Chevallier, Bertrand MD*#; Vesikari, Timo MD†#; Brzostek, Jerzy MD‡; Knuf, Markus MD§; Bermal, Nancy MD¶; Aristegui, Javier MD‖; Borys, Dorota MD**; Cleerbout, Jan MD**; Lommel, Patricia BScb**; Schuerman, Lode MD**
It can be expected that reactogenicity of inactivated vaccines increases when several vaccines are coadministered. During clinical trials with the licensed 7-valent pneumococcal conjugate vaccine (7vCRM), a statistically significant increase in the incidence of fever ≥38.0°C (rectal temperature) was observed when 7vCRM was coadministered with standard infant combined vaccines, compared with their separate administration without 7vCRM coadministration.1–5 In 2 studies, an increase in antipyretic use in the coadministration groups was also recorded.2,3 These observations highlight the need to specifically investigate safety and reactogenicity of new pneumococcal conjugate vaccines when coadministered with standard childhood vaccines.
A novel 10-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) uses a recombinant form of protein D, the nonlipidated and highly conserved form of a 42 kD cell-surface lipoprotein of non-typeable H. influenzae, as carrier protein for 8 of 10 vaccine serotypes. PHiD-CV was shown to be immunogenic, with no clinically important interactions when coadministered with different routinely administered pediatric vaccines.6 This article describes the safety and reactogenicity of the PHiD-CV vaccine coadministered with routinely administered pediatric vaccines, in 3 primary vaccination studies conducted in infants, and 2 booster vaccination studies conducted in children during their second year of life, in comparison to 7vCRM.
All 5 vaccination studies were randomized and controlled. The design of each primary and booster vaccination study is summarized in Table 1 (www.clinicaltrials.gov: 105553/NCT00307554, 107005/NCT00334334, 107007/NCT00344318, 107046/NCT00370396, 109507/NCT00463437). The studies were conducted according to Good Clinical Practice, the Declaration of Helsinki (Somerset West, 1996 version), applicable local laws, and with the approval of relevant ethics review committees. Written informed consent was obtained from the parents/guardian of each subject before enrolment.
In each study, immunogenicity, safety, and reactogenicity of the PHiD-CV vaccine in comparison to the licensed 7vCRM vaccine (Prevenar™/Prevnar™), when coadministered with other routinely administered childhood vaccines, were described (Table 1). Results of the analysis of immunogenicity of PHiD-CV and the coadministered vaccines are reported elsewhere.6–9 All studies were conducted between November 04, 2005 and January 21, 2008.
The childhood vaccines coadministered across the 5 studies were: hexavalent DTPa-HBV-IPV/Hib, pentavalent DTPa-HBV-IPV or DTPa-IPV/Hib vaccine, DTPa-IPV, DTPw (whole-cell pertussis)-HBV/Hib vaccine, standalone IPV and oral live attenuated poliovirus vaccine (OPV), Hib-Neisseria meningitidis serogroup C vaccine conjugated to tetanus toxoid (Hib-MenC-TT), and standalone MenC-TT and MenC-CRM vaccines.
The age at which the first vaccine dose should be given to healthy infants in the 3 primary vaccination studies was defined to be between 6 and 16 weeks. In booster studies, vaccination occurred between 11 and 18 months of age. Infants and children were excluded from participation if they had experienced disease caused by, or had received prior vaccination against pathogens targeted by the study vaccines (with the exception of HBV vaccine in Poland and those regions of Spain where it was routinely administered at birth). Children with immunosuppression of any cause, serious chronic illness, a history of seizures or progressive neurologic disease, major congenital defects, or who had received immunoglobulin or blood products since birth were also excluded. In booster studies, children were required to have been vaccinated during infancy in the corresponding clinical primary vaccination study, and were excluded if they had received intercurrent vaccination with antigens present in the booster study vaccines.
The DTPa-HBV-IPV/Hib (Infanrix hexa™), DTPa-HBV-IPV (Infanrix penta™/Pediarix™), DTPw-HBV/Hib (Tritanrix-HepB/Hib™), Hib-MenC-TT (Menitorix™), and OPV (Polio Sabin™) and IPV (Poliorix™) vaccines were manufactured by GlaxoSmithKline Biologicals (GSK), Rixensart, Belgium. The conjugate meningococcal vaccines MenC-TT (NeisVac-C™) and MenC-CRM (Meningitec™) were manufactured by Baxter Healthcare SA, Zurich, Switzerland and Wyeth, Pearl River, New York, respectively. The composition of each of the coadministered vaccines has been described elsewhere.6
All vaccines except OPV were administered intramuscularly. In primary vaccination studies, all vaccines were administered into the thigh. Booster vaccinations were administered into the thigh or deltoid.
Assessment of Safety and Reactogenicity
Reactogenicity and safety were evaluated in all subjects using diary cards that were filled in by parents/guardian of subjects during the primary and booster phases of the studies. Specific adverse events commonly associated with injectable childhood vaccines were actively solicited for 4 days (days 0–3) after each vaccine dose. These included pain, redness and swelling at the injection site and fever, irritability/fussiness, drowsiness, and loss of appetite. In booster studies, the occurrence of large swelling reactions defined as swelling with a diameter >50 mm, noticeable diffuse swelling or noticeable increase of limb circumference, was also actively solicited. In addition to solicited symptoms, all other adverse events that occurred within 31 days after vaccination were recorded. Serious adverse events were reported throughout the entire study period for each study.
The intensity of each symptom was graded on a scale from zero to 3. Pain at the injection site was considered to have a grade 3 intensity if the child cried when the limb was moved/was spontaneously painful, redness and swelling at the injection site when the diameter was >30 mm, and fever when rectal temperature was >40°C. Irritability/fussiness was considered of grade 3 intensity if the child cried and could not be comforted/prevented normal activity, and for loss of appetite when the child did not eat at all. Grade 3 intensity for all other symptoms and adverse events was defined as preventing normal everyday activity.
All solicited local symptoms were defined in the protocol to be considered causally related to vaccination. Using their clinical judgment, the investigators assessed the presence or absence of a possible causal relationship to vaccination of all other adverse events.
The analysis of safety was conducted on the total vaccinated cohort in each study. The total vaccinated cohort included all subjects with at least 1 vaccine administration documented. The primary or first secondary objective of each of the primary and booster vaccination studies was to show that PHiD-CV vaccine when coadministered with other childhood vaccines did not induce more postimmunization febrile reactions than 7vCRM coadministered with the same childhood vaccines. In every study except study E, the objective was reached if the upper limit of the 95% confidence interval (CI) of the difference between groups in the percentage of subjects with rectal temperature >39.0°C within 4 days (days 0–3) after at least 1 vaccine dose, was lower than 10%. In study E, the upper limit of this 95% CI had to be lower than 5% plus half the incidence in the control group.
For each solicited and unsolicited symptom the percentage of doses followed by or the percentage of subjects with the symptom was calculated with exact 95% CI by group, according to the intensity and relationship to vaccination.
In all studies, the PHiD-CV and 7vCRM groups had similar demographic characteristics (Table 2). At the time of the first primary vaccine dose, the mean age in the study groups ranged between 7.4 and 9.0 weeks. The mean age at the time of the booster dose was between 14.2 and 15.3 months across study groups. Females and males were approximately equally represented in all study groups. Except for subjects enrolled in the Philippines in study C, a majority of subjects (>95%) in all studies were Caucasian. Subjects from the Philippines in study C were all South East Asian.
Primary Vaccination Studies (Studies A, B, and C)
Of 4004 subjects enrolled and vaccinated in primary vaccination studies, 20 (0.5%) were withdrawn from further participation by the parents or investigators because of an adverse event. In 3 subjects, adverse events leading to subject withdrawal were considered to be related to the study vaccines and are described below.
Serious Adverse Events
Overall, serious adverse events were reported by 150 of 2996 subjects (5%) in the PHiD-CV groups and 44 of 1008 subjects (4.4%) in the 7vCRM groups. Of the total of 194 subjects reporting serious adverse events in primary vaccination studies, 6 were reporting serious adverse events considered by the investigator to be related to vaccination. In 3 subjects, the related serious adverse events led to withdrawal of the subject from the study: one following pneumonia, gastroenteritis, and nephrotic syndrome 27 days after dose 1; one because of febrile convulsions on the day of vaccination with dose 2 (both occurred in the PHiD-CV group in the 2-, 4-, and 6-month schedule in study C); and one because of irritability and anorexia on the day of dose 1 in the 7vCRM group in study A. The other related serious adverse events leading to subject withdrawal were: crying postvaccination on the day of dose 1 (2 subjects in the PHiD-CV group in study A) and fever (39.4°C for 1 day) after dose 2 in the 7vCRM group in study B.
One death occurred during primary vaccination studies. The child died because of sudden infant death syndrome 16 days after the second dose of PHiD-CV in study A. The event was considered by the investigator to be unrelated to vaccination.
Symptoms Reported Within 4 Days After Vaccination
In study A, which was the largest study conducted in Europe following a 2-, 3-, 4-month schedule and coadministration with DTPa-combined vaccines, no difference was observed in the general reactogenicity profiles of the PHiD-CV and 7vCRM vaccines.
The incidences and intensity of general reactions were within the same ranges in the PHiD-CV and 7vCRM groups except for drowsiness and irritability in study B and irritability and loss of appetite in study C, which tended to be slightly more common in PHiD-CV groups. No such trend was observed for general symptoms with grade 3 intensity.
In study C, in which a whole-cell pertussis combination vaccine was coadministered, higher reactogenicity was observed. Irritability was the most commonly reported general solicited symptom after primary vaccination in all groups, with the exception of the 7vCRM group in study C in the 6-, 10-, and 14-week schedule in which fever was more common (Table 3).
Across studies, the incidences of grade 3 general symptoms were also within the same ranges (after no more than 4.8% of doses), except for substantially higher grade 3 irritability in study C in the 2-, 4-, 6-month schedule (up to 13.3%). Fever >40.0°C was reported after only 2 7vCRM doses and 2 PHiD-CV doses across the 3 primary vaccination studies.
The prevalence of fever after vaccination was within the same range in the PHiD-CV and 7vCRM groups, being highest in the first 48 hours after vaccination (days 0 and 1, Fig. 1). In general, the incidence of solicited general symptoms did not increase after successive doses, but tended to be lower after the third vaccine dose (Table 4).
Redness was the most commonly reported solicited local symptom in all groups in studies A and B, and in the 2-, 4-, 6-month schedule in study C (Table 5). Pain or swelling (>30 mm) at the injection site were the most commonly reported grade 3 local symptoms in all studies. In studies A and B, grade 3 local symptoms were reported up to 3.7% of doses for all groups. In study C where pneumococcal conjugate vaccines were coadministered with DTPw-HBV/Hib, grade 3 local symptoms were more frequent, being reported after up to 12.6% of doses (Fig. 2).
The incidences and intensity of local reactions in the PHiD-CV and 7vCRM groups were within the same ranges in all studies.
Local reactogenicity at the PHiD-CV injection site did not differ from local reactogenicity reported at the 7vCRM injection site (Table 6).
Other Adverse Events
Adverse events (other than those specifically solicited) considered causally related to vaccination, and occurring within 31 days after at least 1 vaccination were reported after 0.1% of PHiD-CV doses in study C (6-, 10-, 14-week schedule) to 6.2% in study A, and after 0.7% of 7vCRM doses in study C (6-, 10-, 14-week schedule) to 5.9% in study A.
In all studies, the most commonly reported adverse events considered to be causally related to vaccination, were injection site reactions including induration, nodule, and hematoma, and adverse events including diarrhea and vomiting.
Booster Vaccination Studies (Studies D and E)
A booster dose of PHiD-CV was well tolerated, either as the fourth consecutive dose or as a booster after primary vaccination with 7vCRM. No subject withdrew from any booster study because of an adverse event. No deaths occurred during the booster studies.
Serious Adverse Events
Twenty-nine subjects reported serious adverse events after a booster dose. One SAE was considered by the investigator to be related to vaccination: this subject (7vCRM boosted with PHiD-CV group in study D) experienced swelling of the hands on the day of vaccination, which resolved after 1 day without sequelae.
Symptoms Reported Within 4 Days After Vaccination
No increase in the incidence or severity of general symptoms including fever was observed after a booster dose, compared with primary vaccination (Table 7). General symptoms of grade 3 intensity were reported after up to 4.3% of booster doses. Fever >40.0°C was reported after up to 1.1% of PHiD-CV booster doses and 2.2% of 7vCRM booster doses.
After meningococcal conjugate vaccine coadministration (study E), higher incidences were observed for all general symptoms in the PHiD-CV + Hib-MenC-TT group compared with the 7vCRM + Hib-MenC-TT group.
Overall, the incidence of all local solicited symptoms increased after the booster dose compared with reactogenicity reported after primary vaccination (Table 8). Pain and redness were the most common local symptoms after the booster dose in both studies, and redness >30 mm was reported by up to 13.1% of subjects (PHiD-CV group). A booster dose of PHiD-CV in 7vCRM primed subjects was not more reactogenic than the fourth consecutive dose of either PHiD-CV or 7vCRM (Tables 8, 9, study D).
Large Swelling Reactions
Large swelling reactions at the injection site were actively solicited after vaccinations in studies D and E. Most large swelling reactions occurred at the DTPa-based combination vaccine injection site (32 of 2549 vaccinees; 1.3%). Twelve (0.6%) large swelling reactions in 2100 subjects were reported after a booster dose of PHiD-CV and 7 in 449 subjects (1.6%) after a booster dose of 7vCRM. Swelling reactions also occurred at the MenC injection site with 2 cases each after MenC-CRM, MenC-TT, and Hib-MenC-TT vaccination. Most swelling reactions were confined to the injection site, but 2 involved an adjacent joint: 1 occurred at a DTPa-HBV-IPV/Hib injection site and the other at a 7vCRM injection site. Across all studies, swelling reactions had an onset by the third day after vaccination and none lasted for more than 7 days. All resolved without sequelae.
Other Adverse Events
Adverse events, other than those specifically solicited, considered causally related to the booster vaccination by the investigator, were reported by 2.0% to 7.4% of subjects who received a booster dose of PHiD-CV and by 4.5% to 8.7% of subjects who received a booster dose of 7vCRM. The most commonly reported related symptoms were injection site reactions, vomiting, diarrhea, and rash.
In all primary and booster vaccination studies, the primary safety objective was met according to the prespecified statistical criteria. There was no evidence that the PHiD-CV vaccine when coadministered with routine childhood vaccines, induced more postimmunization febrile reactions with fever >39.0°C than 7vCRM coadministered with the same childhood vaccines after primary or booster vaccination.
Convulsions were reported by 12 of the 4004 (0.3%) subjects enrolled and vaccinated in the 5 clinical trials. Ten cases were classified as febrile convulsion or had convulsions that occurred when fever was present. Three subjects (all PHiD-CV vaccinees) experienced convulsion after primary vaccination, 5 subjects (4 PHiD-CV and one 7vCRM vaccinee) in the period between the primary and booster study, and 4 subjects (3 PHiD-CV and one 7vCRM vaccinee) experienced convulsion after the booster dose. All except 2 cases had an onset more than 13 days after vaccination and were considered unrelated to vaccination. Of the 2 children (both PHiD-CV recipients) who experienced convulsions considered by the investigator to be related to vaccination, one had a convulsion on the day of receipt of dose 1 in study A (no temperature readings were available postvaccination) and one experienced a febrile convulsion on the day of receipt of dose 2 in study C (2-, 4-, 6-month schedule).
The acceptance of new vaccines that are progressively added to childhood vaccination calendars around the world relies heavily on the demonstrated efficacy of the new vaccines. However, as the diseases targeted by vaccination programs become less common, a satisfactory safety and reactogenicity profile also remains instrumental to acceptance by parents.
In each study, the selected follow-up period for solicited adverse events commonly associated with inactivated injectable childhood vaccines was limited to 4 days. This period was based on results from a previous study of a related 11-valent protein D conjugate pneumococcal vaccine in which most (>95%) of solicited local and general symptoms occurred in the first 3 days after vaccination (days 0–2).10
A potential limitation of this safety review is the absence of studies where PHiD-CV was administered alone. Indeed, assessment of general symptoms occurring after vaccination was confounded by coadministration of other vaccines in all groups in the 5 studies reported here. The studies were designed to evaluate the safety and tolerability of PHiD-CV in the context of routine pediatric immunization practices compared with the licensed 7vCRM vaccine in the same context. Indeed, in usual clinical practice neither the PHiD-CV vaccine nor 7vCRM vaccine is likely to be administered alone except for catch-up vaccination.
Compared with previously published studies, the incidence of general solicited symptoms in PHiD-CV groups where DTPa-based vaccines were coadministered, was within the reported range for 7vCRM coadministered with hexavalent vaccines.2,4 Reported general symptoms after PHiD-CV coadministration with Hib-MenC-TT vaccine were also within the range as those observed after 7vCRM coadministration with Hib-MenC-TT.11 Solicited local and general symptoms after coadministration of PHiD-CV and DTPw-HBV/Hib were within the same ranges as those reported for DTPw-based vaccines administered alone.12,13
Fever after vaccination is frequently a concern for parents and physicians and may lead to medical attention visits and potentially unnecessary investigations and treatment.14 Coadministration of 7vCRM with DTPa-based vaccines is associated with an increase in low grade fever and antipyretic use compared with their separate administration.1–5 The 5 primary and booster clinical trials reported here were specifically designed and adequately powered to show that PHiD-CV coadministered with routine childhood vaccines, compared with 7vCRM coadministered with the same routine childhood vaccines, did not induce more fever >39.0°C beyond what is clinically acceptable for other vaccines. In all studies, we consistently demonstrated no increase in fever >39.0°C in the PHiD-CV groups compared with 7vCRM groups, whether PHiD-CV was coadministered with DTPa-based vaccines or with the more pyrogenic DTPw-HBV/Hib vaccine. Similar to 7vCRM, the onset of fever after PHiD-CV vaccination was rapid (Fig. 1). We noted 2 cases of convulsion within 48 hours of PHiD-CV vaccination (2 cases per 10,800 doses or 1:5400 immunizations) compared with 1:1750 immunizations described after DTPw.15 Adverse reactions after vaccination with PHiD-CV were those typically reported after vaccination with inactivated vaccines, including commercially available 7vCRM vaccine.16
Large swelling reactions involving the entire vaccinated limb have been reported after booster doses of DTPa-based vaccines, DT and DTPw vaccines from all manufacturers, as well as after vaccination with 7vCRM.17 We observed large swelling reactions after 0.6% of PHiD-CV booster doses. The clinical characteristics of the swelling reactions after PHiD-CV were in line with the known characteristics of large swelling reactions.18 The observed incidence of large swelling reactions after PHiD-CV booster dose was below the expected range of 2% to 6% after a booster dose of DTPa-based vaccine.19
In conclusion, the safety and reactogenicity profiles of PHiD-CV and 7vCRM were similar when administered for primary and booster vaccination of children from 6 countries, using a range of vaccination schedules and coadministered with other routinely used pediatric vaccines.
The authors thank the parents and their children who participated in these trials. The authors also thank the investigators, clinicians, study nurses, and other staff members for contributing in many ways to these studies; in particular, all the investigators involved in these studies: N. Lindblad, A. Karvonen, T. Karppa, U. Elonsalo, J. Immonen, T. Korhonen, F. Mokdad, J.P. Arsene, V. Duflo, B. Blanc, F. Thollot, P. Bakhache, P.M. Tran, E. Mothe, R. Amar, M. Guy, E. Jacqz-Aigrain, H. Czajka, J. Pejcz, B. Pajek, A. Galaj, J. Wysocki, U. Behre, F. Bertholdt, P. Bosch, E. Erdmann, D. Grunert, S. Hetzinger, U. Hörnlein, M. Kimmig, K. Kindler, K. Kirsten, R. Knecht, H.P. Loch, K.E. Mai, R. Mangelsdorf-Taxis, L. Maurer, S. Noll, H. Pabel, F. Panzer, C. Pauli, U. Pfletschinger, K. Pscherer, H.H. Rohé, L. Sander, H.C. Sengespeik, M. Steiner, U. Sträubler, K.J. Taube, K. Vogel, M. Völker, M. Vomstein, V. von Arnim, M.H. Wagner, W. Olechowski, R. Konior, E. Miszczak-Kowalska, A. De Vicente, J.M. Merino, X. Pérez-Porcuna, E. Muñoz, M. Moro, D. Moreno, M. Méndez, J. de la Flor, J.C. Tejedor, J. Marés, F. Barrio, M.J. de Torres, F. Centeno, J. García-Sicilia, F. Omeñaca, A. Chrobot, K. Kulczyk, B. Białynicka-Birula, E. Majda-Stanisławska, E. Alberto, C. Wittermann, U. Jacob, B. Acosta, J. Arístegui, C. López, S. Szenborn, U. Wachter, C. Lotz, C. Matela, M. Hernandez, F. Reyes, I. Aquino, L. Casidsid, C. Cuaresma, F. Bajaro, W. Dacasin, and E. La Valle. In addition, the authors thank the clinical and serological laboratory teams of GlaxoSmithKline Biologicals, Belgium, for their input in various aspects of the studies, I. Dieussaert for involvement in the studies, Patricia Lommel and Laurence Bernard (all from GlaxoSmithKline Biologicals) for statistical analyses, Dr. Joanne Wolter (freelance) for providing medical writing, and Dr. Christine Vanderlinden (GlaxoSmithKline Biologicals) for editorial assistance and manuscript coordination.
1. Black S, Shinefield H, Fireman B, et al; Northern California Kaiser Permanente Vaccine Study Center Group. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J. 2000;19:187–195.
2. Tichmann-Schumann I, Soemantri P, Behre U, et al. Immunogenicity and reactogenicity of four doses of diphtheria-tetanus-three-component acellular pertussis-hepatitis B-inactivated polio virus-Haemophilus influenzae type b vaccine coadministered with 7-valent pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2005;24:70–77.
3. Knuf M, Habermehl P, Cimino C, et al. Immunogenicity, reactogenicity and safety of a 7-valent pneumococcal conjugate vaccine (PCV7) concurrently administered with a DTPa-HBV-IPV/Hib combination vaccine in healthy infants. Vaccine. 2006;24:4727–4736.
4. Olivier C, Belohradsky BH, Stojanov S, et al. Immunogenicity, reactogenicity, and safety of a seven-valent pneumococcal conjugate vaccine (PCV7) concurrently administered with a fully liquid DTPa-IPV-HBV-Hib combination vaccine in healthy infants. Vaccine. 2008;26:3142–3152.
5. Schmitt HJ, Faber J, Lorenz I, et al. The safety, reactogenicity and immunogenicity of a 7-valent pneumococcal conjugate vaccine (7VPnC) concurrently administered with a combination DTaP-IPV-Hib vaccine. Vaccine. 2003;21:3653–3662.
6. Knuf M, Szenborn L, Moro M, et al. Immunogenicity of routinely used childhood vaccines when co-administered with the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV). Pediatr Infect Dis J. In press.
7. Vesikari T, Wysocki J, Chevallier B, et al. Immunogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) compared to the licensed 7vCRM vaccine. Pediatr Infect Dis J. In press.
8. Wysocki J, Tejedor JC, Grunert D, et al. Immunogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) when co-administered with different Neisseria meningitidis serogroup C conjugate vaccines. Pediatr Infect Dis J. In press.
9. Bermal N, Szenborn L, Chrobot A, et al. The 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) co-administered with DTPw-HBV/Hib and poliovirus vaccines: assessment of immunogenicity. Pediatr Infect Dis J. In press.
10. Prymula R, Chlibek R, Splino M, et al. Safety of the 11-valent pneumococcal vaccine conjugated to non-typeable Haemophilus influenzae-derived protein D in the first 2 years of life and immunogenicity of the co-administered hexavalent diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated polio virus, Haemophilus influenzae type b and control hepatitis A vaccines. Vaccine. 2008;26:4563–4570.
11. Nolan T, Lambert S, Roberton D, et al. A novel combined Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y-tetanus-toxoid conjugate vaccine is immunogenic and induces immune memory when co-administered with DTPa-HBV-IPV and conjugate pneumococcal vaccines in infants. Vaccine. 2007;25:8487–8499.
12. Gatchalian S, Reyes M, Bernal N, et al. A new DTPw-HBV/Hib vaccine is immunogenic and safe when administered according to the EPI (Expanded Programme for Immunization) schedule and following hepatitis B vaccination at birth. Hum Vaccin. 2005;1:198–203.
13. Bravo L, Carlos J, Gatchalian S, et al. The new DTPw-HBV-Hib combination vaccine can be used at the who schedule with a monovalent dose of hepatitis B vaccine at birth. Southeast Asian J Trop Med Public Health. 1998;29:772–778.
14. El-Radhi AS. Why is the evidence not affecting the practice of fever management? Arch Dis Child. 2008;93:918–920.
15. Carlsson RM, Claesson BA, Selstam U, et al. Safety and immunogenicity of a combined diphtheria-tetanus-acellular pertussis-inactivated polio vaccine-Haemophilus influenzae type b vaccine administered at 2-4-6-13 or 3-5-12 months of age. Pediatr Infect Dis J. 1998;17:1026–1033.
16. Wise RP, Iskander J, Pratt RD, et al. Postlicensure safety surveillance for 7-valent pneumococcal conjugate vaccine. JAMA. 2004;292:1702–1710.
17. Woo EJ, Burwen DR, Gatumu SN, et al.; Vaccine Adverse Event Reporting System Working Group. Extensive limb swelling after immunization: reports to the Vaccine Adverse Event Reporting System. Clin Infect Dis. 2003;37:351–358.
18. Scheifele DW, Halperin SA, Ferguson AC. Assessment of injection site reactions to an acellular pertussis-based combination vaccine, including novel use of skin tests with vaccine antigens. Vaccine. 2001;19:4720–4726.
19. Rennels MB. Extensive swelling reactions occurring after booster doses of diphtheria-tetanus-acellular pertussis vaccines. Semin Pediatr Infect Dis. 2003;14:196–198.
© 2009 Lippincott Williams & Wilkins, Inc.