Continuing challenges in influenza Webster, Robert G.; Govorkova, Elena A.
Annals of the New York Academy of Sciences,
September 2014, Volume:
1323, Issue:
1
Journal Article
Peer reviewed
Open access
Influenza is an acute respiratory disease in mammals and domestic poultry that emerges from zoonotic reservoirs in aquatic birds and bats. Although influenza viruses are among the most intensively ...studied pathogens, existing control options require further improvement. Influenza vaccines must be regularly updated because of continuous antigenic drift and sporadic antigenic shifts in the viral surface glycoproteins. Currently, influenza therapeutics are limited to neuraminidase inhibitors; novel drugs and vaccine approaches are therefore urgently needed. Advances in vaccinology and structural analysis have revealed common antigenic epitopes on hemagglutinins across all influenza viruses and suggest that a universal influenza vaccine is possible. In addition, various immunomodulatory agents and signaling pathway inhibitors are undergoing preclinical development. Continuing challenges in influenza include the emergence of pandemic H1N1 influenza in 2009, human infections with avian H7N9 influenza in 2013, and sporadic human cases of highly pathogenic avian H5N1 influenza. Here, we review the challenges facing influenza scientists and veterinary and human public health officials; we also discuss the exciting possibility of achieving the ultimate goal of controlling influenza's ability to change its antigenicity.
Baloxavir marboxil (BXM) is approved for treating uncomplicated influenza. The active metabolite baloxavir acid (BXA) inhibits cap-dependent endonuclease activity of the influenza virus polymerase ...acidic protein (PA), which is necessary for viral transcription. Treatment-emergent E23G or E23K (E23G/K) PA substitutions have been implicated in reduced BXA susceptibility, but their effect on virus fitness and transmissibility, their synergism with other BXA resistance markers, and the mechanisms of resistance have been insufficiently studied. Accordingly, we generated point mutants of circulating seasonal influenza A(H1N1)pdm09 and A(H3N2) viruses carrying E23G/K substitutions. Both substitutions caused 2- to 13-fold increases in the BXA EC
50
. EC
50
s were higher with E23K than with E23G and increased dramatically (138- to 446-fold) when these substitutions were combined with PA I38T, the dominant BXA resistance marker. E23G/K-substituted viruses exhibited slightly impaired replication in MDCK and Calu-3 cells, which was more pronounced with E23K. In ferret transmission experiments, all viruses transmitted to direct-contact and airborne-transmission animals, with only E23K+I38T viruses failing to infect 100% of animals by airborne transmission. E23G/K genotypes were predominantly stable during transmission events and through five passages in vitro. Thermostable PA–BXA interactions were weakened by E23G/K substitutions and further weakened when combined with I38T. In silico modeling indicated this was caused by E23G/K altering the placement of functionally important Tyr24 in the endonuclease domain, potentially decreasing BXA binding but at some cost to the virus. These data implicate E23G/K, alone or combined with I38T, as important markers of reduced BXM susceptibility, and such mutants could emerge and/or transmit among humans.
•The role of influenza B viruses in morbidity and mortality is often underestimated.•Pediatric patients are at risk for developing severe influenza B virus infections.•Neuraminidase ...inhibitor-resistant influenza B viruses harbor a spectrum of neuraminidase mutations.•Molecular markers and fitness of neuraminidase inhibitor-resistant influenza B viruses are not well defined.
Many aspects of the biology and epidemiology of influenza B viruses are far less studied than for influenza A viruses, and one of these aspects is efficacy and resistance to the clinically available antiviral drugs, the neuraminidase (NA) inhibitors (NAIs). Acute respiratory infections are one of the leading causes of death in children and adults, and influenza is among the few respiratory infections that can be prevented and treated by vaccination and antiviral treatment. Recent data has suggested that influenza B virus infections are of specific concern to pediatric patients because of the increased risk of severe disease. Treatment of influenza B is a challenging task for the following reasons:1.NAIs (e.g., oseltamivir and zanamivir) are the only FDA-approved class of antivirals available for prophylaxis and treatment of influenza.2.The data suggest that oseltamivir is less effective than zanamivir in pediatric patients.3.Zanamivir is not prescribed to patients younger than 7 years of age.4.Influenza B viruses are less susceptible than influenza A viruses to NAIs in vitro.5.Although the level of resistance to NAIs is low, the number of different molecular markers of resistance is higher than for influenza A viruses, and they are not well defined.6.The relationship between levels of NAI phenotypic resistance and known molecular markers, frequency of emergence, transmissibility, and fitness of NAI-resistant variants are not well established.
This review presents current knowledge of the efficacy of NAIs for influenza B virus and antiviral resistance in clinical, surveillance, and experimental studies.
The influenza neuraminidase (NA) enzyme cleaves terminal sialic acid residues from cellular receptors, a process required for the release of newly synthesized virions. A balance of NA activity with ...sialic acid binding affinity of hemagglutinin (HA) is important for optimal virus replication. NA sequence evolution through genetic shift and drift contributes to the continuous modulation of influenza virus fitness and pathogenicity. A simple and reliable method for the determination of kinetic parameters of NA activity could add significant value to global influenza surveillance and provide parameters for the projection of fitness and pathogenicity of emerging virus variants. The use of fluorogenic substrate 2'-(4-methylumbelliferyl)-α-D-N-acetylneuraminic acid (MUNANA) and cell- or egg-grown whole influenza virus preparations have been attractive components of NA enzyme activity investigations. We describe important criteria to be addressed when determining K(m) and V(max) kinetic parameters using this method: (1) determination of the dynamic range of MUNANA and 4-methylumbelliferone product (4-MU) fluorescence for the instrument used; (2) adjustment of reaction conditions to approximate initial rate conditions, i.e. ≤15% of substrate converted during the reaction, with signal-to-noise ratio ≥10; (3) correction for optical interference and inner filter effect caused by increasing concentrations of MUNANA substrate. The results indicate a significant interference of MUNANA with 4-MU fluorescence determination. The criteria proposed enable an improved rapid estimation of NA kinetic parameters and facilitate comparison of data between laboratories.
We don't know whether the next influenza pandemic will be caused by the H5N1 avian influenza virus. But Drs. Robert Webster and Elena Govorkova write that given the number of cases of H5N1 influenza ...that have occurred in humans to date (251) and the rate of death of more than 50%, it would be prudent to develop robust plans for dealing with such a pandemic.
There is no question that there will be another influenza pandemic someday. We simply don't know when it will occur or whether it will be caused by the H5N1 avian influenza virus. But given the number of cases of H5N1 influenza that have occurred in humans to date (251 as of late September 2006) and the rate of death of more than 50%, it would be prudent to develop robust plans for dealing with such a pandemic.
The epicenters of both the Asian influenza pandemic of 1957 and the Hong Kong influenza pandemic of 1968 were in Southeast Asia, and . . .
Highly pathogenic avian influenza A(H5N1) viruses of clade 2.3.4.4b underwent an explosive geographic expansion in 2021 among wild birds and domestic poultry across Asia, Europe, and Africa. By the ...end of 2021, 2.3.4.4b viruses were detected in North America, signifying further intercontinental spread. Here we show that the western movement of clade 2.3.4.4b was quickly followed by reassortment with viruses circulating in wild birds in North America, resulting in the acquisition of different combinations of ribonucleoprotein genes. These reassortant A(H5N1) viruses are genotypically and phenotypically diverse, with many causing severe disease with dramatic neurologic involvement in mammals. The proclivity of the current A(H5N1) 2.3.4.4b virus lineage to reassort and target the central nervous system warrants concerted planning to combat the spread and evolution of the virus within the continent and to mitigate the impact of a potential influenza pandemic that could originate from similar A(H5N1) reassortants.
Effective antivirals provide crucial benefits during the early phase of an influenza pandemic, when vaccines are still being developed and manufactured. Currently, two classes of viral ...protein–targeting drugs, neuraminidase inhibitors and polymerase inhibitors, are approved for influenza treatment and post-exposure prophylaxis. Resistance to both classes has been documented, highlighting the need to develop novel antiviral options that may include both viral and host-targeted inhibitors. Such efforts will form the basis of management of seasonal influenza infections and of strategic planning for future influenza pandemics. This review focuses on the two classes of approved antivirals, their drawbacks, and ongoing work to characterize novel agents or combination therapy approaches to address these shortcomings. The importance of these topics in the ongoing process of influenza pandemic planning is also discussed.
Global analysis of the susceptibility of influenza viruses to neuraminidase (NA) inhibitors (NAIs) and the polymerase acidic (PA) inhibitor (PAI) baloxavir was conducted by five World Health ...Organization Collaborating Centres for Reference and Research on Influenza during two periods (May 2018–May 2019 and May 2019–May 2020). Combined phenotypic and NA sequence-based analysis revealed that the global frequency of viruses displaying reduced or highly reduced inhibition (RI or HRI) or potential to show RI/HRI by NAIs remained low, 0.5% (165/35045) and 0.6% (159/26010) for the 2018–2019 and 2019–2020 periods, respectively. The most common amino acid substitution was NA-H275Y (N1 numbering) conferring HRI by oseltamivir and peramivir in A(H1N1)pdm09 viruses. Combined phenotypic and PA sequence-based analysis showed that the global frequency of viruses showing reduced susceptibility to baloxavir or carrying substitutions associated with reduced susceptibility was low, 0.5% (72/15906) and 0.1% (18/15692) for the 2018–2019 and 2019–2020 periods, respectively. Most (n = 61) of these viruses had I38→T/F/M/S/L/V PA amino acid substitutions. In Japan, where baloxavir use was highest, the rate was 4.5% (41/919) in the 2018–2019 period and most of the viruses (n = 32) had PA-I38T. Zoonotic viruses isolated from humans (n = 32) in different countries did not contain substitutions in NA associated with NAI RI/HRI phenotypes. One A(H5N6) virus had a dual substitution PA-I38V + PA-E199G, which may reduce susceptibility to baloxavir. Therefore, NAIs and baloxavir remain appropriate choices for the treatment of influenza virus infections, but close monitoring of antiviral susceptibility is warranted.
•Seasonal influenza viruses collected globally were analyzed for susceptibilities to NA and PA inhibitors.•Frequency of viruses showing reduced inhibition by NA inhibitors remained low (0.5–0.6%) during 2018–2020.•Frequency of viruses showing reduced baloxavir susceptibility was low (0.1–0.5%) but elevated (4.5%) in Japan in 2018–2019.•NA inhibitors and PA inhibitor baloxavir remain appropriate choices for the treatment of influenza.
The International Society for Influenza and other Respiratory Virus Diseases held its 5th Antiviral Group (isirv-AVG) Conference in Shanghai, China, in conjunction with the Shanghai Public Health ...Center and Fudan University from 14-16 June 2017. The three-day programme encompassed presentations on some of the clinical features, management, immune responses and virology of respiratory infections, including influenza A(H1N1)pdm09 and A(H7N9) viruses, MERS-CoV, SARS-CoV, adenovirus Type 80, enterovirus D68, metapneumovirus and respiratory syncytial virus (RSV). Updates were presented on several therapeutics currently in clinical trials, including influenza polymerase inhibitors pimodivir/JNJ6362387, S033188, favipiravir, monoclonal antibodies MHAA45449A and VIS410, and host directed strategies for influenza including nitazoxanide, and polymerase ALS-008112 and fusion inhibitors AK0529, GS-5806 for RSV. Updates were also given on the use of the currently licensed neuraminidase inhibitors. Given the location in China, there were also presentations on the use of Traditional Chinese Medicines. Following on from the previous conference, there were ongoing discussions on appropriate endpoints for severe influenza in clinical trials from regulators and clinicians, an issue which remains unresolved. The aim of this conference summary is to provide information for not only conference participants, but a detailed referenced review of the current status of clinical trials, and pre-clinical development of therapeutics and vaccines for influenza and other respiratory diseases for a broader audience.
•Details of presentations given at the recent isirv-AVG conference held in Shanghai, June 2017 are summarized.•Topics covered clinical features, management, immune responses and virology of respiratory infections.•Viruses discussed included influenza, RSV, SARS, MERS-CoV, EV-D68, adenovirus Type 80 and metapneumovirus.•Influenza vaccines, polymerase inhibitors, monoclonal antibodies and cell targeted therapies were discussed.•RSV vaccines, polymerase and fusion inhibitors were discussed.
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