Future Pandemic Viruses Research Articles

Pandemic preparedness: On the efficacy of non-pharmaceutical interventions in COVID-19 and about approaches to predict future pandemic viruses.

With three major viral pandemics over the last 100 years, namely the Spanish flu, AIDS and COVID-19 each claiming many millions of lives, pandemic preparedness has become an important issue for public health. The economic, social and political consequences of the upheaval caused by such pandemics also represent a major challenge for governments with respect to sustainable development goals. The field of pandemic preparedness is vast and the current article can only address selected aspects. The article looks first backwards and addresses the question of the efficacy of non-pharmaceutical interventions (NPI) on the trajectory of the COVID-19 pandemic. The article looks then forward by asking to what extent viral candidates for future pandemics can be predicted by virome analyses from metagenome and transcriptome sequencing, by focusing on the virome from specific animal species and using ecological and epidemiological data about spillover viral infections in veterinary and human medicine. As a comprehensive overview on pandemic preparedness is beyond the capacity of a single reviewer, only selected topics will be discussed using recent key scientific publications. Since COVID-19 has not run its course, a computational program able to predict the future evolution of SARS-CoV-2 is mentioned that could assist proactive mRNA vaccine developments against possible future variants of concern. Ending the COVID-19 epidemic necessitates mucosal vaccines that can suppress the transmission of SARS-CoV-2 and therefore this article closes by discussing a promising and versatile protein nanoparticle experimental vaccine approach for inhalation that does not depend on needles nor a cold chain for distribution.

In viral games, refs go to the replay.

After more than 2 years of intensive investigation, the direct ancestors of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain unidentified. Molecular epidemiology strongly supports a timeline marked by multiple, independent zoonoses in late 2019 (Pekar et al, 2022) solidifying the consensus hypothesis that close relatives of SARS-CoV-2 with high zoonotic potential were naturally circulating prior to the start of the pandemic (Andersen et al, 2020). Understanding where and when these ancestors acquired the genomic features that resulted in a virus with epidemic potential could enable the identification and mitigation of future pandemic viruses, even before the first human infection.

Predicting the mutational drivers of future SARS-CoV-2 variants of concern.

SARS-CoV-2 evolution threatens vaccine- and natural infection-derived immunity as well as the efficacy of therapeutic antibodies. To improve public health preparedness, we sought to predict which existing amino acid mutations in SARS-CoV-2 might contribute to future variants of concern. We tested the predictive value of features comprising epidemiology, evolution, immunology, and neural network-based protein sequence modeling, and identified primary biological drivers of SARS-CoV-2 intra-pandemic evolution. We found evidence that ACE2-mediated transmissibility and resistance to population-level host immunity has waxed and waned as a primary driver of SARS-CoV-2 evolution over time. We retroactively identified with high accuracy (area under the receiver operator characteristic curve, AUROC=0.92-0.97) mutations that will spread, at up to four months in advance, across different phases of the pandemic. The behavior of the model was consistent with a plausible causal structure wherein epidemiological covariates combine the effects of diverse and shifting drivers of viral fitness. We applied our model to forecast mutations that will spread in the future and characterize how these mutations affect the binding of therapeutic antibodies. These findings demonstrate that it is possible to forecast the driver mutations that could appear in emerging SARS-CoV-2 variants of concern. We validate this result against Omicron, showing elevated predictive scores for its component mutations prior to emergence, and rapid score increase across daily forecasts during emergence. This modeling approach may be applied to any rapidly evolving pathogens with sufficiently dense genomic surveillance data, such as influenza, and unknown future pandemic viruses.

Genomic epidemiology reveals the reduction of the introduction and spread of SARS-CoV-2 after implementing control strategies in Republic of Korea, 2020.

Genomic epidemiology is a core component in investigating the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this study, the efficacy of control strategies in South Korea was evaluated using genomic epidemiology based on viral genome sequences of 2,065 SARS-CoV-2 cases identified in South Korea from January 2020 to December 2020. Phylogenetic analysis revealed that the majority of viruses introduced from inbound travelers did not further spread throughout South Korea; however, four distinct subgroups (KR.1–4, belonging to B.1.497, B.1, K.1 and B.41) of viruses caused local epidemics. After the introduction of enhanced social distancing, the viral population size and daily case numbers decreased, and KR.2–4 subgroups were extinguished from South Korea. Nevertheless, there was a subsequent increase in KR.1 subgroups after the downgrading of social distancing level. These results indicate that the international traveler quarantine system implemented in South Korea along with social distancing measures efficiently reduced the introduction and spread of SARS-CoV-2, but it was not completely controlled. An improvement of control strategies will be required to better control SARS-CoV-2, its variants, and future pandemic viruses.

Universally Immune: How Infection Permissive Next Generation Influenza Vaccines May Affect Population Immunity and Viral Spread.

Next generation influenza vaccines that target conserved epitopes are becoming a clinical reality but still have challenges to overcome. Universal next generation vaccines are considered a vital tool to combat future pandemic viruses and have the potential to vastly improve long-term protection against seasonal influenza viruses. Key vaccine strategies include HA-stem and T cell activating vaccines; however, they could have unintended effects for virus adaptation as they recognise the virus after cell entry and do not directly block infection. This may lead to immune pressure on residual viruses. The potential for immune escape is already evident, for both the HA stem and T cell epitopes, and mosaic approaches for pre-emptive immune priming may be needed to circumvent key variants. Live attenuated influenza vaccines have not been immunogenic enough to boost T cells in adults with established prior immunity. Therefore, viral vectors or peptide approaches are key to harnessing T cell responses. A plethora of viral vector vaccines and routes of administration may be needed for next generation vaccine strategies that require repeated long-term administration to overcome vector immunity and increase our arsenal against diverse influenza viruses.

Advancing lung organoids for COVID-19 research.

ABSTRACTThe COVID-19 pandemic has emphasised the need to develop effective treatments to combat emerging viruses. Model systems that poorly represent a virus' cellular environment, however, may impede research and waste resources. Collaborations between cell biologists and virologists have led to the rapid development of representative organoid model systems to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We believe that lung organoids, in particular, have advanced our understanding of SARS-CoV-2 pathogenesis, and have laid a foundation to study future pandemic viruses and develop effective treatments.

Severity of influenza A(H1N1) illness and emergence of D225G variant, 2013-14 influenza season, Florida, USA.

Despite a regional decline in influenza A(H1N1)pdm09 virus infections during 2013–14, cases at a Florida hospital were more severe than those during 2009–10. Examined strains had a hemagglutinin polymorphism associated with enhanced binding to lower respiratory tract receptors. Genetic changes in this virus must be monitored to predict the effect of future pandemic viruses.

Human 4F5 single-chain Fv antibody recognizing a conserved HA1 epitope has broad neutralizing potency against H5N1 influenza A viruses of different clades

Influenza A viruses present a significant threat to public health worldwide. High-affinity human scFv antibodies against a conserved epitope can potentially provide immunity to diverse viruses and protect against future pandemic viruses. A library of phage-displayed human scFv containing 6.0×108 members was generated from lymphocytes of H5N1 virus vaccinated individuals. Using the recombinant H5N1 virus hemagglutinin ectodomain (HA1), 4F5 scFv was identified with neutralizing activity against both clade 2 and 9 H5N1 viruses. In embryonated chicken eggs, the antiviral activity of 4F5 scFv conferred a 100% survival rate and at least a 62.5% survival rate against different clades of H5N1 viruses by pre-treatment and post-treatment, respectively. 4F5 scFv belongs to the VH-3-43 family according to the IMGT database, and a peptide (76)WLLGNP(81) containing half of an α-helix in HA1 was identified as the binding pocket. The conserved binding epitope of this novel broadly neutralizing scFv may become key in the design and implementation of vaccines or RNA interference against H5N1 viruses.

Virulence and transmissibility of H1N2 influenza virus in ferrets imply the continuing threat of triple-reassortant swine viruses

Efficient worldwide swine surveillance for influenza A viruses is urgently needed; the emergence of a novel reassortant pandemic H1N1 (pH1N1) virus in 2009 demonstrated that swine can be the direct source of pandemic influenza and that the pandemic potential of viruses prevalent in swine populations must be monitored. We used the ferret model to assess the pathogenicity and transmissibility of predominant Korean triple-reassortant swine (TRSw) H1N2 and H3N2 influenza viruses genetically related to North American strains. Although most of the TRSw viruses were moderately pathogenic, one [A/Swine/Korea/1204/2009; Sw/1204 (H1N2)] was virulent in ferrets, causing death within 10 d of inoculation, and was efficiently transmitted to naive contact ferrets via respiratory droplets. Although molecular analysis did not reveal known virulence markers, the Sw/1204 virus acquired mutations in hemagglutinin (HA) (Asp-225-Gly) and neuraminidase (NA) (Ser-315-Asn) proteins during the single ferret passage. The contact-Sw/1204 virus became more virulent in mice, replicated efficiently in vitro, extensively infected human lung tissues ex vivo, and maintained its ability to replicate and transmit in swine. Reverse-genetics studies further indicated that the HA(225G) and NA(315N) substitutions contributed substantially in altering virulence and transmissibility. These findings support the continuing threat of some field TRSw viruses to human and animal health, reviving concerns on the capacity of pigs to create future pandemic viruses. Apart from warranting continued and enhanced global surveillance, this study also provides evidence on the emerging roles of HA(225G) and NA(315N) as potential virulence markers in mammals.

A human antibody recognizing a conserved epitope of H5 hemagglutinin broadly neutralizes highly pathogenic avian influenza H5N1 viruses.

Influenza A virus infection is a persistent threat to public health worldwide due to its ability to evade immune surveillance through rapid genetic drift and shift. Current vaccines against influenza A virus provide immunity to viral isolates that are similar to vaccine strains. High-affinity neutralizing antibodies against conserved epitopes could provide immunity to diverse influenza virus strains and protection against future pandemic viruses. In this study, by using a highly sensitive H5N1 pseudotype-based neutralization assay to screen human monoclonal antibodies produced by memory B cells from an H5N1-infected individual and molecular cloning techniques, we developed three fully human monoclonal antibodies. Among them, antibody 65C6 exhibited potent neutralization activity against all H5 clades and subclades except for subclade 7.2 and prophylactic and therapeutic efficacy against highly pathogenic avian influenza H5N1 viruses in mice. Studies on hemagglutinin (HA)-antibody complexes by electron microscopy and epitope mapping indicate that antibody 65C6 binds to a conformational epitope comprising amino acid residues at positions 118, 121, 161, 164, and 167 (according to mature H5 numbering) on the tip of the membrane-distal globular domain of HA. Thus, we conclude that antibody 65C6 recognizes a neutralization epitope in the globular head of HA that is conserved among almost all divergent H5N1 influenza stains.

Reassortant between Human-Like H3N2 and Avian H5 Subtype Influenza A Viruses in Pigs: A Potential Public Health Risk

BackgroundHuman-like H3N2 influenza viruses have repeatedly been transmitted to domestic pigs in different regions of the world, but it is still uncertain whether any of these variants could become established in pig populations. The fact that different subtypes of influenza viruses have been detected in pigs makes them an ideal candidate for the genesis of a possible reassortant virus with both human and avian origins. However, the determination of whether pigs can act as a “mixing vessel” for a possible future pandemic virus is still pending an answer. This prompted us to gather the epidemiological information and investigate the genetic evolution of swine influenza viruses in Jilin, China.MethodsNasopharyngeal swabs were collected from pigs with respiratory illness in Jilin province, China from July 2007 to October 2008. All samples were screened for influenza A viruses. Three H3N2 swine influenza virus isolates were analyzed genetically and phylogenetically.ResultsInfluenza surveillance of pigs in Jilin province, China revealed that H3N2 influenza viruses were regularly detected from domestic pigs during 2007 to 2008. Phylogenetic analysis revealed that two distinguishable groups of H3N2 influenza viruses were present in pigs: the wholly contemporary human-like H3N2 viruses (represented by the Moscow/10/99-like sublineage) and double-reassortant viruses containing genes from contemporary human H3N2 viruses and avian H5 viruses, both co-circulating in pig populations.ConclusionsThe present study reports for the first time the coexistence of wholly human-like H3N2 viruses and double-reassortant viruses that have emerged in pigs in Jilin, China. It provides updated information on the role of pigs in interspecies transmission and genetic reassortment of influenza viruses.

Communicating in a crisis: the H1N1 influenza pandemic

In 2009, with the influenza A (H1N1) virus, commonly known as swine flu, the world experienced the first influenza pandemic of the 21st century and the first for 40 years. For the vast majority of GPs and other health professionals, this has been the first experience of pandemic flu in our professional lifetimes. Compared to the influenza pandemics of the previous century, its impact has been relatively mild. However, it has been bad enough, with over 400 deaths in the UK and many thousands of people having been admitted to hospital or to critical care units. In the UK, we were fortunate that the pandemic waves occurred over the summer and autumn rather than at the time of peak winter activity in the NHS, but even so services were hard pressed in general and many general practices and primary care out-of-hours providers, especially in ‘hot-spot areas’, found they were stretched to the limit. Given that there are no guarantees that it will be 40 years or so until the next influenza pandemic and also that a future pandemic virus might well be more virulent, it is imperative that professionals and policy makers examine our recent experience and identify what went well, and more importantly, what needs to be improved to allow us to best meet the challenges of the next flu pandemic, or other major public health crisis. One area for reflection is that of professional communications. The article by Caley et al illustrates the difficulties experienced by GPs in the West Midlands …

Lessons from Pandemic H1N1 2009 to Improve Prevention, Detection, and Response to Influenza Pandemics from a One Health Perspective

In April 2009, a novel influenza A subtype H1N1 triple reassortant virus (novel H1N1 2009), composed of genes from swine, avian, and human influenza A viruses, emerged in humans in the United States and Mexico and spread person-to-person around the world to become the first influenza pandemic of the 21st century. The virus is believed to have emerged from a reassortment event involving a swine virus some time in the past 10 to 20 years, but pigs, pork, and pork products have not been involved with infection or spread of the virus to or among people. Because countries quickly implemented recently developed pandemic influenza plans, the disease was detected and reported and public health authorities instituted control measures in a timely fashion. But the news media's unfortunate and inappropriate naming of the disease as the “swine flu” led to a drop in the demand for pork and several countries banned pork imports from affected countries, resulting in serious negative economic impacts on the pork industry. With the continual circulation and interspecies transmission of human, swine, and avian influenza viruses in countries around the world, there are calls for strengthening influenza surveillance in pigs, birds, and other animals to aid in monitoring and assessing the risk of future pandemic virus emergence involving different species. We identify and discuss several lessons to be learned from pandemic H1N1 2009 from a One Health perspective, as stronger collaboration among human, animal, and environmental health sectors is necessary to more effectively prevent or detect and respond to influenza pandemics and thus improve human, animal, and environmental health and well-being.

Antibody recognition of a highly conserved influenza virus epitope.

Influenza virus presents an important and persistent threat to public health worldwide, and current vaccines provide immunity to viral isolates similar to the vaccine strain. High-affinity antibodies against a conserved epitope could provide immunity to the diverse influenza subtypes and protection against future pandemic viruses. Cocrystal structures were determined at 2.2 and 2.7 angstrom resolutions for broadly neutralizing human antibody CR6261 Fab in complexes with the major surface antigen (hemagglutinin, HA) from viruses responsible for the 1918 H1N1 influenza pandemic and a recent lethal case of H5N1 avian influenza. In contrast to other structurally characterized influenza antibodies, CR6261 recognizes a highly conserved helical region in the membrane-proximal stem of HA1 and HA2. The antibody neutralizes the virus by blocking conformational rearrangements associated with membrane fusion. The CR6261 epitope identified here should accelerate the design and implementation of improved vaccines that can elicit CR6261-like antibodies, as well as antibody-based therapies for the treatment of influenza.

Viral RNA polymerase complex promotes optimal growth of 1918 virus in the lower respiratory tract of ferrets

The 1918 influenza pandemic was the most devastating outbreak of infectious disease in human history, accounting for about 50 million deaths worldwide. In addition to a significant number of cases of secondary bacterial pneumonia, this highly pathogenic strain of influenza A virus caused fatal primary viral pneumonia. To identify the viral gene(s) chiefly responsible for the high virulence of the 1918 virus, we generated a series of reassortants between the 1918 virus and a contemporary human H1N1 virus (A/Kawasaki/173/2001; K173) using reverse genetics. We then assessed their virulence properties in ferrets, a model closely resembling humans in terms of sensitivity to influenza virus infection and pattern of spread after intranasal inoculation. Substitution of single genes from the 1918 virus in the genetic background of K173 virus did not markedly alter the pattern of infection. That is, the reassortants grew well in nasal turbinates, but only sporadically (if at all) in the trachea and lungs. One exception was the 1918PB1/K173 reassortant, which replicated efficiently in lung tissues as well as the upper respiratory tract. A reassortant virus expressing the 1918 viral RNA polymerase complex (PA, PB1, and PB2) and nucleoprotein showed virulence properties in the upper and lower respiratory tracts of ferrets that closely resembled those of wild-type 1918 virus. Our findings strongly implicate the viral RNA polymerase complex as a major determinant of the pathogenicity of the 1918 pandemic virus. This new insight may aid in identifying virulence factors in future pandemic viruses that could be targeted with antiviral compounds.

Influenza antiviral susceptibility monitoring activities in relation to national antiviral stockpiles in Europe during the winter 2006/2007 season

Due to the influenza pandemic threat, many countries are stockpiling antivirals in the hope of limiting the impact of a future pandemic virus. Since resistance to antiviral drugs would probably significantly alter the effectiveness of antivirals, surveillance programmes to monitor the emergence of resistance are of considerable importance. During the 2006/2007 influenza season, an inventory was conducted by the European Surveillance Network for Vigilance against Viral Resistance (VIRGIL) in collaboration with the European Influenza Surveillance Scheme (EISS) to evaluate antiviral susceptibility testing by the National Influenza Reference Laboratories (NIRL) in relation to the national antiviral stockpile in 30 European countries that are members of EISS. All countries except Ukraine had a stockpile of the neuraminidase inhibitor (NAI) oseltamivir. Additionally, four countries had a stockpile of the NAI zanamivir and three of the M2 ion channel inhibitor rimantadine. Of 29 countries with a NAI stockpile, six countries'; NIRLs could determine virus susceptibility by 50% inhibitory concentration (IC50) and in 13 countries it could be done by sequencing. Only in one of the three countries with a rimantadine stockpile could the NIRL determine virus susceptibility, by sequencing only. However, including the 18 countries that had plans to introduce or extend antiviral susceptibility testing, the NIRLs of 21 of the 29 countries with a stockpile would be capable of susceptibility testing appropriate to the stockpiled drug by the end of the 2007/2008 influenza season. Although most European countries in this study have stockpiles of influenza antivirals, susceptibility surveillance capability by the NIRLs appropriate to the stockpiled antivirals is limited.