The following CDC staff members prepared this report:
Dalya

# Pertussis Vaccination: Use of Acellular Pertussis Vaccines Among Infants and Young Children
Recommendations of the Advisory Committee on Immunization Practices (ACIP) Summary Concerns about the safety of whole-cell pertussis vaccines prompted development of acellular vaccines that are less likely to provoke adverse events because they contain purified antigenic components of Bordetella pertussis. Two diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccines-ACEL-IMUNE  - and Tripedia   -have been licensed for several years, but (until recently) only for administration of the fourth and fifth doses in the series to children aged 15 months-6 years who previously had received three or more doses of diphtheria and tetanus toxoids and whole-cell pertussis (DTP) vaccine. Published reports indicate that, when administered to infants aged 2, 4, and 6 months, acellular pertussis vaccines are effective in preventing pertussis disease and associated with fewer local, systemic, and certain more serious adverse events than whole-cell pertussis vaccines. On the basis of these data, the Food and Drug Administration (FDA) has licensed three DTaP vaccines for use among children aged 6 weeks-6 years. Tripedia  is now licensed for the initial four doses, and ACEL-IMUNE  for all five doses of the diphtheria, tetanus and pertussis vaccination series. A third DTaP vaccine (InfanrixTM )  was licensed in January 1997 for the initial four doses of the series. Tripedia  , ACEL-IMUNE  , and InfanrixTM are now recommended for routine vaccination of infants and young children, although whole-cell pertussis vaccines remain acceptable alternatives. Tripedia  , ACEL-IMUNE  , and InfanrixTM are recommended for all remaining doses in the schedule for children who have started the vaccination series with one, two, three, or four doses of whole-cell pertussis vaccines. In September 1996, FDA licensed the use of TriHIBitTM (ActHIB  reconstituted with Tripedia  )  for the fourth dose in the series of vaccinations against diphtheria, tetanus, pertussis, and Haemophilus influenzae type b disease. This statement a) provides general information regarding whole-cell pertussis vaccines currently licensed in the United States; b) summarizes results of recent studies of the immunogenicity, efficacy, and safety of acellular pertussis vaccines administered to infants and young children; c) presents recommendations for the use of Tripedia  , TriHIBitTM , ACEL-IMUNE  , and InfanrixTM vaccines; and d) supplements previous recommendations on pertussis vaccination.

# INTRODUCTION Whole-Cell Pertussis Vaccines
Four diphtheria and tetanus toxoids combined with whole-cell pertussis (DTP) vaccines are presently licensed for use in the United States.- Vaccines of this type, prepared from suspensions of inactivated Bordetella pertussis bacterial cells, have been licensed for routine vaccination of infants since the mid-1940s. Based on controlled efficacy trials conducted in the 1940s and on subsequent observational efficacy studies, a primary series comprising four doses of whole-cell DTP vaccine is considered 70%-90% effective in preventing serious pertussis disease (1)(2)(3)(4).
Whole-cell DTP vaccines are commonly associated with several local adverse events (e.g., erythema, swelling, and pain at the injection site), fever, and other mild systemic events (e.g., drowsiness, fretfulness, and anorexia) (5,6 ). More severe systemic events (e.g., convulsions  and hypotonic hyporesponsive episodes) occur less frequently (ratio of one case to 1,750 doses administered) among children who receive whole-cell DTP vaccine (5 ). Acute encephalopathy occurs even more rarely (ratio of 0-10.5 cases to one million doses administered) (7 ). Experts disagree on whether whole-cell pertussis vaccine causes lasting brain damage, but agree that if the vaccine causes such damage it does so only rarely (7 ). Concerns about safety prompted the development of more purified (acellular) pertussis vaccines that are associated with a lower frequency of adverse events and are effective in preventing pertussis disease.

# Trends in Pertussis Disease in the United States
In the United States, the highest recorded annual incidence of pertussis occurred in 1934 when >260,000 cases were reported. The incidence of reported pertussis disease declined substantially as use of whole-cell DTP vaccines became widespread. By 1970, the reported incidence had declined >99%; the fewest cases (1,010) were reported in 1976. However, since the early 1980s reported pertussis incidence has increased steadily. Cyclical peaks in incidence occurred in 1983,1986,1990, and in 1993 when 6,586 cases were reported-more than in any year since 1976 (8 ). The number of reported cases has increased in all age groups, but the increase is greatest among persons aged 5 years (9 ). Nevertheless, infants and young children continue to have the highest risk for pertussis and its complications (4,8,10  The increase in reported pertussis cases has occurred despite pertussis vaccination coverage levels that are higher than at any time in the past. The proportion of children aged 19-35 months who had received three or more doses of whole-cell DTP or diphtheria and tetanus toxoids vaccine (DT) reached 93% in 1994 (11 ). (Of those vaccinated, <2% are estimated to have received DT .) Possible explanations of this increase in disease include a) decreased vaccine efficacy, b) waning immunity among adolescents and adults vaccinated during childhood, c) increased diagnosis and reporting of pertussis because of greater awareness among physicians about the disease, and d) enhanced surveillance and more complete reporting in some states (12,13 ).
Recent randomized controlled trials in Sweden and in Italy with one of the wholecell DTP vaccines presently licensed in the United States (manufactured by Connaught Laboratories, Inc.) yielded estimates of low clinical efficacy-60% in the 6 months immediately following administration of the third dose. Estimates of vaccine efficacy for the total followup period were even lower-48% in Sweden and 36% in Italy (14,15 ). These estimates were substantially lower than expected on the basis of estimates obtained from observational studies in the United States. One possible explanation for the disparity is the number of doses administered-three in the trials in Sweden and Italy versus five in the United States (doses at ages 2, 4, 6, and 12-18 months and 4-6 years). A recent study in Germany with another whole-cell DTP vaccine currently in use in the United States (distributed by Wyeth-Lederle Vaccines and Pediatrics) demonstrated 83% protective efficacy after the third dose and before administration of the fourth dose and 94% efficacy after four doses (Wyeth-Lederle Vaccines and Pediatrics, ACEL-IMUNE  package insert). The effectiveness of the current pertussis vaccination program in the United States, which has relied on four different whole-cell DTP vaccines for primary vaccination, remains high (3,4 ).

# Acellular Pertussis Vaccines
Acellular pertussis vaccines contain inactivated pertussis toxin (PT) and may contain one or more other bacterial components (e.g., filamentous hemagglutinin , a 69-kilodalton outer-membrane protein-pertactin , and fimbriae  types 2 and 3). PT is detoxified either by treatment with a chemical (e.g., hydrogen peroxide, formalin and/or glutaraldehyde) or by using molecular genetic techniques. Acellular pertussis vaccines contain substantially less endotoxin than whole-cell pertussis vaccines.
Since 1991, two acellular pertussis vaccines (Tripedia  and ACEL-IMUNE  ) have been licensed for use in the United States. Until recently, both vaccines were licensed for use only as the fourth and fifth doses of the diphtheria, tetanus, and pertussis vaccination series among children aged 15 months-6 years who had received three primary doses of whole-cell DTP (16,17 ). This licensure was based on findings of studies conducted in Sweden and Japan. These studies did not evaluate the efficacy of acellular pertussis vaccines administered to infants on a schedule similar to the one used in the United States and did not directly compare the efficacy of DTaP vaccines with that of whole-cell DTP vaccines (18)(19)(20)(21)(22).

# Studies of the Efficacy of DTaP Vaccines in Infants
Since 1991, seven studies conducted in Europe and Africa have evaluated the efficacy of eight DTaP vaccines administered to infants. The vaccines, produced by different manufacturers, contained a varying number and quantity of antigens. The derivation and formulation of the individual antigens also varied among vaccines (Table 1). Four doses of vaccine were administered in one study (Wyeth-Lederle Vaccines and Pediatrics, ACEL-IMUNE  package insert); the other six studies involved three doses (14,15,(23)(24)(25). These studies also differed in other ways (Table 2):
- Design. Three studies were randomized placebo-controlled clinical trials; such studies usually provide the most accurate measure of a treatment effect and are less subject to biases than observational studies.
- Case definition. Estimates of vaccine efficacy tend to be higher when the case definition excludes mild clinical cases.
- Laboratory method used to confirm the diagnosis of pertussis.
Because of these differences, comparisons among studies should be made with caution. Within individual studies, however, the efficacy of acellular pertussis vaccines can be compared directly with that of whole-cell DTP.
The efficacy of three doses of acellular pertussis vaccines in preventing moderate to severe pertussis disease was within the range expected for most whole-cell DTP vaccines. Point estimates of efficacy ranged from 59% to 89%. Mild local and systemic adverse events occurred less frequently among infants vaccinated with acellular pertussis vaccines for the first three or four doses than among those vaccinated with whole-cell DTP. More serious adverse events (e.g., fever 105 F , persistent crying of 3 hours duration, hypotonic hyporesponsive episodes, and seizures) generally occurred less frequently among infants who received acellular pertussis vaccines than among those vaccinated with whole-cell DTP. The number of subjects included in these studies was insufficient to estimate the risk for rare severe reactions (i.e., encephalopathy or anaphylactic shock). Surveillance for these rare adverse events will be needed as acellular pertussis vaccines are used more widely.

# Interpretation of Immunogenicity Data
The findings of efficacy studies have not demonstrated a direct correlation between antibody responses and protection against pertussis disease. However, antibody studies are useful to compare immune responses elicited by a single vaccine under different conditions or in different studies. Thus, efficacy studies are required to measure clinical protection conferred by each pertussis vaccine.

# TRIPEDIA 
On July 31, 1996, the Food and Drug Administration (FDA) licensed Tripedia for use as the initial four doses of the recommended diphtheria, tetanus, and pertussis vaccination series among children aged 6 weeks-6 years. The acellular pertussis vaccine components are purified from B. pertussis by salt precipitation, ultracentrifugation, and ultrafiltration. After purification, fractions containing PT and FHA are   combined to obtain a 1:1 ratio and are treated with formaldehyde to inactivate PT. Each dose of Tripedia  contains approximately 23.4 g protein of inactivated PT (toxoid) and 23.4 g protein of FHA, as well as 6.7 limit of flocculation units (Lf) of diphtheria toxoid and 5.0 Lf of tetanus toxoid. The combined components are adsorbed using aluminum potassium sulfate and preserved with 1:10,000 thimerosal (Table 1).

# Immunogenicity
The Multicenter Acellular Pertussis Trial, an immunogenicity and safety study conducted in six centers in the United States and sponsored by the National Institutes of Health (NIH), compared antibody responses of infants vaccinated at ages 2, 4, and 6 months with whole-cell DTP or with one of 13 different acellular pertussis vaccines, including Tripedia  . Antibody to pertussis antigens was measured in serum samples taken before administration of the first dose and 1 month after administration of the third dose of Tripedia  ; 99% and 86% of children had fourfold or greater increases in titers of antibody to PT and FHA, respectively. More than 90% of children administered Tripedia  developed diphtheria and tetanus antibody levels indicative of immunity to these diseases (i.e., >0.1 antitoxin units  per mL and >0.01 u/mL, respectively), as did 90% of those administered whole-cell DTP (26 ). The immunogenicity of Tripedia  when administered as a fourth dose to children aged 12-14 months has not been studied.

# Clinical Efficacy
Two studies conducted in Sweden and Germany provide data concerning the clinical efficacy of Tripedia  . During 1985-1987, a randomized, placebo-controlled clinical trial in Sweden examined the efficacy of two doses of two acellular pertussis vaccines. The acellular pertussis component of one vaccine was comparable to the acellular pertussis component of Tripedia  (17,18 ). The first dose was administered at age 5-11 months, the second dose 8-12 weeks later. For culture-confirmed disease with cough of any duration, the vaccine's efficacy after two doses was 69% (95% confidence interval =47%-82%) (18 ). Using a more stringent case definition (i.e., 21 days paroxysmal cough and confirmation by culture) resulted in an efficacy estimate of 81% (95% CI=61%-90%) (27 ). A non-blinded follow-up study conducted during the 42-month period following the clinical trial yielded similar results (28 ).
A case-control study in Germany evaluated the efficacy of three doses of Tripedia  administered to children aged approximately 3, 5, and 7 months (Connaught Laboratories, Inc.,Tripedia  package insert). Comparison groups received whole-cell DTP (manufactured by Behringwerke, A.G.), DT, or no vaccine. A case of pertussis was defined as an illness with cough of 21 days duration and confirmation by positive culture for B. pertussis or household contact with a culture-proven case. The estimated clinical efficacy of three doses of Tripedia  compared with DT was 80% (95% CI=59%-90%). For infants who received three doses of whole-cell DTP, the vaccine efficacy estimate was 95% (95% CI=81%-99%) (25 ). However, the two efficacy estimates are not directly comparable because of differences in the way infants were enrolled in the two groups.

# Safety
The safety of Tripedia  was assessed in studies conducted in the United States and Germany. Local reactions (e.g., erythema, swelling, or pain), fever, and other common systemic symptoms (e.g., anorexia, vomiting, drowsiness, or fussiness) occurred less frequently among infants administered Tripedia  than among those who received whole-cell DTP (Connaught Laboratories, Inc., Tripedia  package insert). In the Multicenter Acellular Pertussis Trial, local and common systemic events occurred less frequently among Tripedia  recipients than among recipients of whole-cell DTP (Table 3) ( 29). Among recipients of 41,615 doses of Tripedia  in the trial in Germany, few moderate to severe adverse events occurred within 7 days after vaccination (Connaught Laboratories, Inc., Tripedia  package insert). The following events and rates of occurrence (per 1,000 doses administered) were reported: persistent crying for 3 hours, 0.12; febrile seizures, 0.05; afebrile seizures, 0.02; and hypotonic hyporesponsive episodes, 0.05. Rates of invasive bacterial infections, hospitalizations, and deaths among infants vaccinated with Tripedia  were similar to those observed among recipients of DT. None of the deaths or invasive bacterial infections was vaccine related.
In a study conducted in the United States, children aged 15-20 months who had received Tripedia  (n=109) or whole-cell DTP (n=30) for the first three doses were administered Tripedia  as the fourth dose (30 ). Although the differences were not statistically significant, the percentages of children who had local adverse events (e.g., erythema, swelling, or pain) or certain systemic adverse events (i.e., temperature >101 F  or irritability) within 72 hours after administration of the fourth dose was higher among children who had received Tripedia  for the first three doses. However, the frequency of adverse events was lower than that observed in previous studies in which a fourth dose of whole-cell DTP followed three previous doses of whole-cell DTP.
Limited data are available to evaluate the safety of Tripedia  when administered as a fifth dose to children aged 4-6 years who have received four previous doses of Tripedia  . The frequency of local and mild systemic reactions after the last of five doses was no greater among children administered Tripedia  (n=18) than among children in the same study who were administered five doses of whole-cell DTP (n=10) (M.E. Pichichero, unpublished data). More data concerning the safety of Tripedia  in such circumstances are being collected and will be available before infants who receive Tripedia  for the first four doses require a fifth dose at age 4-6 years. Data are insufficient to assess the safety of Tripedia  administered to persons aged 7 years.

# Simultaneous Administration

# Immunogenicity
In a randomized clinical trial, children aged 15-20 months were administered either Tripedia  and ActHIB  vaccines at separate sites (n=98) or combined as a single dose (n=93) (Connaught Laboratories, Inc., Tripedia  package insert). Before the study began, these children all had received three doses of a Hib conjugate vaccine and three doses of whole-cell DTP at approximately ages 2, 4, and 6 months. One month after administration of the fourth dose, 100% of the children in both groups had anti-PRP antibody concentrations 1 g/mL, an indication of long-term protection against invasive H. influenzae type b disease. The proportions of children with protective antibody responses to diphtheria and tetanus toxoids were also high and similar in the two groups. The proportions of children who had fourfold or greater serum antibody responses to PT (measured by enzyme-linked immunosorbent assay  or Chinese hamster ovary  cell assay) were >85% in both groups. Among children who received TriHIBitTM , the proportion with fourfold or greater antibody responses to FHA was slightly lower. The clinical importance of this difference is not known.

# Clinical Efficacy
TriHIBitTM has been licensed for use as the fourth dose of the two vaccination series on the basis of immunogenicity and safety data. Its protective efficacy when used for this purpose has not been evaluated.

# Safety
The safety of TriHIBitTM was evaluated in two studies involving a total of 960 children who had each received three doses of a Hib vaccine and three doses of whole-cell DTP vaccine at approximately ages 2, 4, and 6 months (Connaught Laboratories, Inc., Tripedia  package insert). At age 15-20 months, these children were administered the fourth dose of Tripedia  and ActHIB  vaccines either combined by reconstitution as a single injection or as two injections at separate sites. Rates of local and systemic reactions were similar in the two groups. Local reactions were mild and resolved within 48 hours following vaccination. The most common local reaction was pain at the injection site.

# Simultaneous Administration
When TriHIBitTM was administered to children aged 15-20 months (n=47) simultaneously with MMR vaccine, >95% developed serum antibody to measles, mumps, and rubella at levels indicative of protection against these diseases (Connaught Laboratories, Inc., Tripedia  package insert). Immune responses to OPV or IPV and hepatitis B vaccine when administered simultaneously with TriHIBitTM have not been studied.

# ACEL-IMUNE 
On December 30, 1996, FDA licensed ACEL-IMUNE  for all five doses of the recommended diphtheria, tetanus, and pertussis vaccination series among children aged 6 weeks-6 years. Each dose of the acellular pertussis component of ACEL-IMUNE  contains approximately 34.4 g of FHA, 3.2 g of inactivated PT, 1.6 g of Pn, and 0.8 g of Fim type 2. The acellular pertussis vaccine components are purified by ammonium sulfate fractionation and sucrose density gradient centrifugation. PT is detoxified by treatment with formaldehyde. Each dose of ACEL-IMUNE  contains 9.0 Lf units of diphtheria toxoid, 5.0 Lf units of tetanus toxoid, and 300 hemagglutinating units of acellular pertussis vaccine. The FHA and PT components both exhibit hemagglutinating activity. The combined components are adsorbed to aluminum hydroxide and aluminum phosphate and preserved with 1:10,000 thimerosal (Table 1).

# Immunogenicity
Data from the Multicenter Acellular Pertussis Trial provide evidence of the immunogenicity of ACEL-IMUNE  (26). Investigators measured levels of serum antibody to each of the four vaccine antigens after administration of three doses. The percentages of vaccinees with fourfold or greater increases in antibody titer (compared with prevaccination levels) were: PT, 67%; FHA, 80%; Pn, 71%; and Fim, 59%. The percentages of these children who developed diphtheria antibody levels of 0.1 u/mL and tetanus antibody levels of 0.01 u/mL (i.e., indications of immunity against these diseases) were 86% and 100%, respectively. Antibody responses observed among children in the United States were similar to those observed among children in the study in Germany that demonstrated the efficacy of ACEL-IMUNE  .
Antibody response to ACEL-IMUNE  when administered to children aged 12-14 months was evaluated in a clinical trial (Wyeth-Lederle Vaccines and Pediatrics, unpublished data). ACEL-IMUNE  was administered as a fourth dose to children aged 12-14 months (n=58) or 15-18 months (n=50) who had previously received three doses of whole-cell DTP. In both age groups, >85% of the children had twofold or greater antibody responses to PT, FHA, Pn, and Fim.

# Clinical Efficacy
Efficacy of ACEL-IMUNE  was assessed in a prospective study in Erlangen, Germany (Wyeth-Lederle Vaccines and Pediatrics, ACEL-IMUNE  package insert). Infants were randomly assigned to groups that were administered either ACEL-IMUNE  or whole-cell DTP (distributed by Wyeth-Lederle Vaccines and Pediatrics) at a mean age of 3, 5, 7, and 17 months. A third group of infants (not selected randomly) received DT at ages 3, 5, and 17 months. In this study, pertussis was defined as cough illness lasting 21 days with at least one pertussis-associated symptom (paroxysms, whoop, or post-tussive vomiting) confirmed by culture, serology, or epidemiologic link to a culture-positive household contact. Between the third and fourth doses, the efficacy of ACEL-IMUNE  (compared with DT) was 73% (95% CI=51%-86%) and the efficacy of whole-cell DTP 83% (95% CI=65%-92%). After four doses, the efficacy of ACEL-IMUNE  was 85% (95% CI=76%-90%), and that of whole-cell DTP was 94% (95% CI=89%-97%). Considering the full observation period after the third and fourth doses, the adjusted efficacy of ACEL-IMUNE  was 81% (95% CI=73%-87%) compared with 91% (95% CI=85%-95%) for whole-cell DTP.

# Safety
Studies from the United States and Germany provide data concerning the frequency and nature of adverse events that occur after administration of ACEL-IMUNE  . In the Multicenter Acellular Pertussis Trial, children who were administered ACEL-IMUNE  experienced fewer local adverse events (e.g., pain, redness, or swelling at the injection site) and systemic adverse events (e.g., temperature >101 F , or fussiness) after any of the first three doses than children who were administered whole-cell DTP (Table 3) (29 ). Similarly, in other studies conducted in the United States and Germany, adverse events (local and systemic) after any of the initial four doses occurred less frequently among children who received ACEL-IMUNE  than among children administered whole-cell DTP (Wyeth-Lederle Vaccines and Pediatrics, ACEL-IMUNE  package insert). Rates of adverse events increased with the number of previous doses of ACEL-IMUNE  administered, but were lower than rates for children who received the same number of doses of whole-cell DTP. Among 357 children who were administered five doses of ACEL-IMUNE  , adverse events occurred no more frequently than among children in previous studies (historical controls) who received five doses of whole-cell DTP (Wyeth-Lederle Vaccines and Pediatrics, ACEL-IMUNE  package insert).
In the efficacy trial in Germany (n=16,642 doses of ACEL-IMUNE  ), the following rates of moderate to severe adverse events (per 1,000 doses administered) were observed within 72 hours after administration of the vaccine: persistent or unusual cry, 1.14; temperature 105 F (40.5 C), 0.06; febrile seizures (no other type of seizure occurred), 0.06; and hypotonic hyporesponsive episodes, 0 (Wyeth-Lederle Vaccines and Pediatrics, ACEL-IMUNE  package insert). Rates of all these adverse events were higher among children who received whole-cell DTP.
A clinical trial examined the frequency of local reactions (e.g., erythema, induration, or tenderness) and systemic reactions (e.g., fever, fussiness, drowsiness, or anorexia) among children aged 12-14 months or 15-18 months, all of whom had previously received three doses of whole-cell DTP. Differences in the frequency of adverse reactions in the two age groups were not statistically significant (Wyeth-Lederle Vaccines and Pediatrics, unpublished data).
Neither anaphylaxis nor encephalopathy occurred during clinical trials that involved administration of 25,899 doses of ACEL-IMUNE  . Six deaths of infants or young children who participated in these trials were reported to study investigators; none was vaccine-related and all occurred >4 weeks after vaccination (Wyeth-Lederle Vaccines and Pediatrics, ACEL-IMUNE  package insert). The reactogenicity of ACEL-IMUNE  among persons aged 7 years has not been evaluated.

# Simultaneous Administration
The immunogenicity of ACEL-IMUNE  when administered simultaneously with other recommended childhood vaccines was evaluated in three studies. ACEL-IMUNE  , Hib vaccine, and hepatitis B vaccine were administered simultaneously to 77 infants at ages 2, 4, and 6 months. After administration of the third dose, serum samples from 94% of the infants demonstrated anti-PRP antibodies indicative of clinical protection (1 g/mL), and all of the infants evaluated (n=74) had antibody levels indicative of protection against hepatitis B (i.e., anti-HBs titers of >10 mIU/mL) (Wyeth-Lederle Vaccines and Pediatrics, ACEL-IMUNE  package insert). In another clinical study, 30 infants were administered OPV simultaneously with ACEL-IMUNE  at ages 2 and 4 months; 90% had protective neutralizing antibody to all three poliovirus types at age 6 months. When MMR vaccine was administered simultaneously with ACEL-IMUNE  to children aged 15-18 months (n=48), 92% developed serum antibody titers indicative of protection against measles, mumps, and rubella. Similar results were obtained when whole-cell DTP was administered simultaneously with OPV or MMR vaccine (31 ). Simultaneous administration of ACEL-IMUNE  and IPV or varicella vaccine has not been evaluated.

# INFANRIXTM TM
On January 29, 1997, FDA licensed InfanrixTM for use as the initial four doses of the recommended diphtheria, tetanus, and pertussis vaccination series among children aged 6 weeks-6 years. InfanrixTM is also licensed for all remaining doses in the schedule for children who have received one or more doses of whole-cell DTP vaccine. Each dose of InfanrixTM contains 25 g PT, 25 g FHA, 8 g Pn, 25 Lf of diphtheria toxoid, and 10 Lf of tetanus toxoid (Table 1). The three antigens in the acellular pertussis vaccine component are separately purified in successive chromatographic steps (hydrophobic, affinity, ion exchange, and size exclusion processes). Formalin and glutaraldehyde are used to detoxify PT; FHA and Pn are treated with formalin. The combined components are adsorbed onto 0.625 mg of aluminum (as aluminum hydroxide) and preserved with 2-phenoxyethanol.

# Immunogenicity
In the Multicenter Acellular Pertussis Trial, three doses of InfanrixTM were administered to children at ages 2, 4, and 6 months. One month after the third dose, investigators measured fourfold or greater antibody responses to PT, FHA, and Pn in 83% of children who received InfanrixTM , a higher proportion than observed among recipients of whole-cell DTP (26 ). All the children who were administered InfanrixTM developed diphtheria antibody titers of 0.1 u/mL and tetanus antibody titers of 0.01 u/mL (i.e., indications of immunity against these diseases). Whether their primary vaccination was with InfanrixTM or whole-cell DTP, >86% of children aged 15-20 months had a fourfold or greater rise in serum antibody to each of the pertussis antigens in the vaccine after administration of InfanrixTM as the fourth dose (M. E. Pichichero, unpublished data). The immunogenicity of InfanrixTM administered as a fourth dose to children aged 12-14 months has not been studied.

# Efficacy
The efficacy of InfanrixTM was evaluated in two separate studies (Table 2). In Italy, researchers compared the efficacy of InfanrixTM , DTaP manufactured by Chiron Biocine, whole-cell DTP manufactured by Connaught Laboratories, and DT in a randomized controlled trial that enrolled more than 15,000 children (15 ). Participants received three doses of one of the vaccines at ages 2, 4, and 6 months. The efficacy of InfanrixTM in preventing pertussis disease (defined as paroxysmal cough 21 days duration, with culture or serologic confirmation of infection with B. pertussis) was 84% (95% CI=76%-89%). The efficacy of whole-cell DTP was 36% (95% CI=14%-52%). After the trial, children were followed in an observational study to an average age of 33 months (range: 20-39 months); the efficacy of InfanrixTM remained high throughout this followup period (78%, 95% CI=62%-87%) (SmithKline Beecham Pharmaceuticals, InfanrixTM package insert).
The second study, conducted in six areas in Germany, was a household contact study. In preparation for this study, three doses of InfanrixTM were administered at ages 3, 4, and 5 months to more than 22,000 infants as part of a large immunogenicity and safety study (23 ). Infants who did not participate in this study could have received whole-cell DTP vaccine (manufactured by Behringwerke, A.G.) or DT vaccine. The efficacy study included 453 households with confirmed cases of pertussis in which 360 contact children aged 6-47 months were eligible for inclusion in the vaccine efficacy calculations. A case of pertussis was defined as 21 days of paroxysmal cough illness plus confirmation of B. pertussis infection by culture and/or serologic testing. The efficacy of InfanrixTM was 89% (95% CI=77%-95%); the efficacy of whole-cell DTP was 98% (95% CI=83%-100%).

# Safety
The occurrence of adverse events following vaccination with InfanrixTM was evaluated in clinical studies involving approximately 30,000 children. In these studies, 28,749 infants received InfanrixTM as a three dose primary series, 5,830 children received InfanrixTM as a fourth dose following three doses of InfanrixTM , and 22 children received InfanrixTM as a fifth dose following four doses of InfanrixTM . In addition, 439 children and 169 children received InfanrixTM as a fourth or fifth dose following three or four doses of whole-cell DTP vaccine, respectively. In comparative studies, administration of InfanrixTM was followed by fewer of the local and systemic adverse reactions commonly associated with whole-cell DTP vaccination (15,29,(32)(33)(34). However, results of these studies demonstrated that the rates of erythema, swelling, and fever increased with each successive dose of InfanrixTM (SmithKline Beecham Pharmaceuticals, InfanrixTM package insert). In the Multicenter Acellular Pertussis Trial, local and common systemic adverse events occurred less frequently following any dose of InfanrixTM in the primary series than following any dose of whole-cell DTP (Table 3) (29 ).
The efficacy study conducted in Italy monitored the frequency of moderate to severe adverse events occurring after administration of any of the primary doses of InfanrixTM . Rates (per 1,000 doses administered) of adverse events occurring 48 hours after administration were: persistent crying 3 hours duration, 0.44; seizures, 0.07; and temperature 104 F(40.0 C), 0.36. These rates were similar to or slightly higher than the rates reported among children who were administered DT, but lower than those for children who received whole-cell DTP. In this trial, no hypotonic hyporesponsive episodes occurred among children to whom InfanrixTM was administered.
In the safety study in Germany, data were available regarding 1,809 children who received three doses of InfanrixTM at ages 3, 4, and 5 months and a fourth dose at a mean age of 20 months. The percentages of children who experienced each of the adverse events 3 days after administration of the fourth dose were: redness, 46%; swelling, 35%; pain, 26%; fever 100.4 F (38 C), 26%; and restlessness, 16%. In this study the rates of redness, swelling, pain, and fever increased with successive doses of InfanrixTM (SmithKline Beecham Pharmaceuticals, Inc., InfanrixTM package insert).
Additional safety data are available from another study conducted in Germany (SmithKline Beecham Pharmaceuticals, Inc., InfanrixTM package insert). Children aged 13-27 months received InfanrixTM or whole-cell DTP (manufactured by Behringwerke, A.G.) as a fourth dose. These children had previously received three doses of the same vaccine. Among children administered InfanrixTM as the fourth dose, the incidence of redness, swelling, pain, fever, and restlessness was lower than among children administered whole-cell DTP as the fourth dose.
InfanrixTM has not been licensed previously for administration of the fourth or fifth dose to children who have received three or four doses of whole-cell DTP. Two studies conducted in the United States examined the frequency of adverse events among children who had previously received three or four doses of whole-cell DTP vaccine at approximately ages 2, 4, 6, and 15-18 months (Table 4). Children aged 15-20 months received InfanrixTM or whole-cell DTP vaccine as the fourth dose; children aged 4-6 years were administered InfanrixTM or whole-cell DTP as the fifth dose (33,34 ). Significantly fewer local and systemic adverse events were reported following administration of InfanrixTM than following whole-cell DTP vaccine.
In the safety study in Germany, edematous swelling of the entire thigh into which the vaccine was injected was reported spontaneously by parents or care-givers of 62 of 5,361 vaccinees (1.2%) after administration of the fourth dose. The swelling generally began within 48 hours of vaccination and resolved spontaneously without sequelae during an average of 4 days. In other countries where InfanrixTM has been licensed, this type swelling has been reported rarely following administration of Infan-rixTM for any dose, including the primary series (SmithKline Beecham Pharmaceuticals, InfanrixTM package insert). Edematous swelling has also been reported following administration of other DTaP vaccines, acellular pertussis vaccine alone (without DT), whole-cell DTP vaccine and other vaccines (19,(35)(36)(37). However, the precise frequency of these reactions among vaccinated children is unknown.
Data are insufficient to evaluate the safety of administration of a fifth dose of Infan-rixTM to children aged 4-6 years who have received InfanrixTM for the previous four doses. Additional information regarding the immunogenicity and safety of a fifth dose of InfanrixTM administered to children who have received four prior doses of the same vaccine is being collected. This information is expected to be available before infants who receive InfanrixTM for the first four doses require a fifth dose at age 4-6 years. The safety of InfanrixTM when administered to persons aged 7 years has not been assessed.
10 mIU/mL and 90% of infants (n=72) who received Hib vaccine simultaneously with InfanrixTM achieved anti-PRP antibodies 1 g/mL (i.e., antibody levels indicative of protection against these diseases). The percentage of infants who were administered OPV simultaneously with InfanrixTM (n=60-61) who developed protective neutralizing antibody to poliovirus types 1, 2, and 3 ranged from 96% to 100% (38 ). No data are available regarding antibody responses to MMR vaccine, varicella vaccine, or IPV when administered simultaneously with InfanrixTM .

# VACCINE USE

# 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 (Table 5). 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 *Diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP); diphtheria and tetanus toxoids and whole-cell pertussis vaccine (DTP) is an acceptable alternative to DTaP for any of the five doses.  Use diphtheria and tetanus toxoids, adsorbed (DT) if encephalopathy has occurred after administration of a previous dose of pertussis-containing vaccine. If the child is age 1 year at the time the first dose of DT is administered, a third dose administered 6-12 months after the second dose completes primary vaccination with DT.  Whenever possible, the same DTaP product should be used for all doses. If the same product is not available, Tripedia  , ACEL-IMUNE  , and InfanrixTM can be used interchangeably.  Prolonging the interval does not require restarting the series.  If the interval between the third and fourth doses is 6 months and the child is not likely to return for a visit at the recommended age, the fourth dose of either DTaP or DTP may be administered as early as age 12 months.   TriHIBitTM can be administered as the fourth dose following a primary series with either DTaP or whole-cell DTP and a primary series with any Haemophilus influenzae type b conjugate vaccine.   Tetanus-diphtheria toxoids absorbed (Td) (for adult use). aged 15-18 months. The fourth dose should be administered 6 months after the third. If the interval between the third and fourth doses is 6 months and the child is not likely to return for a visit at the recommended age, the fourth dose of either DTaP or whole-cell DTP may be administered as early as age 12 months. The fifth (second booster) dose is recommended for children aged 4-6 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.

# Vaccine Preference
DTaP 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 DTaP administration than after administration of wholecell DTP. Therefore, DTaP 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 DTP, DTaP is also recommended for all remaining doses in the schedule. During the period of transition from use of whole-cell DTP to DTaP, whole-cell DTP is an acceptable alternative to DTaP for any of the five doses. For the first four doses, whole-cell DTP combined with Hib vaccine (DTP-Hib vaccine) is an acceptable alternative to DTaP and Hib vaccine administered at separate sites.

# Licensed Products
Three acellular pertussis vaccines (Tripedia  and InfanrixTM for the first four doses and ACEL-IMUNE  for all five doses) are licensed for the diphtheria, tetanus, and pertussis vaccination series. FDA has not approved Tripedia  or InfanrixTM as the fifth dose among persons who have received only Tripedia  or only InfanrixTM 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 4-6 years.
TriHIBitTM (ActHIB  reconstituted with Tripedia  ) is licensed only for the fourth dose of the vaccination series, and is not licensed for the first three doses. TriHIBitTM can be used for the fourth dose following three doses of either DTaP or whole-cell DTP and a primary series of any Hib vaccine.
- 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 DTaP vaccine should be used for all doses of the vaccination series. Data do not exist regarding the safety, immunogenicity, and efficacy of using DTaP 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 DTaP vaccine previously administered to a child. Neither circumstance should present a barrier to administration of the vaccine and any of the licensed DTaP vaccines may be used to complete the vaccination series.

# Simultaneous Administration of Vaccines
Limited data regarding simultaneous administration of the first three doses of DTaP with other childhood vaccines indicate no interference with response to any of these other antigens. Data are available regarding administration of DTaP with the other vaccines recommended at the same time as the fourth and fifth doses of the diphtheria, tetanus, and pertussis series (i.e., Hib vaccine, OPV, MMR vaccine, and varicella vaccine), and regarding administration of whole-cell DTP (all doses in the series) with these vaccines (40 ). On the basis of this experience, DTaP may be administered simultaneously with hepatitis B vaccine, Hib vaccine, and IPV or OPV to infants at ages 2, 4, or 6 months as indicated in the recommended childhood vaccination schedule (41 ). All vaccines appropriate to the age and previous vaccination status of the child should be administered simultaneously including DTaP, Hib vaccine, IPV or OPV, hepatitis B vaccine, MMR 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 (42 ). Because these reactions may be caused by the fever induced by whole-cell DTP and because DTaP is less frequently associated with moderate to high fever, DTaP 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 DTaP. 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 DTaP 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 wholecell DTP vaccination than those without such histories (43 ). However, seizures occur infrequently after administration of whole-cell DTP, are usually febrile in nature, and generally have a benign outcome (44 ). An estimated 5%-7% of children have parents or siblings with a history of convulsions (43 ). 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 DTaP 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 DT 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 (45 ).

# Pertussis Vaccination for Persons Aged 7 Years
Pertussis vaccines are presently licensed for use only among children aged 6 weeks-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 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 DTaP; 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 DTP vaccination and DTaP vaccination. However, data concerning adverse reactions following the first four doses indicate that mild reactions are less common among children who receive DTaP. These reactions are self-limited and can be managed safely with symptomatic treatment.- *For a complete discussion, see the general ACIP statement on diphtheria, tetanus, and pertussis and the supplementary statements on DTaP (16,17,42 ).
- Persistent crying lasting 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), DTaP 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 DTaP is important for assessing its safety in largescale use. The National Childhood Vaccine Injury Act of 1986 requires health-care providers to report serious adverse events that follow pertussis vaccination (47 ). 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 (48 ). 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 (49,50 ).
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 4 hours or encephalopathy with onset 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  The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on Friday of each week, send an e-mail message to listserv@listserv.cdc.gov. The body content should read SUBscribe mmwr-toc. Electronic copy also is available from CDC's World-Wide Web server at / or from CDC's file transfer protocol server at ftp.cdc.gov. To subscribe for paper copy, contact Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone (202) 512-1800.
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All material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated.

# 6U.S. Government Printing Office: 1997-532-228/47066 Region IV

# Simultaneous Administration
In a clinical trial in the United States, InfanrixTM was administered simultaneously, at separate sites, with hepatitis B vaccine, Hib vaccine, and OPV to children aged 2, 4, and 6 months. One month after the third dose, 100% of infants (n=64) administered hepatitis B vaccine simultaneously with InfanrixTM demonstrated anti-HBs antibodies

# Dosage and Administration
The dose of all four vaccines-Tripedia  , TriHIBitTM , ACEL-IMUNE  , and InfanrixTM -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 (39 ).
To administer TriHIBitTM (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  .
Moderate-to-severe systemic events (e.g., temperature of 105 F ; febrile seizures; persistent, crying lasting 3 hours; and hypotonic hyporesponsive episodes) have been reported rarely after administration of DTaP, and occur less frequently among children administered DTaP than among children administered whole-cell DTP.
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 (46 ). During 1991-1993, approximately 5 million doses of DTaP (distributed by Connaught Laboratories, Inc., or Wyeth-Lederle Vaccines and Pediatrics) and 27 million doses of whole-cell DTP were distributed for use among children aged 15 months-6 years. Adverse events were reported significantly less commonly among the children who received DTaP. 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.

# CONTRAINDICATIONS
If either of the following events occurs after administration of DTaP or whole-cell DTP, subsequent vaccination with DTaP or whole-cell DTP is contraindicated:
- An immediate anaphylactic reaction. Further vaccination with any of the three components of DTaP or whole-cell DTP 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, DT 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 DTP or DTaP, vaccine providers and parents should evaluate the risks and benefits of administering subsequent doses of a pertussis-containing vaccine:
- Temperature of 105 F (40.5 C) within 48 hours, not attributable to another identifiable cause.
- Collapse or shock-like state (hypotonic hyporesponsive episode) within 48 hours. *VAERS is a passive surveillance system for reporting of adverse events temporally associated with administration of vaccines.