Control Of Pandemic Influenza Research Articles

Inactivated Whole Virus Particle Influenza Vaccine Induces Anti-Neuraminidase Antibodies That May Contribute to Cross-Protection against Heterologous Virus Infection.

Despite the use of vaccines, seasonal influenza remains a risk to public health. We previously proposed the inactivated whole virus particle vaccine (WPV) as an alternative to the widely used split vaccine (SV) for the control of seasonal and pandemic influenza based on the superior priming potency of WPV to that of SV. In this study, we further examined and compared the immunological potency of monovalent WPV and SV of A/California/7/2009 (X-179A) (H1N1) pdm09 (CA/09) to generate immune responses against heterologous viruses, A/Singapore/GP1908/2015 (IVR-180) (H1N1) pdm09 (SG/15), and A/duck/Hokkaido/Vac-3/2007 (H5N1) (DH/07) in mice. Following challenge with a lethal dose of heterologous SG/15, lower virus titer in the lungs and milder weight loss were observed in WPV-vaccinated mice than in SV-vaccinated ones. To investigate the factors responsible for the differences in the protective effect against SG/15, the sera of vaccinated mice were analyzed by hemagglutination-inhibition (HI) and neuraminidase-inhibition (NI) assays to evaluate the antibodies induced against viral hemagglutinin (HA) and neuraminidase (NA), respectively. While the two vaccines induced similar levels of HI antibodies against SG/15 after the second vaccination, only WPV-vaccinated mice induced significantly higher titers of NI antibodies against the strain. Furthermore, given the significant elevation of NI antibody titers against DH/07, an H5N1 avian influenza virus, WPV was also demonstrated to induce NA-inhibiting antibodies that recognize NA of divergent strains. This could be explained by the higher conservation of epitopes of NA among strains than for HA. Taking these findings together, NA-specific antibodies induced by WPV may have contributed to better protection from infection with heterologous influenza virus SG/15, compared with SV. The present results indicate that WPV is an effective vaccine for inducing antibodies against both HA and NA of heterologous viruses and may be a useful vaccine to conquer vaccine strain mismatch.

Profiling of lung SARS-CoV-2 and influenza virus infection dissects virus-specific host responses and gene signatures.

BackgroundThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which emerged in late 2019 has spread globally, causing a pandemic of respiratory illness designated coronavirus disease 2019 (COVID-19). A better definition of the pulmonary host response to SARS-CoV-2 infection is required to understand viral pathogenesis and to validate putative COVID-19 biomarkers that have been proposed in clinical studies.MethodsHere, we use targeted transcriptomics of formalin-fixed paraffin-embedded tissue using the NanoString GeoMX platform to generate an in-depth picture of the pulmonary transcriptional landscape of COVID-19, pandemic H1N1 influenza and uninfected control patients.ResultsHost transcriptomics showed a significant upregulation of genes associated with inflammation, type I interferon production, coagulation and angiogenesis in the lungs of COVID-19 patients compared to non-infected controls. SARS-CoV-2 was non-uniformly distributed in lungs (emphasising the advantages of spatial transcriptomics) with the areas of high viral load associated with an increased type I interferon response. Once the dominant cell type present in the sample, within patient correlations and patient–patient variation, had been controlled for, only a very limited number of genes were differentially expressed between the lungs of fatal influenza and COVID-19 patients. Strikingly, the interferon-associated gene IFI27, previously identified as a useful blood biomarker to differentiate bacterial and viral lung infections, was significantly upregulated in the lungs of COVID-19 patients compared to patients with influenza.ConclusionCollectively, these data demonstrate that spatial transcriptomics is a powerful tool to identify novel gene signatures within tissues, offering new insights into the pathogenesis of SARS-COV-2 to aid in patient triage and treatment.

Impact of the COVID-19 nonpharmaceutical interventions on influenza and other respiratory viral infections in New Zealand

Stringent nonpharmaceutical interventions (NPIs) such as lockdowns and border closures are not currently recommended for pandemic influenza control. New Zealand used these NPIs to eliminate coronavirus disease 2019 during its first wave. Using multiple surveillance systems, we observed a parallel and unprecedented reduction of influenza and other respiratory viral infections in 2020. This finding supports the use of these NPIs for controlling pandemic influenza and other severe respiratory viral threats.

Harnessing the potential of blood donation archives for influenza surveillance and control.

Many blood donation services around the globe maintain large archives of serum and/or plasma specimens of blood donations which could potentially be used for serologic surveillance and risk assessment of influenza. Harnessing this potential requires robust evidence that the outcomes of influenza serology in plasma, which is rarely used, is consistent with that in serum, which is the conventional choice of specimens for influenza serology. We harvested EDTA-plasma specimens from the blood donation archives of Hong Kong Red Cross Transfusion Services, where EDTA is the type of anticoagulant used for plasma collection, compared their antibody titers and responses to that in serum. Influenza A/H1N1/California/7/2009 and A/H3N2/Victoria/208/2009 were the test strains. Our results showed that antibody titers in 609 matched serum/EDTA-plasma specimens (i.e. obtained from the same donor at the same time) had good agreement inferred by Intraclass Correlation Coefficient, the value of which was 0.82 (95% CI: 0.77–0.86) for hemagglutination inhibition assay and 0.95 (95% CI: 0.93–0.96) for microneutralization assay; seroconversion rates (based on hemagglutination inhibition titers) during the 2010 and 2011 influenza seasons in Hong Kong inferred from paired EDTA-plasma were similar to that inferred from paired sera. Our study provided the proof-of-concept that blood donation archives could be leveraged as a valuable source of longitudinal blood specimens for the surveillance, control and risk assessment of both pandemic and seasonal influenza.

Fifty Years of Influenza A(H3N2) Following the Pandemic of 1968.

In 2018, the world commemorated the centennial of the 1918 influenza A(H1N1) pandemic, the deadliest pandemic in recorded history; however, little mention was made of the 50th anniversary of the 1968 A(H3N2) pandemic. Although pandemic morbidity and mortality were much lower in 1968 than in 1918, influenza A(H3N2) virus infections have become the leading cause of seasonal influenza illness and death over the last 50 years, with more than twice the number of hospitalizations from A(H3N2) as from A(H1N1) during the past six seasons. We review the emergence, progression, clinical course, etiology, epidemiology, and treatment of the 1968 pandemic and highlight the short- and long-term impact associated with A(H3N2) viruses. The 1968 H3N2 pandemic and its ongoing sequelae underscore the need for improved seasonal and pandemic influenza prevention, control, preparedness, and response efforts.

Rapid control of pandemic H1N1 influenza by targeting NKT-cells.

Swine influenza A viruses (IAV) are a major cause of respiratory disease in pigs and humans. Currently approved anti-influenza therapies directly target the virus, but these approaches are losing effectiveness as new viral strains quickly develop drug resistance. To over come this challenge, there is an urgent need for more effective antiviral drugs. Here we tested the anti-influenza efficacy of the invariant natural killer T (NKT) cell superagonist, α-galactosylceramide (α-GalCer), which stimulates a wide array of anti-viral immune responses. We show that intranasal but not systemic administration of α-GalCer to piglets infected with pandemic A/California/04/2009 (CA04) H1N1 IAV ameliorated disease symptoms and resulted in the restoration of weight gain to the level of uninfected pigs. Correspondingly, viral titers in the upper-and lower-respiratory tract were reduced only in piglets that had received intranasal α-GalCer. Most significantly, lung inflammation as a consequence of virus persistence was largely prevented when NKT-cells were targeted via the respiratory route. Thus, targeting mucosal NKT-cells may provide a novel and potent platform for improving the course of disease in swine infected with seasonal and pandemic influenza viruses, and leads to the suggestion that this may also be true in humans and therefore deserves further study.

Re-emergence of amantadine-resistant variants among highly pathogenic avian influenza H5N1 viruses in Egypt

Highly pathogenic avian influenza (HPAI) H5N1 virus continues to undergo substantial evolution. Emergence of antiviral resistance among H5N1 avian influenza viruses is a major challenge in the control of pandemic influenza. Numerous studies have focused on the genetic and evolutionary dynamics of the hemagglutinin and neuraminidase genes; however, studies on the susceptibility of HPAI H5N1 viruses to amantadine and genetic diversity of the matrix (M) gene are limited. Accordingly, we studied the amantadine susceptibility of the HPAI H5N1 viruses isolated in Egypt during 2006–2015 based on genotypic and phenotypic characteristics. We analyzed data on 253 virus sequences and constructed a phylogenetic tree to calculate selective pressures on sites in the M2 gene associated with amantadine-resistance among different clades. Selection pressure was identified in the transmembrane domain of M2 gene at positions 27 and 31. Amantadine-resistant variants emerged in 2007 but were not circulating between 2012 and 2014. By 2015, amantadine-resistant HPAI H5N1 viruses re-emerged. This may be associated with the uncontrolled prescription of amantadine for prophylaxis and control of avian influenza infections in the poultry farm sector in Egypt. More epidemiological research is required to verify this observation.

Pandemic Risk Assessment Model (PRAM): a mathematical modeling approach to pandemic influenza planning.

The Pandemic Risk Assessment Model (PRAM) is a mathematical model developed to analyse two pandemic influenza control measures available to public health: antiviral treatment and immunization. PRAM is parameterized using surveillance data from Alberta, Canada during pandemic H1N1. Age structure and risk level are incorporated in the compartmental, deterministic model through a contact matrix. The model characterizes pandemic influenza scenarios by transmissibility and severity properties. Simulating a worst-case scenario similar to the 1918 pandemic with immediate stockpile release, antiviral demand is 20·3% of the population. With concurrent, effective and timely immunization strategies, antiviral demand would be significantly less. PRAM will be useful in informing policy decisions such as the size of the Alberta antiviral stockpile and can contribute to other pandemic influenza planning activities and scenario analyses.

Amantadine resistance among highly pathogenic avian influenza viruses (H5N1) isolated from India

Emergence of antiviral resistance among H5N1 avian influenza viruses is the major challenge in the control of pandemic influenza. Matrix 2 (M2) inhibitors (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir and zanamivir) are the two classes of antiviral agents that are specifically active against influenza viruses and are used for both treatment and prophylaxis of influenza infections. Amantadine targets the M2 ion channel of influenza A virus and interrupts virus life cycle through blockade of hydrogen ion influx. This prevents uncoating of the virus in infected host cells which impedes the release of ribonucleoprotein required for transcription and replication of virion in the nucleus. The present study was carried out to review the status of amantadine resistance in H5N1 viruses isolated from India and to study their replicative capability. Results of the study revealed resistance to amantadine in antiviral assay among four H5N1 viruses out of which two viruses had Serine 31 Asparagine (AGT—AAT i.e., S31N) mutation and two had Valine 27 Alanine (GTT—GCT i.e., V27A) mutation. The four resistant viruses not only exhibited significant difference in effective concentration 50% (EC50) values of amantadine hydrochloride from that of susceptible viruses (P < 0.0001) but also showed significant difference between two different types (S31N and V27A) of mutant viruses (P < 0.05). Resistance to amantadine could also be demonstrated in a simple HA test after replication of the viruses in MDCK cells in presence of amantadine. The study identifies the correlation between in vitro antiviral assay and presence of established molecular markers of resistance, the retention of replicative capacity in the presence of amantadine hydrochloride by the resistant viruses and the emergence of resistant mutations against amantadine among avian influenza viruses (H5N1) without selective drug pressure.

Assessing the Role of Voluntary Self-Isolation in the Control of Pandemic Influenza Using a Household Epidemic Model.

In the absence of effective vaccines, antiviral drugs and personal protective measures, such as voluntary self-isolation, have been a part of preparedness plans for the next influenza pandemic. We used a household model to assess the effect of voluntary self-isolation on outbreak control when antiviral drugs are not provided sufficiently early. We found that the early initiation of voluntary self-isolation can overcome the negative effects caused by a delay in antiviral drug distribution when enough symptomatic individuals comply with home confinement at symptom onset. For example, for the baseline household reproduction number , if delays of one or two days occur between clinical symptom development and the start of antiviral prophylaxis, then compliance rates of and , respectively, are required to achieve the same level of effectiveness as starting antiviral prophylaxis at symptom onset. When the time to beginning voluntary self-isolation after symptom onset increases from zero to two days, this strategy has a limited effect on reducing the transmission of influenza; therefore, this strategy should be implemented as soon as possible. In addition, the effect of voluntary self-isolation decreases substantially with the proportion of asymptomatic infections increasing.

Southern Hemisphere Influenza and Vaccine Effectiveness Research and Surveillance.

The 2009 influenza A(H1N1)pdm09 pandemic highlighted the need for improved scientific knowledge to support better pandemic preparedness and seasonal influenza control. The Southern Hemisphere Influenza and Vaccine Effectiveness Research and Surveillance (SHIVERS) project, a 5-year (2012–2016) multiagency and multidisciplinary collaboration, aimed to measure disease burden, epidemiology, aetiology, risk factors, immunology, effectiveness of vaccination and other prevention strategies for influenza and other respiratory infectious diseases of public health importance. Two active, prospective, population-based surveillance systems were established for monitoring influenza and other respiratory pathogens among those hospitalized patients with acute respiratory illness and those enrolled patients seeking consultations at sentinel general practices. In 2015, a sero-epidemiological study will use a sample of patients from the same practices. These data will provide a full picture of the disease burden and risk factors from asymptomatic infections to severe hospitalized disease and deaths and related economic burden. The results during the first 2 years (2012–2013) provided scientific evidence to (a) support a change to NZ's vaccination policy for young children due to high influenza hospitalizations in these children; (b) contribute to the revision of the World Health Organization's case definition for severe acute respiratory illness for global influenza surveillance; and (c) contribute in part to vaccine strain selection using vaccine effectiveness assessment in the prevention of influenza-related consultations and hospitalizations. In summary, SHIVERS provides valuable international platforms for supporting seasonal influenza control and pandemic preparedness, and responding to other emerging/endemic respiratory-related infections.

Early vaccine availability represents an important public health advance for the control of pandemic influenza.

BackgroundTraditional processes for the production of pandemic influenza vaccines are not capable of producing a vaccine that could be deployed sooner than 5–6 months after strain identification. Plant-based vaccine technologies are of public health interest because they represent an opportunity to begin vaccinating earlier.MethodsWe used an age- and risk- structured disease transmission model for Canada to evaluate the potential impact of a plant-produced vaccine available for rapid deployment (within 1–3 months) compared to an egg-based vaccine timeline.ResultsWe found that in the case of a mildly transmissible virus (R0 = 1.3), depending on the amount of plant-based vaccine produced per week, severe clinical outcomes could be decreased by 60–100 % if vaccine was available within 3 months of strain identification. However, in the case of a highly transmissible virus (R0 = 2.0), a delay of 3 months does not change clinical outcomes regardless of the level of weekly vaccine availability. If transmissibility is high, the only strategy that can impact clinical outcomes occurs if vaccine production is high and available within 2 months.ConclusionsPandemic influenza vaccines produced by plants, change the timeline of pandemic vaccine availability in a way that could significantly mitigate the impact of the next influenza pandemic.

A Meta-analysis of the incidence of influenza reported during year 2005 to 2012 in China

Objective To investigate the epidemic patterns and the characteristics of influenza in China through a Meta-analysis based on the studies published in domestic literatures. Methods Related articles published during 2005 to 2012 were screened out from domestic databases and analyzed through a Meta-analysis with Review Manager 5.0 software. Results Twenty-two articles covering 957 901 patients with influenza-like-illness (ILI) and 148 233 pathogen samples were screened out according to the inclusion criteria. No significant difference with the ILI diagnosis rate was found between subjects at age 0-4 years and those at age 15-59 years. Higher ILI diagnosis rates were observed in those two groups as compared with subjects elder than 60 years old. Most of the pathogen samples were carried by subjects aged 25-59 years. More influenza virus strains were isolated in 2009 as compared with those of the seven other years (OR=2.25, 95%CI=1.27-3.70). There was statistical difference between the numbers of influenza A H1N1 and seasonal influenza A strains (OR=2.25, 95%CI=1.30-3.91). Significant difference was also observed between the numbers of influenza A and influenza B strains (OR=4.05, 95%CI=2.53-6.47). Conclusion There was significant difference with the diagnosis rate between subjects aged 0-4 years and those aged ≥60 years. More attention should be paid to people at high risk of infection (0-4 years old and ≥60 years old) and those at 25-29 years with high mobility and social intercourse for the timely prevention and control of pandemic influenza. The detection rate of influenza virus strains was increased during the outbreak of novel influenza A H1N1 infection in 2009. After that outbreak, the detection rate of novel influenza A H1N1 strains was 2.25 times the rate of seasonal influenza strains. The detection rate of influenza A was 4.05 times the rate of influenza B virus strains. Therefore, it is necessary to strengthen the surveillance for influenza A virus and other epidemic influenza virus strains. Key words: Influenza virus; Influenza-like-illness; Meta-analysis

Prior population immunity reduces the expected impact of CTL-inducing vaccines for pandemic influenza control.

Vaccines that trigger an influenza-specific cytotoxic T cell (CTL) response may aid pandemic control by limiting the transmission of novel influenza A viruses (IAV). We consider interventions with hypothetical CTL-inducing vaccines in a range of epidemiologically plausible pandemic scenarios. We estimate the achievable reduction in the attack rate, and, by adopting a model linking epidemic progression to the emergence of IAV variants, the opportunity for antigenic drift. We demonstrate that CTL-inducing vaccines have limited utility for modifying population-level outcomes if influenza-specific T cells found widely in adults already suppress transmission and prove difficult to enhance. Administration of CTL-inducing vaccines that are efficacious in "influenza-experienced" and "influenza-naive" hosts can likely slow transmission sufficiently to mitigate a moderate IAV pandemic. However if neutralising cross-reactive antibody to an emerging IAV are common in influenza-experienced hosts, as for the swine-variant H3N2v, boosting CTL immunity may be ineffective at reducing population spread, indicating that CTL-inducing vaccines are best used against novel subtypes such as H7N9. Unless vaccines cannot readily suppress transmission from infected hosts with naive T cell pools, targeting influenza-naive hosts is preferable. Such strategies are of enhanced benefit if naive hosts are typically intensively mixing children and when a subset of experienced hosts have pre-existing neutralising cross-reactive antibody. We show that CTL-inducing vaccination campaigns may have greater power to suppress antigenic drift than previously suggested, and targeting adults may be the optimal strategy to achieve this when the vaccination campaign does not have the power to curtail the attack rate. Our results highlight the need to design interventions based on pre-existing cellular immunity and knowledge of the host determinants of vaccine efficacy, and provide a framework for assessing the performance requirements of high-impact CTL-inducing vaccines.

Assessing the use of antiviral treatment to control influenza.

Vaccines are the cornerstone of influenza control policy, but can suffer from several drawbacks. Seasonal influenza vaccines are prone to production problems and low efficacies, while pandemic vaccines are unlikely to be available in time to slow a rapidly spreading global outbreak. Antiviral therapy was found to be beneficial during the influenza A(H1N1)pdm09 pandemic even with limited use; however, antiviral use has decreased further since then. We sought to determine the role antiviral therapy can play in pandemic and seasonal influenza control using conservative estimates of antiviral efficacy, and to assess if conservative but targeted strategies could be employed to optimize the use of antivirals. Using an age-structured contact network model for an urban population, we compared the transmission-blocking ability of a conservative antiviral therapy strategy to the susceptibility-reducing effects of a robust influenza vaccine. Our results show that while antiviral therapy cannot replace a robust influenza vaccine, it can play a role in reducing attack rates and eliminating outbreaks, and could significantly reduce public health burden when vaccine is either unavailable or ineffective. We also found that antiviral therapy, by treating those who are infected, is naturally a highly optimized strategy, and need not be improved upon with expensive targeted campaigns.

Evaluation of the spread of pandemic influenza A/H1N1 2009 among Japanese university students.

The pandemic influenza A/H1N1 2009 virus is commonly known to affect younger individuals. Several epidemiological studies have clarified the epidemic features of university students in Japan. In this study, we reviewed these studies in Japan in comparison with reports from other countries. The average cumulative incidence rate among university students was 9.6 %, with the major symptoms being cough, sore throat, and rhinorrhea. These epidemiological features were similar between Japan and other countries. Attitudes and behaviors toward pandemic influenza control measures were different before and improved during and after the epidemic. These features were also similar to those in other countries. On the other hand, the epidemic spread through club activities or social events, and transmission was attenuated after temporary closure of such groups in Japan. This transmission pattern was inconsistent among countries, which may have been due to differences in lifestyle and cultural habits. Based on these results, infection control measures of pandemic influenza for university organizations in Japan should be considered.

Implementing hospital-based surveillance for severe acute respiratory infections caused by influenza and other respiratory pathogens in New Zealand.

Recent experience with pandemic influenza A(H1N1)pdm09 highlighted the importance of global surveillance for severe respiratory disease to support pandemic preparedness and seasonal influenza control. Improved surveillance in the southern hemisphere is needed to provide critical data on influenza epidemiology, disease burden, circulating strains and effectiveness of influenza prevention and control measures. Hospital-based surveillance for severe acute respiratory infection (SARI) cases was established in New Zealand on 30 April 2012. The aims were to measure incidence, prevalence, risk factors, clinical spectrum and outcomes for SARI and associated influenza and other respiratory pathogen cases as well as to understand influenza contribution to patients not meeting SARI case definition. All inpatients with suspected respiratory infections who were admitted overnight to the study hospitals were screened daily. If a patient met the World Health Organization's SARI case definition, a respiratory specimen was tested for influenza and other respiratory pathogens. A case report form captured demographics, history of presenting illness, co-morbidities, disease course and outcome and risk factors. These data were supplemented from electronic clinical records and other linked data sources. Hospital-based SARI surveillance has been implemented and is fully functioning in New Zealand. Active, prospective, continuous, hospital-based SARI surveillance is useful in supporting pandemic preparedness for emerging influenza A(H7N9) virus infections and seasonal influenza prevention and control.

Evaluation of strategies for control and prevention of pandemic influenza (H1N1pdm) in Japanese children attending school in a rural town. Simulation using mathematical models.

In 2009, epidemics of influenza (H1N1pdm) occurred worldwide. We evaluated 4 strategies for control and prevention of influenza (treatment with antiviral drugs, preventive actions, cancellation of large events, and school closures) by surveying the H1N1pdm epidemic in a geographically isolated rural town in Japan, and applying the epidemic to mathematical models. Subjects were 291 children attending nursery, primary, and junior high schools in Kounu town. The 4 strategies were evaluated by 3 types of mathematical models with varying parameters. The total number of infected cases, as reported in questionnaires, was 120. In the best-fitting model, treatment with antiviral drugs shortened the epidemic period from 31 to 23 days. Event cancellation reduced the total number of infected cases from 127.1 to 87.6 and the maximum number of cases from 63.7 to 41.7. In this simulation, 56 people were affected by the intervention. Immediate school closure reduced the total and maximum numbers of infected cases to 62.6 and 23.1, respectively. Statistical analysis confirmed that event cancellation and school closure are effective strategies for control of an influenza epidemic. The effective contact rate varied, which reflects a localized and rapidly spreading epidemic in a subpopulation.

Epidemiological consequences of household-based antiviral prophylaxis for pandemic influenza

Antiviral treatment offers a fast acting alternative to vaccination; as such it is viewed as a first-line of defence against pandemic influenza in protecting families and households once infection has been detected. In clinical trials, antiviral treatments have been shown to be efficacious in preventing infection, limiting disease and reducing transmission, yet their impact at containing the 2009 influenza A(H1N1)pdm outbreak was limited. To understand this seeming discrepancy, we develop a general and computationally efficient model for studying household-based interventions. This allows us to account for uncertainty in quantities relevant to the 2009 pandemic in a principled way, accounting for the heterogeneity and variability in each epidemiological process modelled. We find that the population-level effects of delayed antiviral treatment and prophylaxis mean that their limited overall impact is quantitatively consistent (at current levels of precision) with their reported clinical efficacy under ideal conditions. Hence, effective control of pandemic influenza with antivirals is critically dependent on early detection and delivery ideally within 24 h.

Public Health Policy and Law for Pandemic Influenza: A Case for European Harmonization?

This article provides a critical portrait of the current state of public health policies and laws governing pandemic influenza prevention and control in Europe. It examines the role of and relationship between national public health policy and national communicable disease legislation as tools for the prevention and control of pandemic influenza, the role of Europe in pandemic disease preparedness, and the concept of harmonization across European states, including an overview of supranational initiatives and powers created to enhance harmonization of national pandemic disease policy. Short case studies epitomize important concerns around harmonization in Europe. The article considers opportunities and impediments to further harmonization. Particular attention is paid to the essential role of law as a tool to underpin and implement preparedness policies and to protect individual rights against unjustified state intervention.