Analysis of the risk and pre-emptive control of viral outbreaks accounting for within-host dynamics: SARS-CoV-2 as a case study.

In the era of living with COVID-19, the risk of localised SARS-CoV-2 outbreaks remains. Here, we develop a multiscale modelling framework for estimating the local outbreak risk for a viral disease (the probability that a major outbreak results from a single case introduced into the population), accounting for within-host viral dynamics. Compared to population-level models previously used to estimate outbreak risks, our approach enables more detailed analysis of how the risk can be mitigated through pre-emptive interventions such as antigen testing. Considering SARS-CoV-2 as a case study, we quantify the within-host dynamics using data from individuals with omicron variant infections. We demonstrate that regular antigen testing reduces, but may not eliminate, the outbreak risk, depending on characteristics of local transmission. In our baseline analysis, daily antigen testing reduces the outbreak risk by 45% compared to a scenario without antigen testing. Additionally, we show that accounting for heterogeneity in within-host dynamics between individuals affects outbreak risk estimates and assessments of the impact of antigen testing. Our results therefore highlight important factors to consider when using multiscale models to design pre-emptive interventions against SARS-CoV-2 and other viruses.

Infectious virus shedding duration reflects secretory IgA antibody response latency after SARS-CoV-2 infection.

Infectious virus shedding from individuals infected with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is used to estimate human-to-human transmission risk. Control of SARS-CoV-2 transmission requires identifying the immune correlates that protect infectious virus shedding. Mucosal immunity prevents infection by SARS-CoV-2, which replicates in the respiratory epithelium and spreads rapidly to other hosts. However, whether mucosal immunity prevents the shedding of the infectious virus in SARS-CoV-2-infected individuals is unknown. We examined the relationship between viral RNA shedding dynamics, duration of infectious virus shedding, and mucosal antibody responses during SARS-CoV-2 infection. Anti-spike secretory IgA antibodies (S-IgA) reduced viral RNA load and infectivity more than anti-spike IgG/IgA antibodies in infected nasopharyngeal samples. Compared with the IgG/IgA response, the anti-spike S-IgA post-infection responses affected the viral RNA shedding dynamics and predicted the duration of infectious virus shedding regardless of the immune history. These findings highlight the importance of anti-spike S-IgA responses in individuals infected with SARS-CoV-2 for preventing infectious virus shedding and SARS-CoV-2 transmission. Developing medical countermeasures to shorten S-IgA response time may help control human-to-human transmission of SARS-CoV-2 infection and prevent future respiratory virus pandemics.

Multiscale modeling of HBV infection integrating intra- and intercellular viral propagation to analyze extracellular viral markers.

Chronic infection with hepatitis B virus (HBV) is caused by the persistence of closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. Despite available therapeutic anti-HBV agents, eliminating the cccDNA remains challenging. Thus, quantifying and understanding the dynamics of cccDNA are essential for developing effective treatment strategies and new drugs. However, such study requires repeated liver biopsy to measure the intrahepatic cccDNA, which is basically not accepted because liver biopsy is potentially morbid and not common during hepatitis B treatment. We here aimed to develop a noninvasive method for quantifying cccDNA in the liver using surrogate markers in peripheral blood. We constructed a multiscale mathematical model that explicitly incorporates both intracellular and intercellular HBV infection processes. The model, based on age-structured partial differential equations, integrates experimental data from in vitro and in vivo investigations. By applying this model, we roughly predicted the amount and dynamics of intrahepatic cccDNA within a certain range using specific viral markers in serum samples, including HBV DNA, HBsAg, HBeAg, and HBcrAg. Our study represents a significant step towards advancing the understanding of chronic HBV infection. The noninvasive quantification of cccDNA using our proposed method holds promise for improving clinical analyses and treatment strategies. By comprehensively describing the interactions of all components involved in HBV infection, our multiscale mathematical model provides a valuable framework for further research and the development of targeted interventions.

Contact-number-driven virus evolution: A multi-level modeling framework for the evolution of acute or persistent RNA virus infection.

Viruses evolve in infected host populations, and host population dynamics affect viral evolution. RNA viruses with a short duration of infection and a high peak viral load, such as SARS-CoV-2, are maintained in human populations. By contrast, RNA viruses characterized by a long infection duration and a low peak viral load (e.g., borna disease virus) can be maintained in nonhuman populations, and the process of the evolution of persistent viruses has rarely been explored. Here, using a multi-level modeling approach including both individual-level virus infection dynamics and population-scale transmission, we consider virus evolution based on the host environment, specifically, the effect of the contact history of infected hosts. We found that, with a highly dense contact history, viruses with a high virus production rate but low accuracy are likely to be optimal, resulting in a short infectious period with a high peak viral load. In contrast, with a low-density contact history, viral evolution is toward low virus production but high accuracy, resulting in long infection durations with low peak viral load. Our study sheds light on the origin of persistent viruses and why acute viral infections but not persistent virus infection tends to prevail in human society.

Potential Anti-Mpox Virus Activity of Atovaquone, Mefloquine, and Molnupiravir, and Their Potential Use as Treatments.

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 132 approved drugs using an MPXV infection cell system. We quantified antiviral activities of potential drug candidates 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 postentry processes. 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 7 days at clinically relevant drug concentrations. CONCLUSIONS: These data suggest that atovaquone would be a potential candidate for treating mpox.

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

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".

[Digital transformation of COVID-19 research].

In a current life sciences research, we are in an era in which advanced technology emerging and utilize big data. Data-driven approaches such as machine learnings play an important role to analyze these datasets. However, limited clinical (time-course) datasets are available for infectious diseases, cancer, and other diseases. Especially in the case of emerging infectious disease outbreaks, clinical data obtained from a limited number of cases must be used to develop treatment strategies and public health policies. This means that many clinical data are not big data, which often makes the application of data-driven approaches difficult. In this paper, we mainly apply a mathematical model-based approach to the clinical data of COVID-19 and discuss how biologically important information can be extracted from the limited data and how they can benefit society.

Modelling the effectiveness of an isolation strategy for managing mpox outbreaks with variable infectiousness profiles.

The global outbreak of mpox in 2022 and subsequent sporadic outbreaks in 2023 highlighted the importance of nonpharmaceutical interventions such as case isolation. Individual variations in viral shedding dynamics may lead to either premature ending of isolation for infectious individuals, or unnecessarily prolonged isolation for those who are no longer infectious. Here, we developed a modeling framework to characterize heterogeneous mpox infectiousness profiles - specifically, when infected individuals cease to be infectious - based on viral load data. We examined the potential effectiveness of three different isolation rules: a symptom-based rule (the current guideline in many countries) and rules permitting individuals to stop isolating after either a fixed duration or following tests that indicate that they are no longer likely to be infectious. Our analysis suggests that the duration of viral shedding ranges from 23 to 50 days between individuals. The risk of infected individuals ending isolation too early was estimated to be 8.8% (95% CI: 6.7-10.5) after symptom clearance and 5.4% (95% CI: 4.1-6.7) after 3 weeks of isolation. While these results suggest that the current standard practice for ending isolation is effective, we found that unnecessary isolation following the infectious period could be reduced by adopting a testing-based rule.

Modeling and predicting individual variation in COVID-19 vaccine-elicited antibody response in the general population.

As we learned during the COVID-19 pandemic, vaccines are one of the most important tools in infectious disease control. To date, an unprecedentedly large volume of high-quality data on COVID-19 vaccinations have been accumulated. For preparedness in future pandemics beyond COVID-19, these valuable datasets should be analyzed to best shape an effective vaccination strategy. We are collecting longitudinal data from a community-based cohort in Fukushima, Japan, that consists of 2,407 individuals who underwent serum sampling two or three times after a two-dose vaccination with either BNT162b2 or mRNA-1273. Using the individually reconstructed time courses of the vaccine-elicited antibody response based on mathematical modeling, we first identified basic demographic and health information that contributed to the main features of the antibody dynamics, i.e., the peak, the duration, and the area under the curve. We showed that these three features of antibody dynamics were partially explained by underlying medical conditions, adverse reactions to vaccinations, and medications, consistent with the findings of previous studies. We then applied to these factors a recently proposed computational method to optimally fit an "antibody score", which resulted in an integer-based score that can be used as a basis for identifying individuals with higher or lower antibody titers from basic demographic and health information. The score can be easily calculated by individuals themselves or by medical practitioners. Although the sensitivity of this score is currently not very high, in the future, as more data become available, it has the potential to identify vulnerable populations and encourage them to get booster vaccinations. Our mathematical model can be extended to any kind of vaccination and therefore can form a basis for policy decisions regarding the distribution of booster vaccines to strengthen immunity in future pandemics.

Modeling COVID-19 vaccine booster-elicited antibody response and impact of infection history.

The 3-dose COVID-19 vaccine (booster vaccination) has been offered worldwide. As booster vaccinations continue, it is important to understand the antibody dynamics elicited by booster vaccination in order to evaluate and develop vaccination needs and strategies. Here, we investigated longitudinal data by monitoring IgG antibodies against the receptor binding domain (RBD) in health care workers. We extended our previously developed mathematical model to booster vaccines and successfully fitted antibody titers over time in the absence and presence of past SARS-CoV-2 infection. Quantitative analysis using our mathematical model indicated that anti-RBD IgG titers increase to a comparable extent after booster vaccination, regardless of the presence or absence of infection, but infection history extends the duration of antibody response by 1.28 times. Such a mathematical modeling approach can be used to inform future vaccination strategies on the basis of an individual's immune history. Our simple quantitative approach can be extended to any kind of vaccination and therefore can form a basis for policy decisions regarding the distribution of booster vaccines to strengthen immunity in future pandemics.

Isolation may select for earlier and higher peak viral load but shorter duration in SARS-CoV-2 evolution.

During the COVID-19 pandemic, human behavior change as a result of nonpharmaceutical interventions such as isolation may have induced directional selection for viral evolution. By combining previously published empirical clinical data analysis and multi-level mathematical modeling, we find that the SARS-CoV-2 variants selected for as the virus evolved from the pre-Alpha to the Delta variant had earlier and higher peak in viral load dynamics but a shorter duration of infection. Selection for increased transmissibility shapes the viral load dynamics, and the isolation measure is likely to be a driver of these evolutionary transitions. In addition, we show that a decreased incubation period and an increased proportion of asymptomatic infection are also positively selected for as SARS-CoV-2 mutated to adapt to human behavior (i.e., Omicron variants). The quantitative information and predictions we present here can guide future responses in the potential arms race between pandemic interventions and viral evolution.

Multiscale modeling of HBV infection integrating intra- and intercellular viral propagation for analyzing extracellular viral markers.

Chronic infection of hepatitis B virus (HBV) is caused by the persistence of closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. Despite available therapeutic anti-HBV agents, eliminating the cccDNA remains challenging. The quantifying and understanding dynamics of cccDNA are essential for developing effective treatment strategies and new drugs. However, it requires a liver biopsy to measure the intrahepatic cccDNA, which is basically not accepted because of the ethical aspect. We here aimed to develop a non-invasive method for quantifying cccDNA in the liver using surrogate markers present in peripheral blood. We constructed a multiscale mathematical model that explicitly incorporates both intracellular and intercellular HBV infection processes. The model, based on age-structured partial differential equations (PDEs), integrates experimental data from in vitro and in vivo investigations. By applying this model, we successfully predicted the amount and dynamics of intrahepatic cccDNA using specific viral markers in serum samples, including HBV DNA, HBsAg, HBeAg, and HBcrAg. Our study represents a significant step towards advancing the understanding of chronic HBV infection. The non-invasive quantification of cccDNA using our proposed methodology holds promise for improving clinical analyses and treatment strategies. By comprehensively describing the interactions of all components involved in HBV infection, our multiscale mathematical model provides a valuable framework for further research and the development of targeted interventions.

Antibody Profiling of Microbial Antigens in the Blood of COVID-19 mRNA Vaccine Recipients Using Microbial Protein Microarrays.

Although studies have demonstrated that infections with various viruses, bacteria, and parasites can modulate the immune system, no study has investigated changes in antibodies against microbial antigens after the COVID-19 mRNA vaccination. IgG antibodies against microbial antigens in the blood of vaccinees were comprehensively analyzed using microbial protein microarrays that carried approximately 5000 microbe-derived proteins. Changes in antibodies against microbial antigens were scrutinized in healthy participants enrolled in the Fukushima Vaccination Community Survey conducted in Fukushima Prefecture, Japan, after their second and third COVID-19 mRNA vaccinations. Antibody profiling of six groups stratified by antibody titer and the remaining neutralizing antibodies was also performed to study the dynamics of neutralizing antibodies against SARS-CoV-2 and the changes in antibodies against microbial antigens. The results showed that changes in antibodies against microbial antigens other than SARS-CoV-2 antigens were extremely limited after COVID-19 vaccination. In addition, antibodies against a staphylococcal complement inhibitor have been identified as microbial antigens that are associated with increased levels of neutralizing antibodies against SARS-CoV-2. These antibodies may be a predictor of the maintenance of neutralizing antibodies following the administration of a COVID-19 mRNA vaccine.