1284 | www.pidj.com The Pediatric Infectious Disease Journal • Volume 31, Number 12, December 2012
Abstract: We determined the response of 48 Down syndrome children to 2
doses of influenza A/H1N1 vaccination. Ninety-two percent of the children
reached the previously defined protective level (hemagglutination-inhibi-
tion titer ≥1:40), but only 27% of the children reached the level of ≥1:110
which was recently described to predict the conventional 50% clinical pro-
tection rate in children. Further studies, and potentially adaptations of the
schedule, are needed.
Key Words: Down syndrome, influenza A vaccination, H1N1
(Pediatr Infect Dis J 2012;31: 1284–1285)
tion, sepsis and death.1,2 This can be explained by anatomic and
functional ear-nose-throat abnormalities, hypotonia, cardiac abnor-
malities, mental retardation and increased incidence of gastroe-
sophageal reflux,3–5 but also decreased antibody responses to vac-
cination are seen.6–8 The immune response to influenza vaccination
in DS has been described as decreased9 or as normal.10
In 2009, the emergence of a new influenza A virus (H1N1)
led to a worldwide pandemic. Vaccination campaigns were started
in response to the expected high morbidity and mortality. In the
Netherlands, patients with, for example, chronic respiratory, cardiac
or immunological diseases who normally would be offered a yearly
seasonal influenza vaccine were offered H1N1 vaccination as well.
Also, healthy children aged 6 months to 4 years were offered 2 influ-
enza A/H1N1 vaccinations in a nationwide campaign. DS children
are not regarded as a risk group for influenza in the Netherlands,
and therefore are not routinely offered a seasonal influenza vac-
cine, unless they have additional pulmonary or cardiac disease. The
2009 H1N1 vaccination campaign was used to measure the antibody
response after 2 doses of influenza A/H1N1 in 48 DS children.
any children with Down syndrome (DS) suffer from recur-
rent respiratory infections with higher rates of hospitaliza-
Three Dutch hospitals—Jeroen Bosch Hospital in ‘s-Her-
togenbosch, Máxima Medical Centre in Veldhoven, Elkerliek Hos-
pital in Helmond—included 73 DS children after informed parental
consent. During routine visits to the outpatient clinic, extra blood
was drawn. Forty-eight blood samples were collected from 48 vac-
cinated DS children (median age 8.8, range 0.7–17 years; 26 boys)
with a median of 154 days (range 23–267) after 2 doses of the 2009
influenza A/H1N1 vaccine (monovalent MF59-adjuvanted). A
comparison was made with 25 unvaccinated DS children (median
age 8.5, range 0.2–19 years; 17 boys). All assays were performed in
the laboratory of the St. Elisabeth Hospital in Tilburg, the Nether-
lands. Virus-specific antibodies were measured by a hemagglutina-
tion-inhibition (HI) assay, using egg-grown A/California/7/2009 A
(H1N1) pandemic virus and fresh turkey red blood cells in Alsever’s
solution (Biotrading, Mijdrecht, Netherlands), according to stand-
ard methods.11 The HI titer was the reciprocal of the highest dilu-
tion of serum that inhibited virus-induced hemagluttination. Titers
<10 were assigned a value of 5. Comparison of HI assay data from
different laboratories is complicated by a lack of standardization
due to the use of various influenza virus strains, different receptor-
destroying enzymes (homemade or commercially bought) and also
by differences in quality and nature of red blood cells. Red blood
cells and receptor-destroying enzyme were bought commercially to
overcome this problem, and a candidate international standard for
antibody titers to pandemic H1N1 virus was used to calibrate our
A HI titer of ≥1:40 has been reported to result in a 50%
reduction of influenza infections in healthy adult individuals.13 Up
to recently, this titer was used as protective cut-off value in chil-
dren as well. Recently, Black et al14 challenged this cut-off value
in healthy children and suggested a new cut-off value of at least
≥1:110 in healthy children for a 50% influenza infection reduction.
HI titers of DS children are shown in Figure 1. Ninety-two
percent of the 48 vaccinated DS children reached an HI titer of
≥1:40. Only 27% of the 48 vaccinated DS children reached an HI
titer of ≥1:110. In comparison, 28% of unvaccinated DS children
reached an HI titer of ≥1:40 after the influenza season, and no
unvaccinated DS child reached the HI titer of ≥1:110.
In 1 child, parents reported a possible side effect of fever after
the first vaccination. In the vaccinated group, flu-like symptoms
were reported in 1 child, but no influenza tests were performed
during that time. In the unvaccinated group, 4 children had flu-like
symptoms; 1 child was admitted to hospital (test results: influenza
negative, respiratory syncytial virus positive).
Postvaccination HI titers of ≥1:40 have been reported to
result in a 50% reduction of influenza infections in healthy adults.13
Because 92% of our 48 vaccinated DS children reached this HI
titer after 2 doses of the 2009 influenza A/H1N1 vaccine, it would
be logical to conclude that this is an effective vaccination strategy
for DS children. However, this HI cut-off value has not been stud-
ied for influenza A/H1N1 vaccination in children. Prevaccination
Copyright © 2012 by Lippincott Williams & Wilkins
Influenza A/H1N1 Vaccination Response Is Inadequate
in Down Syndrome Children When the Latest Cut-off
Values Are Used
Maaike A. Kusters, MD,* Vinus L.A. Bok, MD,† W.E.A. Bolz, MD, PhD,‡ E.G.W. Huijskens, MD,§
M.F. Peeters, PhD,§ and Esther de Vries, MD, PhD*
Accepted for publication August 21, 2012.
From the *Department of Pediatrics, Jeroen Bosch Hospital, `s-Hertogenbosch;
†Department of Pediatrics, Màxima Medical Centre, Veldhoven; ‡Depart-
ment of Pediatrics, Elkerliek Hospital, Helmond; and §Medical Microbiology
and Immunology Laboratory, St. Elisabeth Hospital, Tilburg, the Netherlands.
M.F. Peeters is deceased.
The authors have no funding or conflicts of interest to disclose.
Address for correspondence: Esther de Vries, MD, PhD, Department of Pediat-
rics, Jeroen Bosch Hospital, PO Box 90153 (C5.02.022), 5200 ME `s-Herto-
genbosch, the Netherlands. E-mail: firstname.lastname@example.org.
The Pediatric Infectious Disease Journal • Volume 31, Number 12, December 2012 H1N1 Vaccination in Down Syndrome
© 2012 Lippincott Williams & Wilkins www.pidj.com | 1285
data from the available literature show that up to 30% of healthy
children already reach an HI titer of ≥1:40 without a history of
previous influenza A/H1N1 vaccination or active influenza A/
H1N1 infection.15,16 Cross-reactive antibodies from other influenza
strains could be held accountable, but it seems that this explanation
is not entirely valid, as recent studies demonstrated no cross-reac-
tivity between antibodies of previous seasonal influenza and H1N1
strains in children.17,18
The applicability in children of the World Health Organi-
zation cut-off value has recently been challenged by Black et al
in this journal.14 They predict that an HI titer of ≥1:110 is needed
for a 50% clinical protection rate in healthy children, at least until
6 years of age. Unfortunately, most pediatric publications do not
show individual HI titers. In a recent Swiss publication,19 postvac-
cination HI titers of ≥1:110 were reached in ≥90% of healthy chil-
dren using 1 dose of influenza A/H1N1 MF59-adjuvanted vaccine.
No large studies correlating HI titer and clinical protection in chil-
dren are as yet available.
Our study shows that DS children only reach the new pro-
posed cut-off value of ≥1:110 in 27% of the cases studied. This is
a lower response than that was reported for non-DS children and is
another example of decreased immunological vaccination response
in DS. A larger study is needed to determine the efficacy of clinical
protection of H1N1 influenza vaccination in DS children.
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FIGURE 1. HI titer in children with DS after influenza A/
H1N1 vaccination. X-axis indicates days after second H1N1
vaccination; Y-axis, HI titer (1:y); dots, DS children vacci-
nated twice with influenza A/H1N1; triangles, unvaccinated
DS children; horizontal dotted line, HI titer = 1:110; horizon-
tal striped line: HI titer = 1:40.