Original Article

doi: 10.1111/joim.13637

SARS-CoV-2 antibody dynamics over time and risk

factors associated with infection and long COVID-19
symptoms in large working environments
Cecilie Bo Hansen1 , Kristina Dvoncova1 , Laura Pérez-Alós1 , Kamille Fogh2 ,
Johannes Roth Madsen1 , Caroline Hartwell Garred1 , Ida Jarlhelt1 , Pernille Brok Nielsen2 ,
Steffan Svejgaard Petersen3 , Charlotte Gandsø Fjordager3 , Klara Tølbøll Lauritsen3 , Linda Hilsted4 ,
Lasse Boding5 , Kasper Karmark Iversen2,6 , Liselotte Hyveled7 & Peter Garred1,6
From the 1 Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet, Copenhagen University
Hospital, Copenhagen, Denmark; 2 Department of Emergency Medicine and Cardiology, Herlev and Gentofte Hospital, Herlev, Denmark;
3
Novo Nordisk A/S, Måløv, Denmark; 4 Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen,
Denmark; 5 The National Biobank, Statens Serum Institut, Copenhagen, Denmark; 6 Department of Clinical Medicine, Faculty of Health and
Medical Sciences, University of Copenhagen, Copenhagen, Denmark; and 7 Novo Nordisk A/S, Søborg, Denmark

Abstract. Hansen CB, Dvoncova K, Pérez-Alós L,
Fogh K, Madsen JR, Garred CH, et al. SARS-CoV-2
antibody dynamics over time and risk factors asso-
ciated with infection and long COVID-19 symp-
toms in large working environments. J Intern Med.
2023;293:763–781.
Background. Factors influencing SARS-CoV-2 anti-
body dynamics, transmission, waning and long
COVID-19 symptomatology are still not fully
understood.
Methods. In the Danish section of the Novo Nordisk
Group, we performed a prospective seroepidemio-
logical study during the first and second waves of
the COVID-19 pandemic. All employees and their
household members (>18 years) were invited to
participate in a baseline (June–August 2020), 6-
month follow-up (December 2020–January 2021),
and 12-month follow-up (August 2021) sampling.
In total, 18,614 accepted and provided at least
one blood sample and completed a questionnaire
regarding socioeconomic background, health sta-
tus, previous SARS-CoV-2 infection, and persistent
symptoms. Total antibody and specific IgM, IgG
and IgA levels against recombinant receptor bind-
ing domain were tested.
Results. At baseline, the SARS-CoV-2-antibody sero-
prevalence was 3.9%. At 6-month follow-up, the
seroprevalence was 9.1%, while at 12-month
follow-up, the seroprevalence was 94.4% (after the
vaccine roll-out). Male sex and younger age (18–
40 years) were significant risk factors for seropos-
itivity. From baseline to the 6-month sampling,
we observed a substantial waning of IgM, IgG and
IgA levels (p < 0.001), regardless of age, sex and
initial antibody level. An increased antibody level
was found in individuals infected prior to vac-
cination compared to vaccinated infection naïves
(p < 0.0001). Approximately a third of the seropos-
itive individuals reported one or more persistent
COVID-19 symptoms, with anosmia and/or ageu-
sia (17.5%) and fatigue (15.3%) being the most
prevalent.
Conclusion. The study provides a comprehensive
insight into SARS-CoV-2 antibody seroprevalence
following infection and vaccination, waning, per-
sistent COVID-19 symptomatology and risk factors
for seropositivity in large working environments.
Keywords: antibody, infection, long COVID, SARS-
CoV-2, transmission, waning, working environ-
ment

Cecilie Bo Hansen and Kristina Dvoncova contributed equally

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SARS-CoV-2 antibody dynamics / C. B. Hansen et al.
Introduction
The outbreak and spread of severe acute respira-
tory syndrome coronavirus 2 (SARS-CoV-2) caused
the declaration of a coronavirus disease 2019
(COVID-19) pandemic in March 2020 by the World
Health Organization [1, 2]. Restrictions imposed to
cease the spread of the disease affected all aspects
of society. The first Danish person was confirmed
infected on the 27 February 2020 [3].
Two waves of infection were identified during the
study period of the present study, the first in
spring 2020 and the second in autumn/winter
2020/2021. The government imposed two nation-
wide lockdowns, from the 11 March to the 15
April 2020, and from the 17 December 2020 to
the 8 February 2021. The Danish Health Author-
ities implemented several preventive measures,
including mandatory face mask use, social dis-
tancing, gathering bans, and testing strategies.
From May 2020, nationwide polymerase chain
reaction (PCR) testing was available. The vaccina-
tion against COVID-19 in Denmark was introduced
on the 27 December 2020 [4].
In earlier studies, workplaces have been found
to be a potential risk of infection [5, 6]. The
increased risk of infection among healthcare work-
ers has been widely addressed. Still, the different
work environments in other labor market indus-
tries may be an important but understudied setting
for infectious disease transmission [7, 8]. Thus,
a substantial knowledge gap still exists in this
area.
The Novo Nordisk Group consists of a founda-
tion, a holding company, a biotechnology company
specialized in enzyme production, Novozymes A/S,
and a pharmaceutical company, Novo Nordisk A/S.
The latter with more than 50,000 employees in 80
countries, whereas the smaller units hold approxi-
mately 6000 employees [9]. Employees’ work envi-
ronment spans from production sites with strict
sterile guidelines to open office spaces and labo-
ratories. Except for employees at production sites,
warehouses, and laboratories, the majority of Novo
Nordisk group employees worked from home dur-
ing the first national lockdown. Many employees
could work from home during the second lock-
down, but if they had to come into the office, they
had to follow preventive measures (social distanc-
ing, work spot sanitizing, seating rules, etc.) on
every site.
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Employees in the Novo Nordisk Group normally
engage in a high level of travel and meetings across
multiple sites and countries, resulting in varied
contact patterns and a potentially high risk of
infection.
During the first and second waves of the COVID-
19 pandemic in Denmark, this study investigates
factors influencing antibody levels, SARS-CoV-
2 transmission, and persistent COVID-19 symp-
tomatology in the Novo Nordisk Group.
Methods
Study design and participants
The aim of this prospective longitudinal seroepi-
demiological study of COVID-19 was to study the
seroprevalence of antibodies against SARS-CoV-
2. Furthermore, the objective of the study was
to assess the impact of behavioral tendencies on
the transmission of SARS-CoV-2 infection and
the prevalence of persistent COVID-19 symptoms.
All employees of Novo Nordisk A/S, Novozymes
A/S, Novo Holdings A/S, and the Novo Nordisk
Foundation (further referred to as Novo Nordisk
Group) in Denmark and their respective house-
hold members at the age of 18 years or older
were invited to participate. Participation was vol-
untary, and all samples were sampled on eight dif-
ferent sites across the Novo Nordisk Group loca-
tions. The participants who volunteered to par-
ticipate had a venous blood sample collected and
answered an online questionnaire regarding their
socioeconomic background, general health infor-
mation, occupation, previous SARS-CoV-2 infec-
tion, COVID-19 vaccination status, travels, work-
place, household size, and persistent COVID-19
symptoms (Supporting Information). Blood sam-
ples were collected in 6 mL serum tubes (456089,
Greiner Bio-One) and kept at 4°C overnight before
aliquotation and storage at −80°C. The partici-
pants enrolled in the study were followed over
three sampling rounds. The first sampling round
(baseline) took place from June to August 2020;
the second round (6-month follow-up) took place
from December 2020 to January 2021, and the
third sampling round (12-month follow-up) took
place in August 2021 after the COVID-19 vaccine
rollout in Denmark. The baseline and 6-month
sampling were split into two sampling sessions
each due to the summer and Christmas holiday
season, respectively. Venous blood samples were
collected under the principles described in the

SARS-CoV-2 antibody dynamics / C. B. Hansen et al.
Declaration of Helsinki. The study was performed
with scientific, ethical approval by the Regional Sci-
entific Ethics Committee of the Capital Region of
Denmark (H-20079890). The questionnaires were
managed using Research Electronic Data Capture
(REDCap), which provides a secure environment
for online surveys and databases during the data
collection [10].
Serological analyses of blood samples
Screening assay—sandwich ELISA. Total Ig
against SARS-CoV-2 were detected using an
in-house, sandwich, S-ELISA described previ-
ously [11], with modifications. Briefly, Clear
Flat-Bottom Immuno Nonsterile 384-Well Plates
(464718, Thermo Fisher Scientific) were coated
with 0.5 μg/mL recombinant receptor binding
domain (RBD) of SARS-CoV-2 in PBS overnight
at 5°C. Plates were blocked with WellCham-
pion blocking solution (4900A, Kem-En-Tec
Diagnostics, Taastrup, Denmark) following the
manufacturer’s instructions. Plates were left to
dry overnight at room temperature, followed by
vacuum sealing for up to 1-year storage at 4°C.
Next, serum samples and control sera were applied
in duplicates at 1:10 in PBS +0.05% Tween (PBS-
T) and incubated for 1.5 h. RBD-bound antibod-
ies were detected by adding a solution consist-
ing of 1:16,000 dilution Pierce HRP-conjugated
streptavidin (21130, Thermo Fisher Scientific) and
0.5 μg/mL recombinant biotinylated RBD [11] for
30 min. Plates were developed using TMB ONE
(4380, Kem-En-Tec Diagnostics) for 12–25 min,
and the reaction was stopped by adding 0.3 M
H2 SO4 . Optical density (OD) was measured at
450–620 nm. Plates were washed with PBS-T
between incubations three times and soaked in
buffer for 10 s. Incubations were stationary and at
room temperature. Plates and all liquid handling
were handled by a Tecan Fluent liquid handler
(Tecan, Männedorf, Switzerland) with the built-in
scheduler and a Tecan HydroSpeed Plate washer
and a Tecan Infinite 200 Pro absorbance reader
attached. Control samples added consisted of a
pre-pandemic SARS-CoV-2 naïve normal human
serum pool as a negative control (BioIVT, West Sus-
sex, UK) and a high and low antibody concentra-
tion spiked in the normal human serum pool as
positive controls. The threshold for assay positivity
was set to ≥3.4 signal-to-noise ratio (SN) between
the mean OD of the duplicated serum samples and
the median of the OD of the negative control sera.
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The levels of total anti-RBD Ig were classified into
low (3.4–13 SN), intermediate (14–19 SN), and high
(≥20) based on the tertiles of all Ig positive sam-
ples (above the positive threshold ≥3.4 SN) in the
3 sampling rounds combined (Fig. S1). A full assay
description is provided in the Supporting Informa-
tion section.
Direct ELISA
Serum samples above threshold positivity in the
S-ELISA were further analyzed for the quantita-
tive determination of different antibody isotypes.
Measurement of IgM, IgG, and IgA antibody lev-
els against RBD was performed using an in-house
ELISA-based assay as described elsewhere [11].
The threshold for assay positivity was set to 200,
225, and 100 AU/mL for IgM, IgG, and IgA, respec-
tively. The levels of anti-RBD IgG were classi-
fied into low (225–780 AU/mL), intermediate (781–
1781 AU/mL), and high (≥1782 AU/mL) based on
the tertiles of all IgG positive samples (above the
positive threshold of 225 AU/mL) in the baseline
sampling (Fig. S1).
Statistical analysis
Total anti-RBD Ig data were analyzed in WATSON
LIMS version 7.6.1 (Thermo Fisher Scientific). Indi-
vidual S-ELISA setups were accepted based on
acceptance ranges calculated during validation for
the three control samples (negative, low positive,
and high positive). Positive samples with a coef-
ficient of variation >20% were reanalyzed. Dur-
ing validation of the screening assay for the fully
automated setup, a receiver operating curve anal-
ysis was performed, and a sensitivity of 98% and a
specificity of 89% were achieved with the cut point
of 3.44. Applying a more conservative approach
and focusing on higher specificity in the ROC anal-
ysis, a sensitivity of 97% and a specificity of 98%
were achieved with a cut point of 5.8.
Estimating specific isotype levels was performed
using GraphPad Prism version 9.2.0 (Graph-
Pad Software, La Jolla, CA, USA) as previously
described [12].
Statistical analyses were performed using R (ver-
sion 4.1.1, R Foundation for Statistical Comput-
ing). Baseline and socioeconomic characteristics
and exposures were presented as counts (%) for
all categorical variables and median for continu-
ous variables. The association of exposures with
the seroprevalence was tested using the chi-square
765
Journal of Internal Medicine, 2023, 293; 763–781
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SARS-CoV-2 antibody dynamics / C. B. Hansen et al.

Fig. 1 Study flowchart. The baseline sampling round (Round 1) took place from June to August 2020, the 6-month follow-up
sampling (Round 2) took place from December 2020 to January 2021, and the 12-month follow-up sampling (Round 3) took
place in August 2021. In total, 18,614 participants provided at least one blood sample and 4776 individuals participated in
all three rounds. Timeline depicting the first (spring 2020) and second (fall/winter 2020/2021) waves of coronavirus disease
2019 (COVID-19) in Denmark. Vaccination against COVID-19 in Denmark was introduced on the 27 December, 2020.

test or Mann–Whitney U test. Binary logistic regres-
sion analyses were conducted to provide esti-
mates of the probability of testing positive on
antibodies against SARS-CoV-2 based on selected
socioeconomic risk factors. Results of the regres-
sion model have been calculated as odds ratios
(OR) of risk factors and presented with 95% confi-
dence intervals (95% CI). All variables were defined
based on the extracted information from com-
pleted questionnaires (Tables S4–S6). Vaccination
types and dates were extracted from the question-
naires, and for the majority of the study cohort
(70.7%) confirmed by cross-checking with vacci-
nation data obtained from the Danish Vaccina-
tion Register from the Capital Region. Unfortu-
nately, due to lack of access to nationwide vacci-
nation data, it was not possible to cross-check the
entire study cohort. Prior infection was defined as
being total Ig seropositive at baseline and/or total
Ig seropositive at the 6-month follow-up and/or
having a positive PCR test prior to the 12-month
follow-up sampling. Data on SARS-CoV-2 PCR test
results were extracted from the Danish national
microbiology database MiBa (Statens Serum Insti-
tut, Copenhagen, Denmark) using the partici-
pants’ unique civil registration numbers. Differ-
ences in IgM, IgG, and IgA levels and differences
between IgG levels in the age and sex groups
between baseline and the 6-month follow-up (anti-
body waning) were analyzed using a nonparamet-
ric paired Wilcoxon rank test. Association between
IgG waning (defined as relative delta; [X(final
IgG) − X(baseline IgG)]/X(baseline IgG) × 100) and
age groups, sex, and initial IgG level were assessed
using multiple linear regression. Cochran’s Q-tests
were applied to identify if self-reported persistent
COVID-19 symptoms after SARS-CoV-2 infection
had been reported with the same probability. The
significance level was set to 95%, and a p-value
<0.05 was considered significant.
Results
Baseline characteristics
Novo Nordisk Group employees and their respec-
tive household members were invited to partici-
pate in three consecutive sampling rounds. A total
of 14,895 individuals were included in round 1
(baseline), 11,354 in round 2 (6-month follow-
up), and 7368 in round 3 (12-month follow-up)
after the exclusion of individuals with, for exam-
ple, an incomplete questionnaire (Fig. 1). The

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Journal of Internal Medicine, 2023, 293; 763–781
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SARS-CoV-2 antibody dynamics / C. B. Hansen et al.

Fig. 2 Overview of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence in all three rounds of sam-
pling. (a) Seroprevalence at baseline (June–August 2020) (left), 6-month follow-up (December 2020–January 2021) (middle),
and 12-month follow-up (August 2021) (right). (b) Seroprevalence at baseline divided into two sampling sessions performed in
June/July 2020 and August 2020. Seroprevalence in the 6-month follow-up divided into two sampling sessions performed
in December 2020 and January 2021. The green color represents seropositive samples, and the orange color represents
seronegative samples for total SARS-CoV-2 antibodies.

characteristics of the participants in the baseline
sampling and the 6-month sampling are reported
in Table 1. Characteristics of participants in the
12-month sampling are presented in Table S1 as
this population was sampled after the COVID-19
vaccine rollout in Denmark and the vast majority
of study participants had completed vaccination.
A total of 18,614 individuals provided at least one
blood sample and 4,776 individuals participated in
all three sampling rounds. In the first two sampling
rounds, 54.6% were female, and the median age
of all participants was 47 years. In the 12-month
sampling, 57.5% were female, and the median age
was 47. The baseline and 6-month sampling were
split into two sampling sessions each to accommo-
date for the holiday seasons (Fig. 2).
Overall seroprevalence
Seroprevalence after SARS-CoV-2 infection. A gen-
eral overview of the seroprevalence of all three
rounds following the detection of total antibod-
ies against SARS-CoV-2 is presented in Fig. 2a.
At baseline, 575 (3.9%) participants tested posi-
tive for SARS-CoV-2 antibodies. At the 6-month
follow-up, 1030 (9.1%) participants were seroposi-
tive. There was a significant increase in seropositiv-
ity from baseline to 6-month sampling (p < 0.0001,
Table 1). No significant difference in seroprevalence
was observed between the two sampling sessions
at baseline (3.8% in June/July 2020 vs. 4.0% in
August 2020, Fig. 2b). However, the seroprevalence
results at 6-month follow-up differed noticeably
between the two sampling sessions (Fig. 2b), with
7.6% seropositive participants in the first sam-
pling session (December 2020) compared to 17.9%
seropositive participants in the second sampling
session (January 2021). Table S2 depicts the base-
line characteristics of 6-month sampling partici-
pants split into the two sampling sessions. The
second sampling session of the 6-month follow-
up (January 2021) was characterized by a younger
population (47 vs. 45 years, p < 0.0001) and a
higher percentage of participants working in an
office environment (34.7% vs. 40.5%, p < 0.0001).
The Danish COVID-19 vaccination campaign was
introduced on the 27 December 2020. However,
only 9 participants had commenced vaccination
in the 6-month sampling round, and these were
therefore excluded from the analysis (Fig. 1).

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Journal of Internal Medicine, 2023, 293; 763–781
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SARS-CoV-2 antibody dynamics / C. B. Hansen et al.

Table 1. Characteristics of participants at baseline (June–August 2020) and at 6-month follow-up (December 2020–January
2021).
Baseline sampling 6-month sampling
Variable (n = 14,895) (n = 11,354) p-Value
Sex 0.967
Female 8126 (54.6%) 6198 (54.6%)
Male 6769 (45.4%) 5156 (45.4%)
Age (years)a 0.392
Median [IQR] 47.0 [37.0, 55.0] 47.0 [37.0, 55.0]
Age groupsa 0.451
18–40 years 5298 (35.6%) 4011 (35.3%)
41–60 years 8446 (56.7%) 6414 (56.5%)
>61 years 1151 (7.7%) 925 (8.1%)
BMIb <0.001
Median [IQR] 24.4 [22.2, 27.4] 24.6 [22.3, 27.4]
BMI groupsb 0.013
Underweight 210 (1.4%) 145 (1.3%)
Normal range 8083 (54.3%) 5883 (51.8%)
Overweight 4649 (31.2%) 3674 (32.4%)
Obese class I 1275 (8.6%) 1034 (9.1%)
Obese class II and III 404 (2.7%) 318 (2.8%)
Smokingc <0.0001
No smoker 12,334 (82.8%) 9659 (85.1%)
Previous smoker 921 (6.2%) 657 (5.8%)
Active smoker 1576 (10.6%) 982 (8.6%)
Educationd <0.001
No formal education 51 (0.3%) 36 (0.3%)
Primary school 628 (4.2%) 445 (3.9%)
High school 1213 (8.1%) 845 (7.4%)
Bachelor’s degree 6325 (42.5%) 5118 (45.1%)
Masters’ degree or 6677 (44.8%) 4907 (43.2%)
higher
Serological status <0.0001
Seronegative 14,320 (96.1%) 10,324 (90.9%)
Seropositive 575 (3.9%) 1030 (9.1%)
Alcohol intakee <0.001
0 units per week 3180 (21.3%) 2617 (23.0%)
1–7 units per week 8961 (60.2%) 6778 (59.7%)
8–14 units per week 2164 (14.5%) 1549 (13.6%)
≥15 units per week 481 (3.2%) 322 (2.8%)
Comorbidities 0.690
0 comorbidities 11,590 (77.8%) 8879 (78.2%)
1–2 comorbidities 3211 (21.6%) 2400 (21.1%)
≥3 comorbidities 94 (0.6%) 75 (0.7%)
(Continued)

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SARS-CoV-2 antibody dynamics / C. B. Hansen et al.

Table 1. (Continued)
Baseline sampling 6-month sampling
Variable (n = 14,895) (n = 11,354) p-Value
Household sizef 0.559
1 member 2326 (15.6%) 1835 (16.2%)
2 members 4558 (30.6%) 3525 (31.0%)
3 members 2716 (18.2%) 2061 (18.2%)
4 members 3592 (24.1%) 2661 (23.4%)
≥5 members 1392 (9.3%) 1047 (9.2%)
Job positiong <0.0001
Office 5549 (37.5%) 4030 (35.5%)
Production 2717 (18.2%) 2365 (20.8%)
Research 1958 (13.1%) 1436 (12.6%)
Customer/patient 37 (0.2%) 24 (0.2%)
contact
Other 577 (3.9%) 405 (3.6%)
Relation to Novo Grouph 0.545
Employee 10,868 (73.0%) 8266 (72.8%)
Cohabitant 3954 (26.5%) 2955 (26.0%)
Travelingi
0 countries 7328 (49.2%) 5918 (52.1%) <0.0001
1–3 countries 7137 (47.9%) 2755 (24.3%)
4–6 countries 358 (2.4%) 66 (0.6%)
≥7 countries 33 (0.2%) 4 (0.0%)
Note: Data are presented as n (%) or median [interquartile range]. p-Values were based on chi-square test for categorical
variables, and Mann–Whitney U test for continuous variables.
a Missing data in the questionnaire; baseline (n = 0), 6 month (n = 1).
b Missing data in the questionnaire; baseline (n = 274), 6 month (n = 300).
c Missing data in the questionnaire; baseline (n = 64), 6 month (n = 56).
d Missing data in the questionnaire; baseline (n = 1), 6 month (n = 3).
e Missing data in the questionnaire; baseline (n = 109), 6 month (n = 88).
f Missing data in the questionnaire; baseline (n = 311), 6 month (n = 225).
g Missing data in the questionnaire; baseline (n = 4057), 6 month (n = 3094).
h Missing data in the questionnaire; baseline (n = 73), 6 month (n = 1174).
i Missing data in the questionnaire; baseline (n = 33), 6-month (n = 2611).

Seroprevalence after COVID-19 vaccination. The
12-month follow-up sample collection coincided
with the national COVID-19 vaccination cam-
paign in Denmark. Figure 2a depicts the sero-
prevalence results of the 12-month sampling,
with 6959 (94.4%) participants seropositive for
SARS-CoV-2 antibodies. A total of 6943 par-
ticipants were fully vaccinated against COVID-
19 at the time of sample collection (Fig. 3a),
with Comirnaty [Pfizer-BioNTech] (84.5%) being
the most frequently administered vaccine, fol-
lowed by Spikevax [Moderna] (10.0%), Jcov-
den [COVID-19 vaccine Janssen] (3.0%), a com-
bination of Vaxzevria/mRNA [AstraZeneca and
Pfizer-BioNTech/Moderna] (1.0%), and Vaxzevria
[AstraZeneca/Oxford] (0.1%). A total of 1.4% failed
to provide the name of the vaccine administered.
Figure 3b depicts the total antibody level distri-
bution among fully vaccinated individuals, illus-
trating that the majority of participants (39.4%)
developed high levels of total antibodies, whereas
35.5% had intermediate levels and 21.9% had low
levels. A total of 3.2% of the participants did not
mount a positive response after complete vaccina-
tion. Figure 3c–h displays antibody levels accord-
ing to vaccine type.
We evaluated the total antibody level in fully vac-
cinated individuals with a previous SARS-CoV-
2 infection (hybrid immunity) compared to fully

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Journal of Internal Medicine, 2023, 293; 763–781
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SARS-CoV-2 antibody dynamics / C. B. Hansen et al.

Fig. 3 Vaccines administered and antibody levels in the 12-month sampling (Round 3). (a) Distribution of vaccines adminis-
tered in the study population in fully vaccinated individuals. Green, orange, dark red, and black colors represent individuals
fully vaccinated with Comirnaty, Spikevax, Jcovden, or Vaxzevria, respectively. Gray represents individuals fully vaccinated
with a first dose of Vaxzevria and a second dose of any of the mRNA vaccines available. White represents not specified. (b)
Distribution of total antibody levels in fully vaccinated individuals with any of the vaccines represented in panel A. Green,
orange, dark gray, and light gray colors represent high, intermediate, low, or negative levels of total antibodies against
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respectively. (c–h) Distribution of total antibody levels in
fully vaccinated individuals divided by vaccine type; (c) Comirnaty, (d) Spikevax, (e) Jcovden, (f) not specified, (g) first dose
of Vaxzevria and a second dose of any of the mRNA vaccines available, (h) Vaxzevria. Green, orange, dark gray, and light
gray colors represent high, intermediate, low, or negative levels of total antibodies against SARS-CoV-2, respectively.

vaccinated naïve individuals to investigate the
difference between these two categories (Fig. 4).
Individuals previously infected (Fig. 4a) had a
higher total antibody response in terms of high
levels (72.2%) compared to 35.4% in infec-
tion naïve individuals (Fig. 4b) (chi-square test,
p < 0.0001).
Quantitative IgM, IgG, and IgA response following
SARS-CoV-2 infection
Samples from the baseline sampling and at the 6-
month follow-up positive for total Ig against SARS-
CoV-2 RBD were further analyzed to quantify the
levels of the isotypes IgM, IgG, and IgA after natu-
ral infection. Figure 5 depicts the antibody levels of
anti-RBD IgG in all individuals (n = 440) with total
anti-RBD Ig seropositivity at baseline who partici-
pated in both rounds. IgG levels were divided into
high, intermediate, low, and negative levels based
on the initial levels measured at baseline (Fig. 5a).
We observed a significant decrease in IgG levels
during approximately 6-month (p < 0.0001, except
for the IgG negative group). The decrease rate (%)
was similar for IgG positive samples regardless of
initial IgG levels (63.7% high, 67.2% intermedi-
ate, and 70.6% low). In contrast to the low IgG
level group, the median levels of the groups with
high and intermediate IgG levels remained above

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Fig. 4 Influence of hybrid immunity on total anti-receptor binding domain (RBD) Ig levels. (a) Total Ig levels detected in
individuals who had a previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and were fully
vaccinated (hybrid immunity). (b) Total Ig levels detected in infection-naïve individuals who were fully vaccinated. Green,
orange, dark gray, and light gray colors represent high, intermediate, low, or negative levels of total Ig against SARS-CoV-2,
respectively.

the positive threshold over the course of time.
Figure 5b illustrates IgG levels at baseline and
at the 6-month sampling in different age groups
(18–40, 41–60, ≥61 years old), where a significant
decrease over time is observed for all age groups
(p < 0.0001). However, the waning of IgG levels
appeared more substantial in the older popula-
tion (99.4% decrease). Similar waning of IgG levels
regardless of the sex was observed (Fig. 5c), with
an 80.4% decrease in females and 81.2% decrease
in males and a significant decrease in IgG levels
for both groups (p < 0.0001). Figure 6a illustrates
the predicted IgG waning according to initial levels
(high, intermediate, and low) and age groups (18–
40, 41–60, ≥61 years old). Multiple linear regres-
sion analysis (Fig. 6b) did not reveal any signifi-
cant association between IgG waning (defined as
relative delta) and baseline antibody level, age, or
sex.
IgM and IgA levels are illustrated in Fig. S2. Figure
S2A depicts IgM responses, split up in whether
they were IgM positive or negative in the baseline
sampling. Those who had a positive IgM response
at baseline had a statistically significant decrease
of 77.8% (p < 0.0001) over 6 months. Regard-
ing waning of positive IgA responses (Fig. S2B),
the median levels of those who had a positive
IgA response at baseline remained above the pos-
itive threshold at the 6-month follow-up, despite
a statistically significant decrease in IgA levels
(p < 0.001, 57.1%).
Seroprevalence and socioeconomic background
Table 2 shows the participant characteristics in
the baseline sampling and at 6 months, strati-
fied by serological status defined as seropositiv-
ity/negativity in the screening assay. Male sex was
associated with a significantly higher seropreva-
lence of SARS-CoV-2 antibodies in both rounds
(p = 0.013, baseline; p = 0.027, 6-month follow-
up). Significant differences in seroprevalence were
observed across age groups (p = 0.034, baseline;
p = 0.002, 6-month follow-up), with the younger
group (18–40 years) having a higher proportion
of seropositive individuals than the group of 41–
60 years olds. However, the group ≥61 years
had an increased proportion of seropositives at
baseline compared to the other age groups but
a decreased proportion of seropositive individuals
at 6-month follow-up compared to the youngest
age group. At baseline, alcohol intake was asso-
ciated with a higher seroprevalence (p = 0.032),
with participants who reported a weekly intake of
8–14 units having a higher proportion of seropos-
itivity. However, no significant differences were
observed at 6-month follow-up. A significant asso-
ciation with seropositivity was observed in the
baseline and 6-month sampling for those partic-
ipants who reported living with a Novo Nordisk
Group employee (p = 0.001, baseline; p < 0.0001,
6-month follow-up). No significant differences were
observed for the other variables (BMI, smoking,
education, comorbidities, household size, job posi-
tion, and traveling). However, there was a tendency
at 6-month follow-up for the comorbidity variable
(Table 2, p = 0.055).
An adjusted logistic model was used to examine
significantly associated variables with a seropos-
itive outcome in order to evaluate the risk fac-
tors associated with SARS-CoV-2 infection (Fig. 7).
Middle-aged and older individuals (41–60 and

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SARS-CoV-2 antibody dynamics / C. B. Hansen et al.

Fig. 5 Anti-receptor binding domain (RBD) IgG waning from baseline to 6 month in total anti-RBD Ig seropositive individuals
who participated in both rounds (n = 440). (a) IgG levels, represented in log10(AU/mL), in individuals with high (left),
intermediate (mid left), low (mid right), and negative (right) baseline IgG levels measured at baseline (orange circles) compared
to the IgG levels measured at 6 months (green circles). (b) IgG levels, represented in log10(AU/mL), in individuals aged 18–40
years old (left), individuals aged 41–60 years old (middle), and individuals aged ≥61 years old (right) measured at baseline
(orange circles) compared to the levels measured at 6 months (green circles). (c) IgG levels, represented in log10(AU/mL), in
females (left) and males (right) measured at baseline (orange circles) compared to the levels measured at 6 months (green
circles). Percentage decreases of IgG levels over approximately 6 months are presented in the table below the graphs.
Data are represented as median ± 95% confidence interval (CI). Horizontal dotted lines represent assay positive threshold
(225 AU/mL). Nonparametric paired Wilcoxon rank test was performed to compare medians between rounds. ns, non-
significant; ****p < 0.0001; p < 0.05 was considered significant.

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SARS-CoV-2 antibody dynamics / C. B. Hansen et al.

Fig. 6 Anti-receptor binding domain (RBD) IgG waning over approximately 6 months in anti-RBD IgG seropositive individuals
at baseline who participated in both rounds (n = 242). (a) Distribution of IgG levels represented in log(AU/mL) over time (days
between baseline sample and 6-month follow-up sample). Dots represent the observed IgG levels. Lines represent predicted
IgG levels. Solid, short dashed, and long dashed lines represent the predicted levels of circulating IgG antibodies calculated
by the multiple regression model according to low, intermediate, and high baseline levels, respectively. Black, yellow, and
blue colors represent individuals with age 18–40, 41–60, and ≥61 years, respectively. Shadowed areas represent the
standard error. Center for the standard error is the predicted (mean) values. (b) Table displaying results from the multiple
linear regression analysis on variables associated with waning (defined as relative delta). Variables: baseline IgG level
(low, intermediate, and high), age groups (18–40, 41–60, and ≥61 years) and sex (female/male). CI, confidence interval.
p < 0.05 was considered significant.

≥61 years) had lower odds of infection than
younger individuals (18–40 years), though this was
more pronounced in the 6-month sampling (OR:
0.79, 95% CI: 0.69–0.91, p = 0.001; OR: 0.75, 95%
CI: 0.58–0.97, p = 0.032, respectively). At base-
line, the male sex was associated with increased
odds of infection (OR: 1.19, 95% CI: 1.00–1.42,
p = 0.046), but not at 6-month (OR: 1.08, 95%
CI: 0.95–1.24, p = 0.253). In both rounds, we
found decreased odds of being seropositive for Novo
Nordisk Group employees compared to cohabitants
of Novo Nordisk Group employees (OR: 0.78, 95%
CI: 0.65–0.93, p = 0.006; OR: 0.66, 95% CI: 0.58–
0.76, p < 0.001, respectively). Although not signifi-
cant, alcohol consumption (in the group 8–14 units
per week) had a tendency toward increased odds of
being seropositive compared to no alcohol intake at
baseline and at 6-month follow-up (OR: 1.25, 95%
CI: 0.95–1.66, p = 0.109; OR: 1.20, 95% CI: 0.96–
1.49, p = 0.114, respectively).
Persistent COVID-19 symptomatology
In the 6-month sampling round, study participants
were asked questions related to experiencing per-
sistent (long-lasting) symptoms after COVID-19.

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SARS-CoV-2 antibody dynamics / C. B. Hansen et al.

Table 2. Characteristics of participants by serological status at baseline (June–August 2020) and at 6-month follow-up
(December 2020–January 2021).
Baseline sampling 6-month sampling
Seronegative Seropositive Seronegative Seropositive
Variable (n = 14,320) (n = 575) p-Value (n = 10,324) (n = 1030) p-Value
Sex 0.013 0.027
Female 7842 (54.8%) 284 (49.4%) 5670 (54.9%) 528 (51.3%)
Male 6478 (45.2%) 291 (50.6%) 465 (45.1%) 502 (48.7%)
Age (years)a 0.085 <0.0001
Median [IQR] 47.0 [37.0, 55.0] 45.0 [35.0, 54.0] 47.0 [37.0, 55.0] 46.0 [34.0, 54.0]
Age groupsa 0.034 0.002
18–40 years 5071 (35.4%) 227 (39.5%) 3595 (34.9%) 416 (40.4%)
41–60 years 8150 (56.9%) 296 (51.5%) 5879 (56.9%) 535 (51.9%)
≥61 years 1099 (7.7%) 52 (9.0%) 846 (8.2%) 79 (7.7%)
BMIb 0.157 0.854
Median [IQR] 24.4 [22.2, 27.1] 24.5 [22.3, 27.5] 24.6 [22.3, 27.4] 24.6 [22.3, 27.2]
BMI groupsb 0.436 0.901
Underweight 202 (1.4%) 8 (1.4%) 129 (1.2%) 16 (1.6%)
Normal weight 7786 (54.4%) 297 (51.7%) 5355 (51.9%) 528 (51.3%)
Overweight 4469 (31.2%) 180 (31.3%) 3333 (32.3%) 341 (33.1%)
Obese class I 1222 (8.5%) 53 (9.1%) 943 (9.1%) 91 (3.8%)
Obese classes II and III 382 (2.7%) 22 (3.8%) 290 (2.8%) 28 (2.7%)
Smokingc 0.567 0.755
No smoker 11,866 (82.9%) 468 (81.4%) 8781 (85.1%) 878 (85.2%)
Previous smoker 882 (6.2%) 39 (6.8%) 593 (5.7%) 64 (6.2%)
Active smoker 1509 (10.5%) 67 (11.7%) 897 (8.7%) 85 (8.3%)
Educationd 0.175 0.962
No formal education 49 (0.3%) 2 (0.3%) 33 (0.3%) 43 (4.2%)
Primary school 594 (4.1%) 34 (5.9%) 402 (3.9%) 43 (4.2%)
High school 1158 (8.1%) 55 (9.6%) 765 (7.4%) 81 (7.9%)
Bachelor’s degree 6086 (42.5%) 239 (41.6%) 4653 (45.1%) 465 (45.1%)
Masters’ degree or 6432 (44.9%) 245 (42.6%) 4469 (43.3%) 438 (42.5%)
higher
Alcohol intakee 0.032 0.284
0 units per week 3061 (21.4%) 119 (20.7%) 2387 (23.1%) 230 (22.3%)
1–7 units per week 8634 (60.3%) 327 (56.9%) 6174 (59.8%) 604 (58.6%)
8–14 units per week 2057 (14.4%) 107 (18.6%) 1388 (13.4%) 28 (2.7%)
≥15 units per week 466 (3.3%) 15 (2.6%) 294 (2.8%) 161 (15.6%)
Comorbidities 0.558 0.055
0 comorbidities 11,152 (77.9%) 438 (76.2%) 8062 (78.1%) 817 (79.3%)
1–2 comorbidities 3077 (21.5%) 134 (23.3%) 2188 (21.2%) 212 (20.6%)
≥3 comorbidities 91 (0.6%) 3 (0.5%) 74 (0.7%) 1 (0.1%)
Household sizef 0.214 0.178
1 member 2240 (15.6%) 86 (15.0%) 1696 (16.4%) 139 (13.5%)
2 members 4399 (30.7%) 159 (27.7%) 3209 (31.1%) 316 (30.7%)
3 members 2598 (18.1%) 118 (20.5%) 1861 (18.0%) 200 (19.4%)
4 members 3465 (24.2%) 127 (22.1%) 2413 (23.4%) 248 (24.1%)
≥5 members 1330 (9.3%) 62 (10.8%) 949 (9.2%) 98 (9.5%)
(Continued)

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SARS-CoV-2 antibody dynamics / C. B. Hansen et al.

Table 2. (Continued)
Baseline sampling 6-month sampling
Seronegative Seropositive Seronegative Seropositive
Variable (n = 14,320) (n = 575) p-Value (n = 10,324) (n = 1030) p-Value
Job positiong 0.534 0.893
Office 5346 (37.3%) 203 (35.3%) 3701 (35.8%) 329 (31.9%)
Production 2631 (18.4%) 86 (15.0%) 2178 (21.1%) 187 (18.2%)
Research 1884 (13.2%) 74 (12.9%) 1324 (12.8%) 112 (10.9%)
Customer/patient 37 (0.3%) 0 (0%) 21 (0.2%) 3 (0.3%)
contact
Other 555 (3.9%) 22 (3.8%) 375 (3.6%) 30 (2.9%)
Relation to Novo Grouph 0.001 <0.0001
Employee 10,482 (73.2%) 386 (67.1%) 7604 (73.7%) 662 (64.3%)
Cohabitant 3767 (26.3%) 187 (32.5%) 2605 (25.2%) 350 (34.0%)
Travelingi
0 countries 7073 (49.4%) 255 (44.3%) 0.100 5425 (52.5%) 493 (47.9%) 0.116
1–3 countries 6833 (47.7%) 304 (52.9%) 2509 (24.3%) 246 (23.9%)
4–6 countries 346 (2.4%) 12 (2.1%) 56 (0.5%) 10 (1.0%)
≥7 countries 32 (0.2%) 1 (0.2%) 3 (0.0%) 1 (0.1%)
Note: Data are presented as n (%) or median [interquartile range]. p-Values were calculated using chi-square test or
Mann–Whitney U test, comparing serostatus with the variables listed.
a Missing data in the questionnaire; baseline negative (n = 0), baseline positive (n = 0), 6-month negative (n = 4), 6-month

positive (n = 0).
b Missing data in the questionnaire; baseline negative (n = 259), baseline positive (n = 15), 6-month negative (n = 274),

6-month positive (n = 26).

c Missing data in the questionnaire; baseline negative (n = 63), baseline positive (n = 1), 6-month negative (n = 53),

6-month positive (n = 3).

d Missing data in the questionnaire; baseline negative (n = 1), baseline positive (n = 0), 6-month negative (n = 3), 6-month

positive (n = 0).
e Missing data in the questionnaire; baseline negative (n = 102), baseline positive (n = 7), 6-month negative (n = 81),

6-month positive (n = 7).

f Missing data in the questionnaire; baseline negative (n = 288), baseline positive (n = 23), 6-month negative (n = 196),

6-month positive (n = 29).

g Missing data in the questionnaire; baseline negative (n = 3867), baseline positive (n = 190), 6-month negative (n = 2725),

6-month positive (n = 369).

h Missing data in the questionnaire; baseline negative (n = 71), baseline positive (n = 2), 6-month negative (n = 115),

6-month positive (n = 18).

i Missing data in the questionnaire; baseline negative (n = 30), baseline positive (n = 3), 6-month negative (n = 2331),

missing 6-month positive (n = 280).

However, the questionnaire was not designed to
specify the duration of symptoms or estimate the
time from the suspected infection. Of all 1030
seropositive individuals at 6-month follow-up, 319
(31.0%) reported having at least one persistent
COVID-19 symptom. A significant difference was
observed between the age groups (p = 0.006,
Fig. 8a), but no trend could be deducted.
Furthermore, females reported more persistent
symptoms than males (p = 0.009, Fig. 8b). Over-
all, the most frequently reported symptoms in
seropositive individuals (Fig. 8c) were loss of smell
and/or taste (180 individuals, 17.5%) and fatigue
(158 individuals, 15.3%). The third most prevalent
persistent symptoms reported were concentration
difficulties (63 individuals, 6.1%) and headache
(63 individuals, 6.1%). Of all 10,324 seronega-
tive individuals in the 6-month sampling round,
145 (1.4%) reported having at least one persistent
COVID-19 symptom, with fatigue (70 individuals,
0.7%) being the most frequently reported symptom
(Fig. S3).

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SARS-CoV-2 antibody dynamics / C. B. Hansen et al.

Fig. 7 Risk factors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seropositivity at baseline and at 6-
month follow-up. Forest plot displaying the results of the logistic regression model at baseline (red) and at 6-month follow-up
(blue). Dots represent values of odds ratios (OR) and 95% confidence interval (CI). Risk factors: age groups (18–40, 41–60,
and ≥61 years), sex (female/male), relation to employer (employee at Novo Nordisk Group or cohabitant of a Novo Nordisk
Group employee), alcohol consumption in units per week (0, 1–7, 8–14, or ≥15 units).

Discussion in December 2020 (n = 4044) [14]. The differ-

In this extensive, prospective seroepidemiological
study we investigated the seroprevalence of SARS-
CoV-2, associated risk factors, waning of anti-
body levels and prevalence of reported persistent
COVID-19 symptoms in a company-based set-
ting in Denmark in a period from 2020 to 2021.
We found comparable yet higher seroprevalence
than nationwide surveys performed in the same
time period in Denmark [13–16]. Erikstrup et al.
reported a combined adjusted seroprevalence of
1.9% (95% CI, 0.8–2.3) in 20,640 blood donors in
April–May 2020 [15]. Espenhain et al. reported a
seroprevalence of 2.1 (95% CI, 1.3–2.6) in August
2020 (n = 11,478) and 4.1 (95% CI, 3.1–4.9)
ences could be due to several factors: particularly
the sociodemographic distribution in the studied
cohorts as well as testing strategies (e.g., ELISAs
vs. point-of-care rapid tests [POCT]). Throughout
the COVID-19 pandemic in Denmark, the high-
est seroprevalence was recorded in the area of the
Capital Region, including Copenhagen [14]. The
vast majority of the present study population lived
or worked in the Capital Region at the time of
sampling. The seroprevalence increased signifi-
cantly from the baseline sampling during the sum-
mer of 2020 to the 6-month follow-up during the
winter of 2020/2021, as expected according to the
increase in the SARS-CoV-2 infection rate nation-
ally. Strikingly, the seroprevalence rose markedly

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SARS-CoV-2 antibody dynamics / C. B. Hansen et al.

Fig. 8 Frequency of persistent coronavirus disease 2019 (COVID-19) symptoms after infection in individuals who partici-
pated in the 6-month sampling (n = 1030). (a) Frequency, represented in percentage (%), of persistent COVID-19 symptoms
in individuals among 18–40, 41–60, and ≥61 years old. Orange, green, and gray bars represent number of symptoms
experienced being no symptoms, 1–3 symptoms, and ≥4 symptoms, respectively. (b) Frequency, represented in percentage
(%), of persistent COVID-19 symptoms in females and males. Orange, green, and gray bars represent number of symptoms
experienced being no symptoms, 1–3 symptoms, and ≥4 symptoms, respectively. (c) Frequency, represented in percentage
(%), of persistent COVID-19 symptoms experienced in all individuals who reported at least one symptom (orange bars). Same
dataset is also presented divided into females (green bars) and males (gray bars).

from 7.6% in the sampling round performed in
December 2020 compared to 17.9% in January
2021. According to the Danish national registries,
there was an increase in the incidence of infected
individuals during the fall/winter of 2020, with a
peaking incidence in mid-December [17]. However,
the stark rise in seroprevalence during the hol-
iday season might partly be due to bias in this
study population as it was not observed to the
same extent in other population-based studies [6].
Participants received a personal serostatus result
following all sampling sessions and therefore sam-
pling bias could be introduced because individu-
als that knew or suspected infection (during the
holidays) would be more prone to participate in the
January sampling. Placement of testing sites, dis-
tance from residence and availability could have
influenced the ability to participate and thereby
skew the sampled population.
A slightly higher seroprevalence was observed in
men than women at baseline and 6-month follow-
up. Moreover, male sex was a significant risk factor
for seropositivity in the binary logistic regression
model at baseline. However, this observed sex dif-
ference does not appear to be a significant factor

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Journal of Internal Medicine, 2023, 293; 763–781

SARS-CoV-2 antibody dynamics / C. B. Hansen et al.
in systematic reviews and meta-analyses on sero-
prevalence [18–20].
Differences in seroprevalence according to age
groups were detected, although the associations
were not consistent over time. The age group,
including individuals aged 41–60, had a lower
risk of seropositivity than individuals aged 18–40
in both sampling rounds. In contrast, individu-
als aged 61 years or older had increased seropos-
itivity at baseline and decreased seropositivity in
the 6-month sampling compared to the other age
groups. The association between age and seroposi-
tivity is somewhat conflicting in Danish seropreva-
lence studies. Fogh et al. reported the highest pro-
portions of seropositivity among older participants
in a nationwide surveillance study conducted in
September and October 2020 [13]. However, the
seroprevalence was determined by POCT, and the
results should be interpreted with caution due to a
lower-than-expected test performance. Espenhain
et al. observed lower seropositivity in the oldest age
group, including individuals aged 65 years or older,
compared to younger age groups in most of the
sampling rounds (August, October, and Decem-
ber 2020) [14]. In-line with our findings, the differ-
ence between the youngest and oldest age groups
was more pronounced in the winter of 2020. Erik-
strup et al. reported no clear age-dependent differ-
ence in seroprevalence in Danish blood donors in
the spring (April–May) of 2020 [15]. The difference
in seroprevalence between blood donors and our
results could be due to some ascertainment bias as
the blood donors are selected as healthy, thereby
skewing the population [21].
We observed a substantial waning of anti-RBD
antibodies (IgG, IgM, and IgA) in the subgroup of
participants that were total anti-RBD Ig seropos-
itive at baseline and participated in the 6-month
sampling as well, corresponding with previous
reports on waning of humoral immunity after
SARS-CoV-2 infection [22–24]. We found similar
waning patterns regardless of age, sex and ini-
tial antibody level by multiple regression. This
meant that individuals generating a low start-
ing level lost detectable antibodies after approxi-
mately 6 months. It is important to note that wan-
ing of humoral immunity following infection ver-
sus the one following vaccination is still debated,
and the results are diverging [25–27]. Additionally,
we observed increased antibody levels postvacci-
nation in individuals infected prior to vaccination
compared to vaccinated infection naïve individu-
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Journal of Internal Medicine, 2023, 293; 763–781
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als, agreeing with existing knowledge on increasing
antibody titers in individuals with hybrid immunity
[12, 28, 29].
The presence of asymptomatic and presymp-
tomatic transmission is a major reason for SARS-
CoV-2’s rapid spread. Asymptomatic or mildly
symptomatic cases account for 30%–60% of all
SARS-CoV-2 infections [30]. A total of 31% of the
seropositive individuals reported 1 or more per-
sistent COVID-19 symptoms in the second round
of sampling. The questionnaire asked participants
whether they experienced persistent symptoms
after initial COVID-19 recovery. However, they
were not asked to specify the duration of symp-
toms or estimated time from suspected infection.
In-line with several studies on long COVID, we
observed a high percentage of seropositive partici-
pants experiencing persisting symptoms: anosmia
and/or ageusia (17.5%) and fatigue (15.3%) being
the most pronounced [31–33]. Michelen et al. have
summarized long COVID symptoms and suggested
that it should be regarded as a multiorgan syn-
drome characterized by, among other less frequent
symptoms, fatigue, weakness, malaise, breathless-
ness, and concentration impairment [34]. However,
they also emphasize that the existing scientific evi-
dence is limited and disposed to bias. A signifi-
cant difference regarding sex and risk of experi-
encing prolonged COVID-19-related symptoms was
observed, as females reported these symptoms at a
higher frequency than males, in-line with previous
studies [35]. Age appeared to have an impact on
symptom presentation as well. Participants in the
age groups, including 18–60 years, reported a sig-
nificantly higher frequency of 1–3 persistent symp-
toms than the older age group. However, the oldest
age group, including 61 years or more, had a higher
frequency of experiencing ≥4 symptoms than the
younger age groups. Although female sex and age
have been proposed as risk factors in long COVID,
the data are not clear, and findings deviate between
study cohorts and study designs [36].
During the pandemic, early case identification and
isolation, social distancing, universal face mask-
ing, and strict hand hygiene were all used to
limit infection transmission in society and at work-
places. COVID-19 incidence reductions are linked
to a variety of social and personal preventative
measures [37]. Previous cross-sectional studies in
Denmark have demonstrated a high level of com-
pliance with national government recommenda-
tions [6, 13, 38]. A higher seroprevalence was

SARS-CoV-2 antibody dynamics / C. B. Hansen et al.
found among cohabitating participants not work-
ing in the Novo Nordisk Group than among employ-
ees in the Novo Nordisk Group (Table 2). This
observation could be due to sampling bias as
employees had easier access to sampling sites than
cohabitating participants not working in the Novo
Nordisk Group. Surprisingly, no difference was
seen between job positions. We expected a lower
proportion of seropositivity among employees in
production due to strict sterile guidelines in these
areas. During the pandemic, the Novo Nordisk
Group implemented several preventive measures
and guidelines to be followed by all employees at
every site and working area (Table S3). This might
be the reason why we did not observe any signifi-
cant differences in seropositivity between working
areas within the Novo Nordisk Group.
Several studies have found that transmission
within households is a significant venue for the
spread of SARS-CoV-2 [39]. A Danish study
showed that being exposed to a SARS-CoV-2-
infected household member significantly increased
the risk of seropositivity, as did living in a multi-
generational household or with at least four people
together [6]. A systematic review and metanalysis
showed that exposure in settings with familiar
contacts increased transmission of SARS-CoV-2
potentially and that households showed the high-
est transmission rates [40]. However, in the present
study, we did not observe an association between
household size and increased risk of seropositivity.
There have been reports of cluster outbreaks and
superspreading events. Even when an epidemic
appears to be under control, greater outbreaks
could still happen due to the importation of SARS-
CoV-2 through traveling. The first reported super-
spreading event with SARS-CoV-2 was in January
2020, with an individual attending a conference in
Singapore, spreading the virus across the United
Kingdom, France, and Japan through exposure at
a ski resort [30]. Another instance of superspread-
ing occurred at an international business confer-
ence in Boston in February 2020, with sustained
community transmission resulting in widespread
regional, national, and international spread [41].
The present data did not show a significant impact
of travel activity on serological status. Only a trend
toward increased seropositivity by increased travel
activity, which was most likely due to private rather
than work-related travel, as participation in inter-
national conferences and meetings was canceled
for all Novo Nordisk Group employees in 2020.
© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
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The present work has limitations. The screening
assay (S-ELISA) was performed with a sensitiv-
ity of 98% and a considerably low specificity of
89% in the fully automated setup, which impacts
the accuracy of the prevalence estimates. There
is an unavoidable risk of recall bias due to the
retrospective reporting of persistent COVID-19
symptoms, which could influence the accuracy
of symptom prevalence estimates and result in
both over- and underestimation. Furthermore,
we did not collect data regarding the duration of
symptoms. Therefore, we could not investigate
the prevalence of symptoms over time. The cohort
consists of Novo Nordisk Group employees and
their respective household members and therefore
does not necessarily resemble the general Danish
population. All Novo Nordisk Group employees in
Denmark were offered to participate in the study.
Still, factors like the placement of testing sites,
distance from the residence, and work schedule
could have influenced the ability to participate
and thereby introduce bias. Nevertheless, our
study reflects the situation in a major working
place comprising different sites and socioeconomic
backgrounds as well as their households. This
setup may indeed provide several strengths and
allow a more in-depth analysis of contributing
factors than nationwide surveys.
Conclusion
In conclusion, this work provides insight into
SARS-CoV-2 antibody seroprevalence, waning,
long COVID, and risk factors for seropositivity in
a sizeable company-based setting. The study illus-
trates how to utilize a delimited group of indi-
viduals in working environments with a diverse
socioeconomic backgrounds as a model system to
comprehensively investigate this complex topic and
unravel factors associated with disease transmis-
sion, humoral immunity, and symptomatology in a
time-dependent manner.
Author contributions
Conceptualization; data curation; formal analy-
sis; investigation; project administration; writing—
original draft: Cecilie Bo Hansen. data curation;
formal analysis; writing—original draft: Kristina
Dvoncova. data curation, formal analysis, writing—
original draft, writing—review and editing: Laura
Pérez-Alós. Conceptualization; investigation; project
administration; writing—original draft; writing—
review and editing: Kamille Fogh. Data curation;
formal analysis; investigation; writing—review and
779
Journal of Internal Medicine, 2023, 293; 763–781

SARS-CoV-2 antibody dynamics / C. B. Hansen et al.
editing: Johannes Roth Madsen. Formal analy-
sis; writing—review and editing: Caroline Hartwell
Garred, Ida Jarlhelt, Steffan Svejgaard Petersen.
formal analysis, writing—review and editing: Char-
lotte Gandsø Fjordager. Formal analysis, Writing—
review and editing: Klara Tølbøll Lauritsen. Con-
ceptualization; investigation; project administration;
writing—review and editing: Pernille Brok Nielsen.
Investigation; writing—review and editing: Linda
Hilsted, Lasse Boding. Conceptualization; fund-
ing acquisition; investigation; project administra-
tion; resources; supervision; writing—review and
editing: Kasper Karmark Iversen. Conceptualiza-
tion; project administration; writing—original draft;
writing—review and editing: Liselotte Hyveled. Con-
ceptualization; funding acquisition; project admin-
istration; resources; supervision; writing—original
draft; writing—review and editing: Peter Garred.
Acknowledgments
First of all, we want to thank all the Novo Nordisk
Group employees and their respective household
members that made this study possible. The
authors wish to thank Sif Kaas Nielsen, Mads
Engelhardt Knudsen, and Bettina Eide Holm from
the Laboratory of Molecular Medicine at Rigshos-
pitalet; Helle Bach Petersen, Berit Engberg, and
Juliano Olsen from Novo Nordisk A/S for their
excellent technical and logistic assistance. The
authors also thank Else Marie Agger from Novo
Nordisk A/S for her invaluable help. Novo Nordisk
A/S is acknowledged for their help in producing
recombinant proteins. This work was financially
supported by grants from the Carlsberg Founda-
tion (CF20-0045) and the Novo Nordisk Foundation
(NFF205A0063505 and NNF20SA0064201).
Conflict of interest statement
The authors declare no conflict of interests.
Data availability statement
Data are available from the corresponding author
upon reasonable request.
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Journal of Internal Medicine, 2023, 293; 763–781
13652796, 2023, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13637 by Cochrane Malaysia, Wiley Online Library on [11/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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Correspondence: Cecilie Bo Hansen, Laboratory of Molecular
Medicine, Department of Clinical Immunology, Section 7631,
Rigshospitalet, Copenhagen University Hospital, Copenhagen,
Denmark.
Email: cecilie.bo.hansen@regionh.dk
Supporting Information
Additional Supporting Information may be found in
the online version of this article:
Table S1: Baseline characteristics of participants
in the 12-month sampling (August 2021).
Table S2: Baseline characteristics of participants
in the first sampling period (December 2020) and
the second sampling period (January 2021) of the
6-month sampling.
Table S3: Novo Nordisk Group recommendations
during the study period.
Table S4: Questionnaire – Round 1 (baseline).
Table S5: Questionnaire – Round 2 (6-month
follow-up).
Table S6: Questionnaire – Round 3 (12-month
follow-up).
Figure S1: Distribution of antibody levels.
Figure S2: IgM and IgA waning from baseline to
6 month.
Figure S3: Persistent COVID-19 symptoms in
seronegative individuals.
781
Journal of Internal Medicine, 2023, 293; 763–781