Stratification of viral shedding patterns in saliva of COVID-19 patients (preprint)

Living with COVID-19 requires continued vigilance against the spread and emergence of variants of concern (VOCs). Rapid and accurate saliva diagnostic testing, alongside basic public health responses, is a viable option contributing to effective transmission control. Nevertheless, our knowledge regarding the dynamics of SARS-CoV-2 infection in saliva is not as advanced as our understanding of the respiratory tract. Here we analyzed longitudinal viral load data of SARS-CoV-2 in saliva samples from 144 patients with mild COVID-19 (a combination of our collected data and published data). Using a mathematical model, we successfully stratified infection dynamics into three distinct groups with clear patterns of viral shedding: viral shedding durations in the three groups were 11.5 days (95% CI: 10.6 to 12.4), 17.4 days (16.6 to 18.2), and 30.0 days (28.1 to 31.8), respectively. Surprisingly, this stratified grouping remained unexplained despite our analysis of 47 types of clinical data, including basic demographic information, clinical symptoms, results of blood tests, and vital signs. Additionally, we quantified the expression levels of 92 micro-RNAs in a subset of saliva samples, but these also failed to explain the observed stratification, although the mir-1846 level may have been weakly correlated with peak viral load. Our study provides insights into SARS-CoV-2 infection dynamics in saliva, highlighting the challenges in predicting the duration of viral shedding without indicators that directly reflect an individual's immune response, such as antibody induction. Given the significant individual heterogeneity in the kinetics of saliva viral shedding, identifying biomarker(s) for viral shedding patterns will be crucial for improving public health interventions in the era of living with COVID-19.

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

In the era of living with COVID-19, the risk of localised SARS-CoV-2 outbreaks remains. Here, we develop a multi-scale 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 multi-scale models to design pre-emptive interventions against SARS-CoV-2 and other viruses.

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

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 found that the SARS-CoV-2 variants selected for as the virus evolved from the pre-Alpha to the Delta variant had earlier and higher infectious periods 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 showed that a decreased incubation period and an increased proportion of asymptomatic infection were also positively selected for as SARS-CoV-2 mutated to the extent that people did not isolate. We demonstrated that the Omicron variants evolved in these ways to adapt to human behavior. The quantitative information and predictions we present here can guide future responses in the potential arms race between pandemic interventions and viral evolution.

The impact of cross-reactive immunity on the emergence of SARS-CoV-2 variants (preprint)

A key feature of the COVID-19 pandemic has been the emergence of SARS-CoV-2 variants with different transmission characteristics. However, when a novel variant arrives in a host population, it will not necessarily lead to many cases. Instead, it may fade out, due to stochastic effects and the level of immunity in the population. Immunity against novel SARS-CoV-2 variants may be influenced by prior exposures to related viruses, such as other SARS-CoV-2 variants and seasonal coronaviruses, and the level of cross-reactive immunity conferred by those exposures. Here, we investigate the impact of cross-reactive immunity on the emergence of SARS-CoV-2 variants in a simplified scenario in which a novel SARS-CoV-2 variant is introduced after an antigenically related virus has spread in the population. We use mathematical modelling to explore the risk that the novel variant invades the population and causes a large number of cases, as opposed to fading out. If cross-reactive immunity is complete (i.e. someone infected by the previously circulating virus is no longer susceptible to the novel variant), the novel variant must be more transmissible than the previous virus to invade the population. However, in a more realistic scenario in which cross-reactive immunity is partial, we show that it is possible for novel variants to invade, even if they are less transmissible than previously circulating viruses. This is because partial cross-reactive immunity effectively increases the pool of susceptible hosts that are available to the novel variant compared to complete cross-reactive immunity. Furthermore, if previous infection with the antigenically related virus assists the establishment of infection with the novel variant, as has been proposed following some experimental studies, then even variants with very limited transmissibility are able to invade the host population. Our results highlight that fast assessment of the level of cross-reactive immunity conferred by related viruses on novel SARS-CoV-2 variants is an essential component of novel variant risk assessments.

A personalized antibody score for predicting individual COVID-19 vaccine-elicited antibody levels from basic demographic and health information (preprint)

Antibody titers wane after two-dose COVID-19 vaccinations, but individual variation in vaccine-elicited antibody dynamics remains to be explored. Here, we created a personalized antibody score that enables individuals to infer their antibody status by use of a simple calculation. We recently developed a mathematical model of B cell differentiation to accurately interpolate the longitudinal data from a community-based cohort in Fukushima, Japan, which consists of 2,159 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 course of the vaccine- elicited antibody response, we first elucidated individual background factors that contributed to the main features of antibody dynamics, i.e., the peak, the duration, and the area under the curve. We found that increasing age was a negative factor and a longer interval between the two doses was a positive factor for individual antibody level. We also found that the presence of underlying disease and the use of medication affected antibody levels negatively, whereas the presence of adverse reactions upon vaccination affected antibody levels positively. We then applied to these factors a recently proposed computational method to optimally fit clinical scores, which resulted in an integer-based score that can be used to evaluate the antibody status of individuals from their basic demographic and health information. This score can be easily calculated by individuals themselves or by medical practitioners. There is a potential usefulness of this score for identifying vulnerable populations and encouraging them to get booster vaccinations.

Stratifying elicited antibody dynamics after two doses of SARS-CoV-2 vaccine in a community-based cohort in Fukushima, Japan (preprint)

Recent studies have provided insights into the effect of vaccine boosters on recall immunity. Given the limited global supply of COVID-19 vaccines, identifying vulnerable populations with lower sustained vaccine-elicited antibody titers is important for targeting individuals for booster vaccinations. Here we investigated longitudinal data in a cohort of 2,526 people in Fukushima, Japan, from April 2021 to December 2021. Antibody titers following two doses of a COVID-19 vaccine were repeatedly monitored and information on lifestyle habits, comorbidities, adverse reactions, and medication use was collected. Using mathematical modeling and machine learning, we stratified the time-course patterns of antibody titers and identified vulnerable populations with low sustained antibody titers. Moreover, we showed that only 5.7% of the participants in our cohort were part of the "durable" population with high sustained antibody titers, which suggests that this durable population might be overlooked in small cohorts. We also found large variation in antibody waning within our cohort. There is a potential usefulness of our approach for identifying the neglected vulnerable population.

Different efficacies of neutralizing antibodies and antiviral drugs on SARS-CoV-2 Omicron subvariants, BA.1 and BA.2 (preprint)

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 the impact of variant emergence on choosing optimal drug treatment.

Factors Associated with COVID-19 Vaccine Booster Hesitancy: a Retrospective Cohort Study, Fukushima Vaccination Community Survey (preprint)

This was a retrospective cohort study, which aimed to investigate the factors associated with hesitancy to receive the third dose of coronavirus disease 2019 (COVID-19) vaccine. A paper-based questionnaire survey was administered to all participants. Accordingly, the study included participants who provided answer in the questionnaire whether they have an intent to receive the third dose of 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 booster vaccination were retrieved. Among the 2439 participants with mean (±SD) age of 52.6±18.9 years, and 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 younger age (OR=0.98; 95% CI: 0.96-1.00) and higher antibody level (OR=2.52; 95% CI: 1.27-4.99) are positively associated with the third vaccine hesitancy. The efficacy of the COVID-19 vaccine and concerns about adverse reactions had significant impact on the third vaccination behavior. A rapid increase in the booster dose rate is needed to control the pandemic, and specific approaches should be taken in these groups that are likely to hesitate the third vaccine, subsequently increasing booster contact rate.

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

Mutations continue to accumulate within the SARS-CoV-2 genome, and the ongoing epidemic has shown no signs of ending. It is critical to predict problematic mutations that may arise in clinical environments and assess their properties in advance to quickly implement countermeasures against future variant infections. In this study, we identified mutations resistant to remdesivir, which is widely administered to SARS-CoV-2-infected patients, and discuss the cause of resistance. First, we simultaneously constructed eight recombinant viruses carrying the mutations detected in in vitro serial passages of SARS-CoV-2 in the presence of remdesivir. Time course analyses of cellular virus infections showed significantly higher infectious titers and infection rates in mutant viruses than wild type virus under treatment with remdesivir. Next, we developed a mathematical model in consideration of the changing dynamic of cells infected with mutant viruses with distinct propagation properties and defined that mutations detected in in vitro passages canceled the antiviral activities of remdesivir without raising virus production capacity. Finally, molecular dynamics simulations of the NSP12 protein of SARS-CoV-2 revealed that the molecular vibration around the RNA-binding site was increased by the introduction of mutations on NSP12. Taken together, we identified multiple mutations that affected the flexibility of the RNA binding site and decreased the antiviral activity of remdesivir. Our new insights will contribute to developing further antiviral measures against SARS-CoV-2 infection.

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

Appropriate isolation guidelines for COVID-19 patients are warranted. Currently, isolating for fixed time is adapted in most countries. However, given the variability in viral dynamics between patients, some patients may no longer be infectious by the end of isolation (thus they are redundantly isolated), whereas others may still be infectious. Utilizing viral test results to determine ending isolation would minimize both the risk of ending isolation of infectious patients and the burden due to redundant isolation of noninfectious patients. In our previous study, we proposed a computational framework using SARS-CoV-2 viral dynamics models to compute the risk and the burden of different isolation guidelines with PCR tests. In this study, we extend the computational framework to design isolation guidelines for COVID-19 patients utilizing rapid antigen tests. Time interval of tests and number of consecutive negative tests to minimize the risk and the burden of isolation were explored. Furthermore, the approach was extended for asymptomatic cases. We found the guideline should be designed considering various factors: the infectiousness threshold values, the detection limit of antigen tests, symptom presence, and an acceptable level of releasing infectious patients. Especially, when detection limit is higher than the infectiousness threshold values, more consecutive negative results are needed to ascertain loss of infectiousness. To control the risk of releasing of infectious individuals under certain levels, rapid antigen tests should be designed to have lower detection limits than infectiousness threshold values to minimize the length of prolonged isolation, and the length of prolonged isolation increases when the detection limit is higher than the infectiousness threshold values, even though the guidelines are optimized for given conditions.

Safely return to schools and offices: early and frequent screening with high sensitivity antigen tests effectively identifies COVID-19 patients (preprint)

Background In-person interaction at school and offices offers invaluable experience to students and benefits to companies. In the midst of the pandemic, ways to safely go back to schools and offices have been argued. Centers for Disease Control and Prevention (CDC) recommends taking all precautions such as vaccination and universal indoor masking. However, even if all the precautions are implemented and transmission is perfectly prevented in the facilities, they may be infected outside of the facilities, which would be a source of transmission in the facilities. Therefore, identifying those infected outside of the facility through screening is essential to safely go back to schools or offices. However, studies investigating the effectiveness of screening are limited. Further, it is not well clarified now which screening strategy (e.g., low or high sensitivity antigen tests, intervals and the number of tests) effectively identify infected and infectious individuals to avoid transmission in facilities Methods We assessed the effectiveness of various screening strategies in schools and offices through quantitative simulation. The effectiveness was assessed by the proportion of identified infected and infectious participants. Infection dynamics in the facility is governed by transmission dynamics of the population they belong to, and the screening is initiated at different epidemic phases: growth, peak, and declining phases. The viral load trajectory over time for each infected individual was modelled by the viral dynamics model, and the transmission process at the population level was modelled by a deterministic compartment model. The model parameters were estimated from clinical and epidemiological data. Screening strategies were varied by antigen tests with different sensitivity and schedules of screening over 10 days. Results Under the daily screening, we found high sensitivity antigen tests (the detection limit: 6.3 × 10 4 copies/mL) yielded 88% (95%CI 86-89) of effectiveness by the end of 10 days screening period, which is about 20% higher than that with low sensitivity antigen tests (2.0 × 10 6 copies/mL). Comparing screening scenarios with different schedules, we found early and frequent screening is the key to maximize the effectiveness. Sensitivity analysis revealed that less frequent tests might be an option when the number of antigen tests is limited especially when the screening is performed at the growth phase. Discussion High sensitivity antigen tests, high frequency screening, and immediate initiation of screening are the key to safely restart educational and economic activities allowing in-person interactions. Our computational framework is useful in assessment of screening strategies by incorporating additional factors for specific situations.

Anti-severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) potency of Mefloquine as an entry inhibitor in vitro (preprint)

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 M, IC90 = 2.31 M, and IC99 = 4.39 M 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.

HIV testing by public health centers and municipalities, and new HIV cases during the COVID-19 pandemic in Japan (preprint)

BackgroundDuring the COVID-19 outbreak, medical resources were primarily allocated to COVID-19, which might have reduced facility capacity for HIV testing. Further, people may have opted against HIV testing during this period to avoid COVID-19 exposure. We investigate the influence of the COVID-19 pandemic on HIV testing and its consequences in Japan. MethodsWe analysed quarterly HIV/AIDS-related data from 2015 to the second quarter of 2020 using an anomaly detection approach. The data included the number of consultations that public health centers received, the number of HIV tests performed by public health centers or municipalities, and the number of newly reported HIV cases with and without AIDS diagnosis. As sensitivity analyses, we performed the same analysis for two subgroups: men who have sex with men (MSM) and non-Japanese. FindingsThe number of HIV tests (9,584 vs. 35,908 in the year-before period) and consultations (11,689 vs. 32,565) performed by public health centers significantly declined in the second quarter of 2020, while the proportion of HIV cases with AIDS diagnosis among all HIV cases (36{middle dot}2% vs. 26{middle dot}4%) significantly increased after removing the trend and seasonality effects. The number of HIV cases without AIDS diagnosis numerically decreased (166 vs. 217), although the reduction was not significant. We confirmed similar trend for the MSM and non-Japanese groups. InterpretationThe current HIV testing system including public health centers misses more HIV cases at the early phase of the infection during the pandemic. Given that the clear epidemiological picture of HIV incidence during the pandemic is still uncertain, continuously monitoring the situation as well as securing sufficient test resources using self-test is essential. FundingJapan Society for the Promotion of Science, Japan Science and Technology Agency, Japan Agency for Medical Research and Development. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSBefore this study, we searched PubMed, Medline, and Google Scholar on Oct 12, 2020, for articles investigated the number of HIV test and HIV cases during the COVID-19 pandemic in Japan, using the search terms "novel coronavirus" or "SARS-CoV-2", and "HIV" or "AIDS", and "Japan", with no time restrictions. We found no published work relevant to our study. Added value of this studyDuring the COVID-19 pandemic in Japan, the public health centers and municipalities temporarily suspended facility-based HIV testing to concentrate their limited resources to COVID-19 testing. We investigated the impact of the COVID-19 pandemic on the number of HIV tests in public health centers and municipalities, and on the number of HIV cases with and without AIDS diagnosis. We confirmed that the number of the test declined in the second quarter (April to June) of 2020, and the proportion of HIV with AIDS diagnosis among all HIV cases increased during the same period. Implications of all the available evidenceProviding sufficient HIV testing opportunities even during the pandemic, when facility-based testing is challenging, is necessary for better clinical and public health outcomes. Self-testing and home specimen collection (e.g. dried blood spot or oral fluid test) could be a key to fill the gap between the need for HIV testing and the constraints related to the COVID-19 outbreak.

Identification of Anti-COVID-19 Agents, Cepharanthine and Nelfinavir, and Their Potential Usage for Combination Treatment (preprint)

Antiviral treatments targeting the coronavirus disease 2019 (COVID-19) 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: the anti-inflammatory drug Cepharanthine and HIV protease inhibitor Nelfinavir. Cepharanthine inhibited SARS-CoV-2 entry into cells, whilst Nelfinavir inhibited the catalytic activity of viral main protease to suppress viral replication. Consistent with their different modes of action, in vitro assays highlight a synergistic effect of this combined treatment to limit SARS-CoV-2 proliferation. Mathematical modeling in vitro antiviral activity coupled with the known pharmacokinetics for these drugs predicts that Nelfinavir will shorten the period until viral clearance by 5.5-days and the combining Cepharanthine/Nelfinavir enhanced their predicted efficacy to control viral proliferation. In summary, this study identifies a new multidrug combination treatment for COVID-19.Funding: This work was supported by The Agency for Medical Research and Development (AMED) emerging/re-emerging infectious diseases project (JP19fk0108111, JP19fk0108110, JP20fk0108104); the AMED Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS, JP19am0101114, JP19am0101069, JP19am0101111) program; The Japan Society for the Promotion of Science 260 KAKENHI (JP17H04085, JP20H03499, JP15H05707, 19H04839); The JST MIRAI program; and Wellcome Trust funded Investigator award (200838/Z/16/Z). Conflict of Interest: None.

Estimation of the incubation period of COVID-19 using viral load data (preprint)

The incubation period, or the time from infection to symptom onset of COVID-19 has been usually estimated using data collected through interviews with cases and their contacts. However, this estimation is influenced by uncertainty in recalling effort 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 the reported viral load data from multiple countries (Singapore, China, Germany, France, and Korea) and estimated the incubation period. The median, 2.5, and 97.5 percentiles of the incubation period were 5.23 days (95% CI: 5.17, 5.25), 3.29 days (3.25, 3.37), and 8.22 days (8.02, 8.46), 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 impractical to directly observe the infection event.

Multidrug treatment with nelfinavir and cepharanthine against COVID-19 (preprint)

Antiviral treatments targeting the emerging coronavirus disease 2019 (COVID-19) 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 antiviral agents: the HIV protease inhibitor Nelfinavir and the anti-inflammatory drug Cepharanthine. In silico modeling shows Nelfinavir binds the SARS-CoV-2 main protease consistent with its inhibition of viral replication, whilst Cepharanthine inhibits viral attachment and entry into cells. Consistent with their different modes of action, in vitro assays highlight a synergistic effect of this combined treatment to limit SARS-CoV-2 proliferation. Mathematical modeling in vitro antiviral activity coupled with the known pharmacokinetics for these drugs predicts that Nelfinavir will facilitate viral clearance. Combining Nelfinavir/Cepharanthine enhanced their predicted efficacy to control viral proliferation, to ameliorate both the progression of disease and risk of transmission. In summary, this study identifies a new multidrug combination treatment for COVID-19.

Inferring Timing of Infection Using Within-host SARS-CoV-2 Infection Dynamics Model: Are "Imported Cases" Truly Imported? (preprint)

Importance: Although the COVID-19 epidemic in some countries such as China are in the last phase by large effort for containment of the disease, another outbreaks can occur because huge susceptible population remains. Further, there remain countries in the early phase of outbreak with zero or limited number of cases in southern hemisphere countries. In those countries at risk of future outbreak, ascertaining whether cases are imported or the result of local secondary transmission is important for government to shape appropriate public health strategies. Objective: To develop a method to estimate timing of infection establishment, which helps differentiate imported and autochthonous cases. Design, Setting and Participants: Of the first 18 cases reported in Singapore, 12 were used in our study (1 case with insufficient data and 5 on anti-viral treatment were excluded from the analysis). The viral load data from these initial cases considered imported due to their travel history to Wuhan were analyzed. Another viral load data from 3 cases reported from Zhuhai, China, for whom exposed day were known, were also analyzed to determine the viral load threshold for infection establishment. Exposures: SARS-CoV-2 infection confirmed by the polymerase-chain-reaction (PCR) test. Main Outcomes and Measures: The timing of infection establishment of each case was assessed by analysing viral load data after symptom onset using a within-host viral dynamics model for SARS-CoV-2. Estimated timing of infection will indicate whether cases are imported or autochthonous transmission within Singapore. Results: Six among the 12 cases were clearly imported cases, whereas we could not rule out the possibility of secondary transmission for the rest of 6 cases, which collectively evidenced ongoing transmission in Singapore. For the 6 cases who could be the results of secondary transmission, further investigation to identify the source of infection within Singapore should be warranted (i.e., contact tracing). Conclusions and Relevance: In an early phase of outbreak due to entrance or re-entrance of the virus to countries/communities, collecting viral load data over time from cases from symptom onset is highly recommended, because viral load data are valuable to infer the timing of infection and distinguish between imported cases and ongoing local transmission.

Modelling SARS-CoV-2 Dynamics: Implications for Therapy (preprint)

The scientific community is focussed on developing antiviral therapies to mitigate the impacts of the ongoing novel coronavirus disease (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 collected from the same specimen (throat / nasal swabs or nasopharyngeal / sputum / tracheal aspirate), we compare within-host dynamics for patients infected in the current outbreak with analogous dynamics for MERS-CoV and SARS-CoV infections. Our quantitative analyses revealed that SARS-CoV-2 infection dynamics are more severe than those for mild cases of MERS-CoV, but are similar to severe cases, and that the viral dynamics of SARS-CoV infection are similar to those of MERS-CoV in mild cases but not in severe case. Consequently, SARS-CoV-2 generates infection dynamics that are more severe than SARS-CoV. Furthermore, we used our viral dynamics model to predict the effectiveness of unlicensed drugs that have different methods of action. The effectiveness was measured by AUC of viral load. Our results indicated that therapies that block de novo infections or virus production are most likely to be effective if initiated before the peak viral load (which occurs around three days after symptom onset on average), but therapies that promote cytotoxicity are likely to have only limited effects. Our unique mathematical approach provides insights into the pathogenesis of SARS-CoV-2 in humans, which are useful for development of antiviral therapies.