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## Complete Summary

#### GUIDELINE TITLE

\(1\) Pertussis vaccination: use of acellular pertussis vaccines among
infants and young children.\
(2) Use of diphtheria toxoid-tetanus toxoid-acellular pertussis vaccine
as a five-dose series. (Addendum)

#### BIBLIOGRAPHIC SOURCE(S)

Notice to readers: FDA approval of diphtheria and tetanus toxoids and
acellular pertussis vaccine adsorbed, (INFANRIX) for fifth consecutive
DTaP vaccine dose. MMWR Recomm Rep 2003 Sep 26;52(38):921. \[4
references\]

Pertussis vaccination: use of acellular pertussis vaccines among infants
and young children. MMWR Recomm Rep 1997 Mar 28;46(RR-7):1-25. \[50
references\]

Use of diphtheria toxoid-tetanus toxoid-acellular pertussis vaccine as a
five-dose series. Supplemental recommendations of the advisory committee
on immunization practices (ACIP). MMWR Recomm Rep 2000 Nov
17;49(RR13):1-8. \[17 references\]

#### GUIDELINE STATUS

The guideline titled \"Use of Diphtheria Toxoid-tetanus Toxoid-acellular
Pertussis Vaccine as a Five-dose Series\" (MMWR Morb Mortal Wkly Rep
2000 Nov 17;49(RR-13):1-8) supplements the previous recommendations
published in the guideline titled \"Pertussis Vaccination: Use of
Acellular Pertussis Vaccines Among Infants and Young Children\" (MMWR
Morb Mortal Wkly Rep 1997 Mar 28;46(RR-7):1-25) regarding use of DTaP
and summarizes new Advisory Committee on Immunization Practices (ACIP)
recommendations regarding DTaP vaccines as a five-consecutive\--dose
series.

Please note that a published erratum has been published for the
guideline: [\"Use of Diphtheria Toxoid-Tetanus Toxoid-Acellular
Pertussis Vaccine as a Five-Dose
Series\"](http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4947a8.htm), MMWR
Morb Mortal Wkly Rep 2000 Dec 1;49(47):1074.

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse**: This guideline
references a drug(s) for which important revised regulatory information
has been released.

On April 7, 2005, after concluding that the overall risk versus benefit
profile is unfavorable, the FDA requested that Pfizer, Inc voluntarily
withdraw Bextra (valdecoxib) from the market. The FDA also asked
manufacturers of all marketed prescription nonsteroidal
anti-inflammatory drugs (NSAIDs), including Celebrex (celecoxib), a
COX-2 selective NSAID, to revise the labeling (package insert) for their
products to include a boxed warning and a Medication Guide. Finally, FDA
asked manufacturers of non-prescription (over the counter \[OTC\])
NSAIDs to revise their labeling to include more specific information
about the potential gastrointestinal (GI) and cardiovascular (CV) risks,
and information to assist consumers in the safe use of the drug. See the
[FDA Web
site](http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm#Bextra) for
more information.

Subsequently, on June 15, 2005, the FDA requested that sponsors of all
non-steroidal anti-inflammatory drugs (NSAID) make labeling changes to
their products. FDA recommended proposed labeling for both the
prescription and over-the-counter (OTC) NSAIDs and a medication guide
for the entire class of prescription products. All sponsors of marketed
prescription NSAIDs, including Celebrex (celecoxib), a COX-2 selective
NSAID, have been asked to revise the labeling (package insert) for their
products to include a boxed warning, highlighting the potential for
increased risk of cardiovascular (CV) events and the well described,
serious, potential life-threatening gastrointestinal (GI) bleeding
associated with their use. FDA regulation 21CFR 208 requires a
Medication Guide to be provided with each prescription that is dispensed
for products that FDA determines pose a serious and significant public
health concern. See the [FDA Web
site](http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm#NSAID) for
more information.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 CONTRAINDICATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Pertussis disease (infection due to *Bordetella pertussis*; whooping
cough)

#### GUIDELINE CATEGORY

Prevention

#### CLINICAL SPECIALTY

Family Practice\
Pediatrics

#### INTENDED USERS

Physicians

#### GUIDELINE OBJECTIVE(S)

*1997 Guideline*

-   To provide general information regarding whole-cell pertussis
    vaccines currently licensed in the United States

-   To summarize results of recent studies of the immunogenicity,
    efficacy, and safety of *acellular* pertussis vaccines administered
    to infants and young children

-   To present recommendations for the use of Tripedia®, TriHIBit™,
    ACEL-IMUNE®, and Infanrix™ vaccines

-   To supplement previous recommendations on pertussis vaccination

*2000 Supplement*

-   To supplement previous recommendations regarding the use of
    diphtheria and tetanus toxoids and acellular pertussis vaccines as a
    five-consecutive-dose series

-   To summarize data regarding reactogenicity of acellular pertussis
    vaccines when administered as the fourth and fifth consecutive doses

*2003 supplement*

To supplement previous recommendations regarding the U.S. Food and Drug
Administration (FDA) approved use of diphtheria and tetanus toxoids and
acellular pertussis vaccine adsorbed (DTaP) (INFANRIX®, SmithKline
Beecham Biologicals, Rixensart, Belgium) as a fifth dose for children
aged 4 to 6 years after 4 previous doses of INFANRIX®.

#### TARGET POPULATION

Children younger than 7 years

#### INTERVENTIONS AND PRACTICES CONSIDERED

1.  Diphtheria and tetanus toxoids and acellular pertussis vaccines
    (DTaP): (Tripedia®, ACEL-IMUNE®, Infanrix®, Certiva™)

2.  Diphtheria and tetanus toxoids and whole-cell pertussis vaccine
    (DTP)

#### MAJOR OUTCOMES CONSIDERED

-   Vaccine efficacy

-   Serum antibody levels following vaccination

-   Incidence of pertussis

-   Incidence of adverse events related to the administration of
    acellular pertussis vaccine

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

Not stated

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Not stated

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

Not applicable

#### METHODS USED TO ANALYZE THE EVIDENCE

Review

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

Not stated

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Not stated

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

Not applicable

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

Not stated

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

***Note from the National Guideline Clearinghouse (NGC)***: Supplemental
guidelines for the use of diphtheria and tetanus toxoids and acellular
pertussis vaccine (DTaP) as a five dose series are included in these
recommendations (MMWR Morbid Mortal Wkly Rep 2000 Nov 17; 49\[RR-13\]:
1-8).

**The most current** supplemental guidelines for the Food and Drug
Administration (FDA) approved use of diphtheria and tetanus toxoids and
acellular pertussis vaccine adsorbed, (INFANRIX®) as a fifth consecutive
DTaP vaccine dose are **also** included in these recommendations (MMWR
Morbid Mortal Wkly Rep 2003 Sept 26; 52 \[38\]; 921-921).

**Recommended Childhood Vaccination Schedule**

The routine diphtheria, tetanus, and pertussis vaccination schedule for
children aged \<7 years comprises five doses of vaccine containing
diphtheria, tetanus, and pertussis antigens. Three (primary) doses
should be administered during the first year of life, generally at ages
2, 4, and 6 months. To maintain adequate immunity during preschool
years, the fourth (first booster) dose is recommended for children aged
15 to 18 months. The fourth dose should be administered greater than or
equal to 6 months after the third. If the interval between the third and
fourth doses is greater than or equal to 6 months and the child is not
likely to return for a visit at the recommended age, the fourth dose of
either diphtheria, tetanus and acellular pertussis or whole-cell
diphtheria, tetanus, and pertussis may be administered as early as age
12 months. The fifth (second booster) dose is recommended for children
aged 4 to 6 years to confer continued protection against disease during
the early years of schooling. A fifth dose is not necessary if the
fourth dose in the series is administered on or after the fourth
birthday.

***\*See Special Notices below***

**Vaccine Preference**

Diphtheria, tetanus, and acellular pertussis vaccines are efficacious
when administered to infants as the primary series (i.e., doses 1-3). In
addition, local reactions, fever, and other systemic events occur
substantially less often after diphtheria, tetanus, and acellular
pertussis administration than after administration of whole-cell
diphtheria, tetanus, and pertussis. Therefore, diphtheria, tetanus, and
acellular pertussis vaccines are recommended for all five doses in the
vaccination schedule. For children who have started the vaccination
series with one, two, three, or four doses of whole-cell diphtheria,
tetanus, and pertussis, diphtheria, tetanus, and acellular pertussis is
also recommended for all remaining doses in the schedule. During the
period of transition from use of whole-cell diphtheria, tetanus, and
pertussis to diphtheria, tetanus, and acellular pertussis, whole-cell
diphtheria, tetanus, and pertussis is an acceptable alternative to
diphtheria, tetanus, and acellular pertussis for any of the five doses.
For the first four doses, whole-cell diphtheria, tetanus, and pertussis
combined with Haemophilus influenza type B (Hib) vaccine (diphtheria,
tetanus, and pertussis-Haemophilus influenza type B vaccine) is an
acceptable alternative to diphtheria, tetanus, and acellular pertussis
and Haemophilus influenza type B vaccine administered at separate sites.

**Licensed Products**

Three acellular pertussis vaccines (Tripedia® and Infanrix™ for the
first four doses and ACEL-IMUNE® for all five doses) are licensed for
the diphtheria, tetanus, and pertussis vaccination series. The Food and
Drug Administration (FDA) has not approved Tripedia® or Infanrix™ as the
fifth dose among persons who have received only Tripedia® or only
Infanrix™ for the first four doses in the vaccination series, because
data are insufficient to evaluate their safety in this situation.
However, such data should be available before infants vaccinated with
four doses of these vaccines require a fifth dose at age 4 to 6 years.
TriHIBit™ (ActHIB® reconstituted with Tripedia®) is licensed only for
the fourth dose of the vaccination series, and is not licensed for the
first three doses. TriHIBit™ can be used for the fourth dose following
three doses of either diphtheria, tetanus, and acellular pertussis or
whole-cell diphtheria, tetanus, and pertussis and a primary series of
any Haemophilus influenza type B vaccine.

***New Information from the 2000 Supplement***

Four vaccines containing diphtheria and tetanus toxoids and acellular
pertussis vaccine (DTaP) are licensed for use among infants in the
United States; two of these, ACEL-IMUNE® (a product of Lederle
Laboratories) and Tripedia® (Aventis Pasteur, Inc.) are licensed for use
as the complete five-dose series (see Table in the 2000 supplement). The
other two licensed vaccines, Infanrix® and Certiva™, are approved for
use for the first four doses of the five-dose series, beginning at ages
2, 4, and 6 months. Licensure of other diphtheria, tetanus and acellular
pertussis vaccines as a five-dose series is anticipated.

***New Information from the 2003 Supplement***

On July 8, 2003, the U.S. Food and Drug Administration (FDA) approved
the use of Diphtheria and Tetanus Toxoids and Acellular Pertussis
Vaccine Adsorbed (Infanrix®, SmithKline Beecham Biologicals, Rixensart,
Belgium) as a fifth dose for children aged 4 to 6 years after 4 previous
doses of Infanrix®.

***\*See Special Notices below***

**Dosage and Administration**

The dose of all four vaccines-Tripedia®, TriHIBit™, ACEL-IMUNE®, and
Infanrix™ is 0.5 mL, administered intramuscularly. Fractional doses
(\<0.5 mL) should not be administered. The preferred injection sites are
the anterolateral aspect of the thigh and the deltoid muscle of the
upper arm.

To administer TriHIBit™ (ActHIB® reconstituted with Tripedia®)
(Connaught Laboratories, Inc., ActHIB® package insert):

-   Cleanse the rubber stoppers of both vials with a suitable germicide.

-   Thoroughly agitate the vial of Tripedia®. Insert the needle of a
    syringe through the vial\'s rubber stopper and withdraw **0.6** mL
    of Tripedia®.

-   Inject Tripedia® into the vial of lyophilized ActHIB®. Agitate vial
    thoroughly; the combined reconstituted vaccines should appear
    whitish in color.

-   Withdraw **0.5** mL dose of the combined vaccines; administer
    intramuscularly within 30 minutes of reconstitution.

**Interchangeable Use of Acellular Pertussis Vaccines**

Whenever feasible, the same brand of diphtheria, tetanus, and acellular
pertussis vaccine should be used for all doses of the vaccination
series. Data do not exist regarding the safety, immunogenicity, and
efficacy of using diphtheria, tetanus, and acellular pertussis vaccines
from different manufacturers for successive doses of the primary or
booster vaccination series. However, the vaccine provider may not know
or may not have available the type of diphtheria, tetanus, and acellular
pertussis vaccine previously administered to a child. Neither
circumstance should present a barrier to administration of the vaccine
and any of the licensed diphtheria, tetanus, and acellular pertussis
vaccines may be used to complete the vaccination series.

***\*See Special Notices below.***

**Simultaneous Administration of Vaccines**

Limited data regarding simultaneous administration of the first three
doses of diphtheria, tetanus, and acellular pertussis with other
childhood vaccines indicate no interference with response to any of
these other antigens. Data are available regarding administration of
diphtheria, tetanus, and acellular pertussis with the other vaccines
recommended at the same time as the fourth and fifth doses of the
diphtheria, tetanus, and pertussis series (i.e., Haemophilus influenza
type B \[Hib\] vaccine, oral poliovirus vaccine \[OPV\], measles, mumps
and rubella \[MMR\] vaccine, and varicella vaccine), and regarding
administration of whole-cell diphtheria, tetanus, and pertussis (all
doses in the series) with these vaccines. On the basis of this
experience, diphtheria, tetanus, and acellular pertussis may be
administered simultaneously with hepatitis B vaccine, Haemophilus
influenza type B vaccine, and inactivated poliovirus vaccine \[IPV\] or
oral poliovirus vaccine to infants at ages 2, 4, or 6 months as
indicated in the recommended childhood vaccination schedule. All
vaccines appropriate to the age and previous vaccination status of the
child should be administered simultaneously including diphtheria,
tetanus, and acellular pertussis, Haemophilus influenza type B vaccine,
inactivated poliovirus vaccine or oral poliovirus vaccine, hepatitis B
vaccine, measles, mumps and rubella vaccine, and varicella vaccine.

**Special Considerations**

*Vaccination of Infants and Young Children Who Have a Personal or Family
History of Seizures*

Infants and young children who have had previous seizures (whether
febrile or nonfebrile) are at greater risk for seizures after
administration of whole-cell pertussis vaccination than are infants who
do not have such a history. Because these reactions may be caused by the
fever induced by whole-cell diphtheria, tetanus, and pertussis and
because diphtheria, tetanus, and acellular pertussis is less frequently
associated with moderate to high fever, diphtheria, tetanus and
acellular pertussis is the vaccine of choice when pertussis vaccination
is considered for these children.

Among infants and children with a history of previous seizures, it is
prudent to delay pertussis vaccination until the child\'s neurologic
status has been assessed. Infants and children with a stable neurologic
condition, including well-controlled seizures, may be vaccinated with
diphtheria, tetanus, and acellular pertussis. Infants with evolving
neurologic conditions should not be vaccinated until a treatment regimen
has been established and the condition has stabilized. Acetaminophen or
ibuprofen may be administered to these children at the time of
diphtheria, tetanus, and acellular pertussis vaccination and every 4
hours for 24 hours thereafter to reduce the possibility of
postvaccination fever.

Data from one study indicate that infants and young children who have a
parent or sibling with a history of convulsions are more likely to have
seizures following whole-cell diphtheria, tetanus, and pertussis
vaccination than those without such histories. However, seizures occur
infrequently after administration of whole-cell diphtheria, tetanus, and
pertussis, are usually febrile in nature, and generally have a benign
outcome. An estimated 5 to 7% of children have parents or siblings with
a history of convulsions. If these children were exempted from pertussis
vaccination, unvaccinated persons and the general population might face
an increased risk for pertussis. Therefore, a family history of
convulsions or other central nervous system disorders is not a
contraindication to pertussis vaccination. Acetaminophen or ibuprofen
may be administered to these children at the time of diphtheria,
tetanus, and acellular pertussis vaccination and every 4 hours for 24
hours thereafter to reduce the possibility of postvaccination fever.

*Children Who Have Had Pertussis Disease*

Although pertussis disease is likely to confer immunity against
pertussis, the duration of such immunity is unknown. Children with
well-documented pertussis disease (i.e., positive culture for *B.
pertussis* or epidemiologic linkage to a culture-positive case) should
be administered diphtheria and tetanus vaccine for the remaining doses
of the vaccination series to ensure that they are protected against
diphtheria and tetanus. Some experts recommend including the pertussis
component for subsequent vaccination of infants who have had
culture-proven pertussis because infants may have a suboptimal immune
response following *B. pertussis* infection.

*Pertussis Vaccination for Persons Aged Greater than or Equal to 7
Years*

Pertussis vaccines are presently licensed for use only among children
aged 6 weeks to 6 years. In the United States, adolescents and adults
whose immunity has waned are an important reservoir for *B. pertussis*
and may infect unvaccinated young children. In the future, booster doses
of adult formulations of acellular pertussis vaccines may be recommended
to prevent the occurrence and spread of the disease among these older
persons. However, acellular pertussis vaccines combined with diphtheria
and tetanus toxoids will need to be reformulated for use in adults
because all infant formulations contain more diphtheria toxoid than is
recommended for persons aged greater than or equal to 7 years.
Recommendations regarding routine vaccination of adults will require
additional research (e.g., studies of the incidence, severity, and cost
of pertussis among adolescents and adults; studies of the effectiveness
and safety of adult formulations of diphtheria, tetanus, and acellular
pertussis; and studies of the cost-effectiveness of a strategy of adult
vaccination).

**Adverse Reactions**

Mild systemic reactions such as fever, drowsiness, fretfulness, and
anorexia may occur after both whole-cell diphtheria, tetanus, and
pertussis vaccination and diphtheria, tetanus, and acellular pertussis
vaccination. However, data concerning adverse reactions following the
first four doses indicate that mild reactions are less common among
children who receive diphtheria, tetanus, and acellular pertussis. These
reactions are self-limited and can be managed safely with symptomatic
treatment.

Moderate-to-severe systemic events (e.g., temperature of greater than or
equal to 105°F \[greater than or equal to 40.5°C\]; febrile seizures;
persistent, crying lasting greater than or equal to 3 hours; and
hypotonic hyporesponsive episodes) have been reported rarely after
administration of diphtheria, tetanus, and acellular pertussis, and
occur less frequently among children administered diphtheria, tetanus,
and acellular pertussis than among children administered whole-cell
diphtheria, tetanus, and pertussis.

Data from the Vaccine Adverse Event Reporting System (VAERS) (VAERS is a
passive surveillance system for reporting of adverse events temporally
associated with administration of vaccines) were used to compare rates
of fever, seizures, and hospitalizations among children who, having had
greater than or equal to 3 previous doses of whole-cell diphtheria,
tetanus, and pertussis, were administered either diphtheria, tetanus,
and acellular pertussis or whole-cell diphtheria, tetanus, and pertussis
vaccines for the fourth or fifth doses. During 1991-1993, approximately
5 million doses of diphtheria, tetanus, and acellular pertussis
(distributed by Connaught Laboratories, Inc., or Wyeth-Lederle Vaccines
and Pediatrics) and 27 million doses of whole-cell diphtheria, tetanus,
and pertussis were distributed for use among children aged 15 months to
6 years. Adverse events were reported significantly less commonly among
the children who received diphtheria, tetanus and acellular pertussis.
VAERS is a passive surveillance system and these data should be
interpreted with caution because the events reported may be linked to
vaccine administration only by temporal coincidence.

***\*See Special Notices below.***

**Contraindications**

If either of the following events occurs after administration of
diphtheria, tetanus, and acellular pertussis or whole-cell diphtheria,
tetanus, and pertussis, subsequent vaccination with diphtheria, tetanus,
and acellular pertussis or whole-cell diphtheria, tetanus, and pertussis
is contraindicated:

-   *An immediate anaphylactic reaction*. Further vaccination with any
    of the three components of diphtheria, tetanus, and acellular
    pertussis or whole-cell diphtheria, tetanus, and pertussis should be
    deferred because of uncertainty as to which component of the vaccine
    might be responsible. Because of the importance of tetanus
    vaccination, persons who experience anaphylactic reactions may be
    referred to an allergist for evaluation and (if specific allergy can
    be demonstrated) desensitized to tetanus toxoid.

-   *Encephalopathy not attributable to another identifiable cause*
    (e.g., an acute, severe central nervous system disorder occurring
    within 7 days after vaccination and generally consisting of major
    alterations in consciousness, unresponsiveness, or generalized or
    focal seizures that persist more than a few hours, without recovery
    within 24 hours.) In such cases, diphtheria and tetanus vaccine
    should be administered for the remaining doses in the vaccination
    schedule to ensure protection against diphtheria and tetanus.

**Precautions**

If any of the following events occurs within the specified period after
administration of either whole-cell diphtheria, tetanus, and pertussis
or diphtheria, tetanus, and acellular pertussis, vaccine providers and
parents should evaluate the risks and benefits of administering
subsequent doses of a pertussis-containing vaccine:

-   Temperature of greater than or equal to 105°F (greater than or equal
    to 40.5°C) within 48 hours, not attributable to another identifiable
    cause

-   Collapse or shock-like state (hypotonic hyporesponsive episode)
    within 48 hours

-   Persistent crying lasting greater than or equal to 3 hours,
    occurring within 48 hours

-   Convulsions with or without fever, occurring within 3 days

In circumstances in which the benefits of further pertussis vaccination
outweigh the possible risks (e.g., during an outbreak of pertussis),
diphtheria, tetanus, and acellular pertussis should be administered for
the subsequent doses.

**Reporting of Adverse Events After Vaccination**

As with any newly licensed vaccine, surveillance for rare adverse events
potentially associated with administration of diphtheria, tetanus, and
acellular pertussis is important for assessing its safety in large-scale
use. The National Childhood Vaccine Injury Act of 1986 requires
health-care providers to report serious adverse events that follow
pertussis vaccination. The events that must be reported are detailed in
the Reportable Events Table within this Act, and include anaphylaxis or
anaphylactic shock, encephalopathy (or encephalitis), shock collapse or
hypotonic hyporesponsive collapse, and any acute complication or sequela
(including death) of these events. Adverse reactions should be reported
to VAERS. VAERS reporting forms and information are available 24 hours a
day by calling (800) 822-7967.

**Vaccine Injury Compensation**

The National Vaccine Injury Compensation Program, established by the
National Childhood Vaccine Injury Act of 1986, provides a mechanism
through which compensation can be paid on behalf of a person thought to
have been injured or to have died as a result of receiving a vaccine
covered by the program.

A Vaccine Injury Compensation Table in the Act lists the vaccines
covered by the program and the injuries, disabilities, and conditions
(including death) for which compensation may be paid. Development or
onset of anaphylaxis or anaphylactic shock less than or equal to 4 hours
or encephalopathy with onset less than or equal to 72 hours after
administration of pertussis vaccine (or sequelae of these conditions)
are potentially compensable under this law. Persons may be compensated
for an injury listed in the established table or one that can be
demonstrated to result from administration of a listed vaccine.
Additional information about the program is available.

**Special Notice**: *On November 17, 2000 the CDC issued supplemental
recommendations on the use of diphtheria and tetanus toxoids and
acellular pertussis vaccine (MMWR Morbid Mortal Wkly Rep 2000 Nov
17;49(RR-13):1-8)*.

**Supplemental Advisory Committee on Immunization Practices
recommendations for using diphtheria and tetanus toxoids and acellular
pertussis (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 currently licensed
diphtheria, tetanus, and acellular pertussis 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 diphtheria, tetanus, and
acellular pertussis vaccines. Additionally, in the majority of studies
of adverse events after receipt of the fourth and fifth doses of
diphtheria, tetanus, and acellular pertussis, 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 diphtheria, tetanus,
and acellular pertussis vaccines from different manufacturers are
associated with higher or lower frequencies of these reactions than
receipt of a single product for the entire diphtheria, tetanus, and
acellular pertussis series. Additional data regarding the reactogenicity
of diphtheria, tetanus, and acellular pertussis vaccines when
administered as a five-dose series are needed.

Whether children who experience entire limb swelling after a fourth dose
of diphtheria, tetanus, and acellular pertussis 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 diphtheria, tetanus, and acellular
pertussis, a history of extensive swelling after the fourth dose should
not be considered a contraindication for receipt of the fifth dose of
the diphtheria, tetanus, and acellular pertussis series.

Parents or caregivers of children receiving the fourth and fifth doses
of the diphtheria, tetanus, and acellular pertussis 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 diphtheria,
tetanus, and acellular pertussis vaccination on a case-by-case basis.

**Interchangeable Use of Acellular Pertussis Vaccines**

Children who began the series with diphtheria, tetanus, and acellular
pertussis at age 2 months began eligibility to receive a fifth dose of
diphtheria, tetanus, and acellular pertussis 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 diphtheria, tetanus, and acellular pertussis vaccines from
different manufacturers in a mixed sequence. For this reason, the ACIP
recommends that whenever feasible, the same brand of diphtheria,
tetanus, and acellular pertussis vaccine should be used for all doses of
the vaccination series. However, the vaccine provider might not know or
have available the type of diphtheria, tetanus, and acellular pertussis
vaccine previously administered to a child. Neither circumstance should
present a barrier to administration of diphtheria, tetanus, and
acellular pertussis vaccine, and any of the available licensed
diphtheria, tetanus, and acellular pertussis vaccines can be used to
complete the vaccination series.

**Special Notice**: *On September 26, 2003 the CDC issued supplemental
recommendations on the use of diphtheria and tetanus toxoids and
acellular pertussis vaccine (MMWR Morbid Mortal Wkly Rep 2003 Sep 26;
52(38); 921-921)*.

Sufficient data are now available to establish the frequency of adverse
events after a fifth dose of INFANRIX® at age 4 to 6 years in children
who have received 4 previous doses of INFANRIX®. The frequency of local
injection site reactions (erythema and swelling) increases with
successive doses of INFANRIX®. In two German studies, 93 and 390
children, respectively, received a fifth dose of INFANRIX® at age 4 to 6
years after 4 previous doses of INFANRIX®. Among solicited adverse
events, swelling [\>]{.underline}5 cm (2 inches) in the injected limb
within the 3 days after vaccination was reported in 15% and 20% of the
vaccinees, respectively. Extensive swelling of the injected limb was
reported spontaneously by parents of nine (9.7%) and 25 (6.4%)
vaccinees, respectively, in these two studies.

The Advisory Committee on Immunization Practices (ACIP), the American
Academy of Pediatrics, and the American Academy of Family Physicians
recommend that children routinely receive a series of 5 doses of vaccine
against diphtheria, tetanus, and pertussis before age 7 years. ACIP
recommends that the first 4 doses be administered at ages 2, 4, 6, and
15 to 18 months and the fifth dose at age 4 to 6 years.

Data are limited on the safety, immunogenicity, and efficacy of using
DTaP vaccines from different manufacturers for successive doses of the
DTaP series. ACIP recommends that, whenever feasible, the same brand of
DTaP should be used for all doses of the series but that vaccination
should not be deferred because the type of DTaP used for previous doses
is not available or is unknown. In such situations, any of the available
licensed DTaP vaccines can be used to continue or complete the series.

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is not specifically stated for each
recommendation.

Seven field studies (three randomized controlled studies and four
observational studies) evaluating the efficacy of diphtheria and tetanus
toxoids and acellular vaccine (DTaP) and whole-cell DTP were cited, in
addition to the Multicenter Acellular Pertussis Trial evaluating the
safety of the vaccines.

Data from the Vaccine Adverse Event Reporting System (VAERS) were used
to compare rates of fever, seizures, and hospitalizations among children
who, having had \>3 previous doses of whole-cell DTP, were administered
either DTaP or whole-cell DTP vaccines for the fourth or fifth doses.

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

-   Elimination of pertussis disease

-   Decreased incidence of adverse events following pertussis
    vaccination

#### POTENTIAL HARMS

*1997 Guideline*

-   Mild systemic reactions such as fever, drowsiness, fretfulness, and
    anorexia may occur after both whole-cell diphtheria, tetanus, and
    pertussis (DTP) vaccination and diphtheria, tetanus and acellular
    pertussis vaccination. However, data concerning adverse reactions
    following the first four doses indicate that mild reactions are less
    common among children who receive diphtheria, tetanus, and acellular
    pertussis vaccine. These reactions are self-limited and can be
    managed safely with symptomatic treatment.

-   Moderate-to-severe systemic events (e.g., temperature of greater
    than or equal to 105°F, febrile seizures; persistent, crying lasting
    greater than or equal to 3 hours; and hypotonic hyporesponsive
    episodes) have been reported rarely after administration of
    diphtheria, tetanus, and acellular pertussis, and occur less
    frequently among children administered diphtheria, tetanus, and
    acellular pertussis than among children administered whole-cell DTP.

*2000 Supplement*

-   Local 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
    diphtheria, tetanus, and acellular pertussis vaccines. These
    reactions typically have onset within 2 days of vaccination and
    resolve completely without sequelae. Data regarding the
    reactogenicity of a fifth dose of diphtheria, tetanus, and acellular
    pertussis administered after four doses of the diphtheria, tetanus,
    and acellular pertussis vaccine are limited, but suggest further
    increases in the local reactogenicity of the fifth dose compared
    with the fourth dose.

-   Swelling involving the entire thigh or upper arm has been reported
    after booster doses of different acellular pertussis vaccines.

*2003 Supplement*

-   Sufficient data are now available to establish the frequency of
    adverse events after a fifth dose of INFANRIX® at age 4 to 6 years
    in children who have received 4 previous doses of INFANRIX®.

-   The frequency of local injection site reactions (erythema and
    swelling) increases with successive doses of INFANRIX®.

### CONTRAINDICATIONS

#### CONTRAINDICATIONS

If either of the following events occurs after administration of
diphtheria, tetanus, and acellular pertussis or whole-cell diphtheria,
tetanus, and pertussis, subsequent vaccination with diphtheria, tetanus,
and acellular pertussis or whole-cell diphtheria, tetanus, and pertussis
is contraindicated:

-   *An immediate anaphylactic reaction*. Further vaccination with any
    of the three components of diphtheria, tetanus, and acellular
    pertussis or whole-cell diphtheria, tetanus, and pertussis should be
    deferred because of uncertainty as to which component of the vaccine
    might be responsible. Because of the importance of tetanus
    vaccination, persons who experience anaphylactic reactions may be
    referred to an allergist for evaluation and (if specific allergy can
    be demonstrated) desensitized to tetanus toxoid.

-   *Encephalopathy not attributable to another identifiable cause*
    (e.g., an acute, severe central nervous system disorder occurring
    within 7 days after vaccination and generally consisting of major
    alterations in consciousness, unresponsiveness, or generalized or
    focal seizures that persist more than a few hours, without recovery
    within 24 hours.) In such cases, diphtheria and tetanus vaccine
    should be administered for the remaining doses in the vaccination
    schedule to ensure protection against diphtheria and tetanus.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

-   In the future, booster doses of adult formulations of acellular
    pertussis vaccines may be recommended to prevent the occurrence and
    spread of the disease among older persons.

-   Vaccine Adverse Event Reporting System (VAERS) is a passive
    surveillance system and these data should be interpreted with
    caution because the events reported may be linked to vaccine
    administration only by temporal coincidence.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Staying Healthy

#### IOM DOMAIN

Effectiveness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Notice to readers: FDA approval of diphtheria and tetanus toxoids and
acellular pertussis vaccine adsorbed, (INFANRIX) for fifth consecutive
DTaP vaccine dose. MMWR Recomm Rep 2003 Sep 26;52(38):921. \[4
references\]

Pertussis vaccination: use of acellular pertussis vaccines among infants
and young children. MMWR Recomm Rep 1997 Mar 28;46(RR-7):1-25. \[50
references\]

Use of diphtheria toxoid-tetanus toxoid-acellular pertussis vaccine as a
five-dose series. Supplemental recommendations of the advisory committee
on immunization practices (ACIP). MMWR Recomm Rep 2000 Nov
17;49(RR13):1-8. \[17 references\]

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

1997 Mar 28 (revised 2000 Nov; addendum released 2003 Sep 26)

#### GUIDELINE DEVELOPER(S)

Centers for Disease Control and Prevention - Federal Government Agency
\[U.S.\]

#### SOURCE(S) OF FUNDING

United States Government

#### GUIDELINE COMMITTEE

Advisory Committee on Immunization Practices (ACIP)

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Advisory Committee on Immunization Practices (ACIP) Membership List,
February 2000*: John F. Modlin, MD (Chairman); Dixie E. Snider, Jr., MD,
MPH (Executive Secretary); Dennis A. Brooks, MD, MPH; David W. Fleming,
MD; Fernando A. Guerra, MD; Charles M. Helms, MD, PhD; David R. Johnson,
MD, MPH; Chinh T. Le, MD; Paul A. Offit, MD; Margaret B. Rennels, MD;
Lucy S. Tompkins, MD, PhD; Bonnie M. Word, MD

*Ex-Officio Members*: William Egan, PhD; Geoffrey S. Evans, MD; Michael
A. Gerber, MD; T. Randolph Graydon; Martin G. Myers, MD; Kristin Lee
Nichol, MD, MPH; Douglas A. Thoroughman, PhD; David H. Trump, MD, MPH

*Liaison Representatives*: American Academy of Family Physicians-Richard
Zimmerman, MD; American Academy of Pediatrics-Larry Pickering, MD and
Jon Abramson, MD; American Association of Health Plans-Eric K. France,
MD; American College of Obstetricians and Gynecologists-Stanley A. Gall,
MD; American College of Physicians-Pierce Gardner, MD; American Hospital
Association-William Schaffner, MD; American Medical Association-H. David
Wilson, MD; Association of Teachers of Preventive Medicine-W. Paul
McKinney, MD; Biotechnology Industry Organization-Yvonne E. McHugh, PhD;
Canadian National Advisory Committee on Immunization-Victor
Marchessault, MD; Hospital Infection Control Practices Advisory
Committee-Jane D. Siegel, MD; Infectious Diseases Society of
America-Samuel L. Katz, MD; National Immunization Council and Child
Health Program, Mexico-Jose Ignacio Santos, MD; National Medical
Association-Rudolph E. Jackson, MD; National Vaccine Advisory
Committee-Georges Peter, MD; Pharmaceutical Research and Manufacturers
of America-Barbara J. Howe, MD

*The following Centers for Disease Control and Prevention (CDC) staff
members prepared the most recent report*: Melinda Wharton, MD, MPH;
Kristine M. Bisgard, DVM, MPH; Trudy V. Murphy, MD

*Epidemiology and Surveillance Division National Immunization Program in
collaboration with the Advisory Committee on Immunization Practices
Acellular Pertussis Vaccine Working Group*: Margaret B. Rennels, M.D.;
John F. Modlin, M.D.; Karen M. Farizo, M.D.

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Not stated

#### GUIDELINE STATUS

The guideline titled \"Use of Diphtheria Toxoid-tetanus Toxoid-acellular
Pertussis Vaccine as a Five-dose Series\" (MMWR Morb Mortal Wkly Rep
2000 Nov 17;49(RR-13):1-8) supplements the previous recommendations
published in the guideline titled \"Pertussis Vaccination: Use of
Acellular Pertussis Vaccines Among Infants and Young Children\" (MMWR
Morb Mortal Wkly Rep 1997 Mar 28;46(RR-7):1-25) regarding use of DTaP
and summarizes new Advisory Committee on Immunization Practices (ACIP)
recommendations regarding DTaP vaccines as a five-consecutive\--dose
series.

Please note that a published erratum has been published for the
guideline: [\"Use of Diphtheria Toxoid-Tetanus Toxoid-Acellular
Pertussis Vaccine as a Five-Dose
Series\"](http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4947a8.htm), MMWR
Morb Mortal Wkly Rep 2000 Dec 1;49(47):1074.

#### GUIDELINE AVAILABILITY

Electronic copies: Available from the Centers for Disease Control and
Prevention (CDC) Web site:

*November 2000 Guideline*

-   [HTML Format](http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4913a1.htm)

-   [Portable Document Format
    (PDF)](http://www.cdc.gov/mmwr/PDF/rr/rr4913.pdf)

*September 2003 Addendum*

[HTML Format](http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5238a9.htm)

Print copies: Available from the Centers for Disease Control and
Prevention, MMWR, Atlanta, GA 30333. Additional copies can be purchased
from the Superintendent of Documents, U.S. Government Printing Office,
Washington, DC 20402-9325; (202) 783-3238.

#### AVAILABILITY OF COMPANION DOCUMENTS

None available

#### PATIENT RESOURCES

None available

#### NGC STATUS

This summary was completed by ECRI on June 30, 1998. It was updated on
November 28, 2000 and April 2, 2004. This summary was updated on May 3,
2005 following the withdrawal of Bextra (valdecoxib) from the market and
the release of heightened warnings for Celebrex (celecoxib) and other
nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). This summary
was updated by ECRI on June 16, 2005, following the U.S. Food and Drug
Administration advisory on COX-2 selective and non-selective
non-steroidal anti-inflammatory drugs (NSAIDs).

#### COPYRIGHT STATEMENT

No copyright restrictions apply.

### DISCLAIMER

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Date Modified: 11/3/2008