Adverse events reported after fourth and fifth dose of DT Vaccine
Martin-Munoz MF, Pereira MJ, Posadas S, Sanchez-Sabate E, Blanca M, Alvarez J.
Allergy Service, University Hospital La Paz, Paseo de la Castellana, 261, 28046 Madrid, Spain. mfmartin@hulp.insalud.es
The present study describes the occurrence of an anaphylactic reaction after the administration of the fifth booster dose of DT vaccine in a six-year-old child. Skin test, in vitro determinations of specific IgE antibodies and immunoblotting assays showed that the IgE response was directed against tetanus and diphtheria toxoids (Dtx). IgG antibodies were also detected by ELISA and immunoblotting. The RAST and immunoblotting inhibitions showed no cross-reactivity between the two toxoids, indicating the presence of co-existing but non-cross-reacting IgE and IgG antibodies. This was maintained in two subsequent determinations done 18 and 30 months after the episode. To our knowledge, this is the first study of cross-reactivity between tetanus and diphtheria antigens. We show that simultaneous IgE antibodies to two different toxoids may occur, indicating that after an immediate reaction to DT, a search for IgE antibodies to both tetanus and Dtx should be undertaken.
Adverse events reported after fourth and fifth doses of DTaP
references
http://www.cdc.gov/mmwr/pdf/rr/rr4913.pdf
Vol. 49 / No. RR-13 MMWR 3
REACTOGENICITY OF DTaP VACCINES
WHEN ADMINISTERED AS FOURTH
AND FIFTH DOSES OF A SERIES
Data regarding use of a single DTaP vaccine for the complete five-dose series
are
limited, but available data demonstrate a substantial increase in the frequency
and magnitude of local reactions after the fourth and fifth doses. Increases
in the frequency of fever after the fourth dose have been reported also, although
increased frequencies of other systemic reactions (e.g., fretfulness, drowsiness,
or decreased appetite) have not been observed. Despite the increased reactogenicity
of the fourth and fifth doses, acellular pertussis vaccines remain the preferred
vaccines for preventing pertussis, diphtheria, and tetanus among children because
of the improved safety profile when compared with whole-cell pertussis vaccines
( 2-5).
Adverse Reactions After the Fourth Dose of DTaP
When Administered as a Four-Dose Series Increases in erythema, swelling, and pain at the injection site and increases in fever have been reported with the fourth dose as compared with the first dose for each of the currently licensed DTaP vaccines. These reactions typically have onset within 2 days of vaccination and resolve completely without sequelae ( 6). During 1991-1994, reactogenicity of ACEL-IMUNE administered as a four-dose series was assessed in an efficacy study in Germany ( 7). DTaP and diphtheria and tetanus toxoids and whole-cell pertussis vaccine (DTP) components of the study were randomized and double-blinded. Local and systemic reactions were reported on standard diary cards for 72 hours after each dose. Of 3,991 children who received the fourth dose of ACEL-IMUNE, 10% experienced erythema >0.9 in. (>2.4 cm), and 9% experienced induration >0.9 in. (>2.4 cm). After the first dose, only 2% of recipients were reported as experiencing erythema or induration of this magnitude. Fever >100.4 F (>38 C) was reported for 7% of recipients of the first dose, but after the fourth dose, 26% of recipients experienced fever >100.4 F (>38 C) ( 4,8). In an open-label trial (i.e., a study in which researchers and subjects know what vaccine and dose is being administered) in the United States, 109 infants who had previously received Tripedia at ages 2, 4, and 6 months received a fourth dose at age 15-20 months ( 9). Reactions were assessed by parents at 6, 24, and 48 hours and daily thereafter for 14 days, and parents were asked to record daily on a standardized diary the presence or absence of injection-site tenderness, redness, or swelling. Of children receiving the fourth dose, 5.5% experienced fever >101 F (>38.3 C) within 72 hours of vaccination; 30.3%, injection site redness >1 in. (>2.54 cm); 29.4%, injection site swelling >1 in. (>2.54 cm); and 19.3%, injection site pain ( 9). In contrast, during the primary series study of 218 infants, no infants experienced fever >101 F (>38.3 C) after the first dose; 2%, erythema >1 in. (>2.54 cm); 2%, swelling >1 in. (>2.54 cm); and 10%, tenderness at the injection site ( 10). Of 22,505 children who had received three doses of Infanrix® (SmithKline Beecham Biologicals) at ages 3, 4, and 5 months during an open-label safety trial in Germany during April 1993-November 1994, 5,361 received a fourth dose at age 10-36 months
4 MMWR November 17, 2000 ( 11). Standardized diaries reporting adverse events occurring within 3 days of vaccination were available for 1,809 children who had received the fourth dose. Age range of this subset of children was 14-28 months. Rates of redness, swelling, pain, and fever increased with successive doses. Redness >0.8 in. (>2 cm) increased from 0% after the first dose to 13.8% after the fourth dose; swelling >0.8 in. (>2 cm), from 0% to 11.4%; pain, from 2.0% to 26.3%; and fever >100.4 F (>38 C), from 6.3% to 26.4% ( 11-13). Increases in the reactogenicity of the fourth dose of Certiva™ (North American Vaccine, Inc.) also have been reported. Fourth-dose data have been reported for 316 infants, a subset of >2,200 who received Certiva as a three-dose primary series during an openlabel trial in the United States ( 14). Safety data were collected using standardized diary cards and telephone follow-up. Fever >100.4 F (>38 C) within 72 hours of vaccination increased in frequency from the first dose to the fourth dose, with fever reported among 1.5% of first-dose recipients and 10.5% of fourth-dose recipients. Frequency of redness >1.2 in. (>3 cm) increased from 0.2% after the first dose to 5.7% after the fourth dose; swelling >1.2 in. (>3 cm), from 0.6% to 4.5%; and tenderness or pain (any), from 5.9% to 19.0% ( 14).
Adverse Reactions After the Fifth Dose of DTaP When Administered as a Five-Dose Series
Data regarding the reactogenicity of a fifth dose of DTaP administered after
four doses of the DTaP vaccine are limited, but are available for three of the
four currently licensed DTaP vaccines. These data demonstrate further increases
in the local reactogenicity of the fifth dose compared with the fourth dose.
No data are available regarding the frequency of adverse events after a fifth
dose of Certiva. Data have been summarized from four clinical trials in the
United States and Germany, during which 357 infants received a fifth dose of
ACEL-IMUNE after having received four previous doses of the same vaccine. Case
definitions of substantial erythema and induration varied by protocol, ranging
from >0.8 in. (>2 cm) to >0.9 in. (>2.4 cm). However, substantial
erythema within 72 hours after the fifth dose was reported for 20% of recipients;
substantial induration for 14%; and tenderness for 38% ( 8). In a study in Germany
during March-September 1998, of 580 children who received a fifth dose of Tripedia
after four previous doses of the same vaccine, 31.0% experienced redness >2
in. (>5 cm) within 3 days of receipt of vaccine; 25.0% experienced swelling
>2 in. (>5 cm); and 2.1% experienced severe pain (i.e., crying when the
arm was moved) ( 15, Aventis Pasteur, Inc., unpublished data, January 2000).
During a safety study in Germany, 413 children received a fifth dose of Infanrix
after four previous doses of the same vaccine. During the 3 days after vaccination,
redness >2 in. (>5 cm) was reported for 30.3% of recipients; swelling
>2 in. (>5 cm), for 20.7%; and grade 3 pain (i.e., pain that prevented
everyday activities and necessitated medical advice) for 1.6% of the 376 children
for whom symptom sheets were completed (SmithKline Beecham Biologicals, unpublished
data, February 2000).
Limb Swelling After Booster Doses of DTaP
Swelling involving the entire thigh or upper arm has been reported after booster
doses of different acellular pertussis vaccines. Swelling of the entire thigh
was reported Vol. 49 / No. RR-13 MMWR 5 among recipients of a booster dose of
JNIH-6 (a two-component acellular pertussis vaccine produced by Biken [Japan]
and comparable to the acellular pertussis component contained in Tripedia).
During a study performed in Sweden during the 1980s, children who had previously
received two or three doses of Biken acellular pertussis vaccine at age 6-8
months received a booster dose deep subcutaneously of the same vaccine at age
2 years. Certain children experienced substantial local reactions, including
swelling of the entire thigh ( 16), although administration of vaccine subcutaneously
could have influenced reaction rates in that study. Occurrence of extensive
swelling involving the entire thigh of vaccinated children was reported among
DTaP recipients in an open-label safety study in Germany during April 1993-November
1994, in which children who had previously received Infanrix at ages 3, 4, and
5 months received a fourth dose at age 10-36 months ( 11). Standardized diaries
were available for 1,809 children, with data collected regarding the occurrence
of specific solicited symptoms for 3 days after receipt of vaccine. Parents
of the remaining 3,498 children were asked to report any symptoms occurring
during the 28 days after vaccination; no specific symptoms were solicited. Among
5,361 vaccinees, an increase in thigh circumference was reported as an unsolicited
reaction for 62 vaccinees (45 in the first group and 17 in the second group;
frequency: 1.2%). One of six centers participating in the study accounted for
a majority of these reports; at that center, this reaction was reported for
51 of 1,583 children (3.2%). Among 17 children whose thighs were measured, the
mean increase in circumference was 0.9 in. (2.2 cm) (range: 0.2-2.0 in. [0.5-5
cm]). Swelling began within 48 hours of booster dose administration for 51 of
62 children; the mean duration of swelling was 3.9 days (range: 1-7 days). For
a limited number of children, the swelling interfered with walking; but for
the majority of children, no limitation of activity was experienced. None of
the children were febrile. Pain when digital pressure was applied was reported
for 51% of the children, and itching was observed among a limited number of
children ( 11). In an analysis of the fourth- and fifth-dose follow-up studies
from the Multicenter Acellular Pertussis Trial (MAPT) that examined 12 different
DTaP vaccines, entire limb swelling was reported as an unsolicited reaction
for 20 (2.0%) of 1,015 children who received four consecutive doses of the same
DTaP ( 17). Entire thigh swelling was reported for 1 of 16 children receiving
four consecutive doses of DTP and for 0 of 246 children receiving a booster
dose of DTaP after three doses of DTP. Among children experiencing entire thigh
swelling after the fourth dose, 70% were described as irritable, compared with
37% of fourth-dose recipients who did not experience entire thigh swelling.
Erythema was reported for 60% of the vaccinees and pain for 60%; the corresponding
frequencies among children without entire thigh swelling were 29% and 30%, respectively.
Fever >100 F (>37.8 C) was reported for approximately 25% of both groups.
Among the 20 children with entire thigh swelling, pain was judged to be mild
for 7, moderate for 2, and severe for 3; pain was not reported for 8 of these
20 children. Of eight children whose swelling began on day 1, five experienced
moderate or severe pain. A total of 12 children experienced swelling that began
on day 2 or 3, none of whom experienced moderate or severe pain. Entire thigh
swelling resolved completely and without sequelae among all 20 children (duration:
1-4 days among 11 children for whom duration was known). Among fifth-dose recipients,
0 of 121 children who had received the same DTaP vaccine experienced swelling
of the entire upper arm; but such swelling occurred among 4 of 146 children
(2.7%) who had received different DTaP vaccines during the five dose series.
Although the numbers of children receiving fourth and fifth doses during
6 MMWR November 17, 2000 MAPT follow-up studies were limited, extensive limb
swelling occurred after receipt of a fourth dose of 9 of the 12 DTaP vaccines
included in the study ( 17). Recent studies of the fifth dose of Tripedia and
Infanrix have also identified cases of extensive limb swelling. During an open-label
trial performed in Germany during March-September 1998, swelling of the entire
upper arm was reported as an unsolicited reaction for 14 of 490 children (2.9%)
who had received a fifth dose of Tripedia (Aventis Pasteur, Inc., unpublished
data, January 2000). For 13 of the 14 children, swelling began within 3 days
of vaccination. Associated symptoms included redness for 10 of the 14 (71.4%)
vaccinees, pain for 5 (35.7%), and fussiness for 2 (14.3%). Pain was graded
as mild for all children for whom it was reported. No children had fever >100.4
F (>38 C), and only two children were evaluated during an office visit. Median
duration of swelling was 4 days (range: 3-6 days) (Aventis Pasteur, Inc., unpublished
data, January 2000). During an open-label trial in Germany of Infanrix as a
fifth dose after four doses of Infanrix, parents or caretakers were informed
of the possibility of limb swelling (SmithKline Beecham Biologicals, unpublished
data, February and May 2000). Although limb swelling was not specifically solicited
on diary cards, parents or caretakers were asked to contact the investigators
if their children experienced such a reaction. Of 413 subjects enrolled, parents
of 26 children contacted the investigators to report that their children had
experienced swelling. A total of 3 of the 26 children (11%) had fever >99.5
F (>37.5 C) when measured axillarily or orally or >100.4 F (>38 C)
when measured rectally. Other associated symptoms included pain for 23 (88.5%)
vaccinees, which was diffuse for 6. Redness occurred for 26 (100%) vaccinees
and was diffuse for 17. Warmth was experienced by 21 (80.8%) vaccinees and was
diffuse for 13. Of the 26 children evaluated, one child experienced swelling
extending from shoulder to elbow. That child experienced localized pain at the
injection site and diffuse redness and warmth and was afebrile. For one child,
swelling was assessed as grade 3 severity (i.e., prevented normal everyday activities
and necessitated medical advice). For all vaccinees experiencing swelling, reaction
began within 3 days of receipt of vaccine. Mean duration of swelling was 4 days
(range: 1-10 days) (SmithKline Beecham Biologicals, unpublished data, February
and May 2000). Pathogenesis of both substantial local reactions and limb swelling
is unknown. In an analysis of data from the MAPT fourth- and fifth-dose follow-up
studies, swelling >2 in. (>5 cm) after the fourth dose was associated
with pertussis toxoid content of the vaccine administered; swelling after the
fifth dose was associated with the aluminum content of the vaccine. Entire thigh
swelling after the fourth dose was associated with diphtheria toxoid content
of the vaccine. Prevaccination antibody levels to diphtheria, tetanus, or pertussis
toxins were not predictive of this reaction. The inconsistent pattern of associations
of vaccine content and swelling could indicate that the associations were a
statistical artifact attributable to a limited sample size or to differential
reporting of entire thigh swelling among the DTaP vaccine groups ( 17).
SUPPLEMENTAL ACIP RECOMMENDATIONS FOR USING DTaP VACCINES
Data are limited regarding differences in reactogenicity among currently licensed
acellular pertussis vaccines. Increases in frequency and magnitude of substantial
local reactions at the injection site with increasing dose number have been
reported for all Vol. 49 / No. RR-13 MMWR 7 currently licensed DTaP vaccines.
Swelling of the thigh or entire upper arm after receipt of fourth and fifth
doses of acellular pertussis vaccines has been documented for multiple products
from different manufacturers. However, because reports of these reactions have
generally not been solicited during safety studies, the frequency is unknown,
and the absence of reports does not establish a lack of reaction after receipt
of particular DTaP vaccines. Additionally, in the majority of studies of adverse
events after receipt of the fourth and fifth doses of DTaP, participants represent
a subset (a substantially limited subset in certain studies) of children who
received the first three doses. Therefore, the observed frequencies of substantial
swelling reactions might have been influenced by selection biases of unknown
direction and magnitude. Data are insufficient to establish that mixed sequences
of DTaP vaccines from different manufacturers are associated with higher or
lower frequencies of these reactions than receipt of a single product for the
entire DTaP series. Additional data regarding the reactogenicity of DTaP vaccines
when administered as a five-dose series are needed. Whether children who experience
entire limb swelling after a fourth dose of DTaP are at increased risk for this
reaction after the fifth dose is unknown. Because reports to date indicate that
the reactions are self-limited and in recognition of the benefits of the preschool
dose of DTaP, a history of extensive swelling after the fourth dose should not
be considered a contraindication for receipt of the fifth dose of the DTaP series.
Parents or caregivers of children receiving the fourth and fifth doses of the
DTaP series should be informed of the increases in reactogenicity that have
been observed. Although available data demonstrate that these reactions are
self-limited and resolve without sequelae, they might be clinically indistinguishable
from other conditions (e.g.,
cellulitis) that require treatment. Therefore, providers must make decisions
regarding evaluation and management of children with suspected reactions after
DTaP vaccination on a case-by-case basis.
Interchangeable Use of Acellular Pertussis Vaccines
Children who began the series with DTaP at age 2 months began eligibility to
receive a fifth dose of DTaP during mid-2000. A child who began the series late
and was vaccinated on an accelerated schedule might have become eligible for
the fifth dose before then. Data are insufficient to document the safety, immunogenicity,
and efficacy of using DTaP vaccines from different manufacturers in a mixed
sequence. For this reason, the ACIP recommends that whenever feasible, the same
brand of DTaP vaccine should be used for all doses of the vaccination series.
However, the vaccine provider might not know or have available the type of DTaP
vaccine previously administered to a child. Neither circumstance should present
a barrier to administration of DTaP vaccine and any of the available licensed
DTaP vaccines can be used to complete the vaccination series.
Are the fourth and fifth doses needed?
http://www.pediatrics.org/cgi/content/abstract/108/5/e81
ELECTRONIC ARTICLE:
Sustained Efficacy During the First 6 Years of Life of 3-Component Acellular
Pertussis Vaccines Administered in Infancy: The Italian Experience
Received Mar 28, 2001; accepted
Jun 18, 2001.
Stefania Salmaso*, Paola Mastrantonio [Dagger ] , Alberto E. Tozzi*, Paola Stefanelli
[Dagger ] , Alessandra Anemona*, Marta L. Ciofi degli Atti*, Anna Giammanco§,
and the Stage III Working Group
From the Laboratories of * Epidemiology and Biostatistics and [Dagger ] Bacteriology and Medical Mycology, Istituto Superiore di Sanità, Rome, Italy; and § Department of Hygiene and Microbiology, University of Palermo, Palermo, Italy.
Background. In 1992-1993, a randomized, double-blind, placebo-controlled clinical trial of two 3-component acellular pertussis vaccines was started in 4 of Italy's 20 regions. During the trial, the children had been randomized to receive 3 doses of 1 of 2 acellular pertussis vaccines combined with diphtheria and tetanus toxoids (DT) or of a DT vaccine only, at 2, 4, and 6 months of age. Both diphtheria-tetanus-acellular pertussis (DTaP) vaccines, 1 manufactured by SmithKline Beecham (DTaP SB; Infanrix) and 1 manufactured by Chiron Biocine (DTaP CB; Triacelluvax), contain pertussis toxin (PT), filamentous hemagglutinin, and pertactin. The results of the first period of follow-up, which ended in 1994 (stage 1), showed that both vaccines had a protective efficacy of 84% in the first 2 years of life; when the trial's follow-up was extended under partial blinding until the participating children had reached 33 months of age (stage 2 of the follow-up), these high levels of efficacy had persisted. Therefore, the objective of this study was to estimate the persistence of protection from 3 to 6 years of age of the 2 3-component DTaP vaccines administered as primary immunization in infancy.
Methods. An unblinded prospective longitudinal study of vaccinated and unvaccinated children in 4 Italian regions, with active surveillance of cough, was conducted by study nurses, and Bordetella pertussis infections were confirmed laboratory. The present study (stage 3) included those children who completed stage 2 of the follow-up and were still under active surveillance as of October 1, 1995, accounting for 4217 children who had received DTaP SB (representing 94% of the vaccine's recipients in the initial phase of the trial), 4215 who had received DTaP CB (95% of the original recipients), and 266 who had received DT only (18% of the original recipients). Because the parents of most of the original DT placebo group accepted pertussis vaccination during stage 2 in 1995, an additional 856 children were recruited in the DT group at the initiation of stage 3. These additional children were identified from the census list of children born in the same period and living in the same areas as the trial participants but who had been vaccinated in infancy with DT only. Eligible children were included in stage 3 if they had no history of either pertussis or pertussis vaccination and if a serum sample obtained at the time of enrollment had undetectable immunoglobulin G (IgG) against PT. Parental consent to participate in the study was obtained. Active surveillance for pertussis was conducted in the field by 72 study nurses through monthly contact with each family in the study. A cough episode that lasted [>= ] 7 days was considered to be a laboratory-confirmed infection by Bordetella pertussis if at least 1 of the following 5 criteria (listed in hierarchic order) was met: 1) B pertussis was obtained from nasopharyngeal culture (culture-confirmed infection); 2) the enzyme-linked immunosorbent assay (ELISA) IgG or IgA titer against PT in the convalescent-phase serum sample increased by at least 100% compared with the acute-phase sample; 3) the PT-neutralizing titers in Chinese hamster ovary assay in the convalescent-phase sample increased by at least 4-fold compared with the acute-phase sample; 4) the ELISA IgG or IgA titer against filamentous hemagglutinin in the convalescent-phase sample increased by at least 100% and the culture or the polymerase chain reaction assay on the nasopharyngeal aspirate was negative for B parapertussis; and 5) the ELISA IgG PT titer in 1 of the 2 serum samples exceeded the geometric mean titer computed on convalescent sera of the children with a culture-confirmed B pertussis infection in each study group. Incidence of laboratory-confirmed B pertussis infection, using case definitions that varied in terms of duration and type of cough, was computed and the proportion of cases prevented among DTaP recipients in comparison with DT recipients was calculated.
Results. A total of 391 laboratory-confirmed infections were identified in the 3-year follow-up period (138 DTaP SB, 126 DTaP CB, 127 DT recipients, respectively). The mean duration of cough in children with laboratory-confirmed infection was 48, 47, and 70 days for the DTaP SB, DTaP CB, and DT recipients, respectively; the mean duration of spasmodic cough was 15, 13, and 23 days, respectively. When using the primary case definition (ie, laboratory-confirmed B pertussis infection and [>= ] 14 days of spasmodic cough or [>= ] 21 days of any cough), the efficacy was 78% for the DTaP SB vaccine (95% confidence interval [CI]: 71%-83%) and 81% for the DTaP CB vaccine (95% CI: 74%-85%). When using the case definition based on a more severe clinical presentation ( [>= ] 21 days of spasmodic cough), the vaccine efficacy was 86% (95% CI: 79%-91%) for both vaccines. When using the case definition based on milder clinical presentation (any cough for [>= ] 7 days), the efficacy was 76% (95% CI: 69%-81%) for the DTaP SB vaccine and 78% (95% CI: 72%-83%) for the DTaP CB vaccine.
Conclusions. The persistence of protection through 6 years of age suggests that the fourth DTaP dose could be postponed until preschool age in children who received 3-component acellular pertussis vaccines in infancy, provided that immunity to diphtheria and tetanus is maintained. Additional booster doses could be administered at older ages to reduce reactogenicity induced by multiple administrations and to optimize the control of pertussis in adolescents and young adults. Key words: pertussis, acellular vaccine, efficacy, follow-up, prospective study, children.
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