Correlates of nucleocapsid antibodies and a combination of spike and nucleocapsid antibodies against protection of SARS-CoV-2 infection during Omicron XBB.1.16 and EG.5 predominant wave (preprint)

BackgroundThe role of nucleocapsid (N) antibodies and their combination with spike (S) antibodies against SARS-CoV-2 reinfection remains unclear. We aimed to examine the association between N antibodies, a combination of N and S antibodies, and protection against SARS-CoV-2 reinfection. MethodsWe conducted a prospective cohort study among staff at a national medical research center in Tokyo and followed them for the incidence of SARS-CoV-2 infection between June and September 2023 (Omicron XBB.1.16/EG.5 predominant wave). At baseline, participants donated blood samples to measure N-and S-specific antibodies in assays from three companies (Roche, Abbott, and Sysmex). Cox regression was used to estimate the hazard ratio (HR) and protection (1-HR*100) against subsequent SARS-CoV-2 infection across these antibody levels. FindingsOf the 2549 staff included in the analysis, 237 SARS-CoV-2 infections were identified during follow-up. Among participants with previous infection, higher pre-reinfection N antibodies were associated with a lower risk of reinfection even after adjusting S antibody levels (P for trend<0.01). Estimation of the protection matrix for N and S antibodies yielded that high levels in both N and S antibodies conferred robust protection (>90%) against subsequent infection. In addition, a pattern of low pre-reinfection N antibodies but high vaccine-enhanced S antibodies showed high protection (>80%). InterpretationPre-reinfection N antibody levels correlated with protection against reinfection, independent of S antibodies. If the N antibodies were low, vaccine-boosted S antibodies could enhance the reinfection protection. FundingNational Center for Global Health and Medicine and Japan Health Research Promotion Bureau Research Fund. Research in context Evidence before this studyWe searched published and preprinted literature with the following keywords: "COVID-19," "SARS-CoV-2," "nucleocapsid," "spike," "antibody," "protection," and "reinfection." We found few prospective or case-control studies examining the association between pre-reinfection anti-SARS-CoV-2 nucleocapsid (N) antibody levels and risk of SARS-CoV-2 reinfection; in particular, no studies were conducted for adults among Omicron-dominant phases. We also found no studies that examined the role of a combination of anti-spike (S) and anti-N antibodies in protection against SARS-CoV-2 infection. Added value of this studyThis study first revealed that pre-reinfection anti-N antibody levels correlated with protection against reinfection during the Omicron XBB.1.16 and EG.5 predominant waves even after adjusting S antibody levels. Further, we first estimated the protection matrix by combining anti-N and S antibody levels and showed that both high levels in N and S conferred robust protection (>90%). Vaccine-induced higher S antibody levels were associated with higher protection among previously infected individuals with low levels of N antibodies. Implications of all the available evidenceThe prolonged COVID-19 pandemic has resulted in diverse immune characteristics across individuals due to varying timing of infection and doses and timing of vaccination, making it challenging to decide the timing of additional vaccination. Our results suggest the utility of assessing both N and S antibody levels for considering the timing of additional vaccination for those with a history of COVID-19. If the N antibody level was low due to waning over time, additional vaccination enhances S antibodies and might improve the protection against reinfection.

COVID-19 severity and corticosteroid treatment have minimal effect on specific antibody production (preprint)

Background Dexamethasone is currently administered for Coronavirus disease 2019(COVID-19); however, there are concerns about its effect on specific antibodies’ production. The aim of this study was to evaluate whether specific antibodies were affected by COVID-19 severity and corticosteroid treatment.Methods Of 251 confirmed COVID-19 patients admitted to our hospital between January 26 and August 10, 2020, the early period of the pandemic, 75 patients with sera within 1 month of onset and 1month or longer were included in the research. A total of 253 serum samples from these patients were collected. The levels of specific antibodies for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), immunoglobulin G (IgG) and M (IgM), were measured retrospectively. The results were compared separately of each COVID-19 severity, and with or without corticosteroid treatment.Results Among the 75 patients, 47, 18, and 10 had mild, moderate, and severe disease, respectively. The median age was 53.0 years and 22 (29%) were women. The most common comorbidities were hypertension and dyslipidemia. Corticosteroids were administered to 20 (27%) and 10 (53%), patients with moderate and severe disease, respectively. The positivity rates IgM increased first, and IgG was almost always positive after day 16, regardless of the severity of COVID-19. On days 6–10, both IgG and IgM positivity rates were higher in patients with moderate disease than in those with mild or severe disease. In patients with moderate disease, IgG positivity was similar over time, regardless of corticosteroid treatment.Conclusions In COVID-19 patients, specific IgG is positive and maintained for a long period of time, even after corticosteroid treatment. The effect of corticosteroid treatment in a COVID-19 epidemiological study using specific IgG antibodies was considered minor. COVID-19 patients were more likely to receive oxygen if IgM was positive 1 week after onset, but not mechanical ventilation. IgM measurement 1 week after onset may predict COVID-19 severity.

Impact of regional heterogeneity on the severity of COVID-19 (preprint)

Background: We aimed to assess the impact of regional heterogeneity on the severity of COVID-19 in Japan. Methods: We included 27,865 cases registered between January 2020 and February 2021 in the COVID-19 Registry of Japan to examine the relationship between the National Early Warning Score (NEWS) of COVID-19 patients on the day of admission and the prefecture where the patients live. A hierarchical Bayesian model was used to examine the random effect of each prefecture in addition to the patients’ backgrounds. In addition, we compared the results of two models; one model included the number of beds secured for COVID-19 patients in each prefecture as one of the fixed effects, and the other model did not. Results: The results indicated that the prefecture had a substantial impact on the severity of COVID-19 on admission. Even when considering the effect of the number of beds separately, the heterogeneity caused by the random effect of each prefecture affected the severity of the case on admission. Conclusions: Our analysis revealed a possible association between regional heterogeneity and increased/decreased risk of severe COVID-19 infection on admission. This heterogeneity was derived not only from the number of beds secured in each prefecture but also from other factors.

Impact of long-COVID on health-related quality of life in Japanese COVID-19 patients (preprint)

Background: The empirical basis for a quantitative assessment of the disease burden imposed by long-COVID is currently scant. We aimed to assess the disease burden caused by long-COVID in Japan. Methods: We conducted a cross sectional self-report questionnaire survey. The questionnaire was mailed to 530 eligible patients, who were recovered from acute COVID-19 in April 2021. Answers were classified into two groups; participants who have no symptom and those who have any ongoing symptoms that lasted longer than four weeks at the time of the survey. We compared health-related quality of life scores estimated by the EQ-5D-3L questionnaire between these two groups after adjusting basic characteristics of the participants by propensity score matching. Results: 349 participants reported no symptoms and 108 reported any symptoms at the time of the survey. The participants who reported any symptoms showed a lower value on a Visual Analogue Scale (median 70 [IQR 60-80]) and on the EQ-5D-3L (median 0.81 [IQR 0.77-1.0]) than those reporting no symptoms (median 85 [IQR 75-90] and 1.0 [IQR 1.0-1.0], respectively). After adjusting for background characteristics, these trends did not change substantially (Visual Analog Scale: median 70 [IQR 60-80] vs 80 [IQR 77-90], EQ-5D-3L: median 0.81 [IQR 0.76-1.0] vs 1.0 [IQR 1.0-1.0]). Conclusions: Due to their long duration, long-COVID symptoms represent a substantial disease burden expressed in impact on health-related quality of life.

Characterization of an EG.5.1 clinical isolate in vitro and in vivo (preprint)

EG.5.1 is a subvariant of the SARS-CoV-2 Omicron XBB variant that is rapidly increasing in prevalence worldwide. EG.5.1 has additional substitutions in its spike protein (namely, Q52H and F456L) compared with XBB.1.5. However, the pathogenicity, transmissibility, and immune evasion properties of clinical isolates of EG.5.1 are largely unknown. In this study, we used wild-type Syrian hamsters to investigate the replicative ability, pathogenicity, and transmissibility of a clinical EG.5.1 isolate. Our data show that there are no obvious differences in growth ability and pathogenicity between EG.5.1 and XBB.1.5, and both EG.5.1 and XBB.1.5 are attenuated compared to a Delta variant isolate. We also found that EG.5.1 is transmitted more efficiently between hamsters compared with XBB.1.5. In addition, unlike XBB.1.5, we detected EG.5.1 virus in the lungs of four of six exposed hamsters, suggesting that the virus tropism of EG.5.1 is different from that of XBB.1.5 after airborne transmission. Finally, we assessed the neutralizing ability of plasma from convalescent individuals and found that the neutralizing activity against EG.5.1 was slightly, but significantly, lower than that against XBB.1.5 or XBB.1.9.2. This suggests that EG.5.1 effectively evades humoral immunity and that the amino acid differences in the S protein of EG.5.1 compared with that of XBB.1.5 or XBB.1.9.2 (i.e., Q52H, R158G, and F456L) alter the antigenicity of EG.5.1. Our data suggest that the increased transmissibility and altered antigenicity of EG.5.1 may be driving its increasing prevalence over XBB.1.5 in the human population.

Efficacy and Safety of 5-Day Oral Ensitrelvir for Patients With Mild-to-Moderate COVID-19: The SCORPIO-SR Randomized Clinical Trial (preprint)

IMPORTANCE Treatment options for coronavirus disease 2019 (COVID-19) that can be used irrespective of risk factors for severe disease are warranted. OBJECTIVE To assess the efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19. DESIGN The phase 3 part of a phase 2/3, double-blind, randomized, placebo controlled study conducted from February 10 to July 10, 2022. SETTING A multicenter study conducted at 92 institutions in Japan, Vietnam, and South Korea. PARTICIPANTS Patients (aged 12 to <70 years) with mild-to-moderate COVID-19 within 120 hours of positive viral testing. INTERVENTIONS Patients were randomized (1:1:1) to receive once-daily ensitrelvir 125 mg (375 mg on day 1), 250 mg (750 mg on day 1), or placebo for 5 days. Among 1821 randomized patients, 1030 (347, 340, and 343 in the ensitrelvir 125-mg, ensitrelvir 250-mg, and placebo groups, respectively) were randomized in less than 72 hours of disease onset and assessed as the primary analysis population. MAIN OUTCOMES AND MEASURES The primary end point was the time to resolution of five COVID-19 symptoms (stuffy or runny nose, sore throat, cough, feeling hot or feverish, and low energy or tiredness). Other end points included virologic efficacy and safety. RESULTS The mean age was 35.7, 35.3, and 34.7 years, and 193 (55.6%), 185 (54.4%), and 174 (50.7%) patients were men in the ensitrelvir 125-mg, ensitrelvir 250-mg, and placebo groups, respectively (intention-to-treat, primary analysis population). A significant difference (P=.04 with a Peto-Prentice generalized Wilcoxon test stratified by vaccination history) was observed in the primary end point between ensitrelvir 125 mg and placebo in the primary analysis population (difference in median, -24.3 hours; 95% confidence interval, -78.7 to 11.7). Viral RNA levels on day 4 and time to negative viral titer demonstrated significant reduction vs placebo. The incidence of adverse events was 44.2%, 53.6%, and 24.8% in the ensitrelvir 125-mg, ensitrelvir 250-mg, and placebo groups, respectively. No treatment-related serious adverse events were reported. CONCLUSIONS AND RELEVANCE Treatment with ensitrelvir 125 mg demonstrated clinical and antiviral efficacy without new safety concerns. Generalizability to non-Asian populations should be confirmed. TRIAL REGISTRATION Japan Registry of Clinical Trials identifier: jRCT2031210350.

Comparative Effectiveness of Tocilizumab vs Standard Care in Patients with severe COVID-19–related Pneumonia: A retrospective cohort study utilizing registry data as a synthetic control (preprint)

Background The severity of coronavirus disease 2019 (COVID-19) infections has led to the development of several therapeutic agents, with tocilizumab becoming increasingly used to treat patients with COVID-19-related pneumonia. Therefore, this study compared the use of tocilizumab treatment with the standard of care (SOC) to determine its efficacy against severe COVID-19-related pneumonia in Japan.Methods This retrospective cohort study was designed to evaluate the efficacy of tocilizumab in two different databases: the JA42434 single-arm study and COVID-19 Registry Japan (COVIREGI-JP) data, with a synthetic control group from the COVIREGI-JP cohort as a benchmark for the tocilizumab group. The study’s primary objective was to evaluate the efficacy of tocilizumab in treating severe COVID-19-related pneumonia compared to the SOC among patients included in the above two databases. The SOC group was extracted as the synthetic control group using exact matching and a propensity score matching in sequence per subject. As a secondary objective, the efficacy of tocilizumab compared to SOC was evaluated exclusively among patients included in the COVIREGI-JP database. In each objective, the primary endpoint was defined as the time to discharge or the status of awaiting discharge.Results For the primary endpoint, the hazard ratio (HR) of the tocilizumab group against the SOC group was 1.070 (95% CI: 0.565 to 2.028). The median time from Study Day 1 to discharge or the state of awaiting discharge was 15 days in the tocilizumab group and 16 days in the SOC group. The HRs for the secondary endpoints, namely, time to improvement in the clinical state, time to clinical failure, and time to recovery, were 1.112 (95% CI: 0.596 to 2.075), 0.628 (95% CI: 0.202 to 1.953), and 1.019 (95% CI: 0.555 to 1.871), respectively. Similarly, the HR of the primary endpoint for the secondary objective was 0.846 (95% CI: 0.582 to 1.230).Conclusions Tocilizumab did not demonstrate a positive effect on time to discharge or the state of awaiting discharge. Furthermore, no statistical differences, such as time to improvement in the clinical state, time to clinical failure, and time to recovery, were observed among the groups in other clinical outcomes.

Pre-infection neutralizing antibodies, Omicron BA.5 breakthrough infection, and long COVID: a propensity score-matched analysis (preprint)

Importance Investigating the role of pre-infection humoral immunity against Omicron BA.5 infection risk and long COVID development is critical to inform public health guidance. Objective To investigate the association between pre-infection immunogenicity after the third vaccine dose and the risks of Omicron BA.5 infection and long coronavirus disease. Design, Setting, and Participants This nested case-control analysis was conducted among tertiary hospital staff in Tokyo, Japan who donated blood samples in June 2022 (1 month before Omicron BA.5 dominant wave onset [July-September 2022]) approximately 6 months after receiving the third dose of the historical monovalent coronavirus disease 2019 mRNA vaccine. Exposures Live virus-neutralizing antibody titers against Wuhan and Omicron BA.5 (NT50) and anti-SARS-CoV-2 spike protein antibody titers with Abbott (AU/mL) and Roche (U/mL) assays at pre-infection. Main Outcomes and Measures Symptomatic SARS-CoV-2 breakthrough infections during the Omicron BA.5 dominant wave vs. undiagnosed controls matched using a propensity score. Incidence of long COVID (persistent symptoms [≥]4 weeks after infection) among breakthrough infection cases. Results Anti-spike antibody titers were compared between 243 breakthrough infection cases and their matched controls among the 2360 staff members who met the criteria. Neutralizing antibodies in 50 randomly selected matched pairs were measured and compared. Pre-infection anti-spike and neutralizing antibody titers were lower in breakthrough cases than in undiagnosed controls. Neutralizing antibody titers against Wuhan and Omicron BA.5 were 64% (95% CI: 42-77) and 72% (95% CI: 53-83) lower, respectively, in breakthrough cases than in undiagnosed controls. Individuals with previous SARS-CoV-2 infections were more frequent among undiagnosed controls than breakthrough cases (19.3% vs. 4.1%), and their neutralizing antibody titers were higher than those of infection-naive individuals. Among the breakthrough cases, pre-infection antibody titers were not associated with the incidence of long COVID. Conclusions and Relevance Pre-infection immunogenicity against SARS-CoV-2 may play a role in protecting against the Omicron BA.5 infection, but not in preventing long COVID.

Prescription of anti-influenza drugs in Japan, 2014-2020: a retrospective study using open data from the national claims database (preprint)

ABSTRACT Background Both physicians and patients are proactive towards managing seasonal influenza in Japan and six drugs are approved. We aimed to clarify the status of anti-influenza drug use by analyzing real-world data. Methods This retrospective study analyzed open data from the National Database of Health Insurance Claims and Specific Health Checkups, which covers most claims data from national health insurance. We estimated the annual number of patients prescribed anti-influenza drugs, their age and sex distribution, drug costs, and regional disparities for the period 2014-2020. Results For 2014-2019, an estimated 6.7-13.4 million patients per year were prescribed anti-influenza drugs, with an annual cost of 22.3-48.0 billion JPY (Japanese Yen). In addition, 21.1-32.0 million rapid antigen tests were performed at a cost of 30.1-47.1 billion JPY. In 2017, laninamivir was the most frequently prescribed anti-influenza drug (48%), followed by oseltamivir (36%), while in 2018, the newly introduced baloxavir accounted for 40.8% of prescriptions. After the emergence of COVID-19, the number of patients prescribed anti-influenza drugs in 2020 dropped to just 14,000. In 2018, 37.6% of prescriptions were for patients aged < 20 years compared with 12.2% for those aged ≥ 65 years. Prescriptions for inpatients accounted for 1.1%, and the proportion of prescriptions for inpatients increased with age. Male were more likely than female to be prescribed anti-influenza drugs for inpatient. Conclusions Based on our clarification of how influenza is clinically managed in Japan, future work should evaluate the clinical and economic aspects of proactively prescribing anti-influenza drugs.

Durability and determinants of anti-SARS-CoV-2 spike antibodies following the second and third doses of mRNA COVID-19 vaccine (preprint)

Background Epidemiological data regarding differences in durability and its determinants of humoral immunity following 2- and 3-dose COVID-19 vaccination are scarce. Methods We repeatedly assessed the anti-spike IgG antibody titers of 2- and 3-dose mRNA vaccine recipients among the staff of a medical and research center in Tokyo. Linear mixed models were used to estimate trajectories of antibody titers from 14 to 180 days after the last immune-conferred event (vaccination or infection) and compare antibody waning rates across prior infection and vaccination status, and across background factors in infection-naive participants. Results A total of 6901 measurements from 2964 participants (median age, 35 years; 30% male) were analyzed. Antibody waning rate (per 30 days [95% CI]) was slower after 3-dose (25% [23 - 26]) than 2-dose (36% [35 - 37]). Participants with hybrid immunity (vaccination and infection) had further slower waning rates: 2-dose plus infection (16% [9 - 22]); 3-dose plus infection (21% [17 - 25]). Older age, male sex, obesity, coexisting diseases, immunosuppressant use, smoking, and alcohol drinking were associated with lower antibody titers, whereas these associations disappeared after 3-dose, except for sex (lower in female participants) and immunosuppressant use. Antibody waning was faster in older participants, females, and alcohol drinkers after 2-dose, whereas it did not differ after 3-dose across except sex. Conclusions The 3-dose mRNA vaccine conferred higher durable antibody titers, and previous infection further enhanced its durability. The antibody levels at a given time point and waning speed after 2-dose differed across background factors; however, these differences mostly diminished after 3-dose.

Neutralizing antibodies following three doses of BNT162b2 vaccine, breakthrough infection, and symptoms during the Omicron predominant wave (preprint)

Background Data on the role of immunogenicity following the third vaccine dose against Omicron infection and coronavirus disease 2019 (COVID-19)-compatible symptoms of infection are limited. Methods First we examined vaccine effectiveness (VE) of the third-dose against the second dose during the Omicron wave among the staff at a tertiary hospital in Tokyo. In a case-control study of a cohort of third vaccine recipients, we compared the pre-infection levels of live-virus neutralizing antibodies (NAb) against Omicron between breakthrough cases and their controls, who had close contact with COVID-19 patients. Among these cases, we examined the association between pre-infection NAb levels and the number of COVID-19-compatible symptoms experienced during the Omicron wave. Results Among the 1456 participants for VE analysis, 60 (4%) breakthrough infections occurred during the Omicron wave (January to March 2022). The third-dose VE for infection, relative to the second dose was 54.6% (95% CI: 14.0-76.0). Among the recipients of the third vaccine, pre-infection NAb levels against Omicron did not significantly differ between the cases and controls. Among the cases, those who experienced COVID-19-compatible symptoms had lower pre-infection NAb levels against Omicron than those who did not. Conclusions The third vaccine dose was effective in decreasing the risk of severe acute respiratory syndrome coronavirus 2 infection during the Omicron wave compared with the second dose. Among third-dose recipients, higher pre-infection NAb levels may not be associated with a lower risk of Omicron infection. Contrarily, they may be associated with fewer symptoms of infection.

T-cell Response and Antibody Production by Booster COVID-19 Vaccination in Japanese Patients with Chronic Kidney Disease Treated with Hemodialysis (preprint)

Most studies on vaccines of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have focused on antibody, but cellular immunities are also critical. We aimed to evaluate the immune reactions of hemodialysis (HD) patients after the administration of the booster dose from the perspective of both humoral and cellular immunities. Hemodialysis patients (HD group) and age- and sex-matched non-dialysis individuals (control group) receiving three doses of BNT162b2 vaccine were measured for anti-SARS-CoV-2 immunoglobulin (IgG) and T-SPOTⓇ.COVID test (T-SPOT) before, 3 weeks, and 3 months after the booster dose. The HD group had significantly higher SARS-CoV-2 IgG levels 3 weeks and 3 months after the booster dose than the control group, although both groups had no difference in SARS-CoV-2 IgG levels before the booster dose. Moreover, the HD group had significantly higher T-SPOT levels before and 3 weeks after the booster dose than the control group, but the difference was not significantly different 3 months after the booster dose. Furthermore, the incidence rates of local and systemic adverse reactions were significantly higher in the HD group than in the control group. HD patients obtained higher SARS-CoV-2 IgG levels and SARS-COV-2-specific T-cell responses after the booster dose than control.

Characterization of SARS-CoV-2 Omicron BA.2.75 clinical isolates (preprint)

The prevalence of the Omicron subvariant BA.2.75 is rapidly increasing in India and Nepal. In addition, BA.2.75 has been detected in at least 34 other countries and is spreading globally. However, the virological features of BA.2.75 are largely unknown. Here, we evaluated the replicative ability and pathogenicity of BA.2.75 clinical isolates in Syrian hamsters. Although we found no substantial differences in weight change among hamsters infected with BA.2, BA.5, or BA.2.75, the replicative ability of BA.2.75 in the lungs was higher than that of BA.2 and BA.5. Of note, BA.2.75 caused focal viral pneumonia in hamsters, characterized by patchy inflammation interspersed in alveolar regions, which was not observed in BA.5-infected hamsters. Moreover, in competition assays, BA.2.75 replicated better than BA.5 in the lungs of hamsters. These results suggest that BA.2.75 can cause more severe respiratory disease than BA.5 and BA.2 and should be closely monitored.

The association between experience of COVID-19-related discrimination and psychological distress among healthcare workers for six national medical research centers in Japan (preprint)

Background: Discrimination has been identified as an important determinant of negative mental health outcomes. This study determined the association between the experience of COVID-19-related discrimination and psychological distress among healthcare workers (HCWs) in Japan. Methods: This cross-sectional study conducted a health survey among 5,703 HCWs of six national medical and research centers in Japan from October 2020 to March 2021. COVID-19-related discrimination was defined either when participants or their family members were badmouthed or when they felt discriminated against in some way. We used the Kessler Psychological Distress Scale (K6) to assess the presence of severe psychological distress ([≥]13 points). We used logistic regression models to examine the association between discrimination and psychological distress. We also identified job-related factors associated with discrimination. Results: Of the participants, 484 (8.4%) reported COVID-19-related discrimination and 486 (8.5%) had severe psychological distress. HCWs who were female vs. male (odds ratio [OR]=1.41, 95% confidence interval [CI]=1.28-1.55), had high vs. low viral exposure (OR=2.31, 95%CI=1.81-2.93), and worked for more than 10 hours/day vs. <8 hours/day (OR=1.42, 95%CI=1.35-1.49) were more likely to have experienced COVID-19-related discrimination. The OR (95%CI) of severe psychological distress was 1.83 (1.29-2.59) among those who experienced discrimination. The analysis was stratified by sociodemographic and job-related factors and the associations trended in the same direction across subgroups. Conclusion: Experience of COVID-19-related discrimination was associated with severe psychological distress among HCWs. During the pandemic, effective measures should be taken to prevent the development of negative mental health outcomes in HCWs who experience discrimination.

Efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19: A protocol for a multicenter, randomized, double-blind, placebo-controlled, phase 3 study (the SCORPIO-SR trial) (preprint)

BackgroundMost antiviral treatments are targeted toward patients with severe or moderate-to-severe illness or those at high risk of developing severe Coronavirus disease 2019 (COVID-19). Limited options exist for patients with mild-to-moderate COVID-19, irrespective of vaccination history or risk status. Ensitrelvir is a novel oral SARS-CoV-2 3C-like protease inhibitor. The phase 2 studies of ensitrelvir have demonstrated promising results in mild-to-moderate COVID-19, whereas the challenge to evaluate the clinical efficacy due to shifting vaccinated status and the emergence of the Omicron variant has been suggested. Here, we describe the protocol for a phase 3 study designed to evaluate the efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19, regardless of risk status or vaccination history. MethodsThis is a multicenter, randomized, double-blind, placebo-controlled, phase 3 study. Patients with mild-to-moderate COVID-19 within 120 hours from onset will be randomized in a 1:1:1 ratio into 3 treatment arms--ensitrelvir 125 mg (375 mg as loading dose on Day 1), ensitrelvir 250 mg (750 mg as loading dose on Day 1), or placebo. The study interventions will be administered orally once daily for 5 days. The primary endpoint will be the time to resolution of the 5 symptoms of COVID-19 (stuffy or runny nose, sore throat, cough, feeling hot or feverish, low energy or tiredness), and the primary population will be patients with <72 hours from COVID-19 onset to randomization in ensitrelvir 125 mg group. The key secondary endpoints include the change from baseline on Day 4 in the amount of SARS-CoV-2 viral RNA and the time to the first negative SARS-CoV-2 viral titer. Closed testing procedure will be used for the primary and key secondary endpoints in both the primary and entire patient population. All safety assessments and adverse events will be reported. DiscussionTime to resolution of the 5 COVID-19 symptoms is a suitable endpoint to assess antiviral treatment in patients infected with the Omicron variant. In the phase 2 studies, ensitrelvir has demonstrated antiviral efficacy against SARS-CoV-2 and a trend toward reducing time to resolution of symptoms in patients with mild-to-moderate COVID-19. Through this study, we will seek to validate and establish the clinical efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19. Trial registrationJapan Registry of Clinical Trials (https://jrct.niph.go.jp): jRCT2031210350.

Impact of dementia, living in a long-term care facility, and physical activity status on COVID-19 severity in older adults (preprint)

Background: Japan is fast becoming an extremely aged society and older adults are known to be at risk of severe COVID-19. However, the impact of risk factors specific to this population for severe COVID-19 caused by the Omicron variant of concern (VOC) are not yet clear. Methods: We performed an exploratory analysis using logistic regression to identify risk factors for severe COVID-19 illness among 4,868 older adults with a positive SARS-CoV-2 test result who were admitted to a healthcare facility between 1 January 2022 and 16 May 2022. We then conducted one-to-one propensity score (PS) matching for three factors-dementia, admission from a long-term care facility, and poor physical activity status-and used Fisher's exact test to compare the proportion of severe COVID-19 cases in the matched data. We also estimated the average treatment effect on treated (ATT) in each PS matching analysis. Results: Of the 4,868 cases analyzed, 1,380 were severe. Logistic regression analysis showed that age, male sex, cardiovascular disease, cerebrovascular disease, chronic lung disease, renal failure and/or dialysis, physician-diagnosed obesity, admission from a long-term care facility, and poor physical activity status were risk factors for severe disease. Vaccination and dementia were identified as factors associated with non-severe illness. The ATT for dementia, admission from a long-term care facility, and poor physical activity status was -0.04 (95% confidence interval -0.07, -0.01), 0.09 (0.06, 0.12), and 0.17 (0.14, 0.19), respectively. Conclusions: Our results suggest that poor physical activity status and living in a long-term care facility have a substantial impact on the risk of severe COVID-19 caused by the Omicron VOC, while dementia might be associated with non-severe illness.

Efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19: the phase 2b part of a randomized, placebo-controlled, phase 2/3 study (preprint)

This phase 2b part of a randomized phase 2/3 study assessed the efficacy and safety of ensitrelvir for mild-to-moderate coronavirus disease 2019 (COVID-19). Patients were randomized (1:1:1) to orally receive ensitrelvir fumaric acid 125 mg (375 mg on day 1; n=140) or 250 mg (750 mg on day 1; n=140) or placebo (n=141) once daily for 5 days. Compared with placebo, the change from baseline in severe acute respiratory syndrome coronavirus 2 titer (measured as log10 50% tissue-culture infectious dose) on day 4 was significantly greater with ensitrelvir 125 mg and 250 mg (differences from placebo: -0.41, P<0.0001 for both). The total score of predefined 12 COVID-19 symptoms showed an improving trend with ensitrelvir treatment without a significant intergroup difference. Most adverse events were mild in severity. Ensitrelvir treatment demonstrated a favorable antiviral efficacy and potential clinical benefit with an acceptable safety profile. (Japan Registry of Clinical Trials identifier: jRCT2031210350)

SARS-CoV-2 breakthrough infection during the Delta-dominant epidemic and neutralizing antibodies against Omicron in comparison with the third dose of BNT162b2: a matched analysis (preprint)

Background Longitudinal data are lacking to compare booster effects of Delta breakthrough infection versus the third vaccine dose on neutralizing antibodies (NAb) against Omicron. Methods Participants were the staff of a national research and medical institution in Tokyo who attended serological surveys on June 2021 (baseline) and December 2021 (follow-up); in between, the Delta-dominant epidemic occurred. Of 844 participants who were infection-naive and had received two doses of BNT162b2 at baseline, we identified 11 breakthrough infections during the follow-up. One control matched to each case was randomly selected from those who completed the booster vaccine and those who were unboosted by the follow-up. We used the generalized estimating equation model to compare live-virus NAb against Wuhan, Delta, and Omicron across groups. Results Persons who experienced breakthrough infection showed marked increases in NAb titers against Wuhan (4.1-fold) and Delta (5.5-fold), and 64% had detectable NAb against Omicron at follow-up, although the NAb against Omicron after breakthrough infection was 6.7- and 5.2-fold lower than that against Wuhan and Delta, respectively. The increase was apparent only in symptomatic cases and as high as in the third vaccine recipients. In contrast, these titers largely decreased (Wuhan, Delta) or remained undetected (Omicron) at follow-up in infection-naive and unboosted persons. Conclusions Symptomatic breakthrough infection during the Delta predominant wave was associated with significant increases in NAb against Wuhan, Delta, and Omicron, similar to the third BNT162b2 vaccine. Given the much lower cross-NAb against Omicron than other virus types, however, infection prevention measures must be continued irrespective of vaccine and infection history while the immune evasive variants are circulating.