Effectiveness of primary series, first, and second booster vaccination of monovalent mRNA COVID-19 vaccines against symptomatic SARS-CoV-2 infections and severe diseases during the SARS-CoV-2 omicron BA.5 epidemic in Japan: vaccine effectiveness real-time surveillance for SARS-CoV-2 (VERSUS)

Figures & data

Figure 1. (a) Sample selection flowchart in the analysis of vaccine effectiveness against symptomatic SARS-CoV-2 infections. (b) Sample selection flowchart in the analysis of vaccine effectiveness against severe diseases.

Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; mRNA, messenger RNA; COVID-19, coronavirus disease 2019.

Figure 2. (a) The weekly number of test-positive episodes for SARS-CoV-2 and test-negative episodes for SARS-CoV-2 by vaccination status included in the analysis of vaccine effectiveness against symptomatic SARS-CoV-2 infection. (b) The weekly number of test-positive hospital admissions for SARS-CoV-2 and test-negative hospital admissions for SARS-CoV-2 by vaccination status included in the analysis of vaccine effectiveness against severe diseases.

X-axis: calendar week; Y-axis: number of episodes or hospital admissions.

COVID-19 vaccination status was defined using doses received prior to symptom onset date and number of days between the receipt of the last vaccination and symptom onset date: (1) unvaccinated, if no vaccine dose was received before symptom onsets; (2) primary vaccination, if two doses were received ≥14 days before symptom onset; (3) 1st booster vaccination, if the first monovalent booster (third dose) was received ≥14 days before symptom onset; and (4) 2nd booster vaccination, if the second monovalent booster (fourth dose) was received ≥14 days before symptom onset. Episodes or hospital admissions involving individuals with vaccination histories of incomplete primary vaccination or within 0 to 13 days after the last vaccination are not show in the figures.

Table 1. Characteristics of individuals included in vaccine effectiveness analysis against symptomatic SARS-CoV-2 infections: VERSUS study, Japan, July 1 to November 30, 2022.

	Total (n = 10,746)	Test-positive cases (n = 6,014)	Test-negative controls (n = 4,732)	P-value^a
Median age (IQR), years	41 (28–57)	41 (29–55)	41 (28–62)	<0.001
Age category in years, no. (%)				<0.001
16–29	2,957 (27.5)	1,640 (27.3)	1,317 (27.8)
30–39	2,145 (20.0)	1,215 (20.2)	930 (19.7)
40–49	1,866 (17.4)	1,150 (19.1)	716 (15.1)
50–59	1,340 (12.5)	851 (14.2)	489 (10.3)
60–69	923 (8.6)	522 (8.7)	401 (8.5)
70–79	870 (8.1)	406 (6.8)	464 (9.8)
80–89	468 (4.4)	167 (2.8)	301 (6.4)
$\ge$90	177 (1.6)	63 (1.0)	114 (2.4)
Male sex, no. (%)	4,887 (45.5)	2,850 (47.4)	2,037 (43.0)	<0.001
Living at home, no. (%)	10,447 (97.2)	5,884 (97.8)	4,563 (96.4)	<0.001
Living at long-term care facility, no. (%)	140 (1.3)	49 (0.8)	91 (1.9)	<0.001
Underlying medical conditions, no. (%)
Any	2,407 (22.4)	1,142 (19.0)	1,265 (26.7)	<0.001
Chronic heart disease	661 (6.2)	304 (5.1)	357 (7.5)	<0.001
Chronic respiratory disease	624 (5.8)	269 (4.5)	355 (7.5)	<0.001
Obesity	184 (1.7)	99 (1.6)	85 (1.8)	0.55
Malignancy	489 (4.6)	175 (2.9)	314 (6.6)	<0.001
Diabetes mellitus	646 (6.0)	324 (5.4)	322 (6.8)	0.002
Chronic kidney disease	270 (2.5)	124 (2.1)	146 (3.1)	0.001
Dialysis	50 (0.5)	22 (0.4)	28 (0.6)	0.12
Liver cirrhosis	33 (0.3)	12 (0.2)	21 (0.4)	0.03
Immunocompromising therapy	148 (1.4)	74 (1.2)	74 (1.6)	0.16
Pregnancy	118 (1.1)	75 (1.2)	43 (0.9)	0.11
Smoking history, no. (%)	3,036 (28.3)	1,648 (27.4)	1,388 (29.3)	0.07
Healthcare workers, no. (%)	1,914 (17.8)	964 (16.0)	950 (20.1)	<0.001
Prior SARS-CoV-2 infection, no. (%)	487 (4.5)	115 (1.9)	372 (7.9)	<0.001
History of contact with COVID-19 patient within last 14 days, no. (%)				<0.001
Yes	3,291 (30.6)	2,475 (41.2)	816 (17.2)
No	6,465 (60.2)	2,887 (48.0)	3,578 (75.6)
Unknown	990 (9.2)	652 (10.8)	338 (7.1)
Test method, no. (%)				<0.001
Nucleic acid amplification test^b	7,491 (69.7)	4,350 (72.3)	3,141 (66.4)
Antigen quantification test	3,255 (30.3)	1,664 (27.7)	1,591 (33.6)
COVID-19 vaccination status^c, no. (%)				<0.001
Unvaccinated	1,339 (12.5)	914 (15.2)	425 (9.0)
One dose within 0–13 days	3 (0.03)	3 (0.05)	0
One dose after $\ge$14 days	75 (0.7)	42 (0.7)	33 (0.7)
Two doses within 0–13 days	7 (0.07)	3 (0.05)	4 (0.1)
Primary vaccination (two doses after $\ge$14 days)	2,226 (20.7)	1,355 (22.5)	871 (18.4)
Three doses within 0–13 days	39 (0.4)	10 (0.2)	29 (0.6)
1st booster vaccination (three doses after $\ge$14 days)	5,524 (51.4)	3,074 (51.1)	2,450 (51.8)
Four doses within 0–13 days	267 (2.5)	138 (2.3)	129 (2.7)
2nd booster vaccination (four doses after $\ge$14 days)	1,266 (11.8)	475 (7.9)	791 (16.7)
Vaccine product received for the last booster dose, no. (%) (n = 6,790)				0.20
BNT162b2	2,660 (39.2)	1,358 (38.3)	1,302 (40.2)
mRNA-1273	1,598 (23.5)	835 (23.5)	763 (23.5)
Unknown	2,532 (37.3)	1,356 (38.2)	1,176 (36.3)

Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; VERSUS, Vaccine Effectiveness Real-time Surveillance for SARS-CoV-2; IQR, interquartile range; COVID-19, coronavirus disease 2019.

^aFor continuous variables, the rank-sum test was used, and for categorical variables, Chi squared and Fisher’s exact tests were used to compare characteristics between test-positive and test-negative individuals.

^bNucleic acid amplification tests included polymerase chain reaction (PCR), loop-medical isothermal amplification (LAMP), nicking endonuclease amplification reaction (NEAR) and transcription-mediated amplification (TMA).

^cCOVID-19 vaccination status was classified based on the number of COVID-19 vaccine doses received before symptom onset.

Figure 3. Vaccine effectiveness of monovalent mRNA COVID-19 vaccines against symptomatic SARS-CoV-2 infections among individuals aged 16 to 59 years and aged $\ge$60 years, VERSUS study, Japan, between July 1 and November 30, 2022. The analysis included test-positive cases with signs or symptoms that tested positive for SARS-CoV-2 and test-negative controls with signs or symptoms that tested negative for SARS-CoV-2. Vaccine effectiveness was adjusted for age, sex, underlying medical conditions, calendar week of test, healthcare professional status, prior SARS-CoV-2 infection history, and medical facilities. The vaccination status was classified into four based on the number of vaccine doses received before symptom onset and number of days between the last vaccination date and symptom onset: unvaccinated, individuals had received no vaccine dose before symptom onset; primary vaccination, individuals had received the second dose $\ge$14 days before symptom onset; 1st booster vaccination, individuals had received the third dose $\ge$14 days before symptom onset; and 2nd booster vaccination, individuals had received the fourth dose $\ge$14 days before symptom onset. Completion of vaccination was defined as 14 days after receiving the last vaccine. When evaluating vaccine effectiveness separated by days after vaccination, the number of days is shown from completion of vaccination.

Abbreviation: VE, vaccine effectiveness.

Figure 4. Relative vaccine effectiveness of monovalent mRNA COVID-19 booster vaccination, compared with the primary vaccination at more than 180 days after the completion of vaccination against symptomatic SARS-CoV-2 infections among individuals aged 16 to 59 years and $\ge$60 years, VERSUS study, Japan, between July 1 and November 30, 2022. The analysis included test-positive cases with signs or symptoms that tested positive for SARS-CoV-2 and test-negative controls with signs or symptoms that tested negative for SARS-CoV-2. Relative vaccine effectiveness was adjusted for age, sex, underlying medical conditions, calendar week of test, healthcare professional status, prior SARS-CoV-2 infection history, and medical facilities. The vaccination status was classified into four based on the number of vaccine doses received before symptom onset and number of days between the last vaccination date and symptom onset: unvaccinated, individuals had received no vaccine dose before symptom onset; primary vaccination, individuals had received the second dose $\ge$14 days before symptom onset; 1st booster vaccination, individuals had received the third dose $\ge$14 days before symptom onset; and 2nd booster vaccination, individuals had received the fourth dose $\ge$14 days before symptom onset. Completion of vaccination was defined as 14 days after receiving the last vaccine. When evaluating vaccine effectiveness separated by days after vaccination, the number of days is shown from completion of vaccination. Abbreviation: VE, vaccine effectiveness.

Table 2. Characteristics of individuals aged $\ge$60 years included in vaccine effectiveness analysis against severe COVID-19: VERSUS study, Japan, July 1 to November 30, 2022.

	Total (n = 935)	Test-positive cases (n = 384)	Test-negative controls (n = 551)	P-value^a
Median age (IQR), years	82 (75–88)	81 (75–87)	83 (75–88)	0.15
Age category in years, no. (%)				0.21
60–69	96 (10.3)	36 (9.4)	60 (10.9)
70–79	264 (28.2)	119 (31.0)	145 (26.3)
80–89	398 (42.6)	166 (43.2)	232 (42.1)
$\ge$90	177 (18.9)	63 (16.4)	114 (20.7)
Male sex, no. (%)	584 (62.5)	227 (59.1)	357 (64.8)	0.09
Living at long-term care facility, no. (%)	244 (26.1)	99 (25.8)	145 (26.3)	0.72
Underlying medical conditions, no. (%)
Any	667 (71.3)	270 (70.3)	397 (72.1)	0.81
Chronic heart disease	279 (29.8)	116 (30.2)	163 (29.6)	0.89
Chronic respiratory disease	227 (24.3)	79 (20.6)	148 (26.9)	0.03
Obesity	4 (0.4)	2 (0.5)	2 (0.4)	>0.90
Malignancy	187 (20.0)	72 (18.8)	115 (20.9)	0.46
Diabetes mellitus	213 (22.8)	99 (25.8)	114 (20.7)	0.07
Chronic kidney disease	103 (11.0)	55 (14.3)	48 (8.7)	0.008
Dialysis	20 (2.1)	15 (3.9)	5 (0.9)	0.002
Liver cirrhosis	5 (0.5)	2 (0.5)	3 (0.5)	>0.90
Immunocompromising therapy	43 (4.6)	17 (4.4)	26 (4.7)	0.88
Smoking history, no. (%)	406 (43.4)	152 (39.6)	254 (46.1)	0.04
Prior SARS-CoV-2 infection, no. (%)	32 (3.4)	5 (1.3)	27 (4.9)	0.003
History of contact with COVID-19 patient within last 14 days, no. (%)				<0.001
Yes	177 (18.9)	160 (41.7)	17 (3.1)
No	491 (52.5)	105 (27.3)	386 (70.1)
Unknown	267 (28.6)	119 (31.0)	148 (26.9)
History of medical visits prior to hospital admission, no. (%)				0.08
Yes	241 (25.8)	111 (28.9)	130 (23.6)
No	682 (72.9)	266 (69.3)	416 (75.5)
Unknown	12 (1.3)	7 (1.8)	5 (0.9)
Test method, no. (%)				0.52
Nucleic acid amplification test^b	633 (67.7)	255 (66.4)	378 (68.6)
Antigen quantification test	302 (32.3)	129 (33.6)	173 (31.4)
COVID-19 vaccination status^c, no. (%)				<0.001
Unvaccinated	143 (15.3)	83 (21.6)	60 (10.9)
One dose within 0–13 days	1 (0.1)	0	1 (0.2)
One dose after $\ge$14 days	17 (1.8)	7 (1.8)	10 (1.8)
Two doses within 0–13 days	1 (0.1)	0	1 (0.2)
Primary vaccination (two doses after $\ge$14 days)	93 (9.9)	39 (10.2)	54 (9.8)
Three doses within 0–13 days	3 (0.3)	2 (0.5)	1 (0.2)
1st booster vaccination (three doses after $\ge$14 days)	365 (39.0)	166 (43.2)	199 (36.1)
Four doses within 0–13 days	46 (4.9)	19 (4.9)	27 (4.9)
2nd booster vaccination (four doses after $\ge$14 days)	266 (28.4)	68 (17.7)	198 (35.9)
Clinical information at the time of hospital admission
SpO2 $\le$90% or oxygen administration or tachypnea (respiratory rate $\ge$30/min), no. (%)				0.09
Yes	525 (56.1)	200 (52.1)	325 (59.0)
No	396 (42.4)	179 (46.6)	217 (39.4)
Unknown	14 (1.5)	5 (1.3)	9 (1.6)
Alternate mental status, no. (%)				<0.001
Yes	235 (25.1)	121 (31.5)	114 (20.7)
No	647 (69.2)	254 (66.1)	393 (71.3)
Unknown	53 (5.7)	9 (2.3)	44 (8.0)
Systolic blood pressure, no. (%)
<90 mmHg	37 (4.0)	11 (2.9)	26 (4.7)	0.24
$\ge$90 mmHg	841 (89.9)	346 (90.1)	495 (89.8)
Unknown	57 (6.1)	27 (7.0)	30 (5.4)
Blood urea nitrogen, no. (%)				0.80
$\le$20 mg/dL	493 (52.7)	205 (53.4)	288 (52.3)
>20 mg/dL	435 (46.5)	177 (46.1)	258 (46.8)
Unknown	7 (0.7)	2 (0.5)	5 (0.9)
CURB-65^d, no. (%)				0.02
0–1	175 (18.7)	87 (22.7)	88 (16.0)
$\ge$2	722 (77.2)	286 (74.5)	436 (79.1)
Unknown	38 (4.1)	11 (2.9)	27 (4.9)
Radiologically confirmed pneumonia, no. (%)
Yes	705 (75.4)	214 (55.7)	491 (89.1)	<0.001
No	214 (22.9)	158 (41.1)	56 (10.2)
Unexamined	16 (1.7)	12 (3.1)	4 (0.7)

Abbreviations: COVID-19, coronavirus disease 2019; VERSUS, Vaccine Effectiveness Real-time Surveillance for SARS-CoV-2; IQR, interquartile range; SpO2, oxygen saturation.

^aFor continuous variables, the rank-sum test was used, and for categorical variables, Chi squared and Fisher’s exact tests were used to compare characteristics between test-positive and test-negative individuals.

^bNucleic acid amplification tests included polymerase chain reaction (PCR), loop-medical isothermal amplification (LAMP), nicking endonuclease amplification reaction (NEAR), and transcription-mediated amplification (TMA).

^cCOVID-19 vaccination status was classified based on the number of COVID-19 vaccine doses received before symptom onset.

^dCURB-65 was scored based on the following five factors: having alternate mental status; uremia (blood urea nitrogen level >20 mg/dL); respiratory distress (SpO₂ $\le$90% or oxygen administration or tachypnea [respiratory rate $\ge$30/min]); hypotension (systolic blood pressure <90 mmHg); and older age ($\ge$65 years).

Figure 5. Vaccine effectiveness of monovalent mRNA COVID-19 vaccines against severe diseases among individuals aged $\ge$60 years, VERSUS study, Japan, between July 1 and November 30, 2022. The analysis included test-positive cases with signs or symptoms that tested positive for SARS-CoV-2, and test-negative controls with signs or symptoms that tested negative for SARS-CoV-2. Vaccine effectiveness was adjusted for age, sex, underlying medical conditions, calendar week of admission, prior SARS-CoV-2 infection history, and medical facilities. The vaccination status was classified into four based on the number of vaccine doses received before symptom onset and number of days between the last vaccination date and symptom onset: unvaccinated, individuals had received no vaccine dose before symptom onset; primary vaccination, individuals had received the second dose $\ge$14 days before symptom onset; 1st booster vaccination, individuals had received the third dose $\ge$14 days before symptom onset; and 2nd booster vaccination, individuals had received the fourth dose $\ge$14 days before symptom onset. Completion of vaccination was defined as 14 days after receiving the last vaccine. When evaluating vaccine effectiveness separated by days after vaccination, the number of days is shown from completion of vaccination. The following subgroup analyses were conducted: a subgroup with respiratory distress at the time of admission by limiting analysis to individuals with hypoxia (oxygen saturation<90%), oxygen administration, or tachypnea (respiratory rate≥30/minute); a subgroup with moderate or severe diseases at the time of admission defined CURB-65≥2; and a subgroup with radiologically confirmed pneumonia at the time of admission.

Abbreviation: VE, vaccine effectiveness.