Time-varying overdispersion of SARS-CoV-2 transmission during the periods when different variants of concern were circulating in Japan.

Japan has implemented a cluster-based approach for coronavirus disease 2019 (COVID-19) from the pandemic's beginning based on the transmission heterogeneity (overdispersion) of severe acute respiratory coronavirus 2 (SARS-CoV-2). However, studies analyzing overdispersion of transmission among new variants of concerns (VOCs), especially for Omicron, were limited. Thus, we aimed to clarify how the transmission heterogeneity has changed with the emergence of VOCs (Alpha, Delta, and Omicron) using detailed contact tracing data in Yamagata Prefecture, Japan. We estimated the time-varying dispersion parameter ([Formula: see text]) by fitting a negative binomial distribution for each transmission generation. Our results showed that even after the emergence of VOCs, there was transmission heterogeneity of SARS-CoV-2, with changes in [Formula: see text] during each wave. Continuous monitoring of transmission dynamics is vital for implementing appropriate measures. However, a feasible and sustainable epidemiological analysis system should be established to make this possible.

Increase in the number of new cases of ANCA-associated vasculitis in the COVID-19 vaccine era.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune vasculitis characterized by the production of antibodies against ANCA, with unclear pathogenesis. With the ongoing COVID-19 pandemic, COVID-19 mRNA vaccination has been available in Japan since February 2021. Although autoimmune symptoms have been reported after COVID-19 vaccinations, there have been no clinical investigations regarding the relationship between COVID-19 mRNA vaccines and the pathogenesis of AAV. Thus, the present study aimed to investigate whether the administration of COVID-19 mRNA vaccines affects the development of AAV. The study identified patients with new-onset AAV who were MPO-ANCA or PR3-ANCA positive and met the entry criteria of the AAV EMA classification algorithm. The study compared the number of new AAV cases per year before and after the start of the COVID-19 mRNA vaccine program in Japan. The study found that the annual number of new cases of AAV in Japan's Nagasaki Prefecture increased by approximately 1.5-fold since the COVID-19 vaccine program was initiated, suggesting a possible link between the COVID-19 mRNA vaccines and the development of AAV. Although the study provides insight into the clinical evaluation and management of autoimmune symptoms following COVID-19 vaccination, further investigation of the possible association between COVID-19 mRNA vaccines and the pathogenesis of AAV is required.

Cartography of SARS-CoV-2 variants based on the susceptibility to therapeutic monoclonal antibodies.

A comprehensive picture of a phenotypic relationship among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has been poorly studied. Here, this study presents cartography showing how the wild-type strain of SARS-CoV-2 and 14 variants are alike or different from the perspective of the susceptibility to 12 therapeutic monoclonal antibodies. The Alpha variant is close to the wild-type strain, whereas the Beta, Gamma, and Delta variants diverge from the wild-type. The map highlights the very unique property of the Omicron variant. Interestingly, sublineages of the Omicron variants, BA.1, BA.2, and BA.4/5, differ substantially in the cartography.

Characteristics of retracted research papers before and during the COVID-19 pandemic.

Objectives: During the COVID-19 pandemic, a large number of research papers were published, and some of them were retracted. The present study aims to reveal the characteristics of retracted papers before and during the pandemic. Methods: The study investigated 24,542,394 publications from 1999 to 2022 and analyzed the profiles of retracted papers from the perspectives of year, disease category, country, and journal. Results: Retraction rates were generally increasing at least until 2019, and were the highest for "Neoplasms." The number of publications for "Infections" and "Respiratory Tract Diseases" dramatically rose during the COVID-19 pandemic; however, the retraction rates in the two categories or of COVID-19-related papers were not especially high compared to other diseases. The association with retraction was strongest for China in most disease categories, whereas for COVID-19 papers, other countries showed higher retraction rates than China. In recent years, retracted papers have become less likely to be published in high-impact journals. Conclusion: The COVID-19 pandemic does not seem to affect the retractions of research papers much. We should keep monitoring retractions and analyze the effects of pandemics for better science.

Age-Stratified Seroprevalence of SARS-CoV-2 Antibodies before and during the Vaccination Era, Japan, February 2020-March 2022.

Japan has reported a relatively small number of COVID-19 cases. Because not all infected persons receive diagnostic tests for COVID-19, the reported number must be lower than the actual number of infections. We assessed SARS-CoV-2 seroprevalence by analyzing >60,000 samples collected in Japan (Tokyo Metropolitan Area and Hokkaido Prefecture) during February 2020-March 2022. The results showed that ≈3.8% of the population had become seropositive by January 2021. The seroprevalence increased with the administration of vaccinations; however, among the elderly, seroprevalence was not as high as the vaccination rate. Among children, who were not eligible for vaccination, infection was spread during the epidemic waves caused by the SARS-CoV-2 Delta and Omicron variants. Nevertheless, seroprevalence for unvaccinated children <5 years of age was as low as 10% as of March 2022. Our study underscores the low incidence of SARS-CoV-2 infection in Japan and the effects of vaccination on immunity at the population level.

Influenza A Virus Agnostic Receptor Tropism Revealed Using a Novel Biological System with Terminal Sialic Acid Knockout Cells.

Avian or human influenza A viruses bind preferentially to avian- or human-type sialic acid receptors, respectively, indicating that receptor tropism is an important factor for determining the viral host range. However, there are currently no reliable methods for analyzing receptor tropism biologically under physiological conditions. In this study, we established a novel system using MDCK cells with avian- or human-type sialic acid receptors and with both sialic acid receptors knocked out (KO). When we examined the replication of human and avian influenza viruses in these KO cells, we observed unique viral receptor tropism that could not be detected using a conventional solid-phase sialylglycan binding assay, which directly assesses physical binding between the virus and sialic acids. Furthermore, we serially passaged an engineered avian-derived H4N5 influenza virus, whose PB2 gene was deleted, in avian-type receptor KO cells stably expressing PB2 to select a mutant with enhanced replication in KO cells; however, its binding to human-type sialylglycan was undetectable using the solid-phase binding assay. These data indicate that a panel of sialic acid receptor KO cells could be a useful tool for determining the biological receptor tropism of influenza A viruses. Moreover, the PB2KO virus experimental system could help to safely and efficiently identify the mutations required for avian influenza viruses to adapt to human cells that could trigger a new influenza pandemic. IMPORTANCE The acquisition of mutations that allow avian influenza A virus hemagglutinins to recognize human-type receptors is mandatory for the transmission of avian viruses to humans, which could lead to a pandemic. In this study, we established a novel system using a set of genetically engineered MDCK cells with knocked out sialic acid receptors to biologically evaluate the receptor tropism for influenza A viruses. Using this system, we observed unique receptor tropism in several virus strains that was undetectable using conventional solid-phase binding assays that measure physical binding between the virus and artificially synthesized sialylglycans. This study contributes to elucidation of the relationship between the physical binding of virus and receptor and viral infectivity. Furthermore, the system using sialic acid knockout cells could provide a useful tool to explore the sialic acid-independent entry mechanism. In addition, our system could be safely used to identify mutations that could acquire human-type receptor tropism.

Properties of the Omicron Variant of SARS-CoV-2 Affect Public Health Measure Effectiveness in the COVID-19 Epidemic.

Nonpharmaceutical and pharmaceutical public health interventions are important to mitigate the coronavirus disease 2019 (COVID-19) epidemic. However, it is still unclear how the effectiveness of these interventions changes with the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) novel variants. This simulation study utilized data from Japan and investigated how the characteristic properties of the Omicron variant, which emerged in late 2021, influence the effectiveness of public health interventions, including vaccination, the reduction of interpersonal contact, and the early isolation of infectious people. Although the short generation time of the Omicron variant increases the effectiveness of vaccination and the reduction of interpersonal contact, it decreases the effectiveness of early isolation. The latter feature may make the containment of case clusters difficult. The increase of infected children during the Omicron-dominant epidemic diminishes the effects of previously adult-targeted interventions. These findings underscore the importance of monitoring viral evolution and consequent changes in epidemiological characteristics. An assessment and adaptation of public health measures against COVID-19 are required as SARS-CoV-2 novel variants continue to emerge.

Integration of publicly available case-based data for real-time coronavirus disease 2019 risk assessment, Japan.

In response to the outbreak of coronavirus disease 2019 (COVID-19) in Japan, a national COVID-19 cluster taskforce (comprising governmental and nongovernmental experts) was established to support the country's Ministry of Health, Labour and Welfare in conducting daily risk assessment. The assessment was carried out using established infectious disease surveillance systems; however, in the initial stages of the pandemic these were not sufficient for real-time risk assessment owing to limited accessibility, delay in data entry and inadequate case information. Also, local governments were publishing anonymized data on confirmed COVID-19 cases on their official web sites as daily press releases. We developed a unique database for nationwide real-time risk assessment that included these case lists from local government web sites and integrated all case data into a standardized format. The database was updated daily and checked systematically to ensure comprehensiveness and quality. Between 15 January 2020 and 15 June 2021, 776 459 cases were logged in the database, allowing for analysis of real-time risk from the pandemic. This semi-automated database was used in daily risk assessments, and to evaluate and update control measures to prevent community transmission of COVID-19 in Japan. The data were reported almost every week to the Japanese Government Advisory Panel on COVID-19 for public health responses.

Secondary transmission of SARS-CoV-2 during the first two waves in Japan: Demographic characteristics and overdispersion.

OBJECTIVES: Super-spreading events caused by overdispersed secondary transmission are crucial in the transmission of COVID-19. However, the exact level of overdispersion, demographics, and other factors associated with secondary transmission remain elusive. In this study, we aimed to elucidate the frequency and patterns of secondary transmission of SARS-CoV-2 in Japan. METHODS: We analyzed 16,471 cases between January 2020 and August 2020. We generated the number of secondary cases distribution and estimated the dispersion parameter (k) by fitting the negative binomial distribution in each phase. The frequencies of the secondary transmission were compared by demographic and clinical characteristics, calculating the odds ratio using logistic regression models. RESULTS: We observed that 76.7% of the primary cases did not generate secondary cases with an estimated dispersion parameter k of 0.23. The demographic patterns of primary-secondary cases differed between phases, with 20-69 years being the predominant age group. There were higher proportions of secondary transmissions among older individuals, symptomatic patients, and patients with 2 days or more between onset and confirmation. CONCLUSIONS: The study showed the estimation of the frequency of secondary transmission of SARS-CoV-2 and the characteristics of people who generated the secondary transmission.

[Comprehensive understanding of viral diseases by field, molecular, and theoretical studies].

Viral diseases are responsible for substantial morbidity and mortality and continue to be of great concern. To ensure better control of viral infections, I have been tackling the issue as a medical doctor, an academic researcher, and a public health officer. Especially, I have studied respiratory viruses, such as the influenza virus, from the perspectives of molecular virology, theoretical modeling, and field epidemiology. RNA biology and its involvement with viral life-cycle and pathogenicity are central topics of molecular study, while mathematical models of transmission dynamics and phylogenetics are major components of theoretical research. As a field epidemiologist, I work with public health authorities during viral disease outbreaks. I was deployed to West Africa for viral hemorrhagic fever outbreak responses as a WHO consultant, and I have served the Japanese Government as an advisor for COVID-19 countermeasures. I would like to integrate various approaches from clinical medicine to epidemiology, theoretical modeling, evolutionary biology, genetics, and molecular biology in my research. In that way, we could gain a more comprehensive understanding of viral diseases. I hope these findings will help ease the disease burden of viral infections around the world.

Analysis of sociodemographic and clinical factors associated with Lassa fever disease and mortality in Nigeria.

Over past decades, there has been increasing geographical spread of Lassa fever (LF) cases across Nigeria and other countries in West Africa. This increase has been associated with significant morbidity and mortality despite increasing focus on the disease by both local and international scientists. Many of these studies on LF have been limited to few specialised centres in the country. This study was done to identify sociodemographic and clinical predictors of LF disease and related deaths across Nigeria. We analysed retrospective surveillance data on suspected LF cases collected during January-June 2018 and 2019. Multivariable logistic regression analyses were used to identify the factors independently associated with laboratory-confirmed LF diagnosis, and with LF-related deaths. There were confirmed 815 of 1991 suspected LF cases with complete records during this period. Of these, 724/815 confirmed cases had known clinical outcomes, of whom 100 died. LF confirmation was associated with presentation of gastrointestinal tract (aOR 3.47, 95% CI: 2.79-4.32), ear, nose and throat (aOR 2.73, 95% CI: 1.80-4.15), general systemic (aOR 2.12, 95% CI: 1.65-2.70) and chest/respiratory (aOR 1.71, 95% CI: 1.28-2.29) symptoms. Other factors were being male (aOR 1.32, 95% CI: 1.06-1.63), doing business/trading (aOR 2.16, 95% CI: 1.47-3.16) and farming (aOR 1.73, 95% CI: 1.12-2.68). Factors associated with LF mortality were a one-year increase in age (aOR 1.03, 95% CI: 1.01-1.04), bleeding (aOR 2.07, 95% CI: 1.07-4.00), and central nervous manifestations (aOR 5.02, 95% CI: 3.12-10.16). Diverse factors were associated with both LF disease and related death. A closer look at patterns of clinical variables would be helpful to support early detection and management of cases. The findings would also be useful for planning preparedness and response interventions against LF in the country and region.

Epidemiological Factors Associated with COVID-19 Clusters in Medical and Social Welfare Facilities.

The characteristics of coronavirus disease 2019 (COVID-19) clusters in medical and social welfare facilities and the factors associated with cluster size are still not yet fully understood. We reviewed COVID-19 cases in Japan identified from January 15 to April 30, 2020 and analyzed the factors associated with cluster size in medical and social welfare facilities. In this study, COVID-19 clusters were identified in 56 medical and 34 social welfare facilities. The number of cases in those facilities peaked after the peak of the general population. The duration of occurrence of new cases in clusters was positively correlated with the number of cases in both types of facilities (rho = 0.44, P < 0.001; and rho = 0.69, P < 0.001, respectively). However, the number of days between the first case in a prefecture and the onset of clusters was negatively correlated with the number of cases only in clusters in social welfare facilities (rho = - 0.4, P = 0.004). Our results suggest that COVID-19 cases in those facilities were prevalent in the latter phase of the disease's community transmission, although the underlying mechanisms for such a trend could differ between medical and social welfare facilities.

Simulation study reveals factors that affect the predominance of SARS-CoV-2 novel variant.

The novel variants of the SARS-CoV-2 are a great global concern for the ongoing COVID-19 pandemic. However, how the novel variants predominate and replace existing strains remains elusive. In this study, I simulated the infection spread to investigate what kinds of viral, immunological, and epidemiological factors affect the predominance of SARS-CoV-2 novel variants. The results showed that the increase of the transmissibility of the novel variant substantially enhanced the predominance probability. In addition, the increasing trend of the infection spread, the large case number of the epidemic, and the ability of immune escape of the novel variant increased the predominance probability. A small number of cases and a decreasing trend of an entire epidemic, including not only the novel variant but also earlier strains, are especially important to reduce the chance of the predominance of the novel variant and delay the process. Good control of the COVID-19 epidemic could make the disease burden small and sequester the spread of the SARS-CoV-2 novel variants.

Simulation of future COVID-19 epidemic by vaccination coverage scenarios in Japan.

BACKGROUND: COVID-19 continues to impose significant morbidity and mortality in Japan even after implementing the vaccination program. It would remain elusive if restrictions for its mitigation were to be lifted or relaxed in the future. METHODS: A simulation study that explored possible vaccination coverage scenarios and changes in the intensity of nonpharmaceutical intervention restrictions was performed to assess the impact of COVID-19 based on death count. RESULTS: Assuming the basic reproduction number of circulating viruses was 5.0, vaccines could prevent 90% of infections and 95% of deaths, and the vaccination coverage rate was high (75%, 80%, and 90% in people aged 12-39 years, 40-59 years, ≥60 years, respectively), approximately 50 000 deaths would occur over 150 days in Japan if all restrictions were lifted. Most deaths would occur among older adults, even if their vaccination coverage was assumed to be especially high. A low vaccination coverage scenario (45%, 60%, and 80% in people aged 12-39 years, 40-59 years, ≥60 years, respectively) would require periodic implementation of strict measures even if the modified lifestyle observed in 2020 was sustained and vaccines were very effective. Some restrictions could be relaxed under high vaccination coverage. However, in the worst-case scenario where vaccines had decreased efficacy, as we have observed for the Delta variant, and people lived a relaxed lifestyle, our simulation suggests that even high vaccination coverage would occasionally require strict measures. CONCLUSIONS: We should carefully explore a manageable degree of restrictions and their relaxation. We will have to keep bracing for occasional surges of COVID-19 infection, which could lead to strict measures, such as those under a state of emergency. Such strategies are essential even after a wide rollout of vaccination.

The One Health approach to incident management of the 2019 Lassa fever outbreak response in Nigeria.

Globally, effective emergency response to disease outbreaks is usually affected by weak coordination. However, coordination using an incident management system (IMS) in line with a One Health approach involving human, environment, and animal health with collaborations between government and non-governmental agencies result in improved response outcome for zoonotic diseases such as Lassa fever (LF). We provide an overview of the 2019 LF outbreak response in Nigeria using the IMS and One Health approach. The response was coordinated via ten Emergency Operation Centre (EOC) response pillars. Cardinal response activities included activation of EOC, development of an incident action plan, deployment of One Health rapid response teams to support affected states, mid-outbreak review and after-action review meetings. Between 1st January and 29th December 2019, of the 5057 people tested for LF, 833 were confirmed positive from 23 States, across 86 Local Government Areas. Of the 833 confirmed cases, 650 (78%) were from hotspot States of Edo (36%), Ondo (26%) and Ebonyi (16%). Those in the age-group 21-40 years (47%) were mostly affected, with a male to female ratio of 1:1. Twenty healthcare workers were affected. Two LF naïve states Kebbi and Zamfara, reported confirmed cases for the first time during this period. The outbreak peaked earlier in the year compared to previous years, and the emergency phase of the outbreak was declared over by epidemiological week 17 based on low national threshold composite indicators over a period of six consecutive weeks. Multisectoral and multidisciplinary strategic One Health EOC coordination at all levels facilitated the swift containment of Nigeria's large LF outbreak in 2019. It is therefore imperative to embrace One Health approach embedded within the EOC to holistically address the increasing LF incidence in Nigeria.

RNA Modifications in Genomic RNA of Influenza A Virus and the Relationship between RNA Modifications and Viral Infection.

Recent studies about the transcriptome-wide presence of RNA modifications have revealed their importance in many cellular functions. Nevertheless, information about RNA modifications in viral RNA is scarce, especially for negative-strand RNA viruses. Here we provide a catalog of RNA modifications including m1A, ac4C, m7G, inosine, and pseudouridine on RNA derived from an influenza A virus infected into A549 cells, as studied by RNA immunoprecipitation followed by deep-sequencing. Possible regions with RNA modifications were found in the negative-strand segments of viral genomic RNA. In addition, our analyses of previously published data revealed that the expression levels of the host factors for RNA modifications were affected by an infection with influenza A virus, and some of the host factors likely have a proviral effect. RNA modification is a novel aspect of host-virus interactions leading to the discovery of previously unrecognized viral pathogenicity mechanisms and has the potential to aid the development of novel antivirals.

Roles of Children and Adolescents in COVID-19 Transmission in the Community: A Retrospective Analysis of Nationwide Data in Japan.

Background: Roles of children and adolescents in spreading coronavirus disease 2019 (COVID-19) in the community is not fully understood. Methods: We analyzed the data of 7,758 children and adolescents with COVID-19 and characteristics of secondary transmission generated by these cases using case information published by local governments. Ratio of pediatric and adolescent cases generating secondary transmission was calculated for various social settings. Results: The incidence of COVID-19 was 24.8 cases per 105 population aged between 0 and 9 years, and 59.2 among those aged between 10 and 19 years, which was lower than that among individuals of all age groups (79.6 per 105 population) between January 15 and October 31, 2020. The proportion of cases generating secondary cases was 8.3% among infants and young children in nursery schools and kindergartens, 16% among children and adolescents attending primary schools, 34% among those attending junior high schools, 43% among those attending high schools, 31% among those attending professional training colleges, and 24% in those attending universities. Households were the most common setting for secondary transmission. Conclusion: The risk of generating secondary cases might be limited among pediatric and adolescent cases with COVID-19, especially in settings outside households. Effectiveness of traditional mitigation measures (e.g., school closures) to suppress COVID-19 transmissions should be carefully evaluated.

Relationship of Test Positivity Rates with COVID-19 Epidemic Dynamics.

Detection and isolation of infected people are believed to play an important role in the control of the COVID-19 pandemic. Some countries conduct large-scale screenings for testing, whereas others test mainly people with high prior probability of infection such as showing severe symptoms and/or having an epidemiological link with a known or suspected case or cluster of cases. However, what a good testing strategy is and whether the difference in testing strategy shows a meaningful, measurable impact on the COVID-19 epidemic remain unknown. Here, we showed that patterns of association between effective reproduction number (Rt) and test positivity rate can illuminate differences in testing situation among different areas, using global and local data from Japan. This association can also evaluate the adequacy of current testing systems and what information is captured in COVID-19 surveillance. The differences in testing systems alone cannot predict the results of epidemic containment efforts. Furthermore, monitoring test positivity rates and severe case proportions among the nonelderly can predict imminent case count increases. Monitoring test positivity rates in conjunction with the concurrent Rt could be useful to assess and strengthen public health management and testing systems and deepen understanding of COVID-19 epidemic dynamics.