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.

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.

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.

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.

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.

Sex-associated differences between body mass index and SARS-CoV-2 antibody titers following the BNT162b2 vaccine among 2,435 healthcare workers in Japan

Obesity may downregulate vaccine-induced immunogenicity, but the epidemiological evidence for the COVID-19 vaccine is limited, and the sex-associated difference is unknown. It was observed that a higher body mass index was associated with lower titers of spike IgG antibodies against SARS-CoV-2 in men but not in women.

Association between reactogenicity and SARS-CoV-2 antibodies after the second dose of the BNT162b2 COVID-19 vaccine

High vaccine reactogenicities may reflect stronger immune responses, but the epidemiological evidence for coronavirus disease 2019 (COVID-19) vaccines is sparse and inconsistent. We observed that a fever of [≥]38{square} after two doses of the BNT162b2 vaccine was associated with higher severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike IgG titers.

Efficacy of remdesivir in Japanese patients hospitalised with COVID-19: A large observational study using the COVID-19 Registry Japan

ObjectivesAlthough several randomised controlled trials have compared the efficacy of remdesivir with that of placebo, there is limited evidence regarding its effect in the early stage of nonsevere COVID-19 cases. MethodsWe evaluated the efficacy of remdesivir on the early stage of nonsevere COVID-19 using the COVID-19 Registry Japan, a nationwide registry of hospitalised COVID-19 patients in Japan. Two regimens (start remdesivir therapy within 4 days from admission vs. no remdesivir during hospitalisation) among patients without the need for supplementary oxygen therapy were compared by a three-step processing (cloning, censoring, and weighting) method. The primary outcome was supplementary oxygen requirement during hospitalisation. Secondary outcomes were 30-day fatality risk and risk of invasive mechanical ventilation or extracorporeal membrane oxygenation (IMV/ECMO). ResultsThe data of 12,657 cases met our inclusion criteria. The start remdesivir regimen showed a lower risk of supplementary oxygen requirement (hazard ratio: 0.861, p < 0.001). Both 30-day fatality risk and risk of IMV/ECMO introduction were not significantly different between the two regimens (hazard ratios: 1.05 and 0.886, p values: 0.070 and 0.440, respectively). ConclusionsRemdesivir might reduce the risk of oxygen requirement during hospitalisation in the early stage of COVID-19; however, it had no positive effect on the clinical outcome and reduction of IMV/ECMO requirement.

A Health Promoting Schools (HPS) program among primary and secondary school children in Southern Province, Sri Lanka: A qualitative study on the program’s effects on the school children, parents, and teachers / 国際保健医療

  A Health Promoting Schools (HPS) program was conducted among primary and secondary school children in Southern Province, Sri Lanka. The HPS program included implementation of health education and workshops, as well as publication of school newsletters that communicated the material the children discussed and learned in school to their families. The study aimed to determine whether the HPS program had any effects on the health of the school children, their parents and teachers.<BR>  A total of 22 adults (nine parents, nine school teachers, and four school principals) were invited for in-depth individual interviews and reported their views on changes after the implementation of the project. The interviewees reported that the school children substantially improved their behaviors regarding dietary habits, basic hygiene, lifestyle, and exercise. They also expressed that the school environment improved. They indicated direct and indirect changes in their own awareness and attitudes, as well as in other family members.<BR>  After the implementation of the HPS program, improved health behaviors and subsequent improved health across two generations were observed. Beyond providing students with health knowledge, more emphasis on motivating children to spread their health knowledge in their communities will make a more effective health intervention.

Can long-lasting insecticide-treated bednets with holes protect children from malaria?

Although long-lasting insecticide-treated bednets (LLINs) have been widely used for malaria control, little is known about how the condition of LLINs affects the risk of malaria infection. The objective of this cross-sectional study was to examine the association between the use of LLINs with holes and caregiver-reported malaria diagnosed in children under five years of age (U5). Data were collected in Boboye health district, Niger, in 2010. Surveyors conducted interviews and bednet inspections in 1,034 households. If a household had a U5 child, the surveyor asked the caregiver whether the child had experienced a fever episode in the past two weeks that entailed standard treatment for uncomplicated malaria at a healthcare facility. The authors analyzed the association between the use of LLINs with holes and caregiver-reported malaria episodes in U5 children using logistic regression, adjusted for possible confounders. Of the 1,165 children included in the analysis, approximately half (53.3%) used an intact LLIN while far fewer (10.6%) used a LLIN with holes. Compared to children using an intact LLIN, children using a LLIN with holes were significantly more likely to have a caregiver-reported malaria episode (8.7% vs. 17.1%; odds ratio: 2.23; 95% confidence interval: 1.24–4.01). In this study site, LLINs with holes were less protective than intact LLINs.

Can Long-lasting Insecticide-treated Bednets with Holes Protect Children from Malaria?

Although long-lasting insecticide-treated bednets (LLINs) have been widely used for malaria control, little is known about how the condition of LLINs affects the risk of malaria infection. The objective of this cross-sectional study was to examine the association between the use of LLINs with holes and caregiver-reported malaria diagnosed in children under five years of age (U5). Data were collected in Boboye health district, Niger, in 2010. Surveyors conducted interviews and bednet inspections in 1,034 households. If a household had a U5 child, the surveyor asked the caregiver whether the child had experienced a fever episode in the past two weeks that entailed standard treatment for uncomplicated malaria at a healthcare facility. The authors analyzed the association between the use of LLINs with holes and caregiver-reported malaria episodes in U5 children using logistic regression, adjusted for possible confounders. Of the 1,165 children included in the analysis, approximately half (53.3%) used an intact LLIN while far fewer (10.6%) used a LLIN with holes. Compared to children using an intact LLIN, children using a LLIN with holes were significantly more likely to have a caregiver-reported malaria episode (8.7% vs. 17.1%; odds ratio: 2.23; 95% confidence interval: 1.24–4.01). In this study site, LLINs with holes were less protective than intact LLINs.

Distribution of Subsidized Insecticide-treated Bed Nets through a Community Health Committee in Boboye Health District, Niger

In Niger, insecticide-treated bed nets (ITNs) have been distributed to the target group of households with young children and/or pregnant women at healthcare facilities in the course of antenatal/immunization clinics. With the aim of universal coverage, ITNs were additionally distributed to households through strengthened community health committees in 2009. This study assessed the impact of the community-based net distribution strategy involving community health committees in the ITN coverage in Boboye Health District, Niger. A cross-sectional survey was carried out on 1,034 households drawn from the intervention area (the co-existence of the community-based system together with the facility-based system) and the control area (the facility-based system alone). In the intervention area, 55.8% of households owned ITNs delivered through the community-based system, and 29.6% of households exclusively owned ITNs obtained through the community-based system. The community-based system not only reached households within the target group (54.6% ownership) but also those without (59.1% ownership). Overall, household ITN ownership was significantly higher in the intervention area than in the control area (82.5% vs. 60.7%). In combination, the community-based system and the facility-based system achieved a high ITN coverage. The community-based system contributed to reducing leakage in the facility-based system.

Application of the child-to-child strategy to change health awareness and behavior among school children and community dwellers in Sri Lanka / 国際保健医療

<B>Introduction</B><br>Recently, the increasing prevalence of chronic and lifestyle-related diseases has become the most crucial global health issue, even in low- and middle-income countries. However, current health systems are often unable to address the large burden of such diseases because of their poor capacity. In Sri Lanka, a country facing such issues, we implemented a school initiative project, the effect of which expanded beyond the school to the student's family as well as the local community. The project was aimed at prevention of chronic and lifestyle-related diseases among adults through school children's activities.<br><B>Activities</B><br>Major interventions such as workshops and regular publication of newsletters including the results of the workshops were implemented at four selected primary and secondary schools in the Southern Province of Sri Lanka. The newsletters the children brought home facilitated their communication with the parents regarding health issues. All the schools conducted health camps, which children planned and managed themselves, and incentive funds were offered to support the children's activities.<br><B>Results</B><br>Through discussion and learning at the workshops, children's self-confidence and self-reliance might be enhanced, particularly in regard to developing their health literacy. The health camps and incentive funds helped promote children's autonomy and capability. The attendance rate of the students at the four schools has increased since the inception of the project, while a questionnaire survey showed that the proportion of parents who smoked has decreased.<br><B>Conclusion</B><br>The trial suggested that school children have the potential not only to improve their own health but also to help their parents and the broader community adopt a healthier lifestyle. Application of the child-to-child strategy may be useful to deal with chronic and lifestyle-related diseases of adulthood as it expands to the child-to-parents and the child-to-community approach.

Behavior of Adult Influenza Patients during the 2009 Pandemic after Outpatient Clinic Presentations at a Hospital in Tokyo, Japan

The 2009 pandemic of novel swine-origin influenza A (H1N1) highlighted the importance of community mitigation measures such as voluntary isolation. During the pandemic, we investigated the voluntary isolation behavior of patients with influenza during the 7-day period after they visited an outpatient clinic at a hospital in Tokyo, Japan. A questionnaire-based survey was conducted on patients diagnosed with influenza. Of a total of 14 patients, 13 (93%) visited a workplace, school or other potentially crowded setting at least once in the 7-day period after presentation. Five patients (36%) visited a potentially crowded setting either with a fever or on the day after having a fever. The voluntary isolation behavior of Japanese people with influenza did not necessarily adhere to the Japanese government recommendation that people with influenza-like illness stay home for 7 days following the onset of symptoms.