Protective Effect of Previous Infection and Vaccination Against Reinfection with BA.5 Omicron Subvariant: A Nation-Wide Population-Based Study in Japan (preprint)

Background: The Omicron variant of SARS-CoV-2 was reported to evade immunity derived from vaccination and previous infection. A better understanding of hybrid immunity informs effective infection control strategies. Since the reinfection risk was not well-assessed in East Asia, this study aims to evaluate the risk of infection with Omicron subvariant BA.5 among previously infected individuals in Japan.Methods: All notified cases were extracted from the Japanese national COVID-19 surveillance database including 20,297,335 records up to 25 September 2022. Reinfection with BA.5 was defined as the second infection notified during the BA.5 dominated period. The protective effect of prior infections against reinfections with BA.5 was estimated by applying a case-population design and the protective effect of vaccination was estimated by a multivariable Cox regression adjusting for age, sex, variants of prior infection, and the time since the last vaccination.Findings: Among 19,830,548 SARS-CoV-2 infections, 233,424 (1·2%) were reinfected with BA.5. The protective effect of prior infection with Wuhan, Alpha, Delta, and BA.1/BA.2 against BA.5 reinfection was 46·2% (45·5–47·0), 35·2% (34·2–36·2), 40·6% (39·9–41·2), and 73·9% (73·4–74·4), respectively. The risk of BA.5 reinfection was reduced by 14%, 41%, and 71% by two, three and four doses of vaccination, respectively, compared with one-dose vaccination.Interpretation: The prior infections with Omicron subvariant BA.1/BA.2 protected BA.5 reinfection more than pre-Omicron variants. Increased frequency of vaccination led to more protection from reinfection with BA.5. Up-to-date vaccination may be encouraged to prevent future reinfection among the previously infected population.Funding: RK received funding from the Japan Society for the Promotion of Science (JSPS) KAKENHI (21K17307). MS and TK received the Ministry of Health Labour and Welfare Science Research Grant (23HA2005).Declaration of Interest: The authors declare that they have no conflict of interest.Ethical Approval: No ethical approval was required because this study was conducted for public health purposes using national surveillance data.

Secondary attack rates of SARS-CoV-2 alpha and delta variants in Japan (preprint)

BackgroundsThis study analysed secondary attack rates (SARs), comparing alpha variants, delta variants and non-variants of concern (non-VOCs), using clinical and close-contact tracing data.MethodsWe analysed coronavirus disease 2019 (COVID-19) case data from a database and contact tracing data between July and October 2020 (Cohort 1) and April 2021 (Cohort 2) and between July and August 2021 (Cohort 3) in a city in Toyama prefecture, Japan. Real-time polymerase chain reaction (PCR) was used to detect the N501Y (alpha variant) and L452R (delta variant) mutations. We calculated the SARs considering close contact, index case and contact setting characteristics. Relative risks (RRs) of secondary attack were analysed using Poisson regression models.ResultsAmong 123 index cases and 530 close contacts in Cohort 1, 246 index cases and 988 close contacts in Cohort 2, and 304 index cases and 984 close contacts in Cohort 3, the SARs associated with alpha and delta variant index cases were 1.47 times and 1.89 times higher than those associated with non-VOC index cases. Delta variant index cases were associated with the highest SAR (29.2%) in the same household and a 2.40-fold (95% CI: 1.62-3.56) higher risk of transmission than non-VOC index cases. The age and symptoms of index cases were associated with the SAR.ConclusionsWe confirmed that VOC index cases were associated with increased transmissibility. Population longitudinal surveillance data linked with contact-tracing data provide valuable information for elucidation of the characteristics of newly emerging variants.

Effectiveness of mRNA COVID-19 vaccines against symptomatic SARS-CoV-2 infections during the Delta variant epidemic in Japan: Vaccine Effectiveness Real-time Surveillance for SARS-CoV-2 (VERSUS) (preprint)

Background: Although high vaccine effectiveness of messenger RNA (mRNA) coronavirus disease 2019 (COVID-19) vaccines was reported in studies in several countries, data is limited from Asian countries, especially against the Delta (B.1.617.2) variant. Methods: We conducted a multicenter test-negative case-control study in patients aged [≥]16 visiting hospitals or clinics with signs or symptoms consistent with COVID-19 from July 1 to September 30, 2021, when the Delta variant was dominant ([≥]90% of severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infections) nationwide in Japan. Vaccine effectiveness of BNT162b2 or mRNA-1273 against symptomatic SARS-CoV-2 infections was evaluated. Waning immunity among patients aged 16 to 64 was also assessed. Results: We enrolled 1936 patients, including 396 test-positive cases and 1540 test-negative controls for SARS-CoV-2. The median age was 49 years, 53.4% were male, and 34.0% had underlying medical conditions. Full vaccination (receiving two doses [≥]14 days before symptom onset) was received by 6.6% of cases and 38.8% of controls. Vaccine effectiveness of full vaccination against symptomatic SARS-CoV-2 infections was 88.7% (95% confidence interval [CI], 78.8 to 93.9) among patients aged 16 to 64 and 90.3% (95% CI, 73.6 to 96.4) among patients aged [≥]65. Among patients aged 16 to 64, vaccine effectiveness within one to three months after full vaccination was 91.8% (95% CI, 80.3 to 96.6), and was 86.4% (95% CI, 56.9 to 95.7) within four to six months. Conclusions: mRNA COVID-19 vaccines had high effectiveness against symptomatic SARS-CoV-2 infections in Japan during July 1 to September 30, 2021, when the Delta variant was dominant nationwide.

Viral and Immunological Characteristics of COVID-19 Vaccine Breakthrough Infections (preprint)

Since little is known about viral and host characteristics of breakthrough infections after COVID-19 vaccination, a nationwide investigation of breakthrough cases was initiated in Japan. 130 cases (90%+ received mRNA vaccines) were reported with respiratory specimens in 117 cases and sera in 68 cases. A subset of cases shed infectious virus regardless of symptom presence or viral lineages. Viral lineages for breakthrough infections matched both temporally and spatially with the circulating lineages in Japan with no novel mutations in spike receptor binding domain that may have escaped from vaccine-induced immunity were found. Anti-spike/neutralizing antibodies of breakthrough infections in the acute phase owing to vaccine-induced immunity were significantly higher than those from unvaccinated convalescent individuals but were comparable to vaccinated uninfected individuals, and followed by boosting in the convalescent phase. Symptomatic cases had low anti-spike/neutralizing antibodies in the acute phase with robust boosting in the convalescent phase, suggesting the presence of serological correlate for symptom development in COVID-19 vaccine breakthrough infections.

A genome epidemiological study of SARS-CoV-2 introduction into Japan (preprint)

BackgroundAfter the first case of COVID-19 in Japan on 15 January 2020, multiple nationwide COVID-19 clusters were identified by the end of February. The Japanese government focused on mitigating emerging COVID-19 clusters by conducting active nationwide epidemiological surveillance. However, an increasing number of cases appeared until early April, many with unclear infection routes exhibiting no recent history of travel outside Japan. We aimed to evaluate the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome sequences from COVID-19 cases until early April and characterise the genealogical networks to demonstrate possible routes of spread in Japan. MethodsNasopharyngeal specimens were collected from patients and a quantitative reverse transcription polymerase chain reaction testing for SARS-CoV-2 was performed. Positive RNA samples were subjected whole genome sequencing and a haplotype network analysis was performed. FindingsSome of the primary clusters identified during January and February in Japan directly descended from Wuhan-Hu-1-related isolates in China and other distinct clusters. Clusters were almost contained until mid-March; the haplotype network analysis demonstrated that COVID-19 cases from late March through early April may have caused an additional large cluster related to the outbreak in Europe, leading to additional spread within Japan. National self-restraint during February was effective in mitigating the COVID-19 spread, but late action on stopping immigration and declaring national emergency in Japan might be involved in the later increase in cases. InterpretationGenome surveillance suggested that at least two distinct SARS-CoV-2 introductions from China and other countries occurred. FundingJapan Agency for Medical Research and Development.

Haplotype networks of SARS-CoV-2 infections in the Diamond Princess cruise ship outbreak (preprint)

The Diamond Princess (DP) cruise ship was put under quarantine offshore Yokohama, Japan, after a passenger who disembarked in Hong Kong was confirmed as a COVID-19 case. We performed whole genome sequencing of SARS-CoV-2 directly from PCR-positive clinical specimens and conducted a haplotype network analysis of the outbreak. All tested isolates exhibited a transversion at G11083T, suggesting that SARS-CoV-2 dissemination on the DP originated from a single introduction event before the quarantine started. Although further spreading might have been prevented by quarantine, some progeny clusters were linked to transmission through mass-gathering events in the recreational areas and direct transmission among passengers who shared cabins during the quarantine. This study demonstrates the usefulness of haplotype network analysis in identifying potential infection routes.

Closed environments facilitate secondary transmission of coronavirus disease 2019 (COVID-19) (preprint)

Objective: To identify common features of cases with novel coronavirus disease (COVID-19) so as to better understand what factors promote secondary transmission including superspreading events. Methods: A total of 110 cases were examined among eleven clusters and sporadic cases, and investigated who acquired infection from whom. The clusters included four in Tokyo and one each in Aichi, Fukuoka, Hokkaido, Ishikawa, Kanagawa and Wakayama prefectures. The number of secondary cases generated by each primary case was calculated using contact tracing data. Results: Of the 110 cases examined, 27 (24.6%) were primary cases who generated secondary cases. The odds that a primary case transmitted COVID-19 in a closed environment was 18.7 times greater compared to an open-air environment (95% confidence interval [CI]: 6.0, 57.9). Conclusions: It is plausible that closed environments contribute to secondary transmission of COVID-19 and promote superspreading events. Our findings are also consistent with the declining incidence of COVID-19 cases in China, as gathering in closed environments was prohibited in the wake of the rapid spread of the disease.