Effectiveness of third vaccine dose for coronavirus disease 2019 during the Omicron variant pandemic: a prospective observational study in Japan |…

Participants

This study enrolled adults aged18years living in Miyagi Prefecture who had a history of recent close (high-risk) contact with COVID-19 cases and had provided their nasopharyngeal swab specimens at a drive-through outpatient clinic for the testing of COVID-19 (Tohoku University Medical Office) at a location away from Tohoku University Hospital in Sendai City, Japan, managed by the local governments and Tohoku University, between January and May 2022. This period corresponded to the sixth nationwide wave of the COVID-19 outbreak, exclusively caused by the Omicron variant. During the study period, a sampling test of the viral genome revealed that more than 99% of the infections in the locality were caused by the Omicron variant. Because the main objective of this study was to evaluate vaccine effectiveness in those who had completed three vaccine doses (three-dose group) compared with those who were not vaccinated (no-vaccine group) or had completed two doses (two-dose group), those who had completed only the first vaccine dose (one-dose group) at the time of the nasopharyngeal swab test were excluded from subsequent analyses. This study was conducted before the fourth dose of COVID-19 mRNA vaccines became available in Japan. A flowchart of the study design is shown in Fig.1.

Flow diagram of the study design. Among the overall individuals tested by reverse transcription-polymerase chain reaction (RT-PCR) test using nasopharyngeal swab samples at a large screening test center in Japan between January and May 2022, (1) adults aged<18years, (2) those without a certain contact history, (3) those who had completed only one vaccine dose, and (4) those who were less than 7days after the last vaccination were excluded. Consequently, 767 adults were eligible for subsequent analyses.

From these tested individuals, information regarding the demographics (age and sex), detailed situation of the contact, vaccine completion status (number of completed vaccine doses and manufacturer of the vaccines), elapsed time from the last vaccination at the time of swab test, and results of nasopharyngeal swab reverse transcription-polymerase chain reaction (RT-PCR) test for SARS-CoV-2 were collected. The timing of nasopharyngeal swab sampling in most enrolled cases was scheduled 45days after contact with COVID-19 cases. Individuals who had already passed more than 14days from the last contact history were not tested at the testing center. To evaluate the effectiveness of the vaccine against COVID-19-associated symptoms 45days after the infection, the presence of symptoms including cough, dyspnea, fatigue and a body temperature37.5 was recorded at the time the PCR swab was taken.

To detect the virus in the sampled swab specimen, RT-PCR was performed to detect the viral nucleocapsid protein set no. 2 (N2) gene. A primer/probe set designed by the National Institute of Infectious Diseases in Japan (NIID_2019-nCoV_N_F2, R2, and P2) was used11. The details of the thermal cycling conditions have been previously reported12.

The closeness of contact with COVID-19 cases was judged using the criteria defined by the government. More specifically, fulfillment of all of the following four criteria was considered to be a close contact history: (1) contact with a patient with COVID-19 from 2 to 14days after the onset of symptoms or positive RT-PCR test results, (2) not wearing masks, (3) contact involving<1m distance, and (4)15min of contact. All other contact patterns with patients with COVID-19 were regarded as lower-risk contacts. The closeness of the contact in each of the tested individuals was assessed in advance before the RT-PCR test by the local government staff in public health centers.

The distributions of non-normally distributed variables were described as the median and interquartile range (IQR; 2575 percentiles). Comparisons of non-normally distributed variables between the two groups were performed using the MannWhitney U test, and those between the groups were performed using the KruskalWallis test, followed by the Scheff post-hoc test. The RT-PCR test positivity rate was used as the marker of the risk of infection in each subgroup, and the rates between those who were not vaccinated (zero-dose group), those who had completed only two doses (two-dose group), and those who had completed all third doses (three-dose group) were compared using the chi-square test. Risk ratios (RR) and 95% confidence intervals (CI) for RT-PCR test-positive participants between those with no vaccination and those who had completed the third booster vaccination were also evaluated. RR was calculated as the risk of infection in the three-dose group divided by the risk in the no-vaccine group. Vaccine effectiveness (%) and 95% CI were estimated as (left(1-RRright)times 100). Sample size calculation was performed before performing the chi-square test, which revealed a required sample size of n=32 in each group for a large effect size of =0.50, (alpha ) = 0.05, and power (i.e., (1-beta ))=0.80. Statistical significance was set at P<0.05. Adjustment for multiple testing was not performed because of the nature of the subgroup analyses in this study. To visually confirm the relationship between the elapsed time from the last vaccination and RT-PCR test-positivity rate in the two- and three-dose groups, the rolling average (5days) of the RT-PCR test positivity rate in these groups was depicted. Statistical comparisons and sample size calculations were performed using R Statistical Software (version 4.0.5; R Foundation, Vienna, Austria).

All methods were performed in accordance with relevant guidelines and regulations. All study protocols were approved by the institutional review board of the Tohoku University Graduate School of Medicine (approval number: 2020-1-535). Informed consent was obtained from all the participants.

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Effectiveness of third vaccine dose for coronavirus disease 2019 during the Omicron variant pandemic: a prospective observational study in Japan |...