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

BackgroundEpidemiological data regarding differences in durability and its determinants of humoral immunity following 2- and 3-dose COVID-19 vaccination are scarce. MethodsWe 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. ResultsA 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. ConclusionsThe 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

BackgroundData 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. MethodsFirst 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. ResultsAmong 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. ConclusionsThe 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. SummaryThe third vaccine dose reduced SARS-CoV-2 infection risk during the Omicron wave. Higher neutralizing antibody levels may not reduce Omicron infection risk in third-dose patients. On the contrary, it may be associated with fewer symptoms of infection.

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

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

BackgroundDiscrimination 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. MethodsThis 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. ResultsOf 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. ConclusionExperience 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)

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

BackgroundJapan 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. MethodsWe 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 Fishers 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. ResultsOf 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. ConclusionsOur 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.

SARS-CoV-2-neutralizing humoral IgA response occurs earlier but modest and diminishes faster compared to IgG response.

Secretory immunoglobulin A (IgA) plays a crucial role in the mucosal immunity for preventing the invasion of the exogenous antigens, however, little has been understood about the neutralizing activity of serum IgA. Here, to examine the role of IgA antibodies against COVID-19 illnesses, we determined the neutralizing activity of serum/plasma IgG and IgA purified from previously SARS-CoV-2-infected and COVID-19 mRNA-vaccine-receiving individuals. We found that serum/plasma IgA possesses substantial but rather modest neutralizing activity against SARS-CoV-2 compared to IgG with no significant correlation with the disease severity. Neutralizing IgA and IgG antibodies achieved the greatest activity at approximately 25 and 35 days after symptom onset, respectively. However, neutralizing IgA activity quickly diminished and went down below the detection limit approximately 70 days after onset, while substantial IgG activity was observed till 200 days after onset. The total neutralizing activity in sera/plasmas of those with COVID-19 largely correlated with that in purified-IgG and purified-IgA and levels of anti-SARS-CoV-2-S1-binding IgG and anti-SARS-CoV-2-S1-binding IgA. In individuals who were previously infected with SARS-CoV-2 but had no detectable neutralizing IgA activity, a single dose of BNT162b2 or mRNA-1273 elicited potent serum/plasma neutralizing IgA activity but the second dose did not further strengthen the neutralization antibody response. The present data show that the systemic immune stimulation with natural infection and COVID-19 mRNA-vaccines elicit both SARS-CoV-2-specific neutralizing IgG and IgA response in serum, but the IgA response is modest and diminishes faster compared to IgG response. Author SummaryImmunoglobulin A (IgA) is the most abundant type of antibody in the body mostly located on mucosal surfaces as a dimeric secretory IgA. Such secretory IgA plays an important role in preventing the adherence and invasions of foreign objects by its neutralizing activity, while monomeric serum IgA is thought to relate to the phagocytic immune system activation. Here, we report that individuals with the novel coronavirus disease (COVID-19) developed both systemic neutralizing IgG and IgA active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the neutralizing IgA response was quick and reached the highest activity 25 days post-symptom-onset, compared to 35 days for IgG response, neutralizing IgA activity was modest and diminished faster than neutralizing IgG response. In individuals, who recovered from COVID-19 but had no detectable neutralizing IgA activity, a single dose of COVID-19 mRNA-vaccine elicited potent neutralizing IgA activity but the second dose did not further strengthen the antibody response. Our study provides novel insights into the role and the kinetics of serum IgA against the viral pathogen both in naturally-infected and COVID-19 mRNA-vaccine-receiving COVID-19-convalescent individuals.

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

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

BackgroundLongitudinal data are lacking to compare booster effects of Delta breakthrough infection versus the third vaccine dose on neutralizing antibodies (NAb) against Omicron. MethodsParticipants 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. ResultsPersons 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. ConclusionsSymptomatic 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. Key pointsSymptomatic, not asymptomatic, SARS-CoV-2 breakthrough infection after the second BNT162b2 vaccination during the Delta-predominant wave enhanced neutralizing antibodies against Wuhan, Delta, and Omicron comparable to the three vaccine doses, although immunity against Omicron was much lower than Wuhan and Delta.

A Randomized Phase 2/3 Study of Ensitrelvir, a Novel Oral SARS-CoV-2 3C-like Protease Inhibitor, in Japanese Patients With Mild-to-Moderate COVID-19 or Asymptomatic SARS-CoV-2 Infection: Results of the Phase 2a Part

For the treatment of coronavirus disease 2019 (COVID-19), antiviral agents that can achieve rapid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reduction are warranted. This double-blind, phase 2a part of a phase 2/3 study assessed the efficacy and safety of ensitrelvir, a novel oral SARS-CoV-2 3C-like protease inhibitor, in Japanese patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 infection. Sixty-nine patients enrolled from 56 sites were randomized (1:1:1) to orally receive 5-day ensitrelvir fumaric acid (375 mg on day 1 followed by 125 mg daily or 750 mg on day 1 followed by 250 mg daily) or placebo and followed up until day 28. The primary outcome was change from baseline in SARS-CoV-2 viral titer. A total of 16, 14, and 17 patients in the ensitrelvir 125 mg, ensitrelvir 250 mg, and placebo groups, respectively, were included in the intention-to-treat population (mean age: 38.8, 40.4, and 38.0 years, respectively). On day 4, the change from baseline in SARS-CoV-2 viral titer (log10 50% tissue culture infectious dose/mL) in patients with positive viral titer and viral RNA at baseline was greater with ensitrelvir 125 mg (mean [standard deviation], -2.42 [1.42]; P = 0.0712) and 250 mg (-2.81 [1.21]; P = 0.0083) versus placebo (-1.54 [0.74]), and ensitrelvir treatment reduced SARS-CoV-2 RNA by -1.4 to -1.5 log10 copies/mL versus placebo. All adverse events were mild to moderate. Ensitrelvir treatment demonstrated rapid SARS-CoV-2 clearance and was well tolerated in patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 infection (Japan Registry of Clinical Trials identifier: jRCT2031210350).

Post COVID-19 condition of the Omicron variant of SARS-CoV-2

BackgroundNo epidemiological data on post coronavirus disease (COVID-19) condition due to Omicron variant has been reported yet. MethodsThis was as a single-center, cross-sectional study, that interviewed via telephone the patients who recovered from Omicron COVID-19 infection (Omicron group), and surveyed via self-reporting questionnaire those patients infected with other strains (control group). Data on patients characteristics, information regarding the acute-phase COVID-19, as well as presence and duration of COVID-19-related symptoms were obtained. Post COVID-19 condition in this study was defined as a symptom that lasted at least 2 months within 3 months since the onset of COVID-19. We investigated and compared the prevalence of post COVID-19 condition in both groups after performing propensity score matching. ResultsWe conducted interviews for 53 out of 128 patients with Omicron, and obtained 502 responses in the control group. After matching, 18 patients each in Omicron and control group had improved covariate balance of the older adult, female sex, obese patients, and vaccination status. There were no significant differences in the prevalence of each post-acute COVID-19 symptoms between the two groups. The numbers of patients with at least one post-acute COVID-19 symptom in the Omicron and the control group were 1 (5.6%) and 10 (55.6%) (p=0.003), respectively. ConclusionThe prevalence of post Omicron COVID-19 conditions was less than that of the other strains. Further research with more participants is needed to investigate the precise epidemiology of post COVID-19 condition of Omicron, and its impact on health-related quality of life and social productivity.

A Qualitative Study Regarding Messages of the COVID-19 Vaccine from Vaccinated Healthcare Providers and Healthy Adults

1.BackgroundTo promote the vaccination against COVID-19, person-to-person communication from vaccinated people will play an important role. The objectives of this study are to identify what messages were shared by vaccinated people, and the relationship between these messages and their background. MethodsThis study was an exploratory and prospective basis with individual interviews. The participants were healthcare providers and healthy adults who were recruited at a vaccination site in Chuo-City, Tokyo. The online interviews were conducted using a semi-structured interview. Based on the Health Belief Model (HBM), the participants were asked about their perspectives on vaccines and what they talked about after their vaccination. The interviews were categorized into each item of the HBM and analyzed using NVivo software. ResultsDuring August to October 2021, five healthcare providers and seven healthy adults were enrolled in the study. One healthy adult could not be contacted resulting in a total of 11 participants interviewed. Both the healthcare providers and the healthy adults mainly talked about side effects after their vaccination, and to ease the other persons concerns based on their experience. Meanwhile, there were differences in the recommendations for vaccination between the two groups. The healthcare providers were strongly aware of the severity of COVID-19 infection and recommended vaccination to others as a useful measure to suppress becoming severely ill. On the other hand, the healthy adults recommended the vaccine with varying degree depending on their expectations and concerns about the vaccine and external factors such as living with a family member. ConclusionBoth the healthcare providers and healthy adults shared similar messages to ease the vaccination concerns of others. However, their vaccine recommendation level was varied, which may be influenced not only by expectations and concerns toward the vaccine, but also by external factors such as family members living together.

Predictive Model of Risk Factors of High Flow Nasal Cannula Using Machine Learning in COVID-19

BackgroundWith the rapid increase in the number of COVID-19 patients in Japan, the number of patients receiving oxygen at home has also increased rapidly, and some of these patients have died. An efficient approach to identify high-risk patients with slowly progressing and rapidly worsening COVID-19, and to avoid missing the timing of therapeutic intervention will improve patient prognosis and prevent medical complications. MethodsPatients admitted to medical institutions in Japan from November 14, 2020 to April 11, 2021 and registered in the COVID-19 Registry Japan were included. Risk factors for patients with High Flow Nasal Cannula invasive respiratory management or higher were comprehensively explored using machine learning. Age-specific cohorts were created, and severity prediction was performed for the patient surge period and normal times, respectively. ResultsWe were able to obtain a model that was able to predict severe disease with a sensitivity of 57% when the specificity was set at 90% for those aged 40-59 years, and with a specificity of 50% and 43% when the sensitivity was set at 90% for those aged 60-79 years and 80 years and older, respectively. We were able to identify lactate dehydrogenase level (LDH) as an important factor in predicting the severity of illness in all age groups. DiscussionUsing machine learning, we were able to identify risk factors with high accuracy, and predict the severity of the disease. Using machine learning, we were able to identify risk factors with high accuracy, and predict the severity of the disease. We plan to develop a tool that will be useful in determining the indications for hospitalisation for patients undergoing home care and early hospitalisation.

Association study of HLA with the kinetics of SARS-CoV-2 spike specific IgG antibody responses to BNT162b2 mRNA vaccine

BNT162b2, an mRNA-based SARS-CoV-2 vaccine (Pfizer-BioNTech), is one of the most effective COVID-19 vaccines and has been approved by more than 130 countries worldwide. However, several studies have reported that the COVID-19 vaccine shows high interpersonal variability in terms of humoral and cellular responses, such as those with respect to SARS-CoV-2 spike protein immunoglobulin (Ig)G, IgA, IgM, neutralizing antibodies, and CD4+ & CD8+ T cells. The objective of this study is to investigate the kinetic changes in anti-SARS-CoV-2 spike IgG (IgG-S) profiles and adverse reactions and their associations with HLA profiles among 100 hospital workers from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan. DQA1*03:03:01 (P = 0.017; Odd ratio (OR) 2.80, 95%Confidence interval (CI) 1.05-7.25) was significantly associated with higher IgG-S production after two doses of BNT162b2 while DQB1*06:01:01:01 (P = 0.028, OR 0.27, 95%CI 0.05-0.94) was significantly associated with IgG-S declines after two doses of BNT162b2. No HLA alleles were significantly associated with either local symptoms or fever. However, C*12:02:02 (P = 0.058; OR 0.42, 95%CI 0.15-1.16), B*52:01:01 (P = 0.031; OR 0.38, 95%CI 0.14-1.03), DQA1*03:02:01 (P = 0.028; OR 0.39, 95%CI 0.15-1.00) and DPB1*02:01:02 (P = 0.024; OR 0.45, 95%CI 0.21-0.97) appeared significantly associated with protection against systemic symptoms after two doses of BNT162b2 vaccination. Further studies with larger sample sizes are clearly warranted to determine HLA allele associations with the production and long-term sustainability of IgG-S after COVID-19 vaccination.

Beyond vaccination: A Cross-Sectional Study of the importance of Behavioral and Native Factors on COVID-19 Infection and Severity.

The COVID-19 pandemic has a major impact on a global scale. Understanding the innate and lifestyle-related factors influencing the rate and severity of COVID-19 is important for making evidence-based recommendations. This cross-sectional study aimed at establishing a potential relationship between human characteristics and vulnerability/resistance to SARS-CoV-2. We hypothesize that the impact of virus is not the same due to cultural and ethnic differences. A cross-sectional study was performed using an online questionnaire. The methodology included a development of a multi-language survey, expert evaluation and data analysis. Data was collected using a 13-item pre-tested questionnaire based on a literature review. Data was statistically analyzed using the logistic regression. For a total of 1125 respondents, 332 (29.5%) were COVID-19 positive, among them 130 (11.5%) required home-based treatment, and 14 (1.2%) intensive care. The significant factors included age, physical activity and health status all found to have a significant influence on the infection (p < 0.05). The severity of infection was associated with preventive measures and tobacco (p < 0.05). This suggests the importance of behavioral factors compared to innate ones. Apparently, the individual behavior is mainly responsible for the spread of the virus. Adopting a healthy lifestyle and scrupulously observing preventive measures including vaccination would greatly limit the probability of infection and prevent the development of severe COVID-19.

A Trial to Establish an Antimicrobial Prescription Monitoring System for Antimicrobial Stewardship in Clinics / 日本プライマリ・ケア連合学会誌

Introduction: We investigated the feasibility and validity of developing a system to monitor prescriptions prescribed by physicians for the promotion of appropriate antimicrobial use in clinics.Methods: The names of injuries and diseases and prescribed drugs stored in the receipt computers of six clinics were output and anonymized. Antimicrobial prescriptions for acute respiratory tract infections and acute diarrhea were compiled and evaluated.Results: Anonymized data were available for all six clinics. We were able to extract data and aggregate prescriptions by linking the name of the injuries and diseases to the prescribed drug.Conclusions: We consider it possible to establish antimicrobial stewardship in clinics through antimicrobial prescription monitoring and to develop such a system. On the other hand, there are multiple ways of naming injuries and diseases, and further investigation is needed to define the names of injuries and diseases to be extracted.

Use of heat-not-burn tobacco products, moderate alcohol drinking, and anti-SARS-CoV-2 IgG antibody titers after BNT162b2 vaccination among Japanese healthcare workers

BackgroundThe effect of heat-not-burn (HNB) tobacco product use and moderate alcohol drinking on immunogenicity to coronavirus disease (COVID-19) vaccines remain elusive. This study aimed to examine the association of tobacco product use and alcohol consumption with anti-SARS-CoV-2 spike IgG antibody titers after the BNT162b2 vaccine. MethodsParticipants were 3,457 fully vaccinated healthcare workers in the 4 national centers for advanced medical and research in Japan. Smoking status and alcohol consumption were assessed via a questionnaire, and anti-SARS-CoV-2 spike IgG titers were measured by chemiluminescent enzyme immunoassay using serum collected on the median of 64 days after the second vaccination. Multilevel linear regression models were used to estimate the geometric mean titers (GMT) and the ratios of means (RoM) between groups. ResultsOf vaccinated participants, 99.5% (3,440/3,457) were seropositive. Compared with never-smokers (GMT=119), IgG antibody titers were significantly lower among HNB tobacco users (including those who also smoked cigarettes) (GMT=105; RoM=0.88 [95%CI: 0.78-0.99]) and exclusive cigarettes smokers (GMT=96; RoM=0.81 [95%CI: 0.71-0.92]). Compared with non-drinkers of alcohol (GMT=123), alcohol drinkers consuming <1 go/day (GMT=114; RoM=0.93 [95%CI: 0.88-0.98]), 1-1.9 go/day (GMT=105; RoM=0.85 [95%CI: 0.79-0.93]), and [≥]2 go/day (GMT=101; RoM=0.82 [95%CI: 0.72-0.94]) had significantly lower antibody titers (P for trend<0.01). Spline analysis showed a large reduction of antibody until around 1 go/day of alcohol consumption, and then they gradually decreased. ConclusionsResults suggest that in addition to conventional cigarette smoking and heavy alcohol drinking, use of HNB tobacco products and moderate alcohol drinking may be predictors of lower immunological response to COVID-19 vaccine. Key MessagesO_LIEpidemiological evidence regarding the association of smoking status and alcohol drinking with COVID-19 vaccine-induced antibody levels is scarce. C_LIO_LIUsers of heat-not-burn (HNB) tobacco products, as well as cigarettes smokers, had lower antibody titers than never-smokers. C_LIO_LINot only high-dose but moderate-dose alcohol intake was also associated with decreased vaccine-induced antibody levels. C_LIO_LIHNB tobacco product use and moderate alcohol drinking may be modifiers of COVID-19 vaccine-induced immunogenicity. C_LI

SARS-CoV-2 specific T cell and humoral immune responses upon vaccination with BNT162b2

IntroductionThe humoral and cellular immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) upon coronavirus disease 2019 (COVID-19) vaccination remain to be clarified. Hence, we aimed to investigate the long-term chronological changes in SARS-CoV-2 specific IgG antibody, neutralizing antibody, and T cell responses during and after receiving the BNT162b2 vaccine. MethodsWe performed serological, neutralization, and T cell assays among 100 hospital workers aged 22-73 years who received the vaccine. We conducted seven surveys up to eight months after the second vaccination dose. ResultsSARS-CoV-2 spike protein-specific IgG (IgG-S) titers and T cell responses increased significantly following the first vaccination dose. The highest titers were observed on day 29 and decreased gradually until the end of the follow-up period. There was no correlation between IgG-S and T cell responses. Notably, T cell responses were detected on day 15, earlier than the onset of neutralizing activity. ConclusionsThis study demonstrated that both IgG-S and T cell responses were detected before acquiring sufficient levels of SARS-CoV-2 neutralizing antibodies. These immune responses are sustained for approximately six-ten weeks but not for seven months or later following the second vaccination, indicating the need for the booster dose (i.e., third vaccination).

COVID-19 breakthrough infections and pre-infection neutralizing antibody

BackgroundWhile increasing coverage of effective vaccines against coronavirus disease 2019 (COVID-19), emergent variants raise concerns about breakthrough infections. Data are limited, however, whether breakthrough infection during the epidemic of the variant is ascribed to insufficient vaccine-induced immunogenicity. MethodsWe described incident COVID-19 in relation to the vaccination program among workers of a referral hospital in Tokyo. During the predominantly Delta epidemic, we followed 2,473 fully vaccinated staff (BNT162b2) for breakthrough infection and selected three matched controls. We measured pre-infection neutralizing antibodies against the wild-type, Alpha (B.1.1.7), and Delta (B.1.617.2) strains using live viruses and anti-spike antibodies using quantitative assays, and compared them using the generalized estimating equation model between the two groups. ResultsNo COVID-19 cases occurred 1-2 months after the vaccination program during the fourth epidemic wave in Japan, dominated by the Alpha variant, while 22 cases emerged 2-4 months after the vaccination program during the fifth wave, dominated by the Delta variant. In the vaccinated cohort, all 17 cases of breakthrough infection were mild or asymptomatic and had returned to work early. There was no measurable difference between cases and controls in pre-infection neutralizing antibody titers against the wild-type, Alpha, and Delta, and anti-spike antibody titers, while neutralizing titers against the variants were considerably lower than those against the wild-type. ConclusionsPre-infection neutralizing antibody titers were not decreased among patients with breakthrough infection under the Delta variant rampage. The result points to the importance of infection control measures in the post-vaccination era, irrespective of immunogenicity profile.

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

BackgroundThe 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. MethodsWe 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. Results349 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]). ConclusionsDue to their long duration, long-COVID symptoms represent a substantial disease burden expressed in impact on health-related quality of life. Trial registrationNot applicable.