechanisms, analyses using sera that contain a mixture of many different antibodies are not useful for developing a mechanistic understanding of vaccine protection. Antibody responses have been qualitatively analyzed by determining B cell receptor sequences to reveal the antibody repertoire at the molecular level. An unbiased antibody repertoire analysis revealed that the inactivated vaccine elicits antibody production from memory and naive B cells 85 . Of the elicited antibodies, many cross-reactive neutralizing clones that recognized the HA RBS and many cross-reactive non-neutralizing protective clones that recognized the lateral surface of the HA head were detected in some individuals 85 , 86 . However, the antibody response to a vaccine differs among individuals owing to differences in their history of influenza infection and vaccination 87 , 88 , 89 .

Generation of broadly protective vaccines

Current inactivated vaccines provide some protection to vaccine recipients from viruses that are antigenically similar to the vaccine viruses. However, such vaccines fail to suppress infections caused by antigenically drifted viruses and offer no protection against an antigenic shifted virus that has the potential to cause a pandemic. Therefore, there is a need for a vaccine capable of inducing immune responses that last for a long time and that protect against a wide range of viruses, ideally all influenza A and B viruses 90 . Several approaches have been taken to produce such vaccines (so-called universal vaccines) based on the concept of inducing immune responses against the conserved protective epitopes in virus proteins. The targets of universal vaccine candidates include the HA stem, the RBS of HA, the extracellular domain of M2 (M2e), and the CTL epitopes in M1 and NP 36 .

Although the antigenicity of the HA head varies between HA subtypes, that of the HA stem is highly conserved among HA group members 79 , 91 . Several epitopes in the HA stem are common across groups 1 and 2 (ref. 80 ), and an epitope conserved in both type A and B viruses has also been reported 81 . Antibodies against the stem are typically heteroreactive and suppress virus replication by inhibiting membrane fusion and virus release as well as the activation of Fc-region-mediated cytotoxicity 84 , 92 , 93 . Therefore, several approaches have been proposed to elicit anti-HA stem antibodies, including immunization with headless HA 94 , 95 , 96 , 97 , sequential chimeric or heterosubtypic HA 98 , 99 , 100 , synthetic fragments or peptides of the HA stem 101 , 102 , and hyperglycosylated HA 103 .

M2 is a relatively conserved tetrameric type III transmembrane protein that functions as a proton-selective ion channel. M2e has been extensively investigated as a target for a universal vaccine. Antibodies against M2e do not interfere with virus entry but prevent virus release and activate effector cells via an Fc–receptor interaction 104 . Since M2e per se is poorly immunogenic, various strategies such as multimerization, display on virus-like particles or phages, and fusion with a carrier protein or a protein with adjuvant activity are being tested to improve the host immune response 105 . Animals vaccinated with M2e were shown to be protected from homologous and heterologous challenge infection 105 , 106 . Although several kinds of M2e vaccine have been evaluated in early-phase clinical trials, no M2e vaccine is as of yet available on the market. To overcome some of the limitations of the M2e-based vaccines, combination with other conserved proteins is now under consideration 105 .

Despite the high variability of the HA head, the RBS is functionally conserved because sialic acid receptor recognition is an essential step for influenza virus entry. Antibodies against the RBS mimic the binding mode of sialic acid to some extent, resulting in a high cross-neutralizing capability 107 , 108 , 109 . Although the RBS could be a target for a broadly protective vaccine, such a vaccine is not being actively investigated because of the lack of an optimally designed antigen. However, efforts towards this goal are underway, as are efforts towards the development of antiviral drugs targeting the RBS 110 , 111 .

NP and M1 are highly conserved among influenza A viruses; however, they are generally considered unsuitable targets for antibody-inducing vaccines owing to their lack of exposure on the virion surface, although NP has been detected on the cell surface 112 . Therefore, the conserved epitopes in these proteins are targets for CTLs, resulting in a broadly cross-reactive response. In fact, NP is the major target for the CTL response in humans 113 . Since activated CD8 + T cells attack infected cells and enhance virus clearance, the CTL-inducing vaccines reduce disease severity and mortality but do not prevent infection. A modified vaccinia Ankara (MVA) expressing NP and M1 (MVA-NP + M1) 114 or a mixture of synthetic polypeptides derived from M1 and NP 115 has been used to induce CTL activation. These vaccines were evaluated in phase 1b or 2a trials and induced a good CTL response in humans 116 , 117 .

If the next-generation vaccines are expected to induce antibodies possessing HI activity, it would seem to be appropriate to evaluate these vaccines by using the current HI assay. However, most of the next-generation vaccines currently under development target areas other than the major antigenic sites of the HA head. Therefore, HI antibody titers are not a suitable measure for assessing such vaccines. Although antibody titers against the HA stem, M2e, or NA, or CTL activation against NP or M1 can be measured in humans and animals, we do not know whether they can serve as immune correlates of protection. Moreover, the evaluation method and threshold values used differ among vaccines. Therefore, regulatory science to control and evaluate next-generation vaccines needs to be established.

Optimal protection by understanding imprinting

Many candidate next-generation vaccines are under investigation in clinical or preclinical trials. One essential issue, ‘immunologic imprinting’ (or the so-called original antigenic sin), remains to be understood and managed. In 1960, it was proposed that the initial exposure to an influenza virus affects the antibody response to subsequent virus exposures 118 .

Recent epidemiological research regarding H5N1 and H7N9 viruses has demonstrated that lifelong immunologic imprinting, which is elicited by infection with the influenza strain circulating during one’s childhood, helps protect against unfamiliar HA subtypes from the same HA group 119 . This immunologic imprinting varies among individuals depending on the year of their birth and the virus strains they encountered, and it likely impacts how individuals will respond to the antigens of next-generation vaccines as well as current inactivated split vaccines (Fig. 3 ). Therefore, this necessitates a complete understanding of immunological imprinting by analyzing its establishment in an individual’s childhood. It may be possible to optimally immunologically imprint individuals in childhood and to induce optimal immune responses in adults and the elderly by avoiding the original antigenic sin. Moreover, scientists must establish animal models for evaluation of immunologic imprinting; most animal experiments are conducted using animals that have never been infected with influenza virus. Optimal immunologic imprinting by vaccination of animals needs to be established to avoid unwanted immunologic imprinting.

Immunologic imprinting varies from generation to generation because the circulating influenza A viruses in childhood differ. The first encounters of individuals born between 1918 and 1957, between 1957 and 1968, between 1968 and 1977, between 1977 and 2009, or after 2009 with an influenza virus would have been with H1N1, H2N2, H3N2, H1N1 or H3N2, or H1N1pdm09 or H3N2 virus, respectively. Even though the virus subtypes were identical between these periods, the antigenicity of the viruses changed over time. Therefore, infections during childhood immunologically imprinted the infected individuals in a variety of ways. This imprinting affects immune responses to subsequent virus infection and vaccination.

Concluding remarks

Many kinds of next-generation vaccines are under development for clinical use. To establish truly universal vaccines, several of these vaccines may need to be combined. Although it will not be easy to develop a universal influenza vaccine, it may be possible with time, money, wisdom, and collaboration between laboratories, companies, and countries.

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Acknowledgements

We thank S. Watson for editing the manuscript. Our work described in this review was supported by the Japan Initiative for Global Research Network on Infectious Diseases (J-GRID) from the Japan Agency for Medical Research and Development (AMED) (JP18fm0108006), by Leading Advanced Projects for medical innovation (LEAP) from AMED (JP18am001007), by Grants-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Science, Sports, and Technology (MEXT) of Japan (16H06429, 16K21723, and 16H06434), by JSPS KAKENHI Grant Number 18K07141, and by the Center for Research on Influenza Pathogenesis (CRIP) funded by National Institute of Allergy and Infectious Disease contract HHSN272201400008C.

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Seiya Yamayoshi & Yoshihiro Kawaoka

Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan

Yoshihiro Kawaoka

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Y.K. has received speaker’s honoraria from Toyama Chemical and Astellas Inc.; has received grant support from Chugai Pharmaceuticals, Daiichi Sankyo Pharmaceutical, Toyama Chemical, Tauns Laboratories, Inc., Otsuka Pharmaceutical Co., Ltd., and Denka Seiken Co., Ltd.; and is a co-founder of FluGen. S.Y. has no conflicts of interest.

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Yamayoshi, S., Kawaoka, Y. Current and future influenza vaccines. Nat Med 25 , 212–220 (2019). https://doi.org/10.1038/s41591-018-0340-z

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Avian flu virus confirmed in Michigan dairy herd

Highly pathogenic avian influenza (HPAI) virus has been confirmed in a dairy herd in Van Buren County, Michigan—the nation's first detection for almost 2 weeks. The last detection in Michigan was on July 26, also in Van Buren County.

The detection brings the number of affected dairy herds in Michigan to 28, and samples have been sent to the US Department of Agriculture's (USDA) National Veterinary Services Laboratories for additional confirmatory testing, according to the Michigan Department of Agriculture & Rural Development.

According to state rules , the detection will now prohibit the exhibition of all lactating dairy cattle, and those in the last 2 months of pregnancy, until there are no new cases of HPAI in Michigan dairy cattle for at least 60 consecutive days.

In the past 30 days , 5 states have reported 20 cases of HPAI in dairy cattle, according to the USDA. The most recent previous detections were in Colorado and Idaho.

Study suggests antibodies to flu common in raptors

In other avian flu news, a preprint study of raptors from the University of Minnesota's Raptor Center and the Hawk Ridge Bird Observatory in Duluth during the 2022-23 H5N1 avian flu outbreak finds that 69.1% of bald eagles were seropositive for influenza virus, and 52 of 67 (77.6%) of them tested positive for antibodies to both H5 and N1.

The study , which has not yet been peer-reviewed, offers new insight on the seroprevalence of influenza viruses in wild birds. According to the authors, the prevalence of influenza antibodies observed in this study was higher than reported from raptors sampled in this same region in 2012

C difficile vaccine candidate fails to meet primary end point in phase 3 trial

A Clostridioides difficile vaccine candidate was safe, well tolerated, and reduced C difficile infection (CDI) severity but did not reduce incidence of CDI in at-risk adults, according to the results of a phase 3 randomized clinical trial published late last week in Clinical Infectious Diseases.

The global, phase 3 CLOVER trial, conducted in 23 countries from March 2017 through December 2021, assessed the efficacy of PF-06425090, a genetically detoxified toxin C difficile vaccine candidate from Pfizer, in adults 50 and older who were considered at increased CDI risk. Overall, 17,535 participants (mean age, 68; 51.5% female; 79.2% White) were randomized to receive three doses of PF-06425090 or placebo. The primary end points were the first CDI episode 14 or more days post–dose three (PD3) and post–dose two (PD2). CDI duration, need for CDI-related medical attention, and antibiotic use PD3 were also evaluated.

Among the participants who received all three doses, 17 PF-06425090 and 25 placebo recipients had a primary CDI episode 14 or more days PD3, resulting in vaccine efficacy (VE) of 31%, but the 96.4% confidence interval ranged well below 0. Among those who received two doses, 24 PF-06425090 and 34 placebo recipients had a first CDI episode 14 or more days PD2, for a VE of 28.6%, with a similarly wide confidence interval. Median CDI duration was lower with PF-06425090 (1 day) versus placebo (4 days). Of participants with a first CDI episode, 0 PF-06425090 and 11 placebo recipients sought CDI-related medical attention (post-hoc analysis estimated VE, 100%) and 0 PF-06425090 and 10 placebo recipients required antibiotic treatment (VE, 100%).

Local reactions were more frequent in PF-06425090 recipients, while systemic events, most of which were mild-to-moderate, were generally similar between groups. Adverse event rates were similar between groups.

Potential public health benefit

The trial investigators say that while the primary end point wasn't met, the results suggest PF-06425090 could provide a public health benefit.

"Together, these findings suggest PF-06425090 may reduce overall disease burden by potentially reducing CDI severity in vaccine recipients and consequent need for medical interventions," trial investigators wrote. "Limiting need for medical attention not only alleviates healthcare resource strains but reduces potential for antibiotic exposure, which may help mitigate increasing global threats of antimicrobial resistance."

Massachusetts to start spraying for Eastern equine encephalitis

Massachusetts officials over the weekend announced plans to start spraying for mosquitoes in two counties to reduce the risk from eastern equine encephalitis (EEE).

Officials from the Massachusetts Department of Health (DPH) and the Massachusetts Department of Agricultural Resources said they will conduct aerial spraying in parts of Plymouth County and truck-mounted spraying in parts of Worcester County to target mosquitoes carrying the virus. On August 16 , the DPH reported the state's first EEE case since 2020, in a man in his 80s who was exposed in Worcester County.

EEE is a rare but serious mosquito-borne illness that can lead to severe neurologic complications and potentially be fatal. In the 2019-20 EEE outbreak in Massachusetts, 17 cases and 7 deaths were reported.

"We have not seen an outbreak of EEE for four years in Massachusetts," DPH Commissioner Robbie Goldstein, MD, PhD, said in a DPH press release . "This year's outbreak and activity raise the risk for communities in parts of the state. We need to use all our available tools to reduce risk and protect our communities."

DPH officials are also advising residents of high-risk areas to schedule outdoor activities to avoid dusk-to-dawn hours to minimize exposure to the mosquitoes most likely to carry EEE.

West Nile virus also a concern

In a separate press release , the DPH said eight municipalities are now to be considered at high risk from another mosquito-borne illness—West Nile virus (WNV). The first WNV-positive mosquitoes in Massachusetts were announced on July 2.

"We are finding evidence of West Nile virus in mosquitoes in multiple parts of the Commonwealth," Goldstein said. "While most people do not get severely ill from WNV, it is still important to take it seriously."

The elevated risk level applies to Boston in Suffolk County and Abington, Brockton, East Bridgewater, Marion, Mattapoisett, Rochester, and Whitman in Plymouth County.

Efforts to reduce antimicrobial resistance in low-resource nations are lagging, survey suggests

A survey of public health experts from low- and middle-income countries (LMICs) highlights significant gaps in implementation and enforcement of policies aimed at mitigating antimicrobial resistance (AMR), researchers reported late last week in BMC Public Health.

The Global Survey of Experts on Antimicrobial Resistance (GSEAR), developed by researchers with the Swiss Tropical and Public Health Institute and University of Basel, was sent to public health experts in 138 LMICs to assess their countries' efforts to address AMR. The main areas covered by the survey were existence of AMR national action plans (NAPs), policies and interventions to restrict the sale and consumption of antibiotics, current antibiotic use, antibiotic prescribing practices, collection and reporting of surveillance data, and AMR awareness.

A total of 352 surveys from 118 LMICs were analyzed. Experts in 67% of the surveyed countries reported a NAP on AMR, 64% reported legislative policies on antimicrobial use, 58% reported national training programs for health professionals, and 10% reported national monitoring systems for antimicrobials. Fifty-one percent of LMICs had specific targeted policies to limit the sale and use of protected or reserve antibiotics. While 72% of LMICs had prescription requirements for accessing antibiotics, getting antibiotics without a prescription was reported to be possible in 74% of LMICs.

Government officials may overestimate policy coverage

When the researchers compared the GSEAR results to the 2020-21 World Health Organization–organized Tripartite AMR Country Self-Assessment Survey (TrACSS), which was completed by government officials in 113 LMICs, they found substantial disagreement. For example, TrACCS results indicated 86% had NAPs and 86% had legislative policies on antimicrobial use.

Based on expert perspectives, there are significant gaps in current policy and implementation efforts to address AMR in LMICs, with a large number of countries falling short of target achievements.

The authors say that while the experts consulted in the GSEAR survey may not always be aware of NAPs and specific policies and programs in their respective countries, the gaps between the GSEAR at TrACSS responses suggests countries may be overestimating their efforts.

"Based on expert perspectives, there are significant gaps in current policy and implementation efforts to address AMR in LMICs, with a large number of countries falling short of target achievements; current policy coverage may be substantially lower than what the TrACSS survey suggests," the authors wrote.

India reports largest Chandipura virus outbreak in 2 decades

India has reported a surge in Chandipura virus infections this summer, with 245 acute encephalitis syndrome (AES) cases reported since July, with 82 of them fatal. So far, polymerase chain reaction testing has confirmed the virus in 64 cases, the World Health Organization (WHO) said in an August 23 outbreak announcement .

Chandipura virus is endemic in India, and it is known to trigger sporadic cases and outbreaks of AES in western, southern, and central part of the country, especially during monsoon season. Outbreaks typically occur every 4 to 5 years in Gujarat state. The virus—a member of the Rhabdoviridae family—is transmitted by vectors that include sandflies, mosquitoes, and ticks.

Children most affected; fast onset of severe symptoms

The disease mainly affects children ages 15 and younger. The main symptoms are fever, with coma and convulsions that can occur within 48 to 72 hours of symptoms onset.

Cases began rising in early June, and 43 of 806 districts in India have reported AES cases. Of the 64 confirmed cases, 61 were in Gujarat state and 3 in Rajasthan state.

The WHO said cases have been declining since the middle of July. Though authorities have deployed control strategies, further transmission is possible in the coming weeks, given favorable conditions from the monsoon season in affected areas.

India's last large Chandipura virus occurred in 2003, when 329 suspected cases, 183 of them fatal, were reported in Andhra Pradesh state. The virus has been detected only in India, but the WHO said it may be present in other countries in Asia and Africa. The sandfly vector is present in Southeast Asia.

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Benefits and Risks of Influenza Research: Lessons Learned

Given the yearly challenge of seasonal influenza and the potential catastrophic consequences of future pandemics, the need for intensive basic and clinical influenza research is unquestionable. Although the fruits of decades of research have enabled dramatic improvements in our ability to prevent and treat influenza, many fundamental questions remain, including those related to the complex factors associated with host switching and transmission of influenza viruses. Recent public concern over two H5N1 influenza manuscripts that studied the transmissibility of influenza viruses has triggered intense discussion on dual-use research and the way forward.

Influenza A virus is an ancient and persistent threat to individual and global health ( Fig. 1 ). Seasonal influenza (which occurs annually, usually in winter) kills ~500,000 people globally and up to 50,000 people in the United States each year. Influenza viruses have animal reservoirs, especially in birds and pigs. They can undergo extensive genetic changes and even jump species, sometimes resulting in a virus to which humans may be highly vulnerable. Such an event can lead to a global health disaster; global influenza pandemics have occurred only three times in this past century. A prime example is the 1918 influenza pandemic, which killed between 50 and 100 million people worldwide and caused enormous social and economic disruption. Influenza A viruses circulate widely and are constantly evolving toward pandemic capability, as seen again in 1957, 1968, and 2009 ( 1 ). There is thus a clear danger of future pandemics.

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H5N1 avian influenza virus particles, colored transmission electron micrograph. Magnification: ×670,000 when printed 10 cm wide.

Over the last decade, a highly pathogenic avian influenza virus (genus A; subtype H5N1) has emerged among chickens ( 2 ). Rarely, the virus has spread to humans, usually individuals with heavy exposure to infected birds. Since 2003, ~600 confirmed cases have occurred in humans in more than a dozen countries. Nearly 60% of these reported cases have resulted in death ( 3 ). Because it has been impossible thus far to completely eliminate the virus from chicken flocks or from wild birds or to prevent transmission to mammals, there is a persistent danger that H5N1 viruses [which have continually mutated and evolved ( 2 )] will eventually become more easily transmissible to and among humans. Because humans are not specifically immune to H5N1 influenza, this scenario would have the makings of a potentially devastating pandemic.

One of the goals of pandemic influenza research is to recognize and anticipate how viruses are evolving in the wild toward a phenotype that is dangerous to humans, thereby staying one step ahead of potential pandemics. In this regard, compelling research questions relevant to global health and pandemic preparedness include determining whether highly pathogenic viruses, such as H5N1, have the ability to mutate and/or reassort with another influenza virus to become readily transmissible by the airborne route among humans. If so, (i) what is the likelihood that such mutations or reassortments will happen in nature? (ii) Is there a genetic signature of such a virus that might be helpful in surveillance? (iii) Would such a virus be highly pathogenic for humans? And (iv), would such a virus be sensitive to currently available antiviral drugs and vaccines, or would new ones be necessary? In response to these and related questions, the National Institutes of Health (NIH) has intensified the research we conduct and support on pandemic influenza. Much of this research is specifically focused on developing improved countermeasures, including a “universal” influenza vaccine that would protect people from multiple influenza subtypes. In complementary research, NIH-supported scientists study the factors involved in the pathogenesis and transmissibility of H5N1 and other influenza viruses to nonhuman mammals (mice, guinea pigs, ferrets, and nonhuman primates) to identify potential clues to the determinants of the same properties in humans.

Within this context, global attention has been paid recently to two NIH-funded studies of H5N1 transmissibility and pathogenesis in ferrets. In those studies, H5N1 viruses were made transmissible via respiratory droplets among ferrets by engineering the virus; well-described and published protocols including reverse genetics, reassortment, and passaging of viruses in mammals were used. Manuscripts describing the studies ( 4 , 5 ) have generated an unprecedented degree of discussion, concern, and disagreement among scientists, as well as the public, regarding whether the experiments should have been performed in the first place and whether they should be published in their entirety. Major sources of concern have been that the results might be used by bioterrorists to harm the public or that the virus might accidentally escape and cause a pandemic.

Research on H5N1 viruses, including the experiments reported in these two papers ( 4 , 5 ), is comparable to that which has been conducted over decades with other seasonal and pandemic influenza viruses in ferrets and other animal models. The use of the ferret as an animal model for influenza transmissibility dates back to the 1930s, as ferrets are easily infected with influenza and sneeze when infected, which is useful for studying the airborne route needed for sustained human-to-human transmission. Understanding the virus characteristics associated with enhanced transmissibility—even in an imperfect animal model, such as the ferret—can benefit surveillance for naturally evolving wild viruses if they continually mutate toward a “genomic signature” that could be recognized as potentially predictive of a certain phenotype. Given the complexities of viral transmission, a virus’s ability to adapt to a host species, pathogenesis (a virus’s ability to cause disease), and the interrelation among these factors, which are likely to be unique to each influenza virus, any particular genomic signature will not necessarily predict how a given virus will act. Nonetheless, studies such as these provide incremental knowledge that the scientific community can build upon. A more in-depth understanding of the genetic evolution of influenza viruses should positively affect our ability to recognize and respond to influenza outbreaks.

However, whenever one deliberately manipulates a virus or a microbe, it is always possible, at least theoretically, that the research results could be used by bioterrorists to intentionally cause harm, or that an accidental release of a pathogen from a laboratory could inadvertently cause harm. Such research is referred to as “dual-use research,” as the research potentially has both positive and negative applications. A particular subset of dual-use research is referred to as “dual-use research of concern” or DURC. DURC is defined as life sciences research that, on the basis of current understanding, can be reasonably anticipated to provide knowledge, information, products, or technologies that can be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment, materiel, or national security ( 6 ). If a particular experiment is identified as DURC, that designation does not inherently mean that such research should be prohibited or not widely published. However, it does call for us to balance carefully the benefit of the research to public health, the biosafety and biosecurity conditions under which the research is conducted, and the potential risk that the knowledge gained from such research may fall into the hands of individuals with ill intent. Research that could enhance the transmissibility of H5N1 viruses clearly is DURC.

In this regard, the question of whether to publish the two H5N1 studies in ferrets has been intensively discussed by an independent federal advisory committee known as the National Science Advisory Board for Biosecurity (NSABB) ( 7 , 8 ). On the basis of their recommendations and other evaluations, the U.S. government agreed that the research is important for the public health and should be published. However, important lessons were learned along the way and, appropriately, triggered an examination of our approach concerning the conduct, oversight, and communication of DURC. In this regard, the U.S. government announced on 29 March 2012 the U.S. Government Policy for Oversight of Life Sciences Dual Use Research of Concern ( 6 ). This policy document outlines, for federal departments and agencies that conduct or fund life sciences research, steps to determine whether projects fall under the definition of DURC, to assess the risks and benefits of these projects, to review them regularly, and to develop risk mitigation plans. In the process of weighing the potential risks and benefits of publishing these two manuscripts ( 4 , 5 ), it also became clear that, when possible, it is critical to identify research with DURC potential before the initiation of the project and, certainly, before the results are submitted for publication. Such monitoring in the case of NIH-funded research requires the concerted effort of all involved, including scientists applying for or in receipt of NIH funding and NIH program officials. Additional guidelines will be needed as well to assist biosafety committees in evaluating DURC at the institutions where the research is conducted.

Furthermore, as a result of the public discussion of these two manuscripts, major gaps in our knowledge of influenza became painfully obvious. For example, there was considerable scientific debate about how well data from the ferret model can be extrapolated to understand influenza virus transmission and pathogenesis in humans. An H5N1 virus strictly adapted for ferret transmissibility may not be entirely relevant to humans. Moreover, although it is likely that the officially reported 60% case-fatality rate for human H5N1 influenza is artificially high (because nonfatal cases are less likely to be reported), there are limited surveillance data on which to base a more accurate estimate. NIH has begun a dialogue with the influenza research community about addressing these and other questions and will initiate a more strategic approach to defining the research gaps that must be addressed in order to responsibly move the field forward. In addition to identifying research gaps, the discussion of these manuscripts underscores the important practical issues of implementing rapid turnaround time between virus isolation and sequencing to provide real-time surveillance.

Finally, despite the importance of performing influenza research that may have DURC potential, this recent experience has underscored the fact that civil society needs to be involved in the dialogue early on. Clearly, research should be conducted and published only if the potential benefits to society outweigh the risks to national security and the potential harm to society. The risk/benefit calculation for certain experiments and their communication is not always obvious, and the current experience reflected considerable disagreement even in the scientific community. The ultimate goal of the new U.S. government-wide DURC policy is to ensure that the conduct and communication of research in this area remain transparent and open and that the risk/ benefit balance of such research clearly tips toward benefitting society. The public, which has a stake in the risks and the benefits of such research, deserves a rational and transparent explanation of how decisions are made. It is hoped that the upcoming dialogue related to the new DURC policy will be productive. A social contract among the scientific community, policy-makers, and the general public that builds trust is essential for success of this process.

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COMMENTS

A Narrative Review of Influenza: A Seasonal and Pandemic Disease
History. The influenza virus has caused recurrent epidemics of acute febrile syndrome every 1 to 4 years for at least the recent centuries. The first epidemic report of an influenza-like illness was noted in 1173-74, 3 but the first definitive epidemic was reported in 1694. 4 The greatest pandemic in recorded history occurred between 1918 and 1919, when approximately 21 million deaths were ...
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Journal of Biomedical Science (2023) The influenza virus is a global threat to human health causing unpredictable yet recurring pandemics, the last four emerging over the course of a hundred years ...
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Abstract. Influenza is an infectious respiratory disease that, in humans, is caused by influenza A and influenza B viruses. Typically characterized by annual seasonal epidemics, sporadic pandemic ...
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During the first half of March 2021, World Health Organization (WHO) laboratories found 375 positive influenza specimens among 291,427 specimens from 85 countries - 35.2% type A and 64.8% type B. 1 Of the type A viruses, 6.1% were influenza A (H1N1)pdm09 and 93.9% were influenza A (H3N2). All the type B viruses were the B/Victoria lineage.
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Influenza virus is an infectious agent belonging to the virus family Orthomyxoviridae that causes a respiratory tract infection (influenza or 'flu') in vertebrates. There are three main species ...
Influenza
Annual seasonal influenza epidemics of variable severity caused by influenza A and B virus infections result in substantial disease burden worldwide. Seasonal influenza virus circulation declined markedly in 2020-21 after SARS-CoV-2 emerged but increased in 2021-22. Most people with influenza have abrupt onset of respiratory symptoms and myalgia with or without fever and recover within 1 ...
PDF Influenza
viruses is crucial to monitoring antigenic drift and emergence of novel influenza A viruses ( appendix pp 1-2). Transmission dynamics and modalities. The basic reproduction number for seasonal influenza is estimated to be approximately 1 ·3, 11. with mean serial intervals for symptomatic influenza A virus infections of 2·2 and 2·8 days. 12
An Overview of Influenza Viruses and Vaccines
It can even lead to the emergence of a new influenza epidemic and a worldwide pandemic. Influenza B viruses also cause the seasonal flu epidemic in humans. There are two circulating influenza B lineages, B/Yamagata and B/Victoria, which are included in the seasonal flu vaccines [ 1 ]. Meanwhile, influenza C viruses commonly cause mild symptoms ...
Influenza and Influenza Vaccine: A Review
Substances. Antiviral Agents. Influenza Vaccines. Influenza is a highly contagious, deadly virus, killing nearly half a million people yearly worldwide. The classic symptoms of influenza are fever, fatigue, cough, and body aches. In the outpatient setting, diagnosis can be made by clinical presentation with optional confirmatory diagnostic ...
Influenza
Seasonal influenza virus circulation declined markedly in 2020-21 after SARS-CoV-2 emerged but increased in 2021-22. Most people with influenza have abrupt onset of respiratory symptoms and myalgia with or without fever and recover within 1 week, but some can experience severe or fatal complications. Prevention is primarily by annual influenza ...
A brief review of influenza virus infection
Abstract. Influenza is an acute viral respiratory infection that affects all age groups and is associated with high mortality during pandemics, epidemics, and sporadic outbreaks. Nearly 10% of the world's population is affected by influenza annually, with about half a million deaths each year. Influenza vaccination is the most effective method ...
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Influenza viruses cause mild to severe respiratory infections in humans and are a major public health problem. According to the World Health Organization, seasonal influenza viruses — including ...
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Influenza is an acute respiratory illness, caused by influenza A, B, and C viruses, that occurs in local outbreaks or seasonal epidemics. Clinical illness follows a short incubation period and presentation ranges from asymptomatic to fulminant, depending on the characteristics of both the virus and the individual host. Influenza A viruses can also cause sporadic infections or spread worldwide ...
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The 1918 "Spanish flu" pandemic was caused by a founder H1N1 influenza A virus. The three subsequent pandemics of 1957, 1968, and 2009 (black arrows) were caused by descendants of the 1918 virus, which acquired one or more genes through reassortment . Colored horizontal lines reflect the years of annual epidemics of seasonal influenza that ...
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Background. Annual seasonal influenza epidemics of variable severity result in significant morbidity and mortality in the United States (U.S.) and worldwide [1-3].In temperate climate countries, including the U.S., influenza activity peaks during the winter months whereas in tropical regions influenza activity may be more variable [4-6].Most persons with symptomatic influenza virus ...
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The development of safe and effective vaccines in a record time after the emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a remarkable achievement, partly based on the experience gained from multiple viral outbreaks in the past decades. However, the Coronavirus Disease 2019 (COVID-19) crisis also revealed weaknesses in the global pandemic response and large ...
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Hemagglutinin enables the flu virus to enter a human cell and initiate infection; neuraminidase allows newly formed flu viruses to exit the host cell and multiply throughout the body. There are 18 types of HA and 11 types of NA, leaving the possibility for dozens of different subtypes of influenza A viruses (such as H1N1, H3N2, H5N8, and H7N9 ...
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The virus has decimated poultry flocks on three continents but has caused fewer than 600 known cases of flu in humans since it emerged in Asia in 1997, although those rare human cases are often fatal. Because the virus spreads very inefficiently between humans it has been unable to set off a chain reaction and circle the globe.
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Abstract. Influenza viruses are highly transmissible, both within and between host species. The severity of the disease they cause is highly variable, from the mild and inapparent through to the ...
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Abstract. Influenza is a highly contagious, deadly virus, killing nearly half a million people yearly worldwide. The classic symptoms of influenza are fever, fatigue, cough, and body aches. In the outpatient setting, diagnosis can be made by clinical presentation with optional confirmatory diagnostic testing.
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Over the past decade, research on influenza viruses has revealed a potential path to improvement. The clues have come from accumulated discoveries from basic and clinical studies. ... (H1N1) virus ...
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1. Introduction. Influenza disease, usually called "the flu", is a contagious respiratory illness caused by influenza viruses. The common symptoms are fever, aches, chills, chest discomfort, cough, and headache [].The incubation period is very short, typically from 1 to 4 days [].While the majority of infected subjects recover, some develop complications, particularly at-risk groups such ...
Avian flu virus confirmed in Michigan dairy herd
In other avian flu news, a preprint study of raptors from the University of Minnesota's Raptor Center and the Hawk Ridge Bird Observatory in Duluth during the 2022-23 H5N1 avian flu outbreak finds that 69.1% of bald eagles were seropositive for influenza virus, and 52 of 67 (77.6%) of them tested positive for antibodies to both H5 and N1.
Benefits and Risks of Influenza Research: Lessons Learned
Research on H5N1 viruses, including the experiments reported in these two papers (4, 5), is comparable to that which has been conducted over decades with other seasonal and pandemic influenza viruses in ferrets and other animal models. The use of the ferret as an animal model for influenza transmissibility dates back to the 1930s, as ferrets ...

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A brief review of influenza virus infection

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Influenza viruses and coronaviruses: Knowns, unknowns, and common research challenges

Introduction

1. Emergence, transmission, and adaptation to humans

1.2. Understanding how selective pressures are shaping viral evolution

1.3. Investigating the mechanisms of transmission through aerosols

2. Determinants of viral load dynamics and disease severity

2.2. Elucidating the mechanisms for extrapulmonary tropism and/or complications

2.3. Tackling the burden of bacterial coinfections and rethinking antimicrobial stewardship

3. Virus- and host-targeted therapies, vaccine development

3.2. Leveraging cutting-edge technologies in structural biology and computational tools to develop highly potent antivirals

3.3. Developing improved vaccines with well-defined correlates of protection

Conclusions

Acknowledgments

Influenza Basic Research

New Hampshire resident dies after infection by mosquito-borne encephalitis virus

Shots - Health News

New COVID Vaccines

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An imperfect vaccine can still provide protection

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Box 1 Types of influenza

Box 2 Historic pandemics

Influenza virus and current epidemics

Emergence and subsequent evolution of pandemic viruses in humans

Current influenza vaccines

Inactivated vaccines

Live attenuated vaccines

Recombinant HA vaccines

Development of next-generation vaccines

Selection of vaccine seed virus

Vaccine targeting

Improvement of cell-based vaccine productivity

Evaluation of host immune responses to vaccines

Generation of broadly protective vaccines

Optimal protection by understanding imprinting

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