Combination therapy with nirmatrelvir and molnupiravir improves the survival of SARS-CoV-2 infected mice

As the SARS-CoV-2 pandemic remains uncontrolled owing to the continuous emergence of variants of concern, there is an immediate need to implement the most effective antiviral treatment strategies, especially for risk groups. Here, we evaluated the therapeutic potency of nirmatrelvir, remdesivir, and molnupiravir and their combinations in SARS-CoV-2-infected K18-hACE2 transgenic mice. Systemic treatment of mice with each drug (20 mg/kg) resulted in slightly enhanced antiviral efficacy and yielded an increased life expectancy of only about 20-40% survival. However, combination therapy with nirmatrelvir (20 mg/kg) and molnupiravir (20 mg/kg) in lethally infected mice showed profound inhibition of SARS-CoV-2 replication in both the lung and brain and synergistically improved survival times up to 80% compared to those with nirmatrelvir (P= 0.0001) and molnupiravir (P= 0.0001) administered alone. This combination therapy effectively reduced clinical severity score, virus-induced tissue damage, and viral distribution compared to those in animals treated with these monotherapies. Furthermore, all these assessments associated with this combination were also significantly higher than that of mice receiving remdesivir monotherapy (P= 0.0001) and the nirmatrelvir (20 mg/kg) and remdesivir (20 mg/kg) combination (P= 0.0001), underscored the clinical significance of this combination. By contrast, the nirmatrelvir and remdesivir combination showed less antiviral efficacy, with lower survival compared to nirmatrelvir monotherapy, demonstrating the inefficient therapeutic effect of this combination. The combination therapy with nirmatrelvir and molnupiravir contributes to alleviated morbidity and mortality, which can serve as a basis for the design of clinical studies of this combination in the treatment of COVID-19 patients. IMPORTANCESince SARS-CoV-2 spread rapidly with the emergence of new variants of concerns, it is necessary to develop effective treatment strategies to treat elderly individuals and those with comorbidities. Antiviral therapy using a combination of drugs is more effective in eradicating viruses and will undoubtedly improve the clinical outcome and survival probability of hospitalized SARS-CoV-2 patients. In the current study, we observed three FDA-approved antivirals nirmatrelvir, remdesivir, and molnupiravir have therapeutic significance with moderate survival for their monotherapies against SARS-CoV-2 infected K18-hACE2 mouse model. The combination of nirmatrelvir and molnupiravir showed significant antiviral activity and a higher survival rate of approximately 80%, providing in vivo evidence of the potential utility of this combination. In contrast, nirmatrelvir and remdesivir combination showed less antiviral potency and emphasized the ineffective significance with less survival. The current study suggests that the nirmatrelvir and molnupiravir combination is an effective drug regimen strategy in treating SARS-CoV-2 patients.

Characterization of Severe Acute Respiratory Syndrome Coronavirus 2Stability in Multiple Water Matrices

The advent of the global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates a thorough study of the stability and transmissibility in the environment. We characterized the stability of SARS-CoV-2 in three water matrices: fresh, tap, and seawater. The minimum infective dose of SARS-CoV-2 in Vero cells was confirmed to be 10 3 PFU/mL. The stability of SARS-CoV-2 varied according to the water matrix: infective SARSCoV-2 was undetectable after treatment with fresh water and seawater, but remained detectable for 2 days in tap water, when starting with an initial concentration of 10 4 PFU/mL. When the starting concentration was increased to 10 5 PFU/mL, a similar trend was observed. In addition, viral RNA persisted longer than infectious virus in all water matrices. This study was conducted in stagnant water containing a significantly high titer of virus, thus, human-to-human transmission of SARS-CoV-2 through the actual aquatic environment is expected to be rare.

Erratum: Seasonal Cycle and Relationship of Seasonal Rhino- and Influenza Virus Epidemics With Episodes of Asthma Exacerbation in Different Age Groups

This erratum is being published to correct the printing error on page 517 of the article. Corrections for Fig. 1 and main text in page 519 are needed. The authors apologize for any inconvenience that this may have caused.

Seasonal Cycle and Relationship of Seasonal Rhino- and Influenza Virus Epidemics With Episodes of Asthma Exacerbation in Different Age Groups

PURPOSE: Seasonal variations in asthma exacerbation (AE) are associated with respiratory virus outbreaks and the return of children to school after vacation. This study aims to elucidate the period, phase, and amplitude of seasonal cycles of AE in 5 different age groups with regard to rhino- and influenza virus epidemics in Korea. METHODS: The number of daily emergency department (ED) visits for AE in all age groups of Korea and the nationwide weekly incidence of rhino- and influenza virus, were obtained for 2008-2012. Fourier regression was used to model rhythmicity, and the Cosinor method was used to determine the amplitude and phase of the cycles in each age group. The cross-correlation function (CCF) between AE and the rhino- and influenza virus epidemics was also calculated. RESULTS: There were 157,559 events of AE (0.62 events/1,000 individuals/year) during the study period. There were spring and fall peaks of AE in children and adults, but only 1 winter peak in the elderly. The amplitude of the AE peak in infants was higher in spring than in fall (9.16 vs 3.04, P<0.010), and the fall peak was approximately 1 month later in infants than in school children (October 11 vs November 13, P<0.010). The association between AE and rhinovirus was greatest in school children (rho=0.331), and the association between AE and influenza virus was greatest in those aged ≥60 years (rho=0.682). CONCLUSIONS: The rhythmicity, amplitude, and phase of the annual cycle of AE differed among different age groups. The patterns of AE were related to the annual rhino- and influenza virus epidemics.

Differentially Expressed Cellular Gene Profiles between Healthy HIV-infected Koreans and AIDS Patients

BACKGROUND: The global effect of HIV infection on the host cell gene expression profiles in healthy HIV-infected patients, as long-term non-progressors, remains largely unknown. To identify the cellular genes related with HIV infection and delayed disease progression in vivo, the host gene expression profiles between healthy HIV-infected Koreans and AIDS patients were investigated. METHODS:Differential expression gene analysis was performed via oligonucleotide microarray with using Magic-oligo 10K chip. Ten HIV-uninfected persons and 10 HIV-infected patients (healthy HIV-infected patients vs. AIDS patients. respectively) were studied. RESULTS: Only 10.8% (1,097 genes) of the total genes, that is, 331 up-regulated genes and 766 down- regulated genes were differentially expressed with more than a two-fold change in the HIV-infected persons as compared to those of the HIV-uninfected persons. Especially, 97 genes (8.8%) among 1,097 genes were commonly up- or down-regulated in both the healthy HIV-infected patients and the AIDS patients. 187 genes were differently expressed on the gene expression analysis between the healthy HIV-infected patients and the AIDS patients. Twenty-eight genes out of them showed very significant differences with a P value <0.01. Especially, tripartite motif (TRIM) 14 protein and interferon gamma receptor 2 were dramatically up-regulated in healthy HIV-infected patients, while death-associated protein, DNA directed RNA polymerase II polypeptide A and STAT were over-expressed in AIDS patients. CONCLUSION: Although this microarray study has some limitations, the above results will be helpful for performing more detailed, future functional studies on the differentially expressed genes related to HIV infection and delayed disease progression in vivo.