Comparison of pneumococcal conjugate polysaccharide and free polysaccharide vaccines in elderly adults: conjugate vaccine elicits improved antibacterial immune responses and immunological memory.

BACKGROUND: High functional antibody responses, establishment of immunologic memory, and unambiguous efficacy in infants suggest that an initial dose of conjugated pneumococcal polysaccharide (PnC) vaccine may be of value in a comprehensive adult immunization strategy. METHODS: We compared the immunogenicity and safety of 7-valent PnC vaccine (7vPnC) with that of 23-valent pneumococcal polysaccharide vaccine (PPV) in adults >/=70 years of age who had not been previously vaccinated with a pneumococcal vaccine. One year later, 7vPnC recipients received a booster dose of either 7vPnC (the 7vPnC/7vPnC group) or PPV (the 7vPnC/PPV group), and PPV recipients received a booster dose of 7vPnC (the PPV/7vPnC group). Immune responses were compared for each of the 7 serotypes common to both vaccines. RESULTS: Antipolysaccharide enzyme-linked immunosorbent assay antibody concentrations and opsonophagocytic assay titers to the initial dose of 7vPnC were significantly greater than those to the initial dose of PPV for 6 and 5 of 7 serotypes, respectively (P < .01 and P < .05, respectively). 7vPnC/7vPnC induced antibody responses that were similar to those after the first 7vPnC inoculation, and 7vPnC/PPV induced antibody responses that were similar to or greater than antibody responses after administration of PPV alone; PPV/7vPnC induced significantly lower antibacterial responses, compared with those induced by 7vPnC alone, for all serotypes (P < .05). CONCLUSION: In adults, an initial dose of 7vPnC is likely to elicit higher and potentially more effective levels of antipneumococcal antibodies than is PPV. In contrast with PPV, for which the induction of hyporesponsiveness was observed when used as a priming dose, 7vPnC elicits an immunological state that permits subsequent administration of 7vPnC or PPV to maintain functional antipolysaccharide antibody levels.

Design of a group-randomized Streptococcus pneumoniae vaccine trial.

A group-randomized, double-masked, phase III trial of a Streptococcus pneumoniae conjugate vaccine is being conducted in American Indian populations in the southwestern United States. Approximately 9000 infants will be enrolled in the primary efficacy cohort with vaccine allocation determined by community of residence. The trial is designed to continue until 48 cases of invasive pneumococcal disease due to vaccine serotypes have accumulated. Thirty-eight geographically and socially distinct areas were randomized within blocks formed by population size and geographic location. This design affords the opportunity to capture the effects of herd immunity (indirect effects) by estimating the impact of the vaccine intervention on nonimmunized infants. Group-randomized trials have challenging design and analysis features, many of which are discussed here in the context of the first such trial designed to lead to licensure of a drug or biologic in the United States.

Safety and immunogenicity of four doses of Neisseria meningitidis group C vaccine conjugated to CRM197 in United States infants.

BACKGROUND: Following widespread use of conjugate pneumococcal vaccine, Neisseria meningitidis likely will become the leading cause of bacterial sepsis and meningitis in US children. This report describes the safety and immunogenicity in US children of four consecutive doses of a meningococcal group C vaccine conjugated to CRM197 via reductive amination (MnCC). METHODS: One hundred six healthy 2-month-old infants received MnCC at 2, 4 and 6 months of age in a randomized, controlled double blind study; children in the other treatment arm were given a 7-valent conjugate pneumococcal vaccine. Parents reenrolled 64 of these children at 12 to 15 months to receive a fourth dose of MnCC. Routine childhood vaccines, including DTP, were coadministered. Temperatures and symptoms were recorded for 3 days after each immunization. Serum enzyme-linked immunosorbent assay IgG and bactericidal antibodies were measured prevaccination and before and 1 month after Doses 3 and 4. RESULTS: Moderate to severe local reactions, defined as erythema or induration > or =2.4 cm or pain that interfered with limb movement was reported after 0 to 3.2% of MnCC injections, depending on the reaction and dose. Fever occurred in 23 to 37% of children, but the contribution of MnCC to the febrile reactions is unknown. Geometric mean concentrations of IgG antibody to group C meningococcal polysaccharide were 3.72 microg/ml after Dose 3 and 8.03 microg/ml after the booster. Geometric mean functional serum bactericidal antibody titers after Doses 3 and 4 were 1:463 and 1:2341, respectively. One hundred percent of children had a serum bactericidal antibody titer of > or =1:64 after three doses and > or = 1:128 after the booster. CONCLUSIONS: The MnCC vaccine had an acceptable safety profile and generated high titers of bactericidal antibody in immunized US infants and toddlers. It appears to be an attractive candidate vaccine for the prevention of serogroup C meningococcal disease in young children.

Comparative study of Lederle/Takeda acellular and Lederle whole-cell pertussis-component diphtheria-tetanus-pertussis vaccines in infants in Germany.

In preparation for a large efficacy trial in Germany, a pilot study was initiated in December 1990. In this study 149 infants were enrolled; with double-blind randomization 75 received Lederle/Takeda acellular pertussis component diphtheria-tetanus-pertussis vaccine (APDT) and 74 received Lederle whole-cell pertussis component diphtheria-tetanus-pertussis vaccine (DTP). The mean age at first dose was 3.5 months, and the second and third doses followed at 6-week intervals. Reactions were relatively mild with both vaccines; in general they were less frequent following APDT. The IgG antibody responses to lymphocytosis promoting factor (LPF) and fimbriae-2 were similar in both groups whereas the responses to pertactin and filamentous haemagglutinin (FHA) were greater in APDT recipients. DTP recipients had greater responses to tetanus and diphtheria toxoids. When age of first dose was examined (8-12 weeks versus 16-20 weeks), it was found that young age had a suppressive effect on antibody responses in DTP but not APDT recipients to LPF toxoid, pertactin, fimbriae-2, and tetanus and diphtheria toxoids. High values of transplacentally acquired antibody lessened the response to LPF toxoid and tetanus toxoid in DTP recipients and to tetanus toxoid in APDT vaccinees. The IgG immune response to LPF toxoid, FHA and fimbriae-2 was found to be more uniform in APDT recipients than in DTP vaccinees. An IgA antibody response to fimbriae-2 was noted in 13% of DTP recipients but in no APDT vaccinees. The broad immunogenicity and mild reactogenicity of this APDT vaccine justifies its use in the German efficacy trial.

Safety of combined oligosaccharide conjugate Haemophilus influenzae type b (HbOC) and whole cell diphtheria-tetanus toxoids-pertussis vaccine in infancy. The Kaiser Permanente Pediatric Vaccine Study Group.

The safety of the combined oligosaccharide conjugate Haemophilus influenzae (Hib) type b (HbOC) and whole cell diphtheria-tetanus toxoids-pertussis (DTP) vaccine (Tetramune, HbOC-DTP; Lederle) in infancy was evaluated in 6644 recipients of this vaccine and compared with 3914 recipients of separate injections of whole cell DTP and HbOC vaccines when given as a three dose regimen to infants at 2, 4 and 6 months of age in each group. Of the total number of infants in the study, a subset of 1435 were enrolled into the study and then randomly assigned to receive either the Hib-DPT combined vaccine or the separate components. This subset was used to assess local and systemic side effects which were evaluated utilizing telephone interviews 48 to 72 hours after vaccine. The remaining children in the study population were enrolled in a nonrandomized manner. For these children parents were offered the experimental Hib-DPT vaccine and refusers were given HbOC and DTP. Both of these groups of children as well as the randomized subset described above were used to assess rates of episodes of hospitalization, emergency room utilization and sudden infant death syndrome in HbOC-DTP recipients and children who received HbOC and DTP separately. Immunogenicity was evaluated in 123 children by collection of a single serum sample 30 days after the third dose of HbOC-DTP. The observed immunogenicity was comparable to that observed in other recent studies for HbOC and DTP component antigens. The profile of local and systemic side effects observed was virtually identical to that observed after DTP plus HbOC given separately.(ABSTRACT TRUNCATED AT 250 WORDS)

Simultaneous administration of a diphtheria and tetanus toxoids and acellular pertussis vaccine with measles-mumps-rubella and oral poliovirus vaccines.

OBJECTIVE: To compare the safety and immunogenicity of Lederle Laboratories' (Pearl River, NY) diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine with diphtheria and tetanus toxoids and whole-cell pertussis (DTwP) vaccine when administered simultaneously with measles-mumps-rubella (MMR) vaccine and trivalent oral poliovirus (OPV) vaccine at 15 to 16 months of age. DESIGN: Randomized and double-blind. SETTING: Two general pediatric practices. PARTICIPANTS: Ninety-seven infants, aged 15 to 16 months, who had received three previous DTwP immunizations. SELECTION PROCEDURES AND INTERVENTIONS: Healthy children received the DTaP or DTwP vaccine. Infants received the MMR vaccine at a separate site and the OPV vaccine concurrently. Blood was obtained on day 0 and at 6 weeks. Adverse events were recorded by parents at specified times after immunization. MEASUREMENTS/RESULTS: Within 3 days of immunization, DTaP vaccine recipients had less fever, drowsiness, and irritability (P = .01, .04, .01, respectively). They also experienced less tenderness, erythema, and induration (.001, .001, and .002, respectively). There was no difference in the frequency of adverse reactions 6 to 14 days after immunization. Enzyme-linked immunosorbent assays were used to determine all antibody values. Antibody responses to filamentous hemagglutinin and pertussis toxoid were significantly greater in the DTaP group (P = .0001 and .02, respectively). Immune responses to the other measured antigens were similar. CONCLUSIONS: Simultaneous administration of the Lederle DTaP with MMR and OPV vaccines did not interfere with antibody response to pertussis antigens measured or measles, mumps, or rubella viruses and was associated with fewer local and systemic adverse events during the first 3 days following immunization when compared with the simultaneous administration of the DTwP, OPV, and MMR vaccines. We conclude that the DTaP vaccine can be administered at 15 months of age concurrently with the MMR and OPV vaccines.

Safety and immunogenicity of acellular pertussis vaccine, combined with diphtheria and tetanus as the Japanese commercial Takeda vaccine, compared with the Takeda acellular pertussis component combined with Lederle's diphtheria and tetanus toxoids in two-, four- and six-month-old infants.

A double blind, randomized, controlled trial compared the safety and immunogenicity of an acellular pertussis vaccine formulated at Lederle using the Takeda acellular pertussis component combined with Lederle diphtheria and tetanus toxoids vaccines (APDT), with the commercially available Japanese Takeda vaccine (APDT-T/J) as a three-dose series to 2-, 4-, and 6-month-old children. Sera were analyzed for antibody to pertussis antigens: lymphocytosis-promoting factor; filamentous hemagglutinin; 69-kDa outer membrane protein; pertussis agglutinogens; neutralizing antibodies to LPF; and to diphtheria and tetanus toxoids. Information concerning local reactions and systemic events were collected daily for 10 days postimmunization. The overall reaction rate was low for both groups. There were no reactions that contraindicated subsequent vaccine and no serious adverse events. For local reactions statistically significant differences between the groups were seen only for a greater incidence of induration in the APDT group at 2 months (12% vs. 0%, P < 0.01), and at 4 months (8% vs. 0%, P = 0.4) compared to the APDT-T/J group. Of the few systemic reactions the only statistically significant difference between the vaccine groups was a greater incidence of fretfulness in the APDT group after the initial immunization (12% vs. 2%, P = 0.05). There were no statistically significant differences in the immune response between the two vaccines at the 7-month visit. We conclude that APDT is equivalent to the commercially available Takeda vaccine (APDT-T/J).

Clinical trials in the United States and Japan with the Lederle-Takeda and Takeda acellular pertussis-diphtheria-tetanus (APDT) vaccines. The Multicenter APDT Vaccine Study Groups.

The results of the following studies are reported: a longitudinal double blind trial comparing Lederle-Takeda APDT vaccine with Lederle DTP vaccine in two, four and six month old infants; two double blind similar APDT vs DTP trials in 18 month old and four to six year old children; a large longitudinal open trial with APDT in two, four and six month old infants and a household contact efficacy trial with Takeda APDT in Japan. APDT vaccine recipients had a lesser frequency and less severe reactions than whole cell vaccine recipients. Antibody responses to lymphocytosis-promoting factor and agglutinogens were higher in DTP recipients; APDT recipients had a better serologic response to filamentous hemagglutinin. Equivalent 69K protein antibody responses were seen. Vaccine efficacy in the household contact study was 98% (95% CI = 84% to 99%) against classical pertussis and 81% (95 CI = 64% to 90%) if all respiratory illnesses are considered.

Neonatal sepsis at The Johns Hopkins Hospital, 1969-1975: bacterial isolates and clinical correlates.

The experience with neonatal sepsis at The Johns Hopkins Hospital during 1969-1975 was reviewed. Major pathogens included Escherichia coli, group B streptococcus, other streptococci, and Klebsiella. Nineteen percent of coliform isolates were kanamycin-resistant. The frequency of recovery of E. coli was increased in early-onset sepsis, and the frequency of recovery of Klebsiella was increased in late-onset sepsis. The mortality rate was 23%. The frequency of recovery of E. coli was increased in fatal cases, and mortality was highly correlated with the presence of gastrointestinal catastrophe. Ampicillin and gentamicin are the initial antibiotics of choice for neonatal sepsis at this institution; a penicillinase-resistant penicillin should be added when Staphylococcus aureus involvement is likely, and addition of chloramphenicol or clindamycin should be considered for infants at increased risk for Bacteroides fragilis sepsis.