Frank Malinoski

Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children.

Objective. To determine the efficacy, safety and immunogenicity of the heptavalent CRM197 pneumococcal conjugate vaccine against invasive disease caused by vaccine serotypes and to determine the effectiveness of this vaccine against clinical episodes of otitis media. Methods. The Wyeth Lederle Heptavalent CRM197 (PCV) was given to infants at 2, 4, 6 and 12 to 15 months of age in a double blind trial; 37 868 children were randomly assigned 1:1 to receive either the pneumococcal conjugate vaccine or meningococcus type C CRM197 conjugate. The primary study outcome was invasive disease caused by vaccine serotype. Other outcomes included overall impact on invasive disease regardless of serotype, effectiveness against clinical otitis media visits and episodes, impact against frequent and severe otitis media and ventilatory tube placement. In addition the serotype‐specific efficacy against otitis media was estimated in an analysis of spontaneously draining ears. Results. In the interim analysis in August, 1998, 17 of the 17 cases of invasive disease caused by vaccine serotype in fully vaccinated children and 5 of 5 of partially vaccinated cases occurred in the control group for a vaccine efficacy of 100%. Blinded case ascertainment was continued until April, 1999. As of that time 40 fully vaccinated cases of invasive disease caused by vaccine serotype had been identified, all but 1 in controls for an efficacy of 97.4% (95% confidence interval, 82.7 to 99.9%), and 52 cases, all but 3 in controls in the intent‐to‐treat analysis for an efficacy of 93.9% (95% confidence interval, 79.6 to 98.5%). There was no evidence of any increase of disease caused by nonvaccine serotypes. Efficacy for otitis media against visits, episodes, frequent otitis and ventilatory tube placement was 8.9, 7.0, 9.3 and 20.1% with P < 0.04 for all. In the analysis of spontaneously draining ears, serotype‐specific effectiveness was 66.7%. Conclusion. This heptavalent pneumococcal conjugate appears to be highly effective in preventing invasive disease in young children and to have a significant impact on otitis media.

Safety and Immunogenicity of Heptavalent Pneumococcal Vaccine Conjugated to CRM197 in United States Infants

Objective. To determine the safety and immunogenicity of heptavalent pneumococcal saccharide vaccine (serotypes 4, 6B, 9V, 14, 18C, 19F, 23F) individually conjugated to CRM197 (PNCRM7), administered at 2, 4, 6, and 12 to 15 months of age. Design. Two hundred twelve healthy 2-month-old infants were equally randomized to receive four consecutive doses of PNCRM7 or an investigational meningococcal group C conjugate vaccine, which served as a control. Concomitantly administered routine vaccines were oral polio vaccine and combined diphtheria toxoid, tetanus toxoid, and whole cell pertussis vaccine/Haemophilus influenzae type b vaccine consisting of capsular oligosaccharides conjugated to CRM197 (DTP/HbOC) at 2, 4, and 6 months, and either measles-mumps-rubella vaccine or HbOC at 12 to 15 months. Active safety surveillance was conducted for 3 days after each dose. Antibody concentrations to each of the 7 pneumococcal serotypes were measured by enzyme-linked immunosorbent assay prevaccination, after doses two and three, prebooster, and postbooster. Results. Significantly fewer children experienced local reactions at the PNCRM7 injection site than at the DTP/HbOC site. There was no increase in the incidence or severity of local reactions at the PNCRM7 site with increasing doses of vaccine. Mild to moderate postvaccination fever was common in both the PNCRM7 and control vaccine groups, however DTP/HbOC was administered concurrently. All 7 vaccine serotypes were immunogenic. The kinetics of the immune responses were serotype-specific. After three doses of PNCRM7, between 92% to 100% of children had ≥0.15 μg/mL of antibody, and 51% to 90% achieved a level of ≥1 μg/mL against specific serotypes. A booster dose of PNCRM7 resulted in a brisk anamnestic response to all 7 vaccine serotypes, demonstrating effective stimulation of T-cell memory by the primary series of vaccinations. Conclusion. Primary immunization followed by a booster dose of PNCRM7 seemed to be acceptably safe and resulted in significant rises in antibody to all 7 serotypes. Implications. Studies to assess vaccine efficacy of PNCRM7 for prevention of systemic disease, nasopharyngeal colonization, and acute otitis media are in progress. If PNCRM7 proves to be protective, there is the potential to prevent up to 85% of invasive pneumococcal disease occurring in US children.

Postlicensure evaluation of the effectiveness of seven valent pneumococcal conjugate vaccine

Objective. To evaluate the impact of the introduction and routine use of seven valent pneumococcal conjugate vaccine on the epidemiology of invasive pneumococcal disease within the Northern California Kaiser Permanente (KP) population. Methods. Surveillance for invasive pneumococcal disease has been in place within KP since 1995. Isolates from normally sterile sites in children are routinely sent for serotyping. Cases of invasive disease are identified through review of automated microbiology records within KP. Incidence rates of invasive disease were compared for the period before and after routine use of pneumococcal conjugate vaccine in children. Results. The incidence of invasive pneumococcal disease caused by vaccine serotypes before the licensure and routine use of pneumococcal conjugate vaccine ranged between 51.52 and 98.15 cases per 100 000 person years in children <1 year of age and fell to 9.35 after introduction of vaccine. The incidence in children <2 years of age was 81.67 to 113.80 before introduction and 38.22 cases per 100 000 person years after introduction of the vaccine into the general population. These reductions in disease rates exceeded the average vaccine coverage substantially in each age group. No increase in disease incidence was observed for possibly cross-reacting serotypes or nonvaccine serotypes. Conclusion. The introduction and routine use of pneumococcal conjugate vaccine in our population have been associated with a substantial reduction in invasive disease incidence in children <5 years of age.

Purified fusion protein vaccine protects against lower respiratory tract illness during respiratory syncytial virus season in children with cystic fibrosis

OBJECTIVE To test in a double blind, placebo-controlled study a purified fusion protein (PFP-2) vaccine against respiratory syncytial virus (RSV) in RSV-seropositive children with cystic fibrosis (CF). METHODS Seventeen CF children, mean age 4.5 years, received PFP-2 vaccine and 17 CF children, mean age 5.8 years, received a saline vaccine. At enrollment the Shwachman clinical score, Brasfield radiographic score, oxygen saturation (SpO2), anthropometric indices and other variables were recorded. After vaccination the reactions were assessed daily for 7 days. During the RSV season weekly telephone interviews were performed and children with an acute respiratory illness were evaluated and cultured for RSV. Serum was drawn before vaccination, 1 month after vaccination and at the end of the RSV season and tested for antibodies to RSV. RESULTS Other than age the baseline measurements at enrollment were similar between groups. The PFP-2 vaccine produced mild local reactions and induced a significant neutralizing antibody response in two-thirds of the vaccinees and a significant enzyme-linked immunosorbent assay-fusion glycoprotein antibody response in nearly all the PFP-2 vaccinees. Vaccine-enhanced disease was not observed in PFP-2 vaccines infected with RSV. Protection against RSV infection was not observed; however, a significant reduction (t test, P < 0.01) in mean number of lower respiratory tract illnesses (0.8 vs. 2.1), antibiotic courses (2.2 vs 4.5) and days ill (30.5 vs. 67) occurred among RSV-infected PFP-2 vaccinees. CONCLUSIONS Efficacy of the PFP-2 vaccine against lower respiratory tract illness during the RSV season was shown in RSV-seropositive children with CF.

Comparison of the safety and immunogenicity of a pneumococcal conjugate with a licensed polysaccharide vaccine in human immunodeficiency virus and non-human immunodeficiency virus-infected children

OBJECTIVE To compare the safety and immunogenicity of a 5-valent pneumococcal conjugate vaccine to a licensed 23-valent polysaccharide pneumococcal vaccine in HIV-infected and non-HIV-infected children > or = 2 years old. METHODS Thirty HIV-infected and 30 non-HIV-infected children > or = 2 years old were randomized to receive either a 5-valent pneumococcal conjugate vaccine (PCV) or a 23-valent pneumococcal polysaccharide vaccine (PPV) intramuscularly. Children who received PCV initially were given PPV after 6 weeks. Sera were obtained before and at 6 and 12 weeks after the first vaccination to determine IgG pneumococcal antibody titers by enzyme-linked immunosorbent assay to the 5 serotypes represented in the PCV. RESULTS Both vaccines were well-tolerated with no significant differences in the rates of fever (0 to 14%) or local reactions (0 to 40%) noted between PCV and PPV recipients. Pre-first vaccination geometric mean antibody titers (combined PCV and PPV recipients) to 3 of the 5 pneumococcal types tested were significantly lower in HIV-infected than in non-HIV-infected children (in microgram/ml: type 6B, 0.179 vs. 0.565; type 14, 0.026 vs. 0.060; type 23F, 0.025 vs. 0.119, respectively; P < 0.05). Fewer > or = 4-fold titer rises were observed in HIV vs. non-HIV-infected children whether they received PCV initially (60% vs. 79%, P < 0.05) or PPV (31% vs. 59%, P < 0.05). Also PCV elicited more > or = 4-fold titer rises compared with PPV in HIV-infected (60% vs. 31%, P < 0.05) and non-HIV-infected (79% vs. 59%, P < 0.05) children. No consistent antibody-boosting effect was noted in subjects who received PPV after PCV. CONCLUSIONS We conclude that antibody responses to natural infection, PCV and particularly PPV are poorer in HIV-infected than in non-HIV-infected children. PCV is as safe as and more immunogenic than the currently licensed PPV among HIV-infected and non-HIV-infected children.

Infant Immunization with Pneumococcal CRM197 Vaccines: Effect of Saccharide Size on Immunogenicity and Interactions with Simultaneously Administered Vaccines

Six pentavalent pneumococcal conjugate vaccines (Pn-CRM197) were evaluated among 400 infants. The vaccines differed in saccharide chain length (oligosaccharide [OS] or polysaccharide [PS]) and saccharide quantity (0.5, 2, or 5 microg). Subjects were randomized into groups 1-6 (Pn-CRM197 recipients) or 7 (controls) for immunization at 2, 4, and 6 months of age. Pn-CRM197 were well tolerated and elicited mean antibody concentrations that exceeded those in controls for all 5 capsular serotypes. PS formulations were generally more immunogenic than their OS counterparts. For PS vaccines, a dose-response was documented (5 microg > 2 microg > 0.5 microg), but the differences between the 5- and 2-microg formulations were insignificant. The mean anti-PRP antibody concentration was significantly higher among Pn-CRM197 recipients. It is concluded that PS vaccines are more immunogenic than OS vaccines. The improved immunogenicity from Haemophilus type b oligosaccharide conjugate (HbOC) vaccine when given with Pn-CRM197 suggests that a decreased dose of HbOC vaccine may be sufficient to elicit protection.

Sequential annual administration of purified fusion protein vaccine against respiratory syncytial virus in children with cystic fibrosis

BACKGROUND We recently showed the clinical benefit of the PFP-2 vaccine for respiratory syncytial virus (RSV) for children with cystic fibrosis (CF). OBJECTIVE To determine the safety and immunogenicity of yearly sequential administration of the PFP-2 vaccine in CF children. STUDY DESIGN Twenty-nine of the 34 CF children who participated in the previous study were enrolled in this open label vaccine study. All of the CF children ages 2.6 to 8.9 years received the PFP-2 vaccine, the PFP/PFP group received the PFP-2 vaccine in 1993 and 1994 and the saline/PFP group received the vaccine for the first time in 1994. At entry demographic data and measurements of lung function and nutrition were collected. Microneutralization test, enzyme-linked immunosorbent assay to F protein and Western blot assay were performed on plasma drawn before and 4 weeks after vaccination and at the end of the RSV season. During the study weekly telephone calls were made and acute respiratory illnesses were evaluated. RESULTS Baseline measurements were similar between groups. Systemic and local vaccine reactions were mild and similar for both groups. A 4-fold or greater neutralizing antibody rise to RSV occurred in 4 of 14 (28.6%) and 9 of 14 (64.3%) in PFP/PFP and saline/PFP groups (P = 0.13), respectively. Four children in the PFP/PFP group and 7 in the saline/PFP group were infected with RSV. A reduction in lower respiratory illnesses (1.0 vs. 2.0), antibiotic courses (2.5 vs. 5.6) and days of illnesses (37.3 vs. 93.1) was observed in the PFP/PFP vaccinees infected with RSV compared with the saline/PFP group (t test; P < or = 0.05). One death occurred in the PFP/PFP group; the cause of death was consistent with septic shock and unrelated to vaccination or RSV infection. CONCLUSION Sequential annual PFP-2 vaccination was safe and not associated with exaggerated respiratory disease.

IMMUNOGENICITY OF A PNEUMOCOCCAL PROTEIN CONJUGATE VACCINE IN INFANTS WITH SICKLE CELL DISEASE. ▴ 946

Pneumococcal infections are an important cause of morbidity/mortality in children with sickle cell disease (SCD). Pneumococcal conjugate vaccines linked to protein carriers are immunogenic in healthy infants < 2 yrs of age, but have not been evaluated in children with SCD. Infants with SCD were immunized with a 7-valent pneumococcal polysaccharide-protein conjugate vaccine (CRM; cross-reacting diphtheria mutant) at 2, 4, and 6 mos. Type specific antibodies were measured by ELISA after pre-absorption with C-polysaccharide. No side effects have been observed. This vaccine appears to be safe and immunogenic, and should provide protection against pneumococcal infections in infants with SCD. (Funded in part by Lederle-Praxis Biologicals.) Table

SAFETY AND IMMUNOGENICITY OF 3 DOSES OF A 5-VALENT PNEUMOCOCCAL CONJUGATE VACCINE (PCV) IN HIV AND NON HIV-INFECTED CHILDREN ▴ 1037

SAFETY AND IMMUNOGENICITY OF 3 DOSES OF A 5-VALENT PNEUMOCOCCAL CONJUGATE VACCINE (PCV) IN HIV AND NON HIV-INFECTED CHILDREN ▴ 1037

SAFETY AND IMMUNOGENICITY OF HEPTAVALENT PNEUMOCOCCAL CONJUGATE VACCINE(Wyeth-Lederle) IN INFANCY. 986

SAFETY AND IMMUNOGENICITY OF HEPTAVALENT PNEUMOCOCCAL CONJUGATE VACCINE(Wyeth-Lederle) IN INFANCY. 986