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.

[Effectiveness of COVID-19 mRNA vaccine against hospitalization during the alpha and delta variant surges in Tokyo].

Objective　Evidence on COVID-19 vaccine effectiveness outside of clinical trials is insufficient. We aimed to determine the real-world effectiveness of mRNA vaccines in preventing hospitalization via data from the Health Center Real-time Information-sharing System on COVID-19 (HER-SYS), a national public database on COVID-19 cases in Japan.Methods　This case-control study targeted residents of Minato-ward, Tokyo, aged ≥50 years, who were COVID-19 positive between May 17 and Sep 30, 2021 (the alpha and delta strains-dominant period). Those hospitalized within 10 days of onset or diagnosis were considered the case group and control patients were not hospitalized. Patients were grouped according to vaccination status; group 1, unvaccinated, groups 2 and 3, who received the first dose ≤14 days and ≥15 days, respectively, and groups 4 and 5, who received the second dose ≤14 and ≥15 days before onset, respectively. To estimate vaccine effectiveness, adjusted odd ratios (OR) were calculated for each group against group 1. Furthermore, to determine other risk factors for hospitalization, OR were calculated for age, sex, and presence of any underlying diseases.Results　This study analyzed 192 case and 366 control patients. The adjusted OR were 1.48 (95% Cl=0.88-2.50), 0.71 (95% Cl=0.27-1.80), 0.58 (95% Cl=0.20-1.66), and 0.30 (95% Cl=0.13-0.67) for groups 2-5, respectively. Additionally, the adjusted OR were 1.57 (95% Cl=1.07-2.29), 1.05 (95% Cl=1.03-1.07), and 1.69 (95% Cl=1.15-2.48) for presence of underlying disease, 1-year increase of age, and men, respectively.Conclusion　Patients aged ≥50 years who received the second dose of the mRNA vaccine ≥15 days before onset had a significantly lower risk of hospitalization. Additionally, older age, men, and presence of underlying diseases were risk factors for hospitalization. Further studies on vaccine effectiveness to prevent severe diseases, hospitalization, and death following booster immunization during the omicron strain-dominant period are warranted.

Coronavirus Disease 19 (COVID-19) Vaccine Effectiveness Against Symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection During Delta-Dominant and Omicron-Dominant Periods in Japan: A Multicenter Prospective Case-control Study (Factors Associated with SARS-CoV-2 Infection and the Effectiveness of COVID-19 Vaccines Study).

BACKGROUND: Although several coronavirus disease 2019 (COVID-19) vaccines initially showed high efficacy, there have been concerns because of waning immunity and the emergence of variants with immune escape capacity. METHODS: A test-negative design case-control study was conducted in 16 healthcare facilities in Japan during the Delta-dominant period (August-September 2021) and the Omicron-dominant period (January-March 2022). Vaccine effectiveness (VE) against symptomatic severe acute respiratory syndrome coronavirus 2 infection was calculated for 2 doses for the Delta-dominant period and 2 or 3 doses for the Omicron-dominant period compared with unvaccinated individuals. RESULTS: The analysis included 5795 individuals with 2595 (44.8%) cases. Among vaccinees, 2242 (55.8%) received BNT162b2 and 1624 (40.4%) received messenger RNA (mRNA)-1273 at manufacturer-recommended intervals. During the Delta-dominant period, VE was 88% (95% confidence interval [CI], 82-93) 14 days to 3 months after dose 2 and 87% (95% CI, 38-97) 3 to 6 months after dose 2. During the Omicron-dominant period, VE was 56% (95% CI, 37-70) 14 days to 3 months since dose 2, 52% (95% CI, 40-62) 3 to 6 months after dose 2, 49% (95% CI, 34-61) 6+ months after dose 2, and 74% (95% CI, 62-83) 14+ days after dose 3. Restricting to individuals at high risk of severe COVID-19 and additional adjustment for preventive measures (ie, mask wearing/high-risk behaviors) yielded similar estimates, respectively. CONCLUSIONS: In Japan, where most are infection-naïve, and strict prevention measures are maintained regardless of vaccination status, 2-dose mRNA vaccines provided high protection against symptomatic infection during the Delta-dominant period and moderate protection during the Omicron-dominant period. Among individuals who received an mRNA booster dose, VE recovered to a high level.

Immunological responses following the third dose of the BNT162b2 SARS-CoV-2 vaccine among Japanese healthcare workers.

INTRODUCTION: A limited number of studies have shown a decline in antibody titers in healthcare workers beyond six months after the second dose of the BNT162b2 vaccine, and has been insufficiently investigated yet in the respective Asian ethnic groups. METHODS: We conducted a longitudinal observational study on 187 healthcare workers and other personnel and healthy adults at least eight months after vaccination at the International University of Health and Welfare. RESULTS: The baseline (before the third dose of BNT162b2) anti-receptor binding domain (RBD) IgG level was 569[377-943] AU/mL 245[240-250] days after the second dose. The mean antibody titer of participants aged 20-29 years was 4.6 times higher than that of participants aged 70-79 years. After booster vaccination, serum anti-RBD antibody levels were elevated in all participants with a median titer of 23,250[14,612-33,401] AU/mL 21[19-23] days after the third dose. The median post-booster antibody titers in the 20-29, 30-39, 40-49, 50-59, 60-69, and 70-79 years age groups were 30.6, 33.0, 33.8, 27.4, 50.1, and 90.3 times, respectively, higher than the pre-booster ones. Antibody levels were 15% lower in daily drinkers compared to nondrinkers, suggesting that daily alcohol consumption can prevent antibody levels from increasing after vaccination. Our results show decreased antibody titers after two doses of the vaccine, especially in the elderly; however, the third dose of the vaccine resulted in a significant increase in antibody titers in all age groups. CONCLUSIONS: We provided information on antibody responses following primary and booster doses of the BNT162b2 mRNA COVID-19 vaccine in Japan.

Primaquine plus clindamycin as a promising salvage therapy for Pneumocystis jirovecii pneumonia: A retrospective analysis in Japanese patients.

Treatment of intractable Pneumocystis jirovecii pneumonia (PCP) patients with primaquine (PQ) in combination with clindamycin (CLDM) was conducted by the Research Group on Chemotherapy of Tropical Diseases (RG-CTD), as a kind of compassionate use. Primaquine was not nationally licensed at the time but imported by RG-CTD for the use in a clinical research to investigate safety and efficacy in malaria treatment. Eighteen Japanese adult patients thus treated were analyzed. Prior to the treatment with PQ-CLDM, most of the patients had been treated with trimethoprim-sulfamethoxazole first, all of which being followed by pentamidine and/or atovaquone treatment. This combination regimen of PQ-CLDM was effective in 16 (89%) patients and developed adverse events (AEs) in five (28%) patients. AEs included skin lesions, methemoglobinemia, and hepatic dysfunction, though none of them were serious. As a second-line or salvage treatment for PCP, PQ-CLDM appears to be a better option than pentamidine or atovaquone. Currently in Japan, both PQ and CLDM are licensed drugs but neither of them is approved for treatment of PCP. Considering the potentially fatal nature of PCP, approval of PQ-CLDM for treating this illness should be urged.

Epidemiology of COVID-19: What changed in one year?

A coronavirus brought the first pandemic attack of this century as a flu virus did a hundred years ago. This greatest pandemic of the century brings us new opportunities to understand and explore the dynamics of a contagious disease. Nearly two years later, we are still collecting the evidence to understand the disease. Some basic epidemiological properties are still urgently needed. Not only the origin of the virus but also Ro value, possible transmission routes, epidemiologic curves, case fatality rates, seasonality, severity and mortality risk factor, effects on the risk groups, differences between countries and so on still require strong evidence prior to making final suggestions. In this review, we tried to evaluate the epidemiological evidence to scrutinize where exactly we are in this pandemic.

Varicella in Adult Foreigners at a Referral Hospital, Central Tokyo, Japan, 2012-2016.

We report a case series of varicella among adult foreigners at a referral hospital in central Tokyo, Japan, during 2012-2016. This series highlights differences in varicella vaccination schedules by country and epidemiology by climate and identifies immigrants and international students as high-risk populations for varicella.

A Prospective, Randomized, Open-Label Trial of Early versus Late Favipiravir Therapy in Hospitalized Patients with COVID-19.

Favipiravir is an oral broad-spectrum inhibitor of viral RNA-dependent RNA polymerase that is approved for treatment of influenza in Japan. We conducted a prospective, randomized, open-label, multicenter trial of favipiravir for the treatment of COVID-19 at 25 hospitals across Japan. Eligible patients were adolescents and adults admitted with COVID-19 who were asymptomatic or mildly ill and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned at a 1:1 ratio to early or late favipiravir therapy (in the latter case, the same regimen starting on day 6 instead of day 1). The primary endpoint was viral clearance by day 6. The secondary endpoint was change in viral load by day 6. Exploratory endpoints included time to defervescence and resolution of symptoms. Eighty-nine patients were enrolled, of whom 69 were virologically evaluable. Viral clearance occurred within 6 days in 66.7% and 56.1% of the early and late treatment groups (adjusted hazard ratio [aHR], 1.42; 95% confidence interval [95% CI], 0.76 to 2.62). Of 30 patients who had a fever (≥37.5°C) on day 1, times to defervescence were 2.1 days and 3.2 days in the early and late treatment groups (aHR, 1.88; 95% CI, 0.81 to 4.35). During therapy, 84.1% developed transient hyperuricemia. Favipiravir did not significantly improve viral clearance as measured by reverse transcription-PCR (RT-PCR) by day 6 but was associated with numerical reduction in time to defervescence. Neither disease progression nor death occurred in any of the patients in either treatment group during the 28-day participation. (This study has been registered with the Japan Registry of Clinical Trials under number jRCTs041190120.).

Clinical Evaluation of Self-Collected Saliva by Quantitative Reverse Transcription-PCR (RT-qPCR), Direct RT-qPCR, Reverse Transcription-Loop-Mediated Isothermal Amplification, and a Rapid Antigen Test To Diagnose COVID-19.

The clinical performances of six molecular diagnostic tests and a rapid antigen test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were clinically evaluated for the diagnosis of coronavirus disease 2019 (COVID-19) in self-collected saliva. Saliva samples from 103 patients with laboratory-confirmed COVID-19 (15 asymptomatic and 88 symptomatic) were collected on the day of hospital admission. SARS-CoV-2 RNA in saliva was detected using a quantitative reverse transcription-PCR (RT-qPCR) laboratory-developed test (LDT), a cobas SARS-CoV-2 high-throughput system, three direct RT-qPCR kits, and reverse transcription-loop-mediated isothermal amplification (RT-LAMP). The viral antigen was detected by a rapid antigen immunochromatographic assay. Of the 103 samples, viral RNA was detected in 50.5 to 81.6% of the specimens by molecular diagnostic tests, and an antigen was detected in 11.7% of the specimens by the rapid antigen test. Viral RNA was detected at significantly higher percentages (65.6 to 93.4%) in specimens collected within 9 days of symptom onset than in specimens collected after at least 10 days of symptoms (22.2 to 66.7%) and in specimens collected from asymptomatic patients (40.0 to 66.7%). Self-collected saliva is an alternative specimen option for diagnosing COVID-19. The RT-qPCR LDT, a cobas SARS-CoV-2 high-throughput system, direct RT-qPCR kits (except for one commercial kit), and RT-LAMP showed sufficient sensitivities in clinical use to be selectively used in clinical settings and facilities. The rapid antigen test alone is not recommended for an initial COVID-19 diagnosis because of its low sensitivity.

Epidemiology of COVID-19

It seems that coronaviruses take an important place in the 21th century history. Five of seven human coronavirus was isolated in this century. Unfortunately, last three of them entered our life with a fear of outbreak, pandemic or death. Last human coronavirus which emerged world from Wuhan China, SARS CoV-2 and its clinical expression, Coronavirus disease (COVID-19) recently taken a significant place in our daily practice. Initial reports showed that, its origin was bats. It transmitted human to human by droplet and contact routes, but some doubt about airborne, fecal or intrauterine transmission also should be removed. Its R0 value is 2.3 but it could be as high as 5.7. Its case fatality rate was 6.3, but it was different in different ages and counties, and it could be over 15%. According to early models total 10­12 weeks is required to control an outbreak in the community. While different countries show different daily case numbers, total number of case, case mortality rates or R0, it seems they show a similar epidemic curve. Every day we learn new data about the current outbreak. Since the outbreak is not over yet, every detail should be evaluated carefully and the updates should be followed closely to monitor the epidemiological properties of COVID-19.

Rabies post-exposure prophylactic vaccination for returning travelers to Japan.

BACKGROUND: Rabies post-exposure prophylaxis (PEP) in Japan is administered using 6 subcutaneous doses (on days 0, 3, 7, 14, 30, and 90), which is not in line with international recommendations of 4 or 5 intramuscular doses. For reducing dose frequency, we evaluate the immunogenicity of PEP with a regimen of 6 subcutaneous doses. METHOD: This prospective single-center cross-sectional study was performed between September 2013 and December 2014. We included patients underwent rabies PEP by purified chick embryo-cultured rabies vaccine Kaketsuken (PCEC-K) at our clinic, and excluded patients with a history of pre-exposure prophylaxis or PEP using rabies immunoglobulin. The rabies virus-neutralizing antibody tests were performed at the first visit to our office (doses 1-4) and at the fifth and sixth doses. RESULTS: Data were available for 43 of 59 enrolled patients. Thirty-two patients did not start PEP within 48 h after exposure to animals. The seroprotection rates (≥0.5 IU/mL) were 90.7% and 75.7%, at days 30 and 90, respectively. Despite receiving a fifth dose, 85.3% of the patients exhibited decreasing antibody titers during days 30-90 (p < 0.001). CONCLUSIONS: The seroprotection rates of PCEC-K induced subcutaneously were insufficient to prevent rabies at day 30 and 90.

Wohlfahrtiimonas chitiniclastica Bacteremia Hospitalized Homeless Man with Squamous Cell Carcinoma.

We report a case of Wohlfahrtiimonas chitiniclastica bacteremia in an elderly man in Japan who had squamous cell carcinoma. Blood cultures were initially negative for W. chitiniclastica but were positive on day 20. Careful attention needs to be paid to this organism in patients who have chronic wounds with maggots.

Cryptococcus gattii genotype VGIIa infection imported from Vancouver Island to Japan.

A 71-year-old Japanese man with travel history to the Vancouver Island, Canada was diagnosed the pulmonary and central nervous system infections caused by Cryptococcus gattii genotype VGIIa. This is the first imported case of Cryptococcus gattii genotype VGIIa infection from endemic area of North America to Japan. He was recovery with no residual neurological dysfunction by early resection of brain mass and antifungal therapy. Early surgical resection of cerebellar cryptococcoma may shorten the length of induction therapy with antifungal drugs.

Imported Leptospira licerasiae Infection in Traveler Returning to Japan from Brazil.

We describe a case of intermediate leptospirosis resulting from Leptospira licerasiae infection in a traveler returning to Japan from Brazil. Intermediate leptospirosis should be included in the differential diagnosis for travelers with fever returning from South America. This case highlights the need for strategies that detect pathogenic and intermediate Leptospira species.

Dengue Virus Type 2 in Travelers Returning to Japan from Sri Lanka, 2017.

In June 2017, dengue virus type 2 infection was diagnosed in 2 travelers returned to Japan from Sri Lanka, where the country's largest dengue fever outbreak is ongoing. Travelers, especially those previously affected by dengue fever, should take measures to avoid mosquito bites.

Importation of Zika Virus from Vietnam to Japan, November 2016.

We report a case of Zika virus infection that was imported to Japan by a traveler returning from Vietnam. We detected Zika virus RNA in the patient's saliva, urine, and whole blood. In the Zika virus strain isolated from the urine, we found clearly smaller plaques than in previous strains.

Chikungunya Fever in Traveler from Angola to Japan, 2016.

Simultaneous circulation of multiple arboviruses presents diagnostic challenges. In May 2016, chikungunya fever was diagnosed in a traveler from Angola to Japan. Travel history, incubation period, and phylogenetic analysis indicated probable infection acquisition in Angola, where a yellow fever outbreak is ongoing. Thus, local transmission of chikungunya virus probably also occurs in Angola.

Dengue Virus Exported from Côte d'Ivoire to Japan, June 2017.

Since April 2017, a dengue fever outbreak has been ongoing in Côte d'Ivoire. We diagnosed dengue fever (type 2 virus) in a traveler returning to Japan from Côte d'Ivoire. Phylogenetic analysis revealed strain homology with the Burkina Faso 2016 strain. This case may serve as an alert to possible disease spread outside Africa.

Spin-Liquid-to-Spin-Liquid Transition in Kitaev Magnets Driven by Fractionalization.

While phase transitions between magnetic analogs of the three states of matter-a long-range ordered state, paramagnet, and spin liquid-are extensively studied, the possibility of "liquid-liquid" transitions, namely, between different spin liquids, remains elusive. By introducing the additional Ising coupling into the honeycomb Kitaev model with bond asymmetry, we discover that the Kitaev spin liquid turns into a spin-nematic quantum paramagnet before a magnetic order is established by the Ising coupling. The quantum phase transition between the two liquid states accompanies a topological change driven by fractionalized excitations, the Z_{2} gauge fluxes, and is of first order. At finite temperatures, this yields a persisting first-order transition line that terminates at a critical point located deep inside the regime where quantum spins are fractionalized. It is suggested that similar transitions may occur in other perturbed Kitaev magnets with bond asymmetry.