key: cord-0267496-i08f1nvr
authors: Maeda, H.; Saito, N.; Igarashi, A.; Ishida, M.; Suami, K.; Yagiuchi, A.; Kimura, Y.; Komino, M.; Arai, H.; Morikawa, T.; Motohashi, I.; Miyazawa, R.; Moriyama, T.; Kamura, H.; Terada, M.; Kuwamitsu, O.; Hayakawa, T.; Sando, E.; Ohara, Y.; Teshigawara, O.; Suzuki, M.; Morimoto, K.
title: 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)
date: 2022-01-23
journal: nan
DOI: 10.1101/2022.01.17.22269394
sha: cbc5c07e754a3ac2052f3be41d9875497692f6b0
doc_id: 267496
cord_uid: i08f1nvr

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.

Since December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally, including Japan, and has significantly impacted health, livelihoods, and economics. To counter the coronavirus disease 2019 (COVID-19) pandemic, COVID-19 vaccines were developed and distributed globally. Clinical trials of COVID-19 vaccines found high vaccine efficacy [1] [2] [3] , and observational studies evaluated vaccine effectiveness in several countries [4] [5] [6] . However, data on vaccine effectiveness of messenger RNA (mRNA) COVID-19 vaccines, especially against the Delta (B.1.617.2) variant, from Asian countries is limited.

In February 2021, the Japanese government initiated a national COVID-19 vaccination campaign (Supplementary Figure 1) . It is crucial to assess COVID-19 vaccine effectiveness domestically when evaluating the national policy and, going forward, determining the optimal vaccination policy. Vaccine effectiveness has been estimated to attenuate due to the emergence of new variants [7] . Accordingly, we started surveillance activity from July 1, 2021 to monitor vaccine effectiveness of COVID-19 vaccines in Japan, named Vaccine Effectiveness Real-time Surveillance for SARS-CoV-2 (VERSUS). In this study, we evaluated vaccine effectiveness of mRNA COVID-19 vaccines, BNT165b2 and mRNA-1273, against symptomatic SARS-CoV-2 infections during the Delta variant epidemic in Japan using data registered for our surveillance. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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We conducted a prospective test-negative case-control study in patients visiting hospitals or clinics with signs or symptoms compatible with COVID-19 [8, 9] . The case group included individuals having signs or symptoms compatible with COVID-19 and positive test results of SARS-CoV-2. The following test methods were included, which have high sensitivity and specificity and are commonly used for diagnosis in Japan as well as globally [10, 11] : nucleic acid amplification tests including polymerase chain reaction (PCR), loop-medical isothermal amplification (LAMP) [12] , and nicking endonuclease amplification reaction [13] ; and antigen quantification tests [14, 15] . Individuals having signs or symptoms compatible with COVID-19 but negative test results of SARS-CoV-2 were included in the control group.

This study enrolled individuals visiting medical institutes from July 1 through September 30, 2021, at nine hospitals and four clinics in nine prefectures on four main islands in Japan.

During this study period, Japan experienced a fifth epidemic wave due to the Delta variant, starting late in June 2021 (Supplementary Figure 2) [16, 17] .

Before the fifth wave in Japan, the Japanese government approved and introduced . CC-BY-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Figure 2) [19].

Patients aged ≥16 years were included who had signs or symptoms compatible with . CC-BY-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint 

Attending physicians in each medical institute identified eligible patients. Demographic and clinical information was collected from medical charts and recorded on an electronic database using REDCap [23].

We collected demographic and clinical information, including age, sex, place of residence, presence of underlying medical conditions (i.e. chronic heart disease, chronic is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 23, 2022. 

We obtained vaccination histories (i.e., vaccination date of administration, type of vaccine product, and vaccination frequency) through interviews with patients or their family members. COVID-19 vaccines are administered as two-dose series. Vaccination status was classified into six categories based on the number of vaccine doses received before symptom onset and the number of days between the last vaccination and symptom onset date; specifically, 1) unvaccinated where individuals had received no vaccine dose before symptom onset; 2) first vaccine dose within 13 days before symptom onset; 3) partially vaccinated where individuals received one dose ≥14 days before symptom onset; 4) second vaccine dose within 13 days before symptom onset; 5) fully vaccinated where individuals received two doses ≥14 days before symptom onset; and 6) unknown vaccination status where vaccination histories were not documented. For patients whose precise vaccination date was not documented (for example, only the month of the vaccination was documented), the . CC-BY-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 23, 2022. midpoint between the two possible dates was assumed to be the vaccination date.

Additionally, those for whom only the number of vaccine doses were recorded were included in either the partially or fully vaccinated groups depending on the number of vaccine doses.

The odds ratio (OR) was calculated by comparing the odds of antecedent COVID-19 vaccination in test-positive versus test-negative patients. A mixed-effects logistic regression model was used to calculate adjusted ORs. Age, sex, presence of underlying medical conditions, calendar weeks, and history of contact with COVID-19 patients were applied as the fixed effects, and study sites as the random effect to the logistic model. Vaccine effectiveness was defined as one minus adjusted ORs, expressed as a percentage [8, 9] .

Vaccine effectiveness estimates were calculated for full vaccinated versus unvaccinated and for partially vaccinated versus unvaccinated. We analyzed vaccine effectiveness separately in patients aged 16 to 64 years and in patients aged ≥65 years, taking into consideration the possibility of confounders due to the priority vaccination strategy for patients aged ≥65 years. For BNT162b2 or mRNA-1273 analysis, we pooled patients who received either BNT162b2 or mRNA-1273mRNA COVID-19 vaccines. We also performed analyses on each vaccine product separately. We excluded the episodes with undocumented vaccine products from the analysis of each vaccine product. Additionally, to . CC-BY-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 23, 2022. ; https://doi.org/10.1101/2022.01.17.22269394 doi: medRxiv preprint assess the extent of waning immunity of mRNA COVID-19 vaccines against the Delta variant in Japan, we evaluated vaccine effectiveness separately between two groups: episodes within one to three months and episodes within four to six months after full vaccination status (14 days after the second vaccine receipt) among patients aged 16 to 64 years. We also conducted subgroup analyses by sex or presence of underlying medical conditions. Several sensitivity analyses were performed to strengthen our results since some of the vaccination histories were vacant: when the precise vaccination date was uncertain, we set the vaccination date as the most recent possible date (scenario A) or the earliest possible date (scenario B) from symptom onset; we excluded patients with no information of vaccination dates (scenario C); and multiple imputations were performed for those with undocumented vaccination histories (scenario D). All analysis was performed using Stata version 16 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 23, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 23, 2022. ; https://doi.org/10.1101/2022.01.17.22269394 doi: medRxiv preprint one to three months before symptom onset.

Vaccine effectiveness of mRNA COVID-19 vaccines against symptomatic SARS-CoV-2 infections are shown in Figure 2 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 23, 2022. among patients aged ≥65 years, while the 95% CI overlapped in both age groups (Figure 3) .

In a subgroup analysis by the presence of underlying medical conditions, vaccine effectiveness was similar for both age groups. The results of sensitivity analysis are shown in Supplementary Table 1 and are similar to the primary analysis.

In this prospective test-negative case-control study, we confirmed high mRNA COVID-19 vaccine effectiveness against symptomatic SARS-CoV-2 infections in Japan. We estimated is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 23, 2022. [32] . The Japanese national COVID-19 vaccination campaign started more than two months after these countries [33] , and the symptom onset date for approximately 87% of the fully vaccinated patients in our study was one to three months after full vaccination. One reason for the difference between our estimates of vaccine effectiveness and those in Israel, the United States, and Qatar could be due to waning immunity [29, 34, 35] . On the other hand, the study in the UK included SARS-CoV-2 test results in late April to is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 23, 2022. ; https://doi.org/10.1101/2022.01.17.22269394 doi: medRxiv preprint consistent with previous studies [31, 32] ; however, there was no statistically significant difference (p-value=0.877).

As mentioned above, COVID-19 vaccinations were publicly funded in Japan, just after the market approval. This policy would be reasonable under the first phase of the pandemic situation. However, when we re-consider the national COVID-19 vaccination policy, such as a re-setting of priority-based booster vaccinations, subgroup analyses, such as is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 23, 2022. Table 1 ). Vaccine effectiveness obtained from sensitivity analyses was similar to the primary analysis, and we considered our results robust. Third, since we didn't conduct SARS-CoV-2 genome sequencing for test-positive patients, it was impossible to obtain an accurate estimation of vaccine effectiveness of mRNA COVID-19 vaccines against the Delta variant. Fourth, we included test methods other than PCR when determining cases and controls because in Japan, test methods such as LAMP and antigen quantification have been used as commonly as PCR. Since these tests have acceptable levels of sensitivity and specificity, we thought it reasonable to include these test methods.

In conclusion, mRNA COVID-19 vaccines were highly effective for preventing is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 23, 2022. ; https://doi.org/10.1101/2022.01.17.22269394 doi: medRxiv preprint symptomatic SARS-CoV-2 infections in Japan from July to September 2021, when the Delta variant circulated nationwide. Thus, vaccine effectiveness of mRNA COVID-19 vaccines remained high in Japan despite the dominancy of a variant virus. As we only evaluated the waning immunity up to six months after the full vaccination, and the sample size within three to six months after the full vaccination was limited, further follow-up research is needed.

Vaccination is one of the essential strategies to tackle the COVID-19 pandemic, and it is crucial to continue this surveillance activity, including the evaluation of vaccine effectiveness against the Omicron variant, to assess the optimal domestic COVID-19 vaccination strategy.

This work was supported by Japan Agency for Medical Research and Development under grant number, JP21fk0108612.

We are grateful to the medical staff at the participating hospitals and clinics. For their assistance, we thank Yumi Araki, Kyoko Uchibori, Rina Shiramizu, Fumiyo Tsujita (Institute of Tropical Medicine, Nagasaki University), and Daichi Hatahara (Nagasaki University). We thank Yura Ko (National Institution of Infectious Diseases) for his technical support. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 23, 2022. ;

World Health Organization. Weekly epidemiological update on COVID-19 -14

December 2021. Available at: https://www.who.int/publications/m/item/weeklyepidemiological-update-on-covid-19---14-december-2021. Accessed 10 January, . CC-BY-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 23, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 23, 2022. ; https://doi.org/10.1101/2022.01.17.22269394 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 23, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 23, 2022. ; https://doi.org/10.1101/2022.01.17.22269394 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 23, 2022. ; https://doi.org/10.1101/2022.01.17.22269394 doi: medRxiv preprint

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