To the editor,
While the mRNA COVID-19 vaccines are highly effective in decreasing the risk of infection,
hospitalization, and death [1], a significant variation in the immune response among
vaccine recipients has been identified. Specifically, male sex, older age, and chronic
diseases have been associated with lower anti-spike antibody levels after two vaccine
doses [2, 3]. It remains elusive, however, whether such a difference in humoral immune
response persists after the third vaccine dose, which is currently administered in
many countries. Here, we report immunogenicity after the third dose of the BNT162b2
vaccine in relation to the correlates of that after the second dose.
We analyzed data of a repeat serological study among the staff of the National Center
for Global Health and Medicine, Japan [4]. In the Toyama ward of the center in Tokyo,
1949 staff attended a survey at least 14 days after the second vaccine (baseline survey);
of these, 1446 attended the follow-up survey at least 14 days after the third vaccine.
Then, we excluded 180 participants who had a history of COVID-19 (n = 55), were seropositive
on anti-N antibodies at either or both surveys (n = 65), or lacked information on
covariates (n = 60), leaving 1266 participants for analysis (Section S1). These participants
had their anti-spike antibodies measured with both Roche (mature antibodies including
IgG) and Abbott (IgG) assays at both baseline and follow-up surveys (Section S2).
We used multivariable linear mixed models to examine the spike antibody titers in
relation to potential determinants after the second and third doses (Section S3).
Written informed consent was obtained from all participants, and the study procedure
was approved by the NCGM ethics committee (approved number: NCGM-G-003598).
The interval from the second vaccine dose to the baseline survey was 68 (interquartile
range [IQR]: 62–70) days, and that from the third vaccine dose to the follow-up survey
was 74 (IQR: 68–81) days. The spike antibody titers with Roche assay after the third
dose were increased 11.7-fold from the titers after the second dose (geometric mean
titers, 12,765 vs. 1,091), and all subgroups showed substantial elevation in antibody
levels (Table 1). Male sex, older age, coexisting diseases, and immunosuppression
were associated with lower antibody levels after the second vaccine dose. After the
third vaccine dose, the associations with age and coexisting diseases disappeared,
while the significant association with immunosuppression remained. Unexpectedly, males
had significantly higher antibody levels than females after the third vaccine dose.
The antibody correlates with the Abbott assay were materially the same except for
obesity (defined as body mass index ≥ 27.5 kg/m2), which was associated with lower
antibody titer after the second dose and not after the third dose (Table S2).
Table 1
Anti-SARS-CoV-2 spike antibody titers (Roche) and their correlates after receipt of
the second and third vaccine doses
Variables
N (%)
After the second dose (N = 1266)a
After the third dose (N = 1266)a
Change from the second dose to the third dose
P for interaction by time*group
Adjusted GMT (95% CI)b
Adjusted RoM (95% CI)b
Adjusted GMT (95% CI)b
Adjusted RoM (95% CI)b
Adjusted RoM (95% CI)b,e
Overall
1266
1091 (1050–1133)
–
12,765 (12,287–13,262)
–
11.7 (11.2–12.2)
Sex
< 0.001
Male
346 (27)
952 (884–1025)
Reference
14,367 (13,343–15,469)
Reference
15.1 (14.0–16.3)
Female
920 (73)
1150 (1100–1203)
1.21 (1.11–1.32)
12,154 (11,622–12,711)
0.85 (0.78–0.92)
10.6 (10.1–11.1)
Age
< 0.001
< 30 yr
354 (28)
1407 (1304–1518)
Reference
12,988 (12,074–13,972)
Reference
9.2 (8.6–10.0)
30 to < 40 yr
318 (25)
1219 (1132–1312)
0.88 (0.78–0.99)
12,878 (11,950–13,879)
1.00 (0.90–1.14)
10.6 (9.8–11.4)
40 to < 50 yr
311 (25)
926 (859–998)
0.68 (0.60–0.77)
11,325 (10,498–12,218)
0.90 (0.80–1.02)
12.2 (11.3–13.2)
≥ 50 yr
283 (22)
847 (781–919)
0.59 (0.52–0.68)
13,851 (12,770–15,025)
1.04 (0.92–1.18)
16.4 (15.1–17.7)
P for trendd
< 0.001
0.97
Interactions between sex and age
Male
< 0.001
< 30 yr
56 (16)
1215 (1019–1448)
Reference
14,158 (11,889–16,861)
Reference
11.7 (9.8–13.9)
30 to < 40 yr
91 (26)
1140 (994–1308)
0.94 (0.75–1.17)
14,452 (12,592–16,588)
1.02 (0.82–1.28)
12.7 (11.0–14.6)
40 to < 50 yr
103 (30)
917 (806–1044)
0.76 (0.61–0.94)
13,491 (11,855–15,354)
0.95 (0.77–1.18)
14.7 (12.9–16.8)
≥ 50 yr
96 (28)
667 (581–766)
0.55 (0.44–0.69)
14,015 (12,202–16,097)
0.99 (0.79–1.24)
21.0 (18.4–24.0)
P for trendd
< 0.001
0.78
Female
< 0.001
< 30 yr
298 (32)
1463 (1352–1584)
Reference
12,857 (11,912–13,877)
Reference
8.8 (8.1–9.5)
30 to < 40 yr
227 (25)
1254 (1149–1368)
0.86 (0.76–0.96)
12,263 (11,233–13,387)
0.95 (0.85–1.07)
9.8 (8.9–10.7)
40 to < 50 yr
208 (23)
940 (858–1028)
0.64 (0.57–0.72)
10,446 (9530–11,450)
0.81 (0.72–0.92)
11.1 (10.1–12.2)
≥ 50 yr
187 (20)
944 (857–1040)
0.65 (0.57–0.73)
13,516 (12,271–14,889)
1.05 (0.93–1.19)
14.3 (13.0–15.8)
P for trendd
< 0.001
0.96
Body mass index
0.08
< 27.5 kg/m2
1204 (95)
1096 (1054–1140)
Reference
12,691 (12,204–13,197)
Reference
11.6 (11.1–12.1)
≥ 27.5 kg/m2
62 (5)
997 (839–1184)
0.91 (0.76–1.09)
14,236 (11,978–16,921)
1.12 (0.94–1.34)
14.3 (11.9–17.1)
Specific coexisting diseases c
< 0.001
No
1147 (91)
1119 (1075–1164)
Reference
12,656 (12,164–13,167)
Reference
11.1 (10.6–11.6)
Yes
119 (9)
899 (788–1025)
0.80 (0.70–0.92)
13,172 (11,550–15,020)
1.04 (0.91–1.20)
18.9 (16.7–21.5)
Use of immunosuppressive drug
0.34
No
1242 (98)
1111 (1069–1154)
Reference
12,964 (12,474–13,473)
Reference
11.7 (11.2–12.2)
Yes
24 (2)
426 (324–558)
0.38 (0.29–0.50)
5715 (4356–7498)
0.44 (0.34–0.58)
13.4 (10.1–17.9)
Bold font indicates statistical significance (P < 0.05)
aThe median (interquartile range) intervals from the second or third dose to blood
sampling were 68 (62–70) days or 74 (68–81) days, respectively.
bThe geometric mean titer (GMT) with its 95% confidence intervals (CI) and the ratio
of means with its 95% CI were estimated by the multivariable mixed model with adjustment
for all variables in the table and the interval between vaccine doses and surveys.
cSpecific coexisting diseases included hypertension, diabetes, dyslipidemia, cardiovascular
disease, and cancer.
d
P for trend was calculated using a post-estimation orthogonal polynomial contrast
of marginal linear trends (i.e., “contrast” command in Stata).
eReference category is each corresponding group at baseline survey (i.e., after the
second dose) CI confidence interval, GMT geometric mean titer, RoM ratio of mean
After the third vaccine, we observed a substantial increase in anti-SARS-CoV-2 spike
antibody levels, which appears to be larger among subgroups with lower antibody titers
after the second dose, eliminating the difference in post-vaccine immune response
across the population. The third dose may not only enhance post-vaccine immunogenicity
but also minimize the discrepancy observed after the second dose across groups with
a different background in terms of age, comorbidity, and obesity.
Supplementary Information
Below is the link to the electronic supplementary material.
Supplementary file1 (DOCX 63 KB)