Saturation time of exposure interval for cross-neutralization response to SARS-CoV-2: implications for vaccine dose interval

Evaluating the serum cross-neutralization responses after breakthrough infection with various SARS-CoV-2 variants provides valuable insight for developing variant-proof COVID-19 booster vaccines. However, fairly comparing the impact of breakthrough infections with distinct epidemic timing on cross-neutralization responses, influenced by the exposure interval between vaccination and infection, is challenging. To compare the impact of pre-Omicron to Omicron breakthrough infection, we estimated the effects on cross-neutralizing responses by the exposure interval using Bayesian hierarchical modeling. The saturation time required to generate saturated cross-neutralization responses differed by variant, with variants more antigenically distant from the ancestral strain requiring longer intervals of 2-4 months. The breadths of saturated cross-neutralization responses to Omicron lineages were comparable in pre-Omicron and Omicron breakthrough infections. Our results highlight the importance of vaccine dosage intervals of 4 months or longer, regardless of the antigenicity of the exposed antigen, to maximize the breadth of serum cross-neutralization covering SARS-CoV-2 Omicron lineages. Graphical

Specific COVID-19 risk behaviors and the preventive effect of personal protective equipment among healthcare workers in Japan

Summary As coronavirus disease 2019 (COVID-19) outbreaks in healthcare facilities are a serious public health concern, we performed a case-control study to investigate the risk of COVID-19 infection in healthcare workers. We collected data on participants' sociodemographic characteristics, contact behaviors, installation status of personal protective equipment, and polymerase chain reaction testing results. We also collected whole blood and assessed seropositivity using the electrochemiluminescence immunoassay and microneutralization assay. In total, 161 (8.5%) of 1,899 participants were seropositive between August 3 and November 13, 2020. Physical contact (adjusted odds ratio 2.4, 95% confidence interval 1.1-5.6) and aerosol-generating procedures (1.9, 1.1-3.2) were associated with seropositivity. Using goggles (0.2, 0.1-0.5) and N95 masks (0.3, 0.1-0.8) had a preventive effect. Seroprevalence was higher in the outbreak ward (18.6%) than in the COVID-19 dedicated ward (1.4%). Results showed certain specific risk behaviors of COVID-19;proper infection prevention practices reduced these risks.

National seroepidemiological study of COVID-19 after the initial rollout of vaccines: Before and at the peak of the Omicron-dominant period in Japan.

Background: Based on routine surveillance data, Japan has been affected much less by COVID-19 compared with other countries. To validate this, we aimed to estimate SARS-CoV-2 seroprevalence and examine sociodemographic factors associated with cumulative infection in Japan. Methods: A population-based serial cross-sectional seroepidemiological investigation was conducted in five prefectures in December 2021 (pre-Omicron) and February-March 2022 (Omicron [BA.1/BA.2]-peak). Anti-nucleocapsid and anti-spike antibodies were measured to detect infection-induced and vaccine/infection-induced antibodies, respectively. Logistic regression was used to identify associations between various factors and past infection. Results: Among 16 296 participants (median age: 53 [43-64] years), overall prevalence of infection-induced antibodies was 2.2% (95% CI: 1.9-2.5%) in December 2021 and 3.5% (95% CI: 3.1-3.9%) in February-March 2022. Factors associated with past infection included those residing in urban prefectures (Tokyo: aOR 3.37 [95% CI: 2.31-4.91], Osaka: aOR 3.23 [95% CI: 2.17-4.80]), older age groups (60s: aOR 0.47 [95% CI 0.29-0.74], 70s: aOR 0.41 [95% CI 0.24-0.70]), being vaccinated (twice: aOR 0.41 [95% CI: 0.28-0.61], three times: aOR 0.21 [95% CI: 0.12-0.36]), individuals engaged in occupations such as long-term care workers (aOR: 3.13 [95% CI: 1.47-6.66]), childcare workers (aOR: 3.63 [95% CI: 1.60-8.24]), food service workers (aOR: 3.09 [95% CI: 1.50-6.35]), and history of household contact (aOR: 26.4 [95% CI: 20.0-34.8]) or non-household contact (aOR: 5.21 [95% CI:3.80-7.14]) in February-March 2022. Almost all vaccinated individuals (15 670/15 681) acquired binding antibodies with higher titers among booster dose recipients. Conclusions: Before Omicron, the cumulative burden was >10 times lower in Japan (2.2%) compared with the US (33%), the UK (25%), or global estimates (45%), but most developed antibodies owing to vaccination.

National seroepidemiological study of COVID‐19 after the initial rollout of vaccines: Before and at the peak of the Omicron‐dominant period in Japan

Background Based on routine surveillance data, Japan has been affected much less by COVID‐19 compared with other countries. To validate this, we aimed to estimate SARS‐CoV‐2 seroprevalence and examine sociodemographic factors associated with cumulative infection in Japan. Methods A population‐based serial cross‐sectional seroepidemiological investigation was conducted in five prefectures in December 2021 (pre‐Omicron) and February–March 2022 (Omicron [BA.1/BA.2]‐peak). Anti‐nucleocapsid and anti‐spike antibodies were measured to detect infection‐induced and vaccine/infection‐induced antibodies, respectively. Logistic regression was used to identify associations between various factors and past infection. Results Among 16 296 participants (median age: 53 [43–64] years), overall prevalence of infection‐induced antibodies was 2.2% (95% CI: 1.9–2.5%) in December 2021 and 3.5% (95% CI: 3.1–3.9%) in February–March 2022. Factors associated with past infection included those residing in urban prefectures (Tokyo: aOR 3.37 [95% CI: 2.31–4.91], Osaka: aOR 3.23 [95% CI: 2.17–4.80]), older age groups (60s: aOR 0.47 [95% CI 0.29–0.74], 70s: aOR 0.41 [95% CI 0.24–0.70]), being vaccinated (twice: aOR 0.41 [95% CI: 0.28–0.61], three times: aOR 0.21 [95% CI: 0.12–0.36]), individuals engaged in occupations such as long‐term care workers (aOR: 3.13 [95% CI: 1.47–6.66]), childcare workers (aOR: 3.63 [95% CI: 1.60–8.24]), food service workers (aOR: 3.09 [95% CI: 1.50–6.35]), and history of household contact (aOR: 26.4 [95% CI: 20.0–34.8]) or non‐household contact (aOR: 5.21 [95% CI:3.80–7.14]) in February–March 2022. Almost all vaccinated individuals (15 670/15 681) acquired binding antibodies with higher titers among booster dose recipients. Conclusions Before Omicron, the cumulative burden was >10 times lower in Japan (2.2%) compared with the US (33%), the UK (25%), or global estimates (45%), but most developed antibodies owing to vaccination.

COVID-19 vaccine effectiveness against symptomatic SARS-CoV-2 infection during Delta-dominant and Omicron-dominant periods in Japan: a multi-center prospective case-control study (FASCINATE study).

BACKGROUND: Although several COVID-19 vaccines initially showed high efficacy, there have been concerns due to 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 SARS-CoV-2 infection was calculated for 2 doses for the Delta-dominant period and 2 or 3 doses for the Omicron-dominant period, compared to 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 mRNA-1273 at manufacturer-recommended intervals. During the Delta-dominant period, VE was 88% (95% CI: 82-93) 14 days-3 months after dose 2 and 87% (95% CI: 38-97) 3-6 months after dose 2. During the Omicron-dominant period, VE was 56% (95% CI: 37-70) 14 days-3 months since dose 2, 52% (95% CI: 40-62) 3-6 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 (i.e. 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.

Non-Omicron breakthrough infection with higher viral load and longer vaccination-infection interval improves SARS-CoV-2 BA.4/5 neutralization.

The immune responses to SARS-CoV-2 variants in COVID-19 cases are influenced by various factors including pre-existing immunity via vaccination and prior infection. Elucidating the drivers for upgrading neutralizing activity to SARS-CoV-2 in COVID-19 cases with pre-existing immunity will aid in improving COVID-19 booster vaccines with enhanced cross-protection against antigenically distinct variants, including the Omicron sub-lineage BA.4/5. This study revealed that the magnitude and breadth of neutralization activity to SARS-CoV-2 variants after breakthrough infections are determined primarily by upper respiratory viral load and vaccination-infection time interval. Extensive neutralizing breadth, covering even the most antigenically distant BA.4/5, was observed in cases with higher viral load and longer time intervals. Antigenic cartography depicted a critical role of the time interval in expanding the breadth of neutralization to SARS-CoV-2 variants. Our results illustrate the importance of dosing interval optimization as well as antigen design in developing variant-proof booster vaccines.

Impact of the COVID-19 pandemic on pathological autopsy practices in Japan.

During the coronavirus disease 2019 (COVID-19) pandemic, autopsies have provided valuable insights into the pathogenesis of COVID-19. The precise effect of this pandemic on autopsy procedures in Japan, especially in instances unrelated to COVID-19, has not yet been established. Therefore, we conducted a questionnaire survey from December 2020 to January 2021 regarding the status of pathological autopsy practices in Japan during the first year of the COVID-19 pandemic. The questionnaire was sent to 678 medical facilities with pathologists, of which 227 responded. In cases where a confirmed diagnosis of COVID-19 was not made at the time of autopsy, many facilities counted them as suspected COVID-19 cases if pneumonia was suspected clinically. At around half of the sites, autopsies were prohibited for suspected COVID-19 cases. In addition, the number of autopsies of non-COVID-19 cases during the pandemic period was also investigated, and a significant decrease was observed compared with the incidence in the pre-pandemic period. The COVID-19 pandemic has affected not only the autopsies of COVID-19 cases but also the entire practice of pathological autopsies. It is necessary to establish a system that supports the implementation of pathological autopsy practices during the pandemic of an emerging infectious disease.

Replacement of SARS-CoV-2 strains with variants carrying N501Y and L452R mutations in Japan: an epidemiological surveillance assessment.

Objective: Monitoring the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is important due to concerns regarding infectivity, transmissibility, immune evasion and disease severity. We evaluated the temporal and regional replacement of previous SARS-CoV-2 variants by the emergent strains, Alpha and Delta. Methods: We obtained the results of polymerase chain reaction screening tests for variants conducted in multiple commercial laboratories. Assuming that all previous strains would be replaced by one variant, the new variant detection rate was estimated by fitting a logistic growth model. We estimated the transmission advantage of each new variant over the pre-existing virus strains. Results: The variant with the N501Y mutation was first identified in the Kinki region in early February 2021, and by early May, it had replaced more than 90% of the previous strains. The variant with the L452R mutation was first detected in the Kanto-Koshin region in mid-May, and by early August, it comprised more than 90% of the circulating strains. Compared with pre-existing strains, the variant with the N501Y mutation showed transmission advantages of 48.2% and 40.3% in the Kanto-Koshin and Kinki regions, respectively, while the variant with the L452R mutation showed transmission advantages of 60.1% and 71.9%, respectively. Discussion: In Japan, Alpha and Delta variants displayed regional differences in the replacement timing and their relative transmission advantages. Our method is efficient in monitoring and estimating changes in the proportion of variant strains in a timely manner in each region.

Impact of the Coming-of-Age Day and ceremony on the risk of SARS-CoV-2 transmission in Japan: A natural-experimental study based on national surveillance data.

BACKGROUND: Quantifying the impact on COVID-19 transmission from a single event has been difficult due to the virus transmission dynamics, such as lag from exposure to reported infection, non-linearity arising from the person-to-person transmission, and the modifying effects of non-pharmaceutical interventions over time. To address these issues, we aimed to estimate the COVID-19 transmission risk of social events focusing on the Japanese Coming-of-Age Day and Coming-of-Age ceremony in which "new adults" practice risky behavior on that particular day. METHODS: Using national surveillance data in Japan in 2021 and 2022, we conducted difference-in-differences regression against COVID-19 incidences by setting "new adults" cases as the treatment group and the cases 1 year younger or older than these "new adults" as the control group. In addition, we employed a triple differences approach to estimate the risk of holding the Coming-Age ceremony by using a binary variable regarding the presence or absence of the ceremony in each municipality. RESULTS: We estimated the relative risks (RRs) of the Coming-of-Age Day as 1.27 (95% confidence interval [CI] 1.02-1.57) in 2021 and 3.22 (95% CI 2.68-3.86) in 2022. The RR of the Coming-of-Age ceremony was also large, estimated as 2.83 (1.81-4.43) in 2022. CONCLUSIONS: When planning large social events, it is important to be aware of the unique risks associated with these gatherings, along with effective public health messages to best communicate these risks.

Social and Behavioral Factors Associated with Lack of Intent to Receive COVID-19 Vaccine, Japan.

Persons in Japan who did not intend to receive COVID-19 vaccines after widespread rollout were less likely than others to engage in preventive measures or to be afraid of getting infected or infecting others. They were also not less likely to engage in potentially high-risk behaviors, suggesting similar or higher exposure risks.

Behavioral factors associated with SARS-CoV-2 infection in Japan.

BACKGROUND: The relative burden of COVID-19 has been less severe in Japan. One reason for this may be the uniquely strict restrictions imposed upon bars/restaurants. To assess if this approach was appropriately targeting high-risk individuals, we examined behavioral factors associated with SARS-CoV-2 infection in the community. METHODS: This multicenter case-control study involved individuals receiving SARS-CoV-2 testing in June-August 2021. Behavioral exposures in the past 2 weeks were collected via questionnaire. SARS-CoV-2 PCR-positive individuals were cases, while PCR-negative individuals were controls. RESULTS: The analysis included 778 individuals (266 [34.2%] positives; median age [interquartile range] 33 [27-43] years). Attending three or more social gatherings was associated with SARS-CoV-2 infection (adjusted odds ratio [aOR] 2.00 [95% CI 1.31-3.05]). Attending gatherings with alcohol (aOR 2.29 [1.53-3.42]), at bars/restaurants (aOR 1.55 [1.04-2.30]), outdoors/at parks (aOR 2.87 [1.01-8.13]), at night (aOR 2.07 [1.40-3.04]), five or more people (aOR 1.81 [1.00-3.30]), 2 hours or longer (aOR 1.76 [1.14-2.71]), not wearing a mask during gatherings (aOR 4.18 [2.29-7.64]), and cloth mask use (aOR 1.77 [1.11-2.83]) were associated with infection. Going to karaoke (aOR 2.53 [1.25-5.09]) and to a gym (aOR 1.87 [1.11-3.16]) were also associated with infection. Factors not associated with infection included visiting a cafe with others, ordering takeout, using food delivery services, eating out by oneself, and work/school/travel-related exposures including teleworking. CONCLUSIONS: We identified multiple behavioral factors associated with SARS-CoV-2 infection, many of which were in line with the policy/risk communication implemented in Japan. Rapid assessment of risk factors can inform decision making.

Vaccination-infection interval determines cross-neutralization potency to SARS-CoV-2 Omicron after breakthrough infection by other variants.

Background: The immune profile against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has dramatically diversified due to a complex combination of exposure to vaccines and infection by various lineages/variants, likely generating a heterogeneity in protective immunity in a given population. To further complicate this, the Omicron variant, with numerous spike mutations, has emerged. These circumstances have created the need to assess the potential of immune evasion by Omicron in individuals with various immune histories. Methods: The neutralization susceptibility of the variants, including Omicron and their ancestors, was comparably assessed using a panel of plasma/serum derived from individuals with divergent immune histories. Blood samples were collected from either mRNA vaccinees or from those who suffered from breakthrough infections of Alpha/Delta with multiple time intervals following vaccination. Findings: Omicron was highly resistant to neutralization in fully vaccinated individuals without a history of breakthrough infections. In contrast, robust cross-neutralization against Omicron was induced in vaccinees that experienced breakthrough infections. The time interval between vaccination and infection, rather than the variant types of infection, was significantly correlated with the magnitude and potency of Omicron-neutralizing antibodies. Conclusions: Immune histories with breakthrough infections can overcome the resistance to infection by Omicron, with the vaccination-infection interval being the key determinant of the magnitude and breadth of neutralization. The diverse exposure history in each individual warrants a tailored and cautious approach to understanding population immunity against Omicron and future variants. Funding: This study was supported by grants from the Japan Agency for Medical Research and Development (AMED).

Duration of Infectious Virus Shedding by SARS-CoV-2 Omicron Variant-Infected Vaccinees.

To determine virus shedding duration, we examined clinical samples collected from the upper respiratory tracts of persons infected with severe acute respiratory syndrome coronavirus 2 Omicron variant in Japan during November 29-December 18, 2021. Vaccinees with mild or asymptomatic infection shed infectious virus 6-9 days after onset or diagnosis, even after symptom resolution.

A case report of breakthrough infection with the SARS-CoV-2 delta variant and household transmission: Role of vaccination, anti-spike IgG and neutralizing activity.

There have been several reports of breakthrough infections, which are defined as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections among individuals who had received at least two doses of vaccine at least 14 days before the onset of infection, but data on the antibody titers, including SARS-CoV-2 neutralizing antibody activity, and the clinical course of individuals with breakthrough infections are limited. We encountered a case of breakthrough infection with the SARS-CoV-2 delta variant in a 31-year-old female healthcare worker (the index case, Case 1) and a secondary case (Case 2) in her unvaccinated 33-year-old husband. We studied the role of the anti-spike immunoglobulin G (IgG) and neutralizing antibody activity in the two case patients. Case 1 had high anti-spike IgG detected on day 3 of the illness, with low neutralizing antibody activity. The neutralizing antibody activity started to increase on day 5 of the illness. In Case 2 both the anti-spike IgG and the neutralizing antibody activity remained low from days 4-11 of illness, and the anti-spike IgG gradually increased from day 9. In Case 1, the fever broke within 4 days of onset, coinciding with the rise in neutralizing antibodies, whereas the fever took 7 days to resolve in Case 2. SARS-CoV-2 infection can occur even in vaccinated individuals, but vaccination may contribute to milder clinical symptoms because neutralizing antibodies are induced earlier in vaccinated individuals than in unvaccinated individuals.

Epidemiology of Coronavirus Disease 2019 in Japan: Descriptive Findings and Lessons Learned through Surveillance during the First Three Waves.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) has caused unprecedented global morbidity and mortality. Japan has faced three epidemic "waves" of COVID-19 from early 2020 through early 2021. Here we narratively review the three waves in Japan, describe the key epidemiologic features of COVID-19, and discuss lessons learned. METHODS: We assessed publicly available surveillance data, routine surveillance reports, and other relevant sources-multiple indicators were monitored to improve interpretation of surveillance data. Weekly trends for each wave were described based on the number of case notifications; number of tests performed; proportion of those tests that were positive for the novel coronavirus; the prevalent number of COVID-19 hospitalizations (total hospitalizations and those categorized as severe); and number of COVID-19 deaths. For each indicator and wave, we recorded the first calendar week to show an increase over two consecutive previous weeks, along with the peak week. RESULTS: The spring wave was characterized by detection of cases imported from China, followed by notifications of sporadic cases without travel history, clusters, and mild/asymptomatic cases. The summer wave saw a large increase in notifications and a younger age distribution, but in the context of increased testing with lower test positivity. The winter wave brought considerable morbidity and mortality, surpassing the cumulative case counts and fatalities from the earlier waves, with high peak values. Overall, relative to the first wave, the burden of severe outcomes was lower in the second and higher in the third wave, but varied by prefecture. In all three waves, severe outcomes peaked after notification counts and test positivity peaked; severe outcomes were also consistently skewed toward the elderly. CONCLUSIONS: Important lessons were learned from each wave and across waves-some aspects remained constant, while others changed over time. In order to rapidly detect an increase in incidence, continuous, timely, and sensitive surveillance-using multiple information sources with careful interpretations-will be key in COVID-19 control.

Insights into Pathology and Pathogenesis of Coronavirus Disease 2019 from a Histopathological and Immunological Perspective.

Since the first case of COVID-19 was reported in Wuhan, China, in December 2019, the SARS-CoV-2 epidemic has spread all over the world and has become a significant public health issue. The development of treatments for COVID-19 is currently in progress; however, their effects remain limited, and the development of more effective therapeutics is desired. Thus, sufficient understanding of the pathophysiology of COVID-19 is essential to develop effective therapeutics for this disease. Pathological analyses in particular play an important role to demonstrate the causal link between an infectious disease and the pathogen and elucidate the mechanism of pathogenesis. As per pathological analyses to date, respiratory organs are identified as the major affected organs in most COVID-19 cases; also, various lesions were noted in other organs. Further, there have been increasing reports that show that the immune responses of the host contribute to the deterioration of the pathological condition of COVID-19, and a novel concept of MIS-C/MIS-A is also being established. Thus, in this article, we have provided an overview of the pathology of COVID-19 from a histopathological and immunological perspective focusing on the mechanisms of COVID-19 pathogenesis.

Clinical validation of an immunochromatographic SARS-Cov-2 IgM/IgG antibody assay with Japanese cohort.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has become a major health threat. To overcome COVID-19, appropriate diagnosis methods are urgently needed. The aim of this study was to clinically evaluate the colloidal gold immunochromatography assay for SARS-Cov-2 IgM/IgG antibody (Ab). METHODS: Patients confirmed COVID-19 (n = 51) were recruited prospectively from the Musashino Red Cross hospital and Tokyo Medical and Dental University Medical Hospital, between March and May 2020. And the analytical specificity was assessed with serum samples of patients without COVID-19 (n = 100) collected between August to September 2019 before SARS-CoV-2 was first reported in China. RESULTS: Among COVID-19 patients, a total of 87 serum samples were tested for SARS-Cov-2 IgM/IgG Ab assay. IgM was detected 71.0 %, 86.9 %, and 83.3 % at day8-14, 15-28, >29 after symptom onset and IgG was detected in 81.6 %, 87.0 %, and 94.4 %, respectively. The sensitivity of IgM and IgG Ab after day8 assay was significantly higher than before day7, respectively (p=0.0016, 0.0003). There were no positive results in 100 serum samples from patients without COVID-19. CONCLUSION: The SARS-Cov-2 IgM/IgG Ab assay had 79.7% / 86.1% sensitivity (the 8 days after from onset) and 100% specificity in this population.