. . . REPORTS . . .

Efficacy, Safety, and Immunogenicity of Heptavalent Pneumococcal Conjugate in Children

Steven Black, MD; Henry Shinefield, MD; Bruce Fireman, MA; Edwin Lewis, MPH; Paula Ray, MPH; John R. Hansen, BA; Laura Elvin; Kathy M. Ensor, RN; Jill Hackell, MD; , MD; Frank Malinoski, MD, PhD; Dace Madore, PhD; Ih Chang, PhD; Robert Kohberger, PhD; Wendy Watson, MD; Robert Austrian, MD; Kathy Edwards, MD; and The Northern California Kaiser Permanente Vaccine Study Center Group*

Abstract pneumococcal conjugate vaccine, or Objective: To determine the effica- meningococcus type C CRM197 conju- cy, safety, and immunogenicity of the gate. The primary study outcome was heptavalent CRM197 pneumococcal invasive disease caused by vaccine conjugate vaccine (PCV) against inva- serotype. Other outcomes included sive disease caused by vaccine overall impact on invasive disease serotypes and to determine the effec- regardless of serotype, effectiveness tiveness of this vaccine against clinical against clinical otitis media visits and episodes of otitis media. episodes, and impact against frequent Methods: The Wyeth Lederle and severe otitis media and ventilato- heptavalent CRM197 PCV was given ry tube placement. In addition the to infants at 2, 4, 6 and 12 to 15 serotype-specific efficacy against oti- months of age in a double-blind trial; tis media was estimated in an analysis 37,868 children were randomly of spontaneously draining ears. assigned 1:1 to receive either the Results: In the interim analysis in August 1998, 17 of the 17 cases of invasive disease caused by vaccine From the Kaiser Permanente Vaccine Study serotype in fully vaccinated children Center, Oakland, CA (SB, HS, BF, EL, PR, JRH, LE, KME); Wyeth Lederle and Pediatrics, and 5 of 5 of partially vaccinated cases Pearl River, NY (JH, GS, FM, DM, IC, RK, WW); occurred in the control group for a University of Pennsylvania, School of Medicine, vaccine efficacy of 100%. Blinded Philadelphia, PA (RA); and Vanderbilt University case ascertainment was continued Medical Center, Nashville, TN (KE). until April 1989. As of that time 40 *Members of the Northern California Kaiser Permanente Vaccine Study Center Group: Drs. fully vaccinated cases of invasive dis- Janet Aguilar, Marissa Bartlett, Randy Bergen, ease caused by vaccine serotype had Mel Burman, Steve Dorfman, Wayne Easter, been identified, all but 1 in controls for Annette Finkel, Hervey Froehlich, James an efficacy of 97.4% (95% confidence Glauber, Arnd Herz, David Honeychurch, Robert Klainrock, Irene Landaw, Allan Lavetter, interval, 82.7% to 99.9%), and 52 Chinh Le, Steve McMurtry, Pius Morozumi, Pat cases, all but 3 in controls in the Mullin, Michael Rehbein, Richard Rossin, intent-to-treat analysis for an efficacy Garwin Soe, Irene Takahashi, Gail Udkow, of 98.9% (95% confidence interval, Robert Whitson. 79.6% to 98.5%). There was no evi- Address correspondence to: Steven Black, MD, Kaiser Permanente Vaccine Study Center, 1 dence of any increase of disease Kaiser Plaza, Oakland, CA 94612. Fax: 510-267- caused by nonvaccine serotypes. 7524; E-mail: [email protected]. Efficacy for otitis media against visits, This article originally appeared in Pediatr episodes, frequent otitis, and ventilato- Infec Dis J 2000;19:187-195. Reprinted with per- mission. Copyright © 2000 by Lippincott ry tube placement was 8.9%, 7.0%, Williams & Wilkins, Inc. 9.3% and 20.1% with P < 0.04 for all.

S536 THE AMERICAN JOURNAL OF MANAGED CARE JULY 2000 . . . HEPTAVALENT PNEUMOCOCCAL CONJUGATE VACCINE IN CHILDREN . . .

In the analysis of spontaneously drain- overwhelming sepsis. Unlike Hib, ing ears, serotype-specific effective- where only one serotype accounted ness was 66.7%. for virtually all H. influenzae disease, Conclusion: This heptavalent there are more than 90 described pneumococcal conjugate appears to serotypes of the pneumococcus, be highly effective in preventing inva- many of which cause disease in adults sive disease in young children and to and children. However, within the have a significant impact on otitis United States 7 serotypes are respon- media. sible for 83% of invasive disease in (Am J Manag Care 2000;6(suppl):S536-S549) children younger than 4 years of age. We report the results of the Kaiser Permanente trial evaluating the effica- cy, safety, and immunogenicity of the heptavalent pneumococcal conjugate lthough the pneumococcus vaccine (Wyeth; PNCRM7) conducted was first isolated more than in Northern California between A 100 years ago and the first October 1995 and August 1998 and pneumococcal vaccine trials began in the posttrial blinded efficacy follow- 1911, there is still no routinely rec- up through April 20, 1999. ommended pneumococcal vaccine for use in childhood. The currently avail- ...... able 23-valent pneumococcal polysac- METHODS charide vaccine is not effective in This study was a randomized, dou- children younger than 2 years of age ble-blind trial conducted at 23 med- in whom 80% of invasive pneumococ- ical centers within Northern cal disease in childhood occurs. This California Kaiser Permanente vaccine has also not been effective in (NCKP). The study was approved by the control of otitis media in children. the Institutional Review Board of the During recent years there has been Kaiser Foundation Research Institute. considerable effort devoted toward Written informed consent was developing a pneumococcal vaccine obtained from parents or guardians. A that is effective in infants and chil- Study Advisory Committee (Drs. dren. After the licensure of conjugate Donna Ambrosino, William Haemophilus influenzae type b (Hib) Blackwelder, and Jerome Klein) mon- vaccines in late 1990, there has been itored the conduct of the study and a more than 98% elimination of Hib functioned as a Safety Monitoring disease in this country.1 This leaves Committee. the pneumococcus as the most com- Healthy infants were randomized mon cause of bacterial in 1:1 to receive either the heptavalent young children. In addition there has pneumococcal conjugate or the been a rapid emergence of drug-resis- meningococcus type C conjugate vac- tant pneumococci that have caused cine at 2, 4, 6, and 12 to 15 months of invasive worldwide and in age. Children with sickle-cell disease, the United States.2 The increasing known immunodeficiency, any seri- prominence of pneumococcal infec- ous chronic or progressive disease, a tions and of antimicrobial resistance history of seizures, or a history of has emphasized the need for the either pneumococcal or meningococ- development of an effective vaccina- cal disease were excluded. tion program to reduce the risk of The pneumococcal conjugate vac- pneumococcal disease in childhood. cine contained 2µg each of saccha- The pneumococcus is responsible rides of serotypes 4, 9V, 14, 18C, 19F, for a wide spectrum of infection rang- and 23F and 4µg of 6B coupled to the ing from asymptomatic carriage to protein carrier CRM197 (a nontoxic

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mutant of diphtheria toxin). The con- pneumococcal disease. To be included trol meningococcal conjugate vaccine in the main efficacy analysis, cases contained 10µg of group C oligosac- must have been caused by a pneumo- charide conjugated to the same carri- coccal serotype included in the vac- er protein. The 2 vaccines were cine, must have occurred longer than identical in appearance. Multiple lots 14 days after the third dose of study of both the pneumococcal and vaccine, and must have occurred in meningococcal conjugate vaccines subjects vaccinated according to pro- were used in this study. The following tocol. In addition potential cases were routine childhood vaccines were tested for immunocompetence evalu- administered at the recommended ated by obtaining quantitative ages: diphtheria-tetanus toxoid-whole immunoglobulins, a complete blood cell pertussis vaccine (DTwP) or diph- count with differential, and CD4/CD8 theria-tetanus toxoid-acellular pertus- cell counts. sis vaccine (DTaP); oral poliovirus This trial incorporated a sequen- vaccine or inactivated poliovirus vac- tial design with an interim evaluation cine; Hib; hepatitis B; measles- by the Study Advisory Committee at mumps-rubella vaccine; varicella. 17 cases in fully vaccinated per pro- Initially all subjects received TETRA- tocol cases of invasive disease caused MUNE (a vaccine combining by vaccine serotype in fully vaccinat- Haemophilus b conjugate and DTwP) ed immunocompetent children. For into the opposite leg and oral each child follow-up ended for the poliovirus vaccine concurrently. When main efficacy analysis at the earliest recommendations changed the proto- of the following dates: the onset of col was amended to allow administra- invasive pneumococcal disease of any tion of DTaP and inactivated poliovirus serotype; the child died; or at the end vaccine. Vaccines not given concomi- of the trial. A child younger than 16 tantly were given at least 2 weeks apart months of age was considered fully from study vaccine. vaccinated if the child had received 3 or more doses of vaccine, and a child Efficacy 16 months of age or older was consid- The primary endpoint for the eval- ered fully vaccinated after receipt of a uation of efficacy of the pneumococ- fourth dose of vaccine. Protective effi- cal conjugate vaccine was the cacy was estimated by calculating the protective efficacy of the heptavalent ratio of the number of cases of inva- pneumococcal conjugate vaccine sive disease in the pneumococcal against invasive pneumococcal dis- conjugate group to the number of ease caused by vaccine serotypes. cases in the meningococcal group Secondary endpoints included the and subtracting this ratio from 1. efficacy of the vaccine against clinical Vaccine efficacy against invasive episodes of otitis media as defined disease was evaluated with the bino- below. An additional outcome, pneu- mial test of the null hypothesis that monia, will be reported separately. the vaccine has no efficacy for the 7 Active surveillance for cases of serotypes. In the interim analysis this invasive pneumococcal disease in the was to be rejected if the case split was study population was conducted using 15:2 or more favorable, P = 0.0023 at automated clinical and laboratory this interim assessment with a final databases. Invasive pneumococcal evaluation at 26 cases, and an overall disease was defined as a positive cul- 2-tailed P value of < 0.05. Exact bino- ture of Streptococcus pneumoniae mial confidence intervals were from a normally sterile body fluid calculated by the conservative obtained from a child presenting with Klopper-Pearson method.3 an acute illness compatible with In addition an intent-to-treat

S538 THE AMERICAN JOURNAL OF MANAGED CARE JULY 2000 . . . HEPTAVALENT PNEUMOCOCCAL CONJUGATE VACCINE IN CHILDREN . . . analysis included all invasive disease The difference in the number of spon- caused by any pneumococcal taneously draining and cultured otitis serotype occurring after randomiza- media episodes was determined with tion regardless of whether the child the binomial test. completed the 3-dose primary series or received the booster dose. For this Assessment of Vaccine Safety analysis the null hypothesis was 0 effi- Multiple methods were used to asses cacy and the statistical test used was the safety of the study vaccine. Local the exact binomial test. and systemic reactions were collected Clinical diagnoses of acute otitis at 48 to 72 hours and 14 days after media for the study population were each dose by telephone inter- obtained from computerized data sources using diagnoses registered by emergency physicians and pediatri- The frequency of uncommon events requiring cians in the NCKP population. There medical attention after vaccination was eval- was no cross-training of the estimated uated for all study participants through the 500 observers, and cultures were not routinely obtained. Several outcomes use of comprehensive hospitalization and were evaluated for otitis media. The emergency room utilization databases within primary otitis media outcome was the Northern California Kaiser Permanente. number of episodes of otitis media in fully vaccinated per protocol follow- up time in the 2 vaccine groups. For this analysis each clinic visit consti- tuted a new episode unless it was clas- views conducted on 2 subsets of the sified as a follow-up visit. A visit less study population: 1 subset receiving than 21 days after another otitis visit DTwP, and 1 set receiving DTaP con- was always considered a follow-up currently. visit. A visit 42 days or more after the The frequency of uncommon most recent otitis visit was considered events requiring medical attention a new episode. Visits occurring after vaccination was evaluated for all between 21 and 42 days, if the study participants through the use of appointment was made less than 3 comprehensive hospitalization and days in advance, were considered new emergency room utilization databases episodes. within NCKP. Rates of utilization for Additional otitis outcomes includ- specific diagnoses were compared for ed differences between treatment 30-day and 60-day exposure windows groups in the time to diagnosis of fre- for emergency room and hospitaliza- quent otitis, in placement of ventila- tion, respectively. Mortality was eval- tory tympanostomy tubes in each uated by deaths reported within group, and in the number of cases of utilization databases and supplement- spontaneously draining ruptured tym- ed by California State mortality tapes panic membranes with culture of a to identify all mortality within the vaccine serotype pneumococcus. population. In addition surveillance of Frequent otitis was defined as at least utilization databases maintained at 3 episodes in 6 months, or 4 or more NCKP was used to generate line list- episodes within 1 year. To evaluate ings for review by the investigators. the effectiveness of the pneumococcal All events were classified as to severi- vaccine in reducing the total number ty, recovery, and relation to vaccine. of otitis media episodes, the Events that were severe, were unex- Anderson-Gill formulation of the pro- pected, or had a possible causal rela- portional hazards model was used tionship to study vaccination were (with robust variance estimation).4,5 further investigated through chart

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review, parent contact, or both. more doses of pneumococcal conju- Telephone interview data evaluat- gate and 18,941 received 1 dose or ing local and systemic reactions were more of the control meningococcal analyzed by chi square or Fisher’s conjugate vaccine. Of the children exact test as appropriate for the who received at least 1 dose of pneu- expected cell counts in each 2 by 2 mococcal conjugate vaccine, 17,174 table. For a paired analysis of local received at least 2 doses, 15,565 reactions, the sign test was used to received at least 3 doses, and 10,940 assess differences between injection received at least 4 doses. Of the chil- sites. Analyses of hospitalizations and dren who received at least 1 dose of emergency room visits were per- meningococcal conjugate vaccine, formed with person-time-based rela- 17,196 received at least 2 doses, tive risk estimates, and the associated 15,536 received at least 3 doses, and 95% confidence limits were calculated 10,995 received at least 4 doses. by the exact test of incidence density function with a mid-P correction. Efficacy Against Invasive Disease: Interim Analysis Immunogenicity At the time of the interim evalua- Immunogenicity of the conjugate tion there were by design 17 cases of vaccine was evaluated in a subset of invasive disease caused by vaccine children who received DTwP concur- serotype in fully vaccinated children. rently and in a subset given DTaP in All of these cases were in the control the first year of life. Serum antibody group with a point estimate of 100% responses (IgG) to the 7 pneumococcal for vaccine efficacy (95% confidence vaccine serotypes were determined by interval, 75.7% to 100%; P < 0.0001). enzyme-linked immunosorbent assay Of the 17 fully vaccinated cases of as previously described.6 Serum sam- vaccine serotype, 13 had a diagnosis ples were obtained before the first vac- of bacteremia, 2 of sepsis, 1 of bac- cination and 1 month after the third teremic cellulitis, and 1 of bacteremic dose. Additional samples were pneumonia. The 17 cases included obtained in a subset before and after cases of serotypes 6B, 9V, 14, 18C, the fourth dose. Specimens were sent 19F, and 23F. to Wyeth Lederle Laboratories for In the intent-to-treat analysis of blinded analysis. effectiveness against vaccine serotype Geometric mean titers of antibody disease after 1 dose or more of vac- against each pneumococcal vaccine cine, all 22 cases of disease occurred serotype and the percentage of sub- in the control group, for a point esti- jects achieving titers of 0.15, 0.5, and mate for effectiveness after 1 dose or 1.0 µg/mL were determined for both more of vaccine of 100% (95% confi- treatment groups. Means were evalu- dence interval, 81.4% to 100%; ated for statistically significant differ- P < 0.0001). The point estimate of the ences using the 2 sample t test on a effectiveness of partial vaccination log scale. Comparison of proportions was 100%, but this was not statistical- of children achieving at least a given ly significant, P = 0.06. Of the 5 par- concentration were made using tially vaccinated controls, 2 had a Fisher’s exact test. diagnosis of bacteremia, 2 of meningi- tis, and 1 of sepsis. There were also 8 ...... cases of invasive disease caused by RESULTS nonvaccine serotype including cases Study Population caused by serotypes 3, 10F, 11A, 18B, Between October 1995 and August 19A, 23A, and 38. 1998, 37,868 children were enrolled Because of the high level of efficacy into the trial; 18,927 received 1 or demonstrated at this interim evalua-

S540 THE AMERICAN JOURNAL OF MANAGED CARE JULY 2000 . . . HEPTAVALENT PNEUMOCOCCAL CONJUGATE VACCINE IN CHILDREN . . . tion, termination of the trial was rec- reacting serotype, and that child did ommended by the Study Advisory not have a bloodstream infection. Group. Enrollment therefore was dis- There was no evidence in this trial of continued at the end of August 1998, an increased risk of disease among but blinded follow-up and per-proto- pneumococcal vaccine recipients col vaccination of the 2 groups was caused by serotypes not contained in continued until April 20, 1999. the vaccine. Subsequently pneumococcal conju- To evaluate the overall potential gate vaccine was offered to children impact of vaccination against pneu- who had received control vaccine. mococcal disease, an analysis was performed that compared the risk of Final Efficacy Analysis invasive disease regardless of pneu- At the time of the unblinding of the mococcal serotype. This analysis study there were 40 fully vaccinated included all the cases in the intent-to- cases of invasive disease caused by treat analysis as well as the cases that vaccine serotypes, of which 39 had were caused by nonvaccine serotypes. occurred in controls, for an efficacy of There was a 89.1% (95% confidence 97.4% (95% confidence interval, 82.7% interval, 73.7% to 95.85%; P < 0.001) to 99.9%; P < 0.001) (Table 1). The 1 reduction in the total invasive pneu- vaccine failure was a child with bac- mococcal disease burden in children teremic pneumonia caused by who had received 1 or more doses of serotype 19F who had received 4 the pneumococcal conjugate. doses of vaccine. There were 52 cases There were sufficient cases to eval- of invasive disease in the intent-to- uate the serotype-specific efficacy of treat analysis in the pneumococcal vaccination against 4 of the 7 group for an effectiveness of 93.9% serotypes in an intent-to-treat analy- (95% confidence interval, 79.6% to sis (Table 2). Point estimates for 98.5%; P < 0.001). The 3 vaccine fail- serotype-specific efficacy ranged ures in the intent-to-treat analysis between 84.6% and 100%. No cases included the fully vaccinated child were seen during the study caused by mentioned above, 1 child who devel- serotype 4. oped acute myelogenous leukemia after vaccination and became bac- teremic from serotype 19F while receiving immunosuppressive chemo- therapy, and a partially vaccinated child who developed infection caused by type 6B, 317 days after a Table 1. Invasive Disease Efficacy Results as of April 20, 1999 single dose. There were 9 cases of invasive dis- Case Split ease caused by nonvaccine serotype Analysis for Serotypes Control: Pneumococcal Efficacy pneumococci. Six cases occurred in Contained in the Vaccine Vaccine Groups (%) P the control group (3, 6A, 11A, 18B, 19A, and 38) and 3 in children who Per protocol fully vaccinated 39:1 97.4 < 0.001 (82.7-99.9)* received pneumococcal conjugate vaccine (types 10F and 38 in 2 fully Intent to treat 49:3 93.9 < 0.001 (79.6-98.5) vaccinated children and 1 case of an infected thyroglossal duct cyst caused Partially vaccinated only 7:1 85.7 0.05 (0-100) by serotype 23A in a child who had received 2 doses of vaccine). Only 1 All cases regardless of 55:6 89.1 < 0.001 serotype case of nonvaccine serotype disease in pneumococcal vaccine recipients (73.7-95.8) was caused by a potentially cross- *Numbers in parentheses, 95% confidence interval.

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Efficacy Against Otitis Media effective in preventing otitis media Data on otitis media have been ana- episodes (Table 3). The effectiveness of lyzed through April 30, 1998. A total of the vaccine against frequent otitis 73,041 visits for otitis media and media increased from 9.3% to 22.8% as 52,789 episodes of otitis had occurred the frequency of episodes increased. in the study population as of that time. Four hundred thirty-two children had A total of 5451 children had frequent ventilatory tube placement (VTP) dur- otitis as defined by 3 episodes or more ing the study. Children who had within 6 months or 4 episodes or more received the pneumococcal conjugate within 1 year. The vaccine was 7.0% vaccine were 20.1% less likely to require tube placement than controls. Twenty-three children in the study population had positive cultures for pneumococci of vaccine serotype Table 2. Serotype Distribution of Invasive Disease as of obtained from cultures of spontaneous- April 20, 1999 ly ruptured tympanic membranes. In the intent-to-treat analysis there were Case Split 17 control cases and 6 cases in the Control: Pneumococcal Effectiveness Serotype Vaccine Groups (%) pneumococcal vaccine group for a point estimate of efficacy of 64.7%, P = 19F 13:2 84.6 0.035. In the analysis of fully vaccinat- (32.0-98.4)* ed children there were 12 cases in con- 14 11:0 100 trols and 4 in the pneumococcal group (60.2-100) with a point estimate of 66.7% efficacy, 18C 9:0 100 P = 0.077. All of the vaccine failures in (49.3-100) both analyses were serotype 19F. 23F 6:0 100 The impact of vaccination on (15.1-100) severity of otitis media episodes was 6B 7:1 85.7 also evaluated. The number of chil- (-11.2-99.7) dren with a given number of medical 9V 3:0 100 visits for 1 episode was compared in (-142-100) the 2 vaccine groups. In children 6 to 4 0:0 12 months of age, the reduction in the *Numbers in parentheses, 95% confidence interval. number of children experiencing 1, 2, 3, or 5 or more visits per episode was 2%, 6%, 15%, and 18%, respectively. Similarly for children older than 12 months of age, the reduction in the number of children experiencing 1, 2, Table 3. Efficacy Results for Otitis Media 3, or 5 or more visits per episode was 7%, 8%, 15%, and 43%, respectively.

Per Protocol Intent to Treat Analysis (%) (%) Safety Reactogenicity as assessed through Otitis media visits 8.9 (5.8-11.8)* 7.8 (5.2-10.5) telephone interviews was analyzed sep- Otitis media episodes 7.0 (4.1-9.7) 6.4 (3.9-8.7) arately for children who had received Frequent otitis 3/4† 9.3 (3.0-15.1) 9.1 (4.1-13.8) DTaP and DTwP vaccine concurrently. Frequent otitis 4/5† 11.9 (1.6-21.1) 10.0 (2.4-17.0) Rates of these local and systemic reac- Frequent otitis 5/6† 22.8 (6.7-36.2) 12.3 (0-23.2) tions for children who received whole- cell pertussis vaccine concurrently Ventilatory tube placement 20.1 (1.5-35.2) 20.3 (3.6-34.1) were very similar to those we have 7 *Numbers in parentheses, 95% confidence interval. reported in a prior publication. For the †Number of episodes in 6 months/number of episodes in 1 year. children who received acellular pertus-

S542 THE AMERICAN JOURNAL OF MANAGED CARE JULY 2000 . . . HEPTAVALENT PNEUMOCOCCAL CONJUGATE VACCINE IN CHILDREN . . .

Table 4. Local Reactions Comparing Pneumococcal Conjugate and Meningococcal Conjugate as Well as Each of These with DTaP

PNCRM7 PNCRM7 DTaP P MnCC DTaP P vs. MnCC Reaction (%) (%) (%) (%) P

Redness Dose 1 10.0 6.7 < 0.001 6.5 5.6 0.345 0.124 Dose 2 11.6 10.5 0.512 7.6 10.8 0.011 0.003 Dose 3 13.8 11.4 0.143 9.3 8.2 0.557 0.011 Dose 4 10.9 3.6 0.004 4.5 4.0 > 0.999 0.226 Redness > 3 cm Dose 1 0.3 0 0.500 0.1 0.3 > 0.999 > 0.999 Dose 2 0.0 0.2 > 0.999 0.2 0.4 > 0.999 0.481 Dose 3 0.2 0.2 1.3 0.8 0.625 0.105 Dose 4 0.6 0.6 > 0.999 0.0 0.0 0.225 Swelling Dose 1 9.8 6.6 0.002 4.2 4.3 > 0.999 0.013 Dose 2 12.0 10.5 0.312 5.1 7.4 0.080 0.001 Dose 3 10.4 10.4 > 0.999 6.9 8.3 0.473 0.001 Dose 4 12.1 5.5 0.013 4.5 3.4 0.688 0.247 Swelling > 3 cm Dose 1 0.1 0.1 0.0 0.0 > 0.999 Dose 2 0.4 0.6 > 0.999 0.2 0.0 > 0.999 > 0.999 Dose 3 0.5 1.0 0.500 0.3 0.5 > 0.999 > 0.999 Dose 4 0.6 0.6 > 0.999 0.0 0.0 0.224 Tenderness Dose 1 17.9 16.0 0.053 17.9 18.9 0.265 0.970 Dose 2 19.4 17.3 0.080 15.0 15.6 0.677 0.069 Dose 3 14.7 13.1 0.265 12.3 12.0 > 0.999 0.280 Dose 4 23.3 18.4 0.096 15.4 14.9 > 0.999 0.052

MnCC = meningococcal conjugate.

Table 5. Fever Within 48 Hours of Vaccination Among Infants Receiving PNCRM7 or MnCC Vaccine*

PNCRM7 MnCC %N% N P

Fever ≥ 38ºC Dose 1 15.1 709 9.4 710 0.001 Dose 2 23.9 556 10.9 507 0.001 Dose 3 19.1 461 11.8 414 0.003 Dose 4 21.0 224 17.0 230 0.274 Fever > 39ºC Dose 1 0.9 709 0.3 710 0.178 Dose 2 2.5 556 0.8 507 0.029 Dose 3 1.7 461 0.7 414 0.180 dose 4 1.3 224 1.7 230 > 0.999

*Concomitantly with DTaP and other recommended vaccines. MnCC = meningococcal conjugate.

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sis vaccine concurrently, rates of local P = 0.039). In those who had received and systemic reactions for doses 1 DTaP concomitantly, there was no through 4 of the study are shown in such difference (4:5, respectively; Tables 4 and 5. P = 0.76). There was no clustering of Swelling, redness, and fever were febrile seizures within the 3-day peri- more common in the pneumococcal od after receipt of vaccine in either conjugate vaccine group than in the group of children. Elective admissions control DTaP limb. For the local reac- (including ventilatory tube place- tions these differences were observed ment) occurred more commonly in for mild reactions only, and there was the control group (116 controls vs. 87 no statistical difference in the rate of pneumococcal recipients, P = 0.048). more severe reactions. In the primary Review of emergency room visits series but not after the booster dose, within 30 days of vaccination revealed fever of 38ºC or higher was observed 1188 visits in pneumococcal vaccine more commonly in the pneumococcal recipients and 1169 visits in controls vaccine recipients than in the (P = 0.679). Comparisons of 80 differ- meningococcal vaccine controls. For ent diagnoses were made, revealing sig- a fever of 39ºC or higher, this was true nificant differences only for breath only after dose 2. Reactions were self- holding (0 controls vs. 5 pneumococcal limited and resolved by the 14-day vaccine recipients, P = 0.031) and cel- telephone interview. lulitis (7 controls vs. 1 pneumococcal Overall 513 pneumococcal vaccine vaccine recipient, P = 0.039). Cellulitis recipients and 579 controls were hos- was not observed at the injection site, pitalized within 60 days of receipt of a and no episodes were culture-positive. dose of vaccine (P = 0.047). Rate com- Of the 5 children with breath holding, parisons were made for the 92 sepa- 3 had a prior history of similar rate diagnostic categories observed, episodes. None of these statistical but significant differences were seen analyses takes into account the large for only 2. Febrile seizures in children number of multiple comparisons. who had also received DTwP were In an analysis of selected outpa- more common in the pneumococcal tient clinic visit categories, there were vaccine group than in controls (7:1, no significant differences between pneumococcal vaccine recipients and controls for allergic reactions/hives (10 controls vs. 12 pneumococcal recipients, P = 0.677), asthma, wheez- ing, shortness of breath, or breath Table 6. Geometric Mean Concentration to Each holding (46 controls vs. 40 pneumo- Pneumococcal Serotype in Subjects Receiving Primary and coccal recipients, P = 0.522) within 3 Booster Doses of PNCRM7 When Given With DTaP Vaccine days of any dose. There were signifi- cant differences in outpatient clinic Geometric Mean Concentration (µg/mL) visits for seizures overall (11 pneumo- Pneumo Predose 1 Postdose 3 Preboost Postboost coccal vaccine recipients vs. 28 con- Serotype (N = 61) (N = 75) (N = 52) (N = 41) trols, P = 0.041), but none of the subcategories of seizure (epilepsy, 4 0.086 1.365 0.418 2.826 febrile seizures, afebrile seizures or 6B 0.394 2.143 1.099 8.268 seizures, type unknown) was signifi- 9V 0.192 1.234 0.539 2.695 cantly different. In addition there was 14 0.328 5.041 1.481 5.053 no time clustering of these events in 18C 0.203 1.880 0.389 3.005 association with vaccination. 19F 0.629 1.524 0.598 2.543 There were a total of 12 cases of 23F 0.223 1.207 0.310 2.783 sudden infant death syndrome (SIDS) observed in the study population: 4 in

S544 THE AMERICAN JOURNAL OF MANAGED CARE JULY 2000 . . . HEPTAVALENT PNEUMOCOCCAL CONJUGATE VACCINE IN CHILDREN . . . the pneumococcal vaccine group (0.2 safety and immunogenicity of this case per 1000 children) and 8 in con- vaccine.6-9 It is clear from this study trols (0.4 case per 1000 children). that PNCRM7 is efficacious in pre- This compares favorably with 0.5 case venting pneumococcal invasive dis- per 1000 children observed in the ease as well as clinical otitis media. state of California during 1996 and 1997, the most recent data available (Carole Traylor, RNC, MSN, Program Coordinator, California SIDS Program, personal communication). Of the SIDS cases 1 was observed Figure 1. Serotype-Specific Pneumococcal Antibody Response within 1 week of pneumococcal vac- in Children Receiving DTaP cine, and 2 were observed within 1 week of meningococcal vaccine. In an age- and seasonality-adjusted analysis based on the California State SIDS data, we would have expected 1.06 cases within 1 week of either vaccine.

Immunogenicity The antibody responses to pneumo- coccal serotypes in children receiving pneumococcal conjugate vaccine in controls can be seen in Table 6. A sub- stantial immunologic response to pneumococcal polysaccharide was elicited to all 7 pneumococcal serotypes by the heptavalent pneumo- coccal conjugate as shown in Figure 1. There was variability in the magnitude of this response and the kinetics of decay of antibody titers before the booster dose was dependent on serotype. Before the booster dose geo- Figure 2. Reverse Cumulative Distribution Curves of Postdose 3 metric mean antibody titers fell below Antibody Concentrations: PNCRM7 Concurrent with DTwP or DTaP 1 µg/mL for all serotypes except types 6B and 14. A booster response was seen for all serotypes. Reverse cumula- tive distribution curves for the 7 vac- cine serotypes after the primary series are shown in Figure 2. More than 95% of pneumococcal conjugate recipients developed antibody concentrations of 0.15 µg/mL or higher after dose 3 whereas more than 95% of controls were below 0.5 µg/mL.

. . . DISCUSSION. . . This is the first report of the effica- cy of pneumococcal conjugate vac- cine in healthy infants and toddlers. Previous reports have detailed the

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The 89.1% reduction in all cases of However, the reverse cumulative dis- invasive disease is striking consider- tribution curves were different for ing the fact that PNCRM7 contains each serotype in both vaccines and serotypes that are responsible for only controls. A more conservative protec- an estimated 85% of pneumococcal tive estimate could be inferred to be disease in infants and children.10 This as high as 0.5 µg/mL. Between 82% may be a result of cross-protection (for type 23F) and 97% (for type 14) of among related serotypes. It is reason- vaccines achieved this titer compared able to expect a marked diminution in with less than 6% of all controls. In the total pneumococcal disease bur- fact the proportion of vaccine with den with licensure and widespread titers of 0.5 µg/mL or more was less use of this vaccine. than 90% for 4 of 7 serotypes (types 4, Knowledge of the protection afford- 6B, 19F, and 23F). Because the pro- ed by this vaccine may have a pro- portion of immunized individuals found effect on the management of achieving titers of 0.5 µg/mL is lower infants who present to physicians with than the proportion protected by the fever and no localized signs of infec- vaccine, this estimate is likely to be tion. It is likely that clinical laboratory higher than the minimum protective diagnostic procedures, hospitaliza- level. We therefore propose that the tions, and presumptive use minimum antibody titer after the in the vaccinated children will be sig- primary series associated with long- nificantly reduced. Because the pneu- term protection against invasive dis- mococcal vaccine strains are the same ease is in the range of 0.15 to 0.5 strains that exhibit resistance to peni- µg/mL. Establishing a more precise cillin and other ,11,12 there correlate would require assessment should also be less pressure to utilize of the specific serotype involved, the broad-spectrum antibiotics, which avidity of the antibody in question, cause further antibiotic resistance. and the role of priming for a Previous studies have hypothesized response to polysaccharide antigen immunologic correlates of protection in protection. It is likely that titers against invasive disease ranging associated with protection against between 0.06 and 2 µg/mL.13-16 By mucosal pneumococcal disease and comparing the antibody concentra- pneumonia will be different and that tions of pneumococcal antibodies they might vary by serotype. obtained in the immunized popula- The success of PNCRM7 in causing tion in this trial with those in con- a reduction in otitis media must be trols, it is possible to infer the evaluated with an awareness of the antibody concentrations that are like- role of the pneumococcus in the etiol- ly to be associated with protection ogy of otitis media and the trial against invasive disease in infants and design. Visits and diagnosis for otitis children.16 As seen in Figure 2 we media were based on the clinical diag- observed that more than 97% of pneu- nosis of otitis media. It has been esti- mococcal vaccine recipients achieved mated that 50% to 60% of otitis media 0.15 µg/mL or greater of anticapsular cases are bacterial.17 Of these an esti- antibody for all serotypes after the mated 20% to 40% are caused by primary series. This correlates with pneumococci.18 The vaccine contains the observed protective efficacy of approximately 85% of the serotypes 97.3%. Conversely the majority of responsible for pneumococcal disease controls for each serotype did not in infants and children.7 Multiplying have 0.5 µg/mL or more antibody. The these fractions together the maximum percent of controls achieving concen- impact on vaccination of clinical otitis trations of 0.15 µg/mL or more ranged media would be expected to be 8.5% from 5% for type 4 to 35% for type 19F. to 20%. The observed 8.9% reduction

S546 THE AMERICAN JOURNAL OF MANAGED CARE JULY 2000 . . . HEPTAVALENT PNEUMOCOCCAL CONJUGATE VACCINE IN CHILDREN . . . in otitis media visits is at the lower against middle-ear disease caused by end of expected percentages. More serotype 19F. Our study did not eval- impressive is the protection against uate antibody avidity or immunologic frequent episodes or severe otitis priming, both of which may also be media, bacteriologically confirmed important factors in protection middle-ear pneumococcal disease, against disease.19 Follow-up with larg- and ventilatory tube placement. er numbers of children in a postmar- PNCRM7 reduced clinical otitis media keting study is necessary to further episodes by 22.8% in subjects who evaluate protection induced by the experienced 5 episodes in 6 months. heptavalent pneumococcal conjugate Ventilatory tube placements were vaccine to serotype 19F. More data on reduced by 20.1%, and bacteriologi- the serotype-specific bacteriologic cally confirmed middle-ear disease efficacy of PNCRM7 in otitis media was diminished by 66.7%. The effica- will be forthcoming from a study in cy of PNCRM7 in a subset who Finland by Eskola20 that includes tym- returned for multiple otitis media vis- panocentesis of all otitis media. its within an episode increased from It is worth emphasizing that in the 2% to 18% in infants younger than 12 United States there are approximately months of age and from 7% to 43% in 24.5 million visits for otitis media and infants older than 1 year of age as the more than 500,000 ventilatory tube number of visits per episode placements per year.21,22 Therefore, we increased. Individuals who failed to would expect the widespread use of respond to antibiotics or had more PNCRM7 could eliminate more than severe disease and thus returned 2,000,000 visits for otitis media, with more frequently to the physician had a concomitant reduction in the num- a greater benefit from vaccination. ber of antibiotic prescriptions and a This greater degree of benefit was also reduction of 100,000 VTPs. experienced by children with fre- After the introduction of Hib conju- quent otitis media. These data suggest gate vaccination, a large herd immuni- that both of these groups are more ty effect was seen as a result of likely to have a pneumococcal infec- reduction in carriage of that organism tion and have a greater benefit from in vaccinees. It was not possible in this vaccination. trial to evaluate any potential herd Among the children with sponta- immunity induced by pneumococcal neously draining ears, all 6 vaccine conjugate vaccination. Whether pneu- failures were caused by serotype 19F. mococcal conjugate vaccination will This is the same serotype observed in result in a similar herd immunity the 1 fully vaccinated invasive disease effect awaits the results of an ongoing vaccine failure. Review of the trial by Santosham and colleagues immunologic response to 19F in chil- among Southwest Native Americans dren in our study does not suggest and widespread use of the vaccine that these failures are a result of a after licensure. suboptimal immunologic response to Studies of carriage have suggested this serotype. However, S. Bloch (per- reduction in colonization by vaccine sonal communication) noted that the serotypes after pneumococcal conju- mean antibody titer in children who gate vaccination.23,24 These studies developed otitis caused by types 6A or have also suggested that colonization 6B was 0.23 µg/mL, whereas children with nonvaccine serotypes may occur who developed otitis caused by type in vaccinated individuals. It is not 19F had a mean circulating antibody known, however, whether these titer of 1.35 µg/mL. These data sug- results are caused by true replace- gest that a higher titer of circulating ment by nonvaccine serotypes or antibody may be necessary to protect unmasking of serotypes already pre-

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sent in the same individuals. No evi- 6. Quataert SA, Kirch CS, Wiedl LJ, et al. dence for an increased risk of disease Assignment of weight-based antibody units caused by nonvaccine serotypes was to a human anti-pneumococcal standard ref- observed in our trial. erence serum lot 89-S. Clin Diag Lab This trial included an extensive Immunol 1995;2:590-597. evaluation of the safety of both the 7. Shinefield HR, Black S, Ray P, et al. Safety and immunogenicity of heptavalent pneumo- pneumococcal and meningococcal coccal CRM197 conjugate vaccine in infants conjugate vaccines. Safety monitoring and toddlers. Pediatr Infect Dis J 1999; in this cohort of more than 37,000 18:757-763. children did not reveal any severe 8. Froom J, Culpepper L, Grab P, et al. adverse events related to vaccination Diagnosis and antibiotic treatment of acute that resulted in hospitalization, emer- otitis media: Report from International gency visits, or clinic visits. Local and Primary Care Network. Br Med J systemic reactions observed were 1990;300:582-586. generally relatively mild with either 9. Rannels MB, Edwards KM, Kayserling HL, vaccine, and more severe local and et al. Safety and immunogenicity of heptava- systemic reactions were uncommon lent pneumococcal vaccine conjugated to CRM197 in United States infants. Pediatrics and self-limited. 1998;101:604-611. We conclude that when used in a 4- 10. Black S, Shinefield H. Progress toward dose regimen at 2, 4, and 6 months of effective pneumococcal vaccination in infan- age with a booster dose in the second cy. Contemp Pediatr 1998;Nov(Suppl):2-17. year of life, this heptavalent pneumo- 11. Friedland IR, McCracken GH Jr. coccal conjugate vaccine appeared safe Management of caused by antibi- and immunogenic. This vaccine was otic-resistant . N highly effective in preventing invasive Engl J Med 1994;331:337-342. disease caused by the 7 serotypes con- 12. Zenni MK, Cheatham SH, Thompson JM, tained in the vaccine. In addition, a sig- et al. Streptococcus pneumoniae coloniza- nificant reduction in otitis media and tion in the young child: Association with oti- tis media and resistance to penicillin. otitis media-related events was seen J Pediatr 1995;127:533-537. and was most marked for children with 13. Shurin PA, Rehmus JM, Johnson CE, et al. frequent otitis media and for tympa- Bacterial polysaccharide immune globulin for nostomy tube placement. prophylaxis of acute otitis media in high risk children. J Pediatr 1993;123:801-810. 14. Rubin LG, Mardy GV, Pais L, Carlone G. Human anticapsular antibody concentration required for protection against experimental . . . REFERENCES . . . pneumococcal bacteremia (Abstract G-47). In: Proceedings of the 35th Interscience 1. CDC. Progress toward elimination of Conference of Antimicrobial Agents and Haemophilus influenzae type b among Chemotherapy, San Francisco, CA, infants and children: United States, 1987- September 17 to 20, 1995. Washington, DC: 1993. MMWR Morb Mortal Wkly Rep American Society for Microbiology, 1995. 1994;43:144-1488. 15. Saladino RA, Stack AM, Malley R, 2. CDC. Drug resistant Streptococcus pneumo- Thompson CM, Siver CR, Fleiser GO. niae: Kentucky and Tennessee, 1993. MMWR Bacterial polysaccharide immune globulin Morb Mortal Wkly Rep 1994;43:28-35. (BPIG) protects infant rats with S. pneumoni- 3. STAT EXACT Statistical Package. ae (SP) pneumonia from bacteremia, menin- Cambridge, MA: Cytel Statistical Software; gitis and death. Pediatr Res 1996;36:184A. 1998. 16. Siber GR. Methods for estimating sero- 4. Fleming TR, Harrington DP. Counting logic correlates of protection. Dev Biol Stand processes and survival analysis. New York, 1997;89:283-296. NY: Wiley; 1991. 17. Palton Fl. Otoscopy for the diagnosis of 5. SAS Institute Inc. SAS/STAT Software: otitis media. Pediatr Infect Dis J 1998;17: Changes and enhancements through release 540-543. 6,12. Cary, NC: SAS Institute Inc.; 1997:942.

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18. Bluestone CD, Klein JO. Otitis Media in 22. CDC. Ambulatory and inpatient proce- Infants and Children, 2nd ed. Philadelphia, dures in the United States, 1996. Series 13. PA: WB Saunders; 1995. Data from the National Health Care Survey, 19. Anttilla M, Eskola J, Ahrnan H, Kayhty H. No. 139, PHS 99-1710; November 1998. Differences in the avidity of antibodies 23. Dagan R, Melamed R, Muallem M, et al. evoked by four different pneumococcal con- Reduction of a nasopharyngeal carriage of jugate vaccines in early childhood. Vaccine pneumococci during the second year of life 1999;17:1970-1977. by a heptavalent conjugate pneumococcal 20. Eskola J. Efficacy of pneumococcal con- vaccine. J Infect Dis 1996;174:1271-1278. jugate vaccine against otitis media (Late- 24. Dagan R, Muallem M, Leroy O, Breaker Abstract). Presented at the 39th Yagupeky P. Reduction of pneumococcal Interscience Conference of Antimicrobial nasopharyngeal carriage in early infancy Agents and Chemotherapy, San Francisco, after immunization with tetravalent pneumo- CA, September 26 to 29, 1999. coccal vaccines conjugated to either tetanus 21. Schappert SM. Office visits for otitis toxoid or diphtheria toxoid. Pediatr Infect media: United States, 1975-90. CDC Dis J 1997;16:1060-1064. Advance Data 1992;214:1-20.

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