Updated on 2023/03/24

写真a

 
IWANAMI Shoya
 
Organization
Graduate School of Science Lecturer
Undergraduate School
School of Science Department of Biological Science
Title
Lecturer
Contact information
メールアドレス
External link

Degree 1

  1. 博士(理学) ( 2020.9   九州大学 ) 

Research Areas 2

  1. Natural Science / Biophysics, chemical physics and soft matter physics  / Mathematical Biology

  2. Natural Science / Applied mathematics and statistics

Current Research Project and SDGs 1

  1. 数理科学による感染症の理解

Research History 5

  1. Nagoya University   Graduate School of Science   Assistant Professor

    2022.4

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    Country:Japan

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  2. Nagoya University   Division of Biological Science, Graduate School of Science   Assistant Professor

    2021.4 - 2022.3

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    Country:Japan

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  3. Kyushu University   Department of Biology, Faculty of Science   Postdoctoral fellow   Research Assistant Professor

    2020.12 - 2021.3

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    Country:Japan

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  4. Kyushu University   Department of Biology, Faculty of Science   Postdoctoral fellow

    2020.10 - 2020.11

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    Country:Japan

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  5. Kyushu University   Graduate School of Systems Life Sciences   JSPS Research Fellow DC2

    2019.4 - 2020.9

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    Country:Japan

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Education 1

  1. Kyushu University   Graduate School of Systems Life Sciences

    2016.4 - 2020.9

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    Country: Japan

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Papers 23

  1. Relationship between the inclusion/exclusion criteria and sample size in randomized controlled trials for SARS-CoV-2 entry inhibitors Reviewed

    Tatematsu D., Akao M., Park H., Iwami S., Ejima K., Iwanami S.

    Journal of Theoretical Biology   Vol. 561   page: 111403   2023.3

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Journal of Theoretical Biology  

    The coronavirus disease 2019 (COVID-19) pandemic that has been ongoing since 2019 is still ongoing and how to control it is one of the international issues to be addressed. Antiviral drugs that reduce the viral load in terms of reducing the risk of secondary infection are important. For the general control of emerging infectious diseases, establishing an efficient method to evaluate candidate therapeutic agents will lead to a rapid response. We evaluated clinical trial designs for viral entry inhibitors that have the potential to be effective pre-exposure prophylactic drugs in addition to reducing viral load after infection. We used a previously developed simulation of clinical trials based on a mathematical model of within-host viral infection dynamics to evaluate sample sizes in clinical trials of viral entry inhibitors against COVID-19. We assumed four measures as outcomes, namely change in log10-transformed viral load from symptom onset, PCR positive ratio, log10-transformed viral load, and cumulative viral load, and then sample sizes were calculated for drugs with 99 % and 95 % antiviral efficacy. Consistent with previous results, we found that sample sizes could be dramatically reduced for all outcomes used in an analysis by adopting inclusion/exclusion criteria such that only patients in the early post-infection period would be included in a clinical trial. A comparison of sample sizes across outcomes demonstrated an optimal measurement schedule associated with the nature of the outcome measured for the evaluation of drug efficacy. In particular, the sample sizes calculated from the change in viral load and from viral load tended to be small when measurements were taken at earlier time points after treatment initiation. For the cumulative viral load, the sample size was lower than that from the other outcomes when the stricter inclusion/exclusion criteria to include patients whose time since onset is earlier than 2 days was used. We concluded that the design of efficient clinical trials should consider the inclusion/exclusion criteria and measurement schedules, as well as outcome selection based on sample size, personnel and budget needed to conduct the trial, and the importance of the outcome regarding the medical and societal requirements. This study provides insights into clinical trial design for a variety of situations, especially addressing infectious disease prevalence and feasible trial sizes. This manuscript was submitted as part of a theme issue on “Modelling COVID-19 and Preparedness for Future Pandemics”.

    DOI: 10.1016/j.jtbi.2022.111403

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  2. Potential anti-mpox virus activity of atovaquone, mefloquine, and molnupiravir, and their potential use as treatments. Reviewed International coauthorship International journal

    Daisuke Akazawa, Hirofumi Ohashi, Takayuki Hishiki, Takeshi Morita, Shoya Iwanami, Kwang Su Kim, Yong Dam Jeong, Eun-Sil Park, Michiyo Kataoka, Kaho Shionoya, Junki Mifune, Kana Tsuchimoto, Shinjiro Ojima, Aa Haeruman Azam, Shogo Nakajima, Hyeongki Park, Tomoki Yoshikawa, Masayuki Shimojima, Kotaro Kiga, Shingo Iwami, Ken Maeda, Tadaki Suzuki, Hideki Ebihara, Yoshimasa Takahashi, Koichi Watashi

    The Journal of infectious diseases     2023.3

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    BACKGROUND: Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and brincidofovir are approved as anti-smallpox drugs, their effects in mpox patients have not been well documented. In this study, by a drug repurposing approach, we identified potential drug candidates for treating mpox and predicted their clinical impacts by mathematical modeling. METHODS: We screened approved 132 drugs using an MPXV infection cell system. We quantified antiviral activities of hit drugs by measuring intracellular viral DNA and analyzed the modes of action by time-of-addition assay and electron microscopic analysis. We further predicted the efficacy of drugs under clinical concentrations by mathematical simulation and examined combination treatment. RESULTS: Atovaquone, mefloquine, and molnupiravir exhibited anti-MPXV activity, with 50% inhibitory concentrations of 0.51-5.2 μM, which was more potent than cidofovir. Whereas mefloquine was suggested to inhibit viral entry, atovaquone and molnupiravir targeted post-entry process. Atovaquone was suggested to exert its activity through inhibiting dihydroorotate dehydrogenase. Combining atovaquone with tecovirimat enhanced the anti-MPXV effect of tecovirimat. Quantitative mathematical simulations predicted that atovaquone can promote viral clearance in patients by seven days at clinically relevant drug concentrations. CONCLUSION: These data suggest that atovaquone would be potential candidates for treating mpox.

    DOI: 10.1093/infdis/jiad058

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  3. Designing isolation guidelines for COVID-19 patients with rapid antigen tests. Reviewed International coauthorship International journal

    Yong Dam Jeong, Keisuke Ejima, Kwang Su Kim, Woo Joohyeon, Shoya Iwanami, Yasuhisa Fujita, Il Hyo Jung, Kazuyuki Aihara, Kenji Shibuya, Shingo Iwami, Ana I Bento, Marco Ajelli

    Nature communications   Vol. 13 ( 1 ) page: 4910 - 4910   2022.12

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    Appropriate isolation guidelines for COVID-19 patients are warranted. Currently, isolating for fixed time is adopted in most countries. However, given the variability in viral dynamics between patients, some patients may no longer be infectious by the end of isolation, whereas others may still be infectious. Utilizing viral test results to determine isolation length would minimize both the risk of prematurely ending isolation of infectious patients and the unnecessary individual burden of redundant isolation of noninfectious patients. In this study, we develop a data-driven computational framework to compute the population-level risk and the burden of different isolation guidelines with rapid antigen tests (i.e., lateral flow tests). Here, we show that when the detection limit is higher than the infectiousness threshold values, additional consecutive negative results are needed to ascertain infectiousness status. Further, rapid antigen tests should be designed to have lower detection limits than infectiousness threshold values to minimize the length of prolonged isolation.

    DOI: 10.1038/s41467-022-32663-9

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  4. Estimation of timing of infection from longitudinal SARS-CoV-2 viral load data: mathematical modelling study. Reviewed International coauthorship International journal

    Keisuke Ejima, Kwang Su Kim, Ana I Bento, Shoya Iwanami, Yasuhisa Fujita, Kazuyuki Aihara, Kenji Shibuya, Shingo Iwami

    BMC infectious diseases   Vol. 22 ( 1 ) page: 656 - 656   2022.12

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    BACKGROUND: Multiple waves of the COVID-19 epidemic have hit most countries by the end of 2021. Most of those waves are caused by emergence and importation of new variants. To prevent importation of new variants, combination of border control and contact tracing is essential. However, the timing of infection inferred by interview is influenced by recall bias and hinders the contact tracing process. METHODS: We propose a novel approach to infer the timing of infection, by employing a within-host model to capture viral load dynamics after the onset of symptoms. We applied this approach to ascertain secondary transmission which can trigger outbreaks. As a demonstration, the 12 initial reported cases in Singapore, which were considered as imported because of their recent travel history to Wuhan, were analyzed to assess whether they are truly imported. RESULTS: Our approach suggested that 6 cases were infected prior to the arrival in Singapore, whereas other 6 cases might have been secondary local infection. Three among the 6 potential secondary transmission cases revealed that they had contact history to previously confirmed cases. CONCLUSIONS: Contact trace combined with our approach using viral load data could be the key to mitigate the risk of importation of new variants by identifying cases as early as possible and inferring the timing of infection with high accuracy.

    DOI: 10.1186/s12879-022-07646-2

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  5. Different efficacies of neutralizing antibodies and antiviral drugs on SARS-CoV-2 Omicron subvariants, BA.1 and BA.2. Reviewed International coauthorship International journal

    Hirofumi Ohashi, Takayuki Hishiki, Daisuke Akazawa, Kwang Su Kim, Joohyeon Woo, Kaho Shionoya, Kana Tsuchimoto, Shoya Iwanami, Saya Moriyama, Hitomi Kinoshita, Souichi Yamada, Yudai Kuroda, Tsukasa Yamamoto, Noriko Kishida, Shinji Watanabe, Hideki Hasegawa, Hideki Ebihara, Tadaki Suzuki, Maeda Ken, Shuetsu Fukushi, Yoshimasa Takahashi, Shingo Iwami, Koichi Watashi

    Antiviral research   Vol. 205   page: 105372 - 105372   2022.9

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    The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariant BA.2 has spread in many countries, replacing the earlier Omicron subvariant BA.1 and other variants. Here, using a cell culture infection assay, we quantified the intrinsic sensitivity of BA.2 and BA.1 compared with other variants of concern, Alpha, Gamma, and Delta, to five approved-neutralizing antibodies and antiviral drugs. Our assay revealed the diverse sensitivities of these variants to antibodies, including the loss of response of both BA.1 and BA.2 to casirivimab and of BA.1 to imdevimab. In contrast, EIDD-1931 and nirmatrelvir showed a more conserved activities to these variants. The viral response profile combined with mathematical analysis estimated differences in antiviral effects among variants in the clinical concentrations. These analyses provide essential evidence that gives insight into variant emergence's impact on choosing optimal drug treatment.

    DOI: 10.1016/j.antiviral.2022.105372

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  6. Factors Associated with COVID-19 Vaccine Booster Hesitancy: A Retrospective Cohort Study, Fukushima Vaccination Community Survey Reviewed International journal

    Makoto Yoshida, Yurie Kobashi, Takeshi Kawamura, Yuzo Shimazu, Yoshitaka Nishikawa, Fumiya Omata, Tianchen Zhao, Chika Yamamoto, Yudai Kaneko, Aya Nakayama, Morihito Takita, Naomi Ito, Moe Kawashima, Sota Sugiura, Kenji Shibuya, Shingo Iwami, Kwangsu Kim, Shoya Iwanami, Tatsuhiko Kodama, Masaharu Tsubokura

    Vaccines   Vol. 10 ( 4 ) page: 515 - 515   2022.4

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:MDPI AG  

    This was a retrospective cohort study, which aimed to investigate the factors associated with hesitancy to receive a third dose of a coronavirus disease 2019 (COVID-19) vaccine. A paper-based questionnaire survey was administered to all participants. This study included participants who provided answers in the questionnaire about whether they had an intent to receive a third dose of a vaccine. Data on sex, age, area of residence, adverse reactions after the second vaccination, whether the third vaccination was desired, and reasons to accept or hesitate over the booster vaccination were retrieved. Among the 2439 participants, with a mean (±SD) age of 52.6 ± 18.9 years, and a median IgG-S antibody titer of 324.9 (AU/mL), 97.9% of participants indicated their intent to accept a third vaccination dose. The logistic regression revealed that participants of a younger age (OR = 0.98; 95% CI: 0.96–1.00) and with a higher antibody level (OR = 2.52; 95% CI: 1.27–4.99) were positively associated with hesitancy over the third vaccine. The efficacy of the COVID-19 vaccine and concerns about adverse reactions had a significant impact on behavior regarding the third vaccination. A rapid increase in the booster dose rate is needed to control the pandemic, and specific approaches should be taken with these groups that are likely to hesitate over the third vaccine, subsequently increasing booster contact rate.

    DOI: 10.3390/vaccines10040515

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  7. Antithetic effect of interferon-α on cell-free and cell-to-cell HIV-1 infection Reviewed International coauthorship International journal

    Ryuichi Kumata, Alison L. Hill, Shoya Iwanami, Katrina B. Mar, Yusuke Kakizoe, Naoko Misawa, Shinji Nakaoka, Yoshio Koyanagi, Alan S. Perelson, John W. Schoggins, Shingo Iwami, Kei Sato

    PLOS Computational Biology   Vol. 18 ( 4 ) page: e1010053   2022.4

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Public Library of Science ({PLoS})  

    In HIV-1-infected individuals, transmitted/founder (TF) virus contributes to establish new infection and expands during the acute phase of infection, while chronic control (CC) virus emerges during the chronic phase of infection. TF viruses are more resistant to interferon-alpha (IFN-α)-mediated antiviral effects than CC virus, however, its virological relevance in infected individuals remains unclear. Here we perform an experimental-mathematical investigation and reveal that IFN-α strongly inhibits cell-to-cell infection by CC virus but only weakly affects that by TF virus. Surprisingly, IFN-α enhances cell-free infection of HIV-1, particularly that of CC virus, in a virus-cell density-dependent manner. We further demonstrate that LY6E, an IFN-stimulated gene, can contribute to the density-dependent enhancement of cell-free HIV-1 infection. Altogether, our findings suggest that the major difference between TF and CC viruses can be explained by their resistance to IFN-α-mediated inhibition of cell-to-cell infection and their sensitivity to IFN-α-mediated enhancement of cell-free infection.

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  8. Characterization of various remdesivir-resistant mutations of SARS-CoV-2 by mathematical modeling and molecular dynamics simulation

    Shiho Torii, Kwang Su Kim, Jun Koseki, Rigel Suzuki, Shoya Iwanami, Yasuhisa Fujita, Yong Dam Jeong, Yoshiharu Matsuura, Teppei Shimamura, Shingo Iwami, Takasuke Fukuhara

        2022.2

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Cold Spring Harbor Laboratory  

    DOI: 10.1101/2022.02.22.481436

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  9. Designing isolation guidelines for COVID-19 patients utilizing rapid antigen tests: a simulation study using viral dynamics models

    Yong Dam Jeong, Keisuke Ejima, Kwang Su Kim, Woo Joohyeon, Shoya Iwanami, Yasuhisa Fujita, Il Hyo Jung, Kenji Shibuya, Shingo Iwami, Ana I. Bento, Marco Ajelli

        2022.1

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    DOI: 10.1101/2022.01.24.22269769

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  10. Detection of significant antiviral drug effects on COVID-19 using viral load and PCR-positive rate in randomized controlled trials Reviewed

    Marwa AKAO, Joohyeon WOO, Shingo IWAMI, Shoya IWANAMI

    Translational and Regulatory Sciences   Vol. 3 ( 3 ) page: 85 - 88   2021.12

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:AMED iD3 Catalyst Unit  

    <p>To evaluate the effects of antiviral drugs against coronavirus disease (COVID-19), we calculated the sample size needed to detect significant differences in daily viral load in randomized controlled trials. While calculating sample sizes, simulated viral loads that mimicked longitudinal clinical data were used. The sample size computed from the viral load was the smallest 2 to 4 days after trial participation, while the smallest sample size computed from the positive rate was 4 to 7 days after clinical trial participation.</p>

    DOI: 10.33611/trs.2021-025

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  11. Incomplete antiviral treatment may induce longer durations of viral shedding during SARS-CoV-2 infection Reviewed

    Kwang Su Kim, Shoya Iwanami, Takafumi Oda, Yasuhisa Fujita, Keiji Kuba, Taiga Miyazaki, Keisuke Ejima, Shingo Iwami

    Life Science Alliance   Vol. 4 ( 10 ) page: e202101049 - e202101049   2021.7

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    The duration of viral shedding is determined by a balance between de novo infection and removal of infected cells. That is, if infection is completely blocked with antiviral drugs (100% inhibition), the duration of viral shedding is minimal and is determined by the length of virus production. However, some mathematical models predict that if infected individuals are treated with antiviral drugs with efficacy below 100%, viral shedding may last longer than without treatment because further de novo infections are driven by entry of the virus into partially protected, uninfected cells at a slower rate. Using a simple mathematical model, we quantified SARS-CoV-2 infection dynamics in non-human primates and characterized the kinetics of viral shedding. We counterintuitively found that treatments initiated early, such as 0.5 d after virus inoculation, with intermediate to relatively high efficacy (30–70% inhibition of virus replication) yield a prolonged duration of viral shedding (by about 6.0 d) compared with no treatment.

    DOI: 10.26508/LSA.202101049

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  12. Revisiting the guidelines for ending isolation for COVID-19 patients Reviewed International coauthorship

    Yong Dam Jeong, Keisuke Ejima, Kwang Su Kim, Shoya Iwanami, Ana I Bento, Yasuhisa Fujita, Il Hyo Jung, Kazuyuki Aihara, Koichi Watashi, Taiga Miyazaki, Takaji Wakita, Shingo Iwami, Marco Ajelli

    eLife   Vol. 10   2021.7

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:{eLife} Sciences Publications, Ltd  

    Since the start of the COVID-19 pandemic, two mainstream guidelines for defining when to end the isolation of SARS-CoV-2-infected individuals have been in use: the one-size-fits-all approach (i.e. patients are isolated for a fixed number of days) and the personalized approach (i.e. based on repeated testing of isolated patients). We use a mathematical framework to model within-host viral dynamics and test different criteria for ending isolation. By considering a fixed time of 10 days since symptom onset as the criterion for ending isolation, we estimated that the risk of releasing an individual who is still infectious is low (0–6.6%). However, this policy entails lengthy unnecessary isolations (4.8–8.3 days). In contrast, by using a personalized strategy, similar low risks can be reached with shorter prolonged isolations. The obtained findings provide a scientific rationale for policies on ending the isolation of SARS-CoV-2-infected individuals.

    DOI: 10.7554/eLife.69340

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    Other Link: https://cdn.elifesciences.org/articles/69340/elife-69340-v1.xml

  13. Detection of significant antiviral drug effects on COVID-19 with reasonable sample sizes in randomized controlled trials: A modeling study Reviewed

    Shoya Iwanami, Mirjam E. E. Kretzschmar, Keisuke Ejima, Kwang Su Kim, Koji Noshita, Yasuhisa Fujita, Taiga Miyazaki, Shigeru Kohno, Yoshitsugu Miyazaki, Shimpei Morimoto, Shinji Nakaoka, Yoshiki Koizumi, Yusuke Asai, Kazuyuki Aihara, Koichi Watashi, Robin N. Thompson, Kenji Shibuya, Katsuhito Fujiu, Alan S. Perelson, Shingo Iwami, Takaji Wakita

    PLOS Medicine   Vol. 18 ( 7 ) page: e1003660 - e1003660   2021.7

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    Authorship:Lead author   Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Public Library of Science (PLoS)  

    <sec id="sec001">
    <title>Background</title>
    Development of an effective antiviral drug for Coronavirus Disease 2019 (COVID-19) is a global health priority. Although several candidate drugs have been identified through in vitro and in vivo models, consistent and compelling evidence from clinical studies is limited. The lack of evidence from clinical trials may stem in part from the imperfect design of the trials. We investigated how clinical trials for antivirals need to be designed, especially focusing on the sample size in randomized controlled trials.


    </sec>
    <sec id="sec002">
    <title>Methods and findings</title>
    A modeling study was conducted to help understand the reasons behind inconsistent clinical trial findings and to design better clinical trials. We first analyzed longitudinal viral load data for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) without antiviral treatment by use of a within-host virus dynamics model. The fitted viral load was categorized into 3 different groups by a clustering approach. Comparison of the estimated parameters showed that the 3 distinct groups were characterized by different virus decay rates (<italic>p</italic>-value &lt; 0.001). The mean decay rates were 1.17 d<sup>−1</sup> (95% CI: 1.06 to 1.27 d<sup>−1</sup>), 0.777 d<sup>−1</sup> (0.716 to 0.838 d<sup>−1</sup>), and 0.450 d<sup>−1</sup> (0.378 to 0.522 d<sup>−1</sup>) for the 3 groups, respectively. Such heterogeneity in virus dynamics could be a confounding variable if it is associated with treatment allocation in compassionate use programs (i.e., observational studies).


    Subsequently, we mimicked randomized controlled trials of antivirals by simulation. An antiviral effect causing a 95% to 99% reduction in viral replication was added to the model. To be realistic, we assumed that randomization and treatment are initiated with some time lag after symptom onset. Using the duration of virus shedding as an outcome, the sample size to detect a statistically significant mean difference between the treatment and placebo groups (1:1 allocation) was 13,603 and 11,670 (when the antiviral effect was 95% and 99%, respectively) per group if all patients are enrolled regardless of timing of randomization. The sample size was reduced to 584 and 458 (when the antiviral effect was 95% and 99%, respectively) if only patients who are treated within 1 day of symptom onset are enrolled. We confirmed the sample size was similarly reduced when using cumulative viral load in log scale as an outcome.


    We used a conventional virus dynamics model, which may not fully reflect the detailed mechanisms of viral dynamics of SARS-CoV-2. The model needs to be calibrated in terms of both parameter settings and model structure, which would yield more reliable sample size calculation.


    </sec>
    <sec id="sec003">
    <title>Conclusions</title>
    In this study, we found that estimated association in observational studies can be biased due to large heterogeneity in viral dynamics among infected individuals, and statistically significant effect in randomized controlled trials may be difficult to be detected due to small sample size. The sample size can be dramatically reduced by recruiting patients immediately after developing symptoms. We believe this is the first study investigated the study design of clinical trials for antiviral treatment using the viral dynamics model.


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  14. Estimation of the incubation period of COVID-19 using viral load data Reviewed International journal

    Keisuke Ejima, Kwang Su Kim, Christina Ludema, Ana I. Bento, Shoya Iwanami, Yasuhisa Fujita, Hirofumi Ohashi, Yoshiki Koizumi, Koichi Watashi, Kazuyuki Aihara, Hiroshi Nishiura, Shingo Iwami

    Epidemics   Vol. 35   page: 100454 - 100454   2021.6

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    The incubation period, or the time from infection to symptom onset, of COVID-19 has usually been estimated by using data collected through interviews with cases and their contacts. However, this estimation is influenced by uncertainty in the cases' recall of exposure time. We propose a novel method that uses viral load data collected over time since hospitalization, hindcasting the timing of infection with a mathematical model for viral dynamics. As an example, we used reported data on viral load for 30 hospitalized patients from multiple countries (Singapore, China, Germany, and Korea) and estimated the incubation period. The median, 2.5, and 97.5 percentiles of the incubation period were 5.85 days (95 % CI: 5.05, 6.77), 2.65 days (2.04, 3.41), and 12.99 days (9.98, 16.79), respectively, which are comparable to the values estimated in previous studies. Using viral load to estimate the incubation period might be a useful approach, especially when it is impractical to directly observe the infection event.

    DOI: 10.1016/j.epidem.2021.100454

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  15. Mefloquine, a Potent Anti-severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Drug as an Entry Inhibitor in vitro. Reviewed International journal

    Kaho Shionoya, Masako Yamasaki, Shoya Iwanami, Yusuke Ito, Shuetsu Fukushi, Hirofumi Ohashi, Wakana Saso, Tomohiro Tanaka, Shin Aoki, Kouji Kuramochi, Shingo Iwami, Yoshimasa Takahashi, Tadaki Suzuki, Masamichi Muramatsu, Makoto Takeda, Takaji Wakita, Koichi Watashi

    Frontiers in microbiology   Vol. 12   page: 651403 - 651403   2021.4

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    Coronavirus disease 2019 (COVID-19) has caused serious public health, social, and economic damage worldwide and effective drugs that prevent or cure COVID-19 are urgently needed. Approved drugs including Hydroxychloroquine, Remdesivir or Interferon were reported to inhibit the infection or propagation of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), however, their clinical efficacies have not yet been well demonstrated. To identify drugs with higher antiviral potency, we screened approved anti-parasitic/anti-protozoal drugs and identified an anti-malarial drug, Mefloquine, which showed the highest anti-SARS-CoV-2 activity among the tested compounds. Mefloquine showed higher anti-SARS-CoV-2 activity than Hydroxychloroquine in VeroE6/TMPRSS2 and Calu-3 cells, with IC50 = 1.28 μM, IC90 = 2.31 μM, and IC99 = 4.39 μM in VeroE6/TMPRSS2 cells. Mefloquine inhibited viral entry after viral attachment to the target cell. Combined treatment with Mefloquine and Nelfinavir, a replication inhibitor, showed synergistic antiviral activity. Our mathematical modeling based on the drug concentration in the lung predicted that Mefloquine administration at a standard treatment dosage could decline viral dynamics in patients, reduce cumulative viral load to 7% and shorten the time until virus elimination by 6.1 days. These data cumulatively underscore Mefloquine as an anti-SARS-CoV-2 entry inhibitor.

    DOI: 10.3389/fmicb.2021.651403

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  16. Potential anti-COVID-19 agents, cepharanthine and nelfinavir, and their usage for combination treatment Reviewed International journal

    Hirofumi Ohashi, Koichi Watashi, Wakana Saso, Kaho Shionoya, Shoya Iwanami, Takatsugu Hirokawa, Tsuyoshi Shirai, Shigehiko Kanaya, Yusuke Ito, Kwang Su Kim, Takao Nomura, Tateki Suzuki, Kazane Nishioka, Shuji Ando, Keisuke Ejima, Yoshiki Koizumi, Tomohiro Tanaka, Shin Aoki, Kouji Kuramochi, Tadaki Suzuki, Takao Hashiguchi, Katsumi Maenaka, Tetsuro Matano, Masamichi Muramatsu, Masayuki Saijo, Kazuyuki Aihara, Shingo Iwami, Makoto Takeda, Jane A. McKeating, Takaji Wakita

    iScience   Vol. 24 ( 4 ) page: 102367 - 102367   2021.4

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Elsevier {BV}  

    Antiviral treatments targeting the coronavirus disease 2019 are urgently required. We screened a panel of already approved drugs in a cell culture model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and identified two new agents having higher antiviral potentials than the drug candidates such as remdesivir and chroloquine in VeroE6/TMPRSS2 cells: the anti-inflammatory drug cepharanthine and human immunodeficiency virus protease inhibitor nelfinavir. Cepharanthine inhibited SARS-CoV-2 entry through the blocking of viral binding to target cells, while nelfinavir suppressed viral replication partly by protease inhibition. Consistent with their different modes of action, synergistic effect of this combined treatment to limit SARS-CoV-2 proliferation was highlighted. Mathematical modeling in vitro antiviral activity coupled with the calculated total drug concentrations in the lung predicts that nelfinavir will shorten the period until viral clearance by 4.9 days and the combining cepharanthine/nelfinavir enhanced their predicted efficacy. These results warrant further evaluation of the potential anti-SARS-CoV-2 activity of cepharanthine and nelfinavir.

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  17. Time variation in the probability of failing to detect a case of polymerase chain reaction testing for SARS-CoV-2 as estimated from a viral dynamics model Reviewed International journal

    Keisuke Ejima, Kwang Su Kim, Shoya Iwanami, Yasuhisa Fujita, Ming Li, Roger S. Zoh, Kazuyuki Aihara, Taiga Miyazaki, Takaji Wakita, Shingo Iwami

    Journal of The Royal Society Interface   Vol. 18 ( 177 ) page: 20200947 - 20200947   2021.4

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    Viral tests including polymerase chain reaction (PCR) tests are recommended to diagnose COVID-19 infection during the acute phase of infection. A test should have high sensitivity; however, the sensitivity of the PCR test is highly influenced by viral load, which changes over time. Because it is difficult to collect data before the onset of symptoms, the current literature on the sensitivity of the PCR test before symptom onset is limited. In this study, we used a viral dynamics model to track the probability of failing to detect a case of PCR testing over time, including the presymptomatic period. The model was parametrized by using longitudinal viral load data collected from 30 hospitalized patients. The probability of failing to detect a case decreased toward symptom onset, and the lowest probability was observed 2 days after symptom onset and increased afterwards. The probability on the day of symptom onset was 1.0% (95% CI: 0.5 to 1.9) and that 2 days before symptom onset was 60.2% (95% CI: 57.1 to 63.2). Our study suggests that the diagnosis of COVID-19 by PCR testing should be done carefully, especially when the test is performed before or way after symptom onset. Further study is needed of patient groups with potentially different viral dynamics, such as asymptomatic cases.

    DOI: 10.1098/rsif.2020.0947

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  18. A quantitative model used to compare withinhost SARS-CoV-2, MERS-CoV, and SARS-CoV dynamics provides insights into the pathogenesis and treatment of SARS-CoV-2 Reviewed

    Kim K.S., Ejima K., Iwanami S., Fujita Y., Ohashi H., Koizumi Y., Asai Y., Nakaoka S., Watashi K., Aihara K., Thompson R.N., Ke R., Perelson A.S., Iwami S.

    PLoS Biology   Vol. 19 ( 3 )   2021.3

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    The scientific community is focused on developing antiviral therapies to mitigate the impacts of the ongoing novel coronavirus disease 2019 (COVID-19) outbreak. This will be facilitated by improved understanding of viral dynamics within infected hosts. Here, using a mathematical model in combination with published viral load data, we compare within-host viral dynamics of SARS-CoV-2 with analogous dynamics of MERS-CoV and SARS-CoV. Our quantitative analyses using a mathematical model revealed that the within-host reproduction number at symptom onset of SARS-CoV-2 was statistically significantly larger than that of MERS-CoV and similar to that of SARS-CoV. In addition, the time from symptom onset to the viral load peak for SARS-CoV-2 infection was shorter than those of MERS-CoV and SARS-CoV. These findings suggest the difficulty of controlling SARS-CoV-2 infection by antivirals. We further used the viral dynamics model to predict the efficacy of potential antiviral drugs that have different modes of action. The efficacy was measured by the reduction in the viral load area under the curve (AUC). Our results indicate that therapies that block de novo infection or virus production are likely to be effective if and only if initiated before the viral load peak (which appears 2-3 days after symptom onset), but therapies that promote cytotoxicity of infected cells are likely to have effects with less sensitivity to the timing of treatment initiation. Furthermore, combining a therapy that promotes cytotoxicity and one that blocks de novo infection or virus production synergistically reduces the AUC with early treatment. Our unique modeling approach provides insights into the pathogenesis of SARSCoV- 2 and may be useful for development of antiviral therapies.

    DOI: 10.2110/JSR.2020.113

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  19. Should a viral genome stay in the host cell or leave? A quantitative dynamics study of how hepatitis C virus deals with this dilemma Reviewed International journal

    Iwanami, S., Kitagawa, K., Ohashi, H., Asai, Y., Shionoya, K., Saso, W., Nishioka, K., Inaba, H., Nakaoka, S., Wakita, T., Diekmann, O., Iwami, S., Watashi, K.

    PLoS Biology   Vol. 18 ( 7 ) page: e3000562   2020.7

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    Virus proliferation involves gene replication inside infected cells and transmission to new target cells. Once positive-strand RNA virus has infected a cell, the viral genome serves as a template for copying ("stay-strategy") or is packaged into a progeny virion that will be released extracellularly ("leave-strategy"). The balance between genome replication and virion release determines virus production and transmission efficacy. The ensuing trade-off has not yet been well characterized. In this study, we use hepatitis C virus (HCV) as a model system to study the balance of the two strategies. Combining viral infection cell culture assays with mathematical modeling, we characterize the dynamics of two different HCV strains (JFH-1, a clinical isolate, and Jc1-n, a laboratory strain), which have different viral release characteristics. We found that 0.63% and 1.70% of JFH-1 and Jc1-n intracellular viral RNAs, respectively, are used for producing and releasing progeny virions. Analysis of the Malthusian parameter of the HCV genome (i.e., initial proliferation rate) and the number of de novo infections (i.e., initial transmissibility) suggests that the leave-strategy provides a higher level of initial transmission for Jc1-n, whereas, in contrast, the stay-strategy provides a higher initial proliferation rate for JFH-1. Thus, theoretical-experimental analysis of viral dynamics enables us to better understand the proliferation strategies of viruses, which contributes to the efficient control of virus transmission. Ours is the first study to analyze the stay-leave trade-off during the viral life cycle and the significance of the replication-release switching mechanism for viral proliferation.

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  20. Revealing uninfected and infected target cell dynamics from peripheral blood data in highly and less pathogenic simian/human immunodeficiency virus infected Rhesus macaque Reviewed

    Hara, A., Iwanami, S., Ito, Y., Miura, T., Nakaoka, S., Iwami, S.

    Journal of Theoretical Biology   Vol. 479   page: 29 - 36   2019.10

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    DOI: 10.1016/j.jtbi.2019.07.005

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  21. 骨髄球バイパスを含む造血システムの数理モデルを用いた1細胞移植実験のデータ解析 (第14回生物数学の理論とその応用 : 構造化個体群ダイナミクスとその応用)

    岩波 翔也, 山本 玲, 岩見 真吾, 波江野 洋

    数理解析研究所講究録   Vol. 2087   page: 77 - 85   2018.8

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  22. 骨髄球バイパスを含む造血システムの数理モデル (第13回生物数学の理論とその応用 : 連続および離散モデルのモデリングと解析)

    岩波 翔也, 山本 玲, 岩見 真吾, 波江野 洋

    数理解析研究所講究録   Vol. 2043   page: 102 - 108   2017.9

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  23. A highly pathogenic simian/human immunodeficiency virus effectively produces infectious virions compared with a less pathogenic virus in cell culture Reviewed

    Iwanami, S., Kakizoe, Y., Morita, S., Miura, T., Nakaoka, S., Iwami, S.

    Theoretical Biology and Medical Modelling   Vol. 14 ( 1 ) page: 9   2017.4

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    DOI: 10.1186/s12976-017-0055-8

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Books 1

  1. Quantitative immunology by data analysis using mathematical models

    Iwanami, S., Iwami, S.

    2018.1  ( ISBN:9780128114148

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MISC 6

  1. ウイルス感染動態に基づいた抗ウイルス薬の評価と臨床試験設計の検討

    岩波翔也

    実験医学   Vol. 40 ( 13 ) page: 2115 - 2121   2022.8

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  2. 新型コロナウイルス感染症研究のデジタルトランスフォーメーション

    朴炯基, 禹周賢, 岩波翔也, 岩見真吾

    ウイルス   Vol. 72 ( 1 ) page: 39 - 46   2022.6

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  3. 疾患の数理モデリングと定量的データ解析

    数理科学   Vol. 699   page: 16 - 22   2021.9

  4. 新型コロナウイルスの生体内感染動態の定量化とその応用/数理科学で挑む新型コロナウイルス感染症治療の確立

    岩波翔也, キム・クァンス, 藤田泰久, 江島啓介, 岩見真吾

    数学セミナー   Vol. 707   page: 33 - 39   2020.9

  5. 骨髄球バイパスを含む造血システムの数理モデルを用いた1細胞移植実験のデータ解析 (第14回生物数学の理論とその応用 : 構造化個体群ダイナミクスとその応用)

    岩波 翔也, 山本 玲, 岩見 真吾, 波江野 洋

    数理解析研究所講究録   ( 2087 ) page: 77 - 85   2018.8

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    Other Link: http://hdl.handle.net/2433/251581

  6. 骨髄球バイパスを含む造血システムの数理モデル (第13回生物数学の理論とその応用 : 連続および離散モデルのモデリングと解析)

    岩波 翔也, 山本 玲, 岩見 真吾, 波江野 洋

    数理解析研究所講究録   ( 2043 ) page: 102 - 108   2017.9

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    Other Link: http://hdl.handle.net/2433/236964

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KAKENHI (Grants-in-Aid for Scientific Research) 2

  1. 細胞群動態の変容を捉える多階層データ解析理論の構築

    Grant number:22K15073  2022.4 - 2024.3

    日本学術振興会  科学研究費助成事業 若手研究  若手研究

    岩波 翔也

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    Grant amount:\4680000 ( Direct Cost: \3600000 、 Indirect Cost:\1080000 )

    細胞集団の数の変化を捉えるための個体群動態を土台として、個々の細胞の分化と頻度の少ない小さなイベントが与える影響を補足するために、確率論的なモデルを用いる。また、確率モデル中で計算される各細胞 個体には、遺伝子配列情報を特性として内包させ、生成した疑似配列の系統樹を構築する。 そして、統計学・集団遺伝学・進化生態学の手法を用いて、細胞集団全体の挙動と配列情報 から得られる指標を比較する。同様の手法を実験から得られるデータにも適用し、細胞群の 変化を説明する指標を導出する。

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  2. 組織維持を担う細胞群個体群動態の理解と定量的データ解析

    Grant number:19J12319  2019.4 - 2021.3

    日本学術振興会  科学研究費助成事業 特別研究員奨励費  特別研究員奨励費

    岩波 翔也, 岩波 翔也

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    生体内では、細胞群が相互に影響を与え合いながら組織の恒常性を維持している。ここでは、幹細胞が維持する組織として老化の研究が盛んに行われている造血組織と、細胞が組織を形成と破壊のバランスを取りながら維持している骨組織に着目した。
    造血幹細胞は全ての血液細胞と免疫細胞に分化する能力を持ち、生涯にわたって造血組織を維持すると考えられている。また、造血幹細胞の分化機構について、様々な研究結果から複数のモデルが提唱されている。さらに、加齢による造血幹細胞の能力の変化が、造血組織の老化を引き起こすという研究成果が報告されている。造血幹細胞が造血組織を維持し、老化するメカニズムを解明するために、造血幹細胞分化を記述する数理モデルを開発した。この数理モデルを用いて、若齢マウスと老齢マウスから取得された造血幹細胞を移植したときの末梢血中での各細胞系統の変動を解析した。このとき、非線形混合効果モデルの手法を取り入れ、マウスでの移植実験のデータのばらつきを統計的に扱うことが可能な解析手法を構築した。若齢マウスと老齢マウスの造血幹細胞の能力を比較し、老化に伴って骨髄球の産生が多くなることを説明した。今後は、造血幹細胞分化の確率シミュレータを開発し、細胞の分化と組織の維持の関係性の定性的・定量的な解釈を目指す。
    骨組織は骨芽細胞と破骨細胞が相互に作用し合うことで、骨形成と骨吸収のバランスをとりながら維持され、一般に、加齢と共に骨量が減少する。また、重力変化や閉経などの摂動によって骨量が変化することが示唆されている。ここでは、マウスで取得された骨代謝マーカーと骨量変動の長期の時系列データと、人工的に重力をかけられたマウスのデータを同時に解析し、骨代謝マーカーの変動から骨量の変動を説明することに成功した。今後は、他の摂動実験を説明しうる数理モデルを開発していく。

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