Clinical Microbiology and Infection 29 (2023) 1201.e1e1201.

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Research Note

Durability and determinants of anti-SARS-CoV-2 spike antibodies

following the second and third doses of mRNA COVID-19 vaccine
Shohei Yamamoto 1, *, Yusuke Oshiro 2, Natsumi Inamura 2, Takashi Nemoto 2,
Kumi Horii 3, Kaori Okudera 4, Maki Konishi 1, Mitsuru Ozeki 2, Tetsuya Mizoue 1,
Haruhito Sugiyama 5, Nobuyoshi Aoyanagi 6, Wataru Sugiura 7, Norio Ohmagari 8
1)
Department of Epidemiology and Prevention, Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan
2)
Department of Laboratory Testing, Center Hospital of the National Center for the Global Health and Medicine, Tokyo, Japan
3)
Infection Control Office, Center Hospital of the National Center for the Global Health and Medicine, Tokyo, Japan
4)
Infection Control Office, Kohnodai Hospital of the National Center for the Global Health and Medicine, Chiba, Japan
5)
Center Hospital of the National Center for the Global Health and Medicine, Tokyo, Japan
6)
Kohnodai Hospital of the National Center for the Global Health and Medicine, Chiba, Japan
7)
Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan
8)
Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: To examine the differences in durability and its determinants of humoral immunity following
Received 16 November 2022 2- and 3-dose COVID-19 vaccination.
Received in revised form Methods: Throughout the pandemic, we evaluated the anti-spike IgG antibody titers of 2- and 3-dose
10 April 2023
mRNA vaccine recipients over time among the staff of a medical and research center in Tokyo. Linear
Accepted 16 May 2023
Available online 24 May 2023
mixed models were used to estimate trajectories of antibody titers from 14 to 180 days after the last
immune-conferred event (vaccination or infection) and compare antibody waning rates across prior
Handling Editor: M. Cevik infection and vaccination status, and across background factors in infection-naïve participants.
Results: A total of 6901 measurements from 2964 participants (median age, 35 years; 30% male) were
Keywords: analyzed. Antibody waning rate (percentage per 30 days [95% CI]) was slower after 3 doses (25% [23e26])
Durability than 2 doses (36% [35e37]). Participants with hybrid immunity (vaccination and infection) had further
Prior infection slower waning rates: 2-dose plus infection (16% [9e22]); 3-dose plus infection (21% [17e25]). Older age,
SARS-CoV-2 male sex, obesity, coexisting diseases, immunosuppressant use, smoking, and alcohol drinking were
Spike antibody
associated with lower antibody titers, whereas these associations disappeared after 3 doses, except for
Vaccination
sex (lower in female participants) and immunosuppressant use. Antibody waned slightly faster in older
participants, females, and alcohol drinkers after 2 doses, whereas it did not differ after 3 doses across
except sex.
Discussion: The 3-dose mRNA vaccine conferred higher durable antibody titers, and previous infection
modestly enhanced its durability. The antibody levels at a given time point and waning speed after 2
doses differed across background factors; however, these differences mostly diminished after 3 doses.
Shohei Yamamoto, Clin Microbiol Infect 2023;29:1201.e1e1201.e5
© 2023 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology
and Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

The widespread use of primary and booster vaccinations against

* Corresponding author. Shohei Yamamoto, Department of Epidemiology and
Prevention, Center for Clinical Sciences, National Center for Global Health and
Medicine, 1-21-1, Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.
E-mail address: syamamoto@hosp.ncgm.go.jp (S. Yamamoto).
COVID-19 substantially decreased the risk of SARS-CoV-2 infection
and hospitalization [1,2]. With the waning of vaccine-induced hu-
moral immunity over time [3], however, vaccine effectiveness (VE)
of 2- and 3-dose vaccination for infection has decreased [1,2]. Un-
derstanding the duration of vaccine-induced immunity and factors

https://doi.org/10.1016/j.cmi.2023.05.020
1198-743X/© 2023 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 1201.e2 S. Yamamoto et al. / Clinical Microbiology and Infection 29 (2023) 1201.e1e1201.e5

accelerating the waning is critical for formulating vaccine policy,

Shown are the estimated GMT of anti-SARS-CoV-2 spike protein antibody titers on 14, 30, 90, and 180 d since the last immune-conferring event (vaccination or infection) and the estimated RoM of antibody waning slopes, with
adjustment for age (<40 or 40 y), sex (male or female), body mass index (<27.5 or 27.5 kg/m2), coexisting diseases (yes or no), immunosuppressant use (yes or no), smoking status (current or non-smoker), and frequency of
1.13 (1.05e1.21)
1.05 (1.01e1.11)
including the recommendation regarding the timing and target
reference population of an additional booster dose.
Epidemiological data are scarce regarding the waning pattern of
humoral immunity following 2- and 3-dose COVID-19 vaccination
and its related factors. Studies among 2-dose recipients showed
Comparison of slopes

that anti-SARS-CoV-2 spike antibody titers waned faster in those

who are older [4] and female [3] and slower in those with a history
Slope of antibody waning, RoM (95% CI)

1.17 (1.16e1.19)
1.32 (1.23e1.43)
1.24 (1.17e1.31)

of COVID-19 [5], but no such investigation has been done following

3-dose vaccination. It remains elusive for both doses whether the
Reference

waning speed of antibody differs depending on obesity [6,7], co-

morbid conditions [7,8], immunosuppression [7,8], or behavioral
factors (smoking and alcohol drinking [9e11]), which have been
linked to lower immune response to COVID-19 vaccine.
(0.63e0.65)
(0.74e0.76)
(0.78e0.91)
(0.75e0.83)

Here, we assess the long-term humoral response and its de-

terminants following 2- and 3-dose COVID-19 mRNA vaccines and
compare the waning rates between 2- and 3-dose recipients.
Per 30 d

0.64
0.75
0.84
0.79

Methods

We analyzed data from a repeat serological study of the staff at

11 167 (8565e14 560)a,b
12 476 (9986e15 586)a,b

the National Center for Global Health and Medicine, Japan [6,7]. We
4699 (4540e4864)a

conducted 6 surveys from July 2020, to June 2022. In each survey,

1034 (983e1089)

we measured anti-SARS-CoV-2 nucleocapsid (N)- and spike- (from

the second survey onward) protein antibodies using Abbott and
Day 180

Roche assays and collected information on histories of SARS-CoV-2

vaccination and infection, body composition, morbid status, and
Waning of antibody titers since the last immune-conferring event (vaccination or infection) among 2- or 3-dose vaccine recipients

behavioral factors. We retrieved 6901 antibody measurements

from 2964 staff who participated in at least one of the third to sixth
Estimated spike antibody titers (AU/mL) after the last immune-conferring event, GMT (95% CI)

surveys more than 7 days after receiving 2 or 3 doses of mRNA

20 995 (17 000e25 928)a,b
35 119 (31 821e38 758)a,b
10 663 (10 317e11 021)a

COVID-19 vaccines for the analysis of antibody waning by vaccine

and infection status (Figs S1eS4). Of these, we used 6576 mea-
3393 (3282e3509)

surements from 2906 infection-naïve participants for the associa-

tion between background factors and antibody waning rate. Linear
mixed models were used to estimate antibody trajectories from 14
Day 90

50,000
Estimated spike antibody titers (AU/mL)
(33 590e41 961)a,b
(19 450e21 146)a
(19 323e33 388)a

20,000
(9893e10 690)

5,000

2,000
Day 30

284
280
400
543
10
20
25
37

1,000

500
032)a,b
783) a
942)a
199)

0 60 120 180
GMT, geometric mean titer; RoM, ratio of means.

Days since the last exposure to SARS−CoV−2

692e15
069e25
164e36
078e41

2−dose 2−dose + infection

3−dose 3−dose + infection
(13
(23
(18
(30

alcohol drinking (<1 or 1 time/wk).

p < 0.05 (reference is 2-dose).

p < 0.05 (reference is 3-dose).
Day 14

426
389
904
131

Fig. 1. Waning of anti-SARS-CoV-2 spike protein antibody titers from the last exposure
to SARS-CoV-2 (infection or vaccination).
14
24
25
35

Curves shown are the estimated trajectories adjusted for age (<40 or 40 years), sex
(male or female), body mass index (<27.5 or 27.5 kg/m2), coexisting diseases (yes or
no), immunosuppressant use (yes or no), smoking status (current or non-smoker), and
2-dose þ infection
3-dose þ infection

frequency of alcohol drinking (<1 or 1 time/wk). A blue line shows participants who
received 2-dose with infection-naïve (N ¼ 2994), and a red line shows those who
received 2-dose with a history of SARS-CoV-2 infection (N ¼ 53). A green line shows
those who received 3-dose with infection-naïve (N ¼ 3582), and an orange line shows
2-dose
3-dose

those who received 3-dose with a history of the infection (N ¼ 272). Solid lines are the
Table 1

estimated geometric mean of anti-SARS-CoV-2 spike protein antibody titers, and

a
b

shaded areas are the corresponding 95% CIs. N, number of measurements.

 S. Yamamoto et al. / Clinical Microbiology and Infection 29 (2023) 1201.e1e1201.e5 1201.e3

Table 2
Characteristics of antibody waning after the second and third vaccination across the background factors among infection-naïve participants

Characteristics Estimated spike antibody titers (AU/mL) after 2-dose, GMT (95% CI) Slope of antibody waning, RoM (95% CI)

Day 14 Day 30 Day 90 Day 180 Per 30 d Comparison of slopes

Age (y)
<40 16 076 (15 103e17 113) 11 618 (11 074e12 189) 3967 (3803e4137) 1210 (1140e1285) 0.64 (0.63e0.65) reference
40 13 405 (12 187e14 744)a 9137 (8538e9778)a 2651 (2502e2809)a 749 (677e829)a 0.61 (0.60e0.63) 0.96 (0.93e0.99)a
Sex
Male 11 947 (10 886e13 112) 8685 (8098e9314) 3041 (2865e3228) 973 (885e1070) 0.65 (0.64e0.67) reference
Female 15 632 (14 706e16 617)a 11 078 (10 588e11 591)a 3585 (3446e3729)a 1070 (1008e1135) 0.63 (0.62e0.64) 0.97 (0.94e0.99)a
Obesity
<27.5 (kg/m2) 14 508 (13 765e15 291) 10 376 (9977e10 791) 3450 (3335e3569) 1050 (997e1106) 0.64 (0.63e0.65) reference
27.5 (kg/m2) 15 147 (11 122e20 627) 9956 (8081e12 266) 2690 (2257e3206)a 827 (622e1101) 0.62 (0.57e0.67) 0.97 (0.89e1.05)
Coexisting diseases
No 14 786 (14 077e11 086) 10 583 (10 167e11 017) 3525 (3404e3650) 1071 (1016e1129) 0.64 (0.63e0.65) reference
Yes 14 077 (11 086e17 875) 9350 (7977e109 59) 2572 (2259e2928)a 764 (621e941)a 0.62 (0.58e0.65) 0.96 (0.91e1.02)
Immunosuppressant use
No 14 564 (13 825e15 343) 10 388 (9993e10,798) 3432 (3319e3549) 1046 (993e1101) 0.64 (0.63e0.65) reference
Yes 8074 (5221e12 486)a 6315 (4588e8694)a 2681 (2108e3409)a 897 (595e1352) 0.68 (0.61e0.76) 1.06 (0.95e1.20)
Smoking
Non-smokers 14 663 (13 881e15 490) 10 463 (10 048e10 894) 3459 (3340e3582) 1052 (998e1110) 0.64 (0.63e0.65) reference
Current smokers 11 911 (10 084e14 069)a 8606 (7563e9793)a 2957 (2642e3309)a 930 (780e1108) 0.65 (0.62e0.68) 1.01 (0.97e1.06)
Alcohol drinking
Non or occasional 14 818 (13 926e15 768) 10 712 (10 220e11 228) 3671 (3522e3826) 1134 (1065e1207) 0.64 (0.63e0.65) reference
Weekly or daily 14 269 (12 962e15 706) 9868 (9212e10 572) 2998 (2830e3176)a 884 (807e968)a 0.62 (0.61e0.64) 0.97 (0.94e0.99)a

Characteristics Estimated spike antibody titers (AU/mL) after 3-dose, GMT (95% CI) Slope of antibody waning, RoM (95% CI)
Day 14 Day 30 Day 90 Day 180 Per 30 days Comparison of slopes

Age (y)
<40 25 788 (24 167e27 517) 21 110 (20 077e22 196) 10 696 (10 242e11 171) 4756 (4543e4980) 0.75 (0.74e0.75) reference
40 23 286 (20 993e25 829) 19 566 (18 132e21 114) 10 517 (9992e11 069) 4552 (4323e4794) 0.75 (0.74e0.76) 1.00 (0.99e1.02)
Sex
Male 25 563 (22 422e29 144) 22 274 (20 255e24 494) 13 168 (12 360e14 029) 5827 (5472e6204) 0.76 (0.75e0.78) reference
Female 24 200 (22 803e25 683) 19 770 (18 889e20 692)a 9926 (9558e10 309)a 4336 (4166e4513)a 0.74 (0.73e0.75) 0.97 (0.95e0.99)a
Obesity (kg/m2)
<27.5 24 455 (23 117e25 870) 20 284 (19 442e21 161) 10 601 (10 251e10 963) 4678 (4517e4845) 0.75 (0.74e0.76) reference
27.5 27 046 (20 590e35 526) 23 099 (18 859e28 291) 12 810 (11 073e14 820)a 5323 (4630e6120) 0.75 (0.72e0.78) 1.00 (0.96e1.04)
Coexisting diseases
No 24 632 (23 250e26 096) 20 342 (19 472e21 250) 10 528 (10 168e10 901) 4668 (4503e4839) 0.75 (0.74e0.75) reference
Yes 24 091 (20 053e28 942) 20 814 (18 166e23 850) 11 966 (10 833e13 216) 5133 (4619e5704) 0.76 (0.74e0.78) 1.01 (0.98e1.04)
Immunosuppressant use
No 24 737 (23 391e26 160) 20 554 (19 708e21 437) 10 788 (10 436e11 151) 4757 (4596e4923) 0.75 (0.74e0.76) reference
Yes 17 168 (12 090e24 379)a 14 067 (10 717e18 465)a 7065 (5580e8945)a 2987 (2331e3828)a 0.74 (0.69e0.78) 0.98 (0.93e1.04)
Smoking
Non-smokers 24 621 (23 232e26 092) 20 479 (19 606e21 392) 10 777 (10 416e11 150) 4750 (4584e4922) 0.75 (0.74e0.76) Reference
Current smokers 23 542 (19 672e28 175) 19 415 (16 893e22 313) 9959 (8824e11 239) 4309 (3829e4848) 0.74 (0.72e0.77) 0.99 (0.96e1.02)
Alcohol drinking
Non or occasional 25 174 (23 477e26 994) 20 807 (19 741e21 931) 10 814 (10 372e11 275) 4839 (4632e5056) 0.75 (0.74e0.76) Reference
Weekly or daily 23 513 (21 483e25 735) 19 708 (18 411e21 097) 10 509 (9961e11 087) 4513 (4272e4769) 0.75 (0.74e0.76) 1.00 (0.98e1.01)

Shown are the estimated GMT of anti-SARS-CoV-2 spike protein antibody titers on 14, 30, 90, and 180 d since the third mRNA vaccination and the estimated RoM of antibody
waning slopes, with adjustment for age (<40 or 40 y), sex (male or female), body mass index (<27.5 or 27.5 kg/m2), coexisting diseases (yes or no), immunosuppressant use
(yes or no), smoking status (current or non-smoker), and frequency of alcohol drinking (<1 or 1 time/wk).
GMT, geometric mean titer; RoM, ratio of means.
a
p <0.05.

to 180 days after the last immune-conferred event (vaccination or
infection) and compare antibody waning rates across prior infec-
tion and vaccination status, and across background factors in
infection-naïve participants. Written informed consent was ob-
tained from all participants, and the study procedure was approved
by the NCGM ethics committee (approved number: NCGM-G-
003598). Details of the study setting, participants, variables infor-
mation, and statistical approach are described in Text S1.
Results
Among the 2964 participants, the median age was 35 (inter-
quartile range: 27e47) and 30.2% were male (Tables S1 and S2).
Those with obesity, coexisting diseases, and immunosuppression
were 5.5%, 11.1%, and 1.8%, respectively, and tobacco product users
and regular drinkers were 7.7% and 37.6%, respectively.
Among the infection-naïve participants, the waning rate of
antibody titers was 17% slower per 30 days after the 3 doses (25%
per 30 days) compared with 2 doses (36% per 30 days) (Table 1 and
Fig. 1). The 2- and 3-dose recipients with a history of infection had
slower antibody waning rates than their infection-naïve counter-
parts. Among the 2-dose recipients, those with a history of infec-
tion had consistently higher antibody titers during days 14e180
and a 32% slower waning rate than those without infection. Among
the 3-dose recipients, those with a history of infection had higher
antibody titers during days 14e180 and a 5% slower decline rate
than those without infection. The 2-dose recipients with infection
had higher antibody titers and a 13% slower waning rate than 3-
dose recipients without infection.
Table 2 and Fig. 2 show the patterns of antibody waning
following 2- and 3-dose vaccines, respectively, according to back-
ground factors among infection-naïve participants. Older age, male
sex, obesity, coexisting diseases, immunosuppressant use, smoking,
1201.e4 S. Yamamoto et al. / Clinical Microbiology and Infection 29 (2023) 1201.e1e1201.e5

A 50,000
Estimated spike antibody titers (AU/mL) B 50,000

Estimated spike antibody titers (AU/mL)

20,000 20,000

5,000 5,000

2,000 2,000

1,000 1,000

500 500
0 60 120 180 0 60 120 180
Days since the vaccination Days since the vaccination

2-dose, Age <40 2-dose, Age ≥40 2-dose, Male 2-dose, Female
3-dose, Age <40 3-dose, Age ≥40 3-dose, Male 3-dose, Female

C 50,000
Estimated spike antibody titers (AU/mL)

20,000

5,000

2,000

1,000

500
0 60 120 180
Days since the vaccination

2-dose, Non/Occasional drinker 2-dose, Weekly/Daily drinker

3-dose, Non/Occasional drinker 3-dose, Weekly/Daily drinker

Fig. 2. Trajectories of anti-SARS-CoV-2 spike protein antibody titers following 2- and 3-dose vaccination by age (A), sex (B), and alcohol drinking status (C) among infection-naïve
participants. Curves shown are the estimated trajectories for individuals who had received 2-dose (blue and red lines) and those who had received 3-dose (green and orange lines)
adjusted for age (<40 or 40 years), sex (male or female), body mass index (<27.5 or 27.5 kg/m2), coexisting diseases (yes or no), immunosuppressant use (yes or no), smoking
status (current or non-smoker), and frequency of alcohol drinking (<1 or 1 time/wk). Solid lines are the estimated geometric mean of anti-SARS-CoV-2 spike protein antibody
titers, and shaded areas are the corresponding 95% CIs.

and alcohol drinking were each associated with lower antibody with vaccination conferred more durable immunity than vaccine
titers after 2 doses, whereas these associations disappeared after 3 alone, which is in line with the results of meta-analysis [13,14].
doses, except for sex (females became lower) and immunosup- Among the infection-naïve participants, we observed that older
pressant use (still lower). Antibody waning rates were slightly but age, male sex, obesity, coexisting diseases, immunosuppressant
significantly faster in those who are older (4%), female (3%), and use use, smoking, and regular alcohol use were each associated with
alcohol (3%) after 2 doses, and somewhat faster in females (3%) lower antibody titers throughout 14e180 days following the second
after 3 doses. dose. These results were consistent with previous cross-sectional
studies [6e10]. After the 3-dose vaccine, these associations dis-
appeared except for sex and immunosuppressant use, suggesting
Discussion that a booster shot can enhance immunity and minimize the dif-
ference between groups. Still, those with immunosuppressive sta-
Among recipients of COVID-19 mRNA vaccines, we found that tus had lower antibody titers after 3 doses, a finding compatible
the durability of antibody titers was higher after 3 doses than 2 with the VE study among 2- and 3-dose vaccine recipients [2]. Our
doses, consistent with a previous study of Israeli healthcare results highlight the need for careful monitoring of infection risk
workers [3] and compatible with previous studies showing a and consideration of additional boosters among individuals
slower waning of VE for infection over time in recipients of 3-dose receiving immunosuppressants.
vaccine relative to those who received 2-dose vaccine [12,13]. In Regarding antibody waning, we observed a slightly faster
addition, we found that hybrid immunity (vaccination and infec- decline (3e4%) associated with older age, female sex, and regular
tion) has added durability over the immunity induced by vaccina- alcohol use after 2 doses. After 3 doses, the differences by age and
tion alone. The novelty of this study is that 3-dose plus infection has alcohol used disappeared, whereas the female sex remained a
led to more durable antibodies than 3-dose alone, albeit the dif- slight but significant driver of antibody decline (3%). This result
ference was modest, which is compatible with a study reporting a suggests that a booster dose plays a role in eliminating gaps in
higher VE against infection for 3-dose plus prior infection versus 3- antibody durability by background factors. We have no plausible
dose alone [13]. Interestingly, we observed that those with 2-dose explanation for the faster waning in females after both 2 and 3
plus infection had more durable antibody titers than those with doses. Interestingly, a meta-analysis of clinical trials on primary
3-dose alone. This result suggests that natural infection combined COVID-19 vaccines showed that females have a significantly lower
 S. Yamamoto et al. / Clinical Microbiology and Infection 29 (2023) 1201.e1e1201.e5
VE than males [15]; nonetheless, subsequence studies on VE after 3
doses and waning of VE after 2 and 3 doses had not examined any
sex difference. Our results highlight the need for further studies
regarding sex difference in vaccine efficacy and immunogenicity.
Study strengths and limitations are described in Text S2.
In summary, among the recipients of mRNA COVID-19 vaccines,
the durability of anti-spike antibody titers over time was higher
after 3-dose than 2-dose vaccine, and hybrid immunologic status
(vaccination and infection) appears to confer additional durability
of antibody titers. The pattern of waning of antibodies was modi-
fied by demographic and lifestyle factors. These results inform
policymakers of the importance of consideration for personal
background, the number of vaccinations received, and the history
of infection in formulating vaccine recommendations.
Author contributions
Conceptualization and methodology: SY and TM. Software: SY
and MK. Formal analysis: SY. Investigation: TM, SY, YO, NI, TN, KH,
KO, MK, and MO. Resources: TM, MO, HS, NA, WS, and NO. Data
curation: SY and MK. Writingdoriginal draft: SY. Writingdreview
and editing: all authors. Visualization: SY. Supervision and project
administration: TM and NO. Funding acquisition: TM.
Transparency declaration
The authors declare that they have no conflicts of interest.
Funding
This work was supported by the NCGM COVID-19 Gift Fund
(grant number 19K059), the Japan Health Research Promotion
Bureau Research Fund (grant number 2020-B-09), and the Grant of
National Center for Global Health and Medicine (grant number
21A2013D). Abbott Japan and Roche Diagnostics provided reagents
for anti-SARS-CoV-2 antibody assays.
Acknowledgements
We thank Mika Shichishima for her contribution to data
collection and the staff of the Laboratory Testing Department for
their contribution to measuring antibody testing.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.cmi.2023.05.020.
1201.e5
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