Bo A. Claesson

Clinical and immunologic responses to the capsular polysaccharide of Haemophilus influenzae type b alone or conjugated to tetanus toxoid in 18- to 23-month-old children.

The safety and immunogenicity of Haemophilus influenzae type b (Hib) capsular polysaccharide (CPS) alone, or covalently bound to tetanus toxoid in saline solution (Hib-TT) or adsorbed onto AI(OH)3 (Hib-TT ads), were evaluated after one injection into 18- to 23-month-old healthy children in Sweden. No side reactions were elicited by Hib CPS; side reactions elicited by the two conjugates were similar and comparable to those reported for diphtheria and tetanus toxoids adsorbed. Hib-TT was the most immunogenic of the three vaccines, eliciting about 10-fold higher antibody levels than Hib CPS; of 28 vaccinees, all had greater than 1.0 microgram Ab/mL serum after immunization with Hib-TT. Increases of Hib CPS antibodies within immunoglobulin classes induced by the three vaccines were, in decreasing order, IgG greater than IgM greater than IgA. Within IgG subclasses, rises in IgG1 Hib CPS antibodies were the most frequent, followed by IgG2; some vaccinees with high postimmunization levels also had rises in IgG3 and one in IgG4. Immunization-induced Hib CPS antibodies were bactericidal. Hib-TT also elicited higher levels of tetanus toxoid antibodies than Hib-TT ads; these tetanus toxoid antibodies neutralized tetanus toxin in vivo.

Protective levels of serum antibodies stimulated in infants by two injections of Haemophilus influenzae type b capsular polysaccharide-tetanus toxoid conjugate*

Bo A. Claesson, MD, Rachel Schneerson, MD, John B. Robbins, MD, Jan Johansson, MD, Teresa Lagerga rd , PhD, John Taranger , MD, Dolores Bryla, MPH, Lily Levi, MSc, Tad Cramton , MS, and Birger Trollfors, MD From the Departments of Infectious Diseases, Pediatrics, and Medical Microbiology, University of Gothenburg, the Department of Pediatrics, Boras Hospital, Pediatric Outpatient Clinic, Vastra Frolunda, Sweden, and the Laboratory of Developmental and Molecular Immunity, and Biometry Branch, National Institute of Child Health and Human DevelopmenL National Institutes of Health, Bethesda, Maryland

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.

METHODS In an open randomized study we compared the safety and immunogenicity of two schedules for priming and booster vaccinations of infants. A pentavalent combination vaccine, including a lyophilized Haemophilus influenzae type b-tetanus toxoid conjugate vaccine reconstituted with a liquid diphtheria, tetanus, acellular pertussis (pertussis toxoid and filamentous hemagglutinin) and inactivated polio vaccine (DTaP-IPV/Act-HIB; Pasteur Mérieux Connaught, Lyon, France) was administered to 236 Swedish infants either at 2, 4 and 6 months or at 3 and 5 months, and a booster dose was administered 7 months after the last primary dose. Adverse events were monitored by diaries for 3 days after each vaccination and by questions at the ensuing visits. Antibodies against the different vaccine components were analyzed after the primary series of vaccinations, before and after the booster injections. RESULTS There were no serious adverse reactions, and the rates of febrile events and local reactions were low in both groups. The three dose primary schedule induced higher geometricmean concentrations for all antigens than did the two dose schedule, but there were no differences between the groups in proportions with protective antibody titers against diphtheria, tetanus, Hib and polio or in proportions with certain defined levels of pertussis antibodies. Prebooster results showed a similar pattern, with the exception that the group primed with three injections showed higher proportions of infants with detectable antibodies against polio-virus types 1 and 3. After booster vaccinations there were no differences between the two schedules in geometric mean or in proportions with antibodies above defined antibody concentrations, indicating effective priming from both primary series of vaccinations. Conclusion. The combined vaccine DTaP-IPV/ Act-HIB vaccine was equally safe and immunogenic when administered according to both time schedules studied.

Invasive pneumococcal infections in Southwestern Sweden: a second follow-up period of 15 years.

In a retrospective study, the incidence, clinical manifestations, concomitant conditions and case fatality rate were studied in patients with invasive pneumococcal infections in the Göteborg area of Sweden during 1981-95, when the pneumococcal polysaccharide vaccine was available but little used. Patients were identified from the records of the Departments of Clinical Bacteriology and from the computer-based hospital discharge registers of the relevant departments. Individual case records were found for 876 patients with invasive pneumococcal infections verified by cultures from blood, cerebrospinal fluid or other sterile body fluids. A study from the same area with the same design covering the years 1964-80 has previously been published. There was an increase in total incidence from 5.3 to 10.3 cases/100,000/y from the previous to the present study. This increase was due to an increase in patients with non-meningitic infections aged > or = 60 y. The incidence of meningitis was virtually unchanged (1.4/100,000/y), as was the incidence of non-meningitic infections in individuals < 60 y. There were no other important changes between the 2 studies, which confirm that invasive pneumococcal infections have the highest incidence rates in children < 2 y and in the elderly, that a wide variety of underlying conditions are seen in the patients and that the case fatality rate, 15% in the present study, is still high.

Persistence of serum antibodies elicited by Haemophilus influenzae type b-tetanus toxoid conjugate vaccine in infants vaccinated at 3, 5 and 12 months of age

Eighty-five children received three injections of a vaccine consisting of Haemophilus influenzae type b (Hib) capsular polysaccharide (CPS) conjugated to tetanus toxoid (TT) (Hib-TT) at 3, 5 and 12 months of age according to the vaccination schedule for Swedish children. Diphtheria-tetanus toxoid vaccine was concurrently injected at another site. Two dosages, 7.5 and 15 micrograms, of Hib CPS were studied. No serious reactions occurred. Hib-TT elicited fewer local reactions than diphtheria-tetanus toxoid vaccine. Significant increases in Hib CPS serum antibodies occurred after all injections in both dosage groups with virtually no differences between the two groups. After the first and second injections geometric mean serum antibody concentrations of both dosage groups combined increased to 0.49 and 3.71 micrograms/ml and 81 and 99% of the vaccinees, respectively, had concentrations greater than 0.15 micrograms/ml. After the third dose geometric mean concentrations increased to 13.7 micrograms/ml and all had concentrations greater than 0.15 micrograms/ml. The geometric mean Hib CPS antibody concentrations decreased to 1.24 micrograms/ml 18 months after the third injection, but 97% still had concentrations greater than 0.15 micrograms/ml. The rise of Hib CPS antibodies was mostly in the IgG class. The most pronounced increase was seen in the IgG1 subclass but there were also increase in IgG2 and IgG3. Protective concentrations of TT antibodies were found in all postimmunization sera. In conclusion Hib-TT is safe and immunogenic in infants and should be protective from 6 to 30 months and probably longer thereafter.

Moraxella catarrhalis — An Uncommon Cause of Community-acquired Pneumonia in Swedish Children

In 284 Swedish children with community-acquired, roentgenologically verified pneumonia, antibodies to Moraxella (Branhamella) catarrhalis were determined in paired serum samples with an enzyme immunoassay using a whole-cell antigen preparation from 10 strains of M. catarrhalis. Only 9 children (3%) had significant increases in antibodies to M. catarrhalis. Among these 9 children, 11-39 months of age, 6 had serologic evidence of concurrent infection with other respiratory pathogens such as S. pneumoniae, non-capsulated H. influenza, RS virus and adenovirus. In 6 (67%) of the 9 children with antibody response and in 74 (27%) of the 275 children without antibody response to M. catarrhalis, nasopharyngeal cultures yielded growth of this bacterium. M. catarrhalis seems to be a common commensal in the upper respiratory tract, but a rare cause of pneumonia in children.

Antibody persistence in five-year-old children who received a pentavalent combination vaccine in infancy

Background. Antibody persistence was studied in 5.5-year-old Swedish children who in infancy completed a vaccine trial of a combined diphtheria toxoid, tetanus toxoid, acellular pertussis, inactivated polio and Haemophilus influenzae type b conjugate vaccine. Three priming doses at ages 2-4-6 months induced higher geometric mean concentrations of antibodies for all antigens than did two doses at 3-5 months, but there were no differences in proportions with protective antibody concentrations. After the booster dose administered at 13 or 12 months of age, respectively, there were no differences in concentrations or proportions between the groups. Methods. In the present follow-up serum samples from 180 of the 228 vaccinees, 88 from the 4-dose and 92 from the 3-dose group, were 4.5 years later again tested for antibodies. Results. The two groups did not differ significantly in antibody concentrations or proportions with antibodies above protective or other defined levels, with the exception of poliovirus type 3 (P ≤ 0.01). In all 89% had ≥0.01 IU/ml antibodies against diphtheria by enzyme-linked immunosorbent assay and 76% by the Vero cell neutralization test, 93% had ≥0.01 IU/ml antibodies against tetanus, 96 to 99% had detectable antibodies against the polioviruses and 97% had ≥0.15 &mgr;g/ml H. influenzae type b antibodies. As for pertussis only 44% had detectable antibodies against pertussis toxoid by enzyme-linked immunosorbent assay but 99% by Chinese hamster ovary cell neutralization test, and 94% had detectable antibodies against filamentous hemagglutinin. Conclusion. We found the persistence of antibodies satisfactory, with no clinically relevant differences in antibody concentrations demonstrated between children vaccinated according to a three dose or a four dose schedule in infancy.

Duration of serum antibodies elicited by Haemophilus influenzae type b capsular polysaccharide alone or conjugated to tetanus toxoid in 18- to 23-month-old children

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Antibodies against Haemophilus influenzae type b and tetanus in infants after subcutaneous vaccination with PRP-T/diphtheria, or PRP-OMP/diphtheria-tetanus vaccines.

In an open randomized study, serum antibodies against Haemophilus influenzae type b capsular polysaccharide (PRP) and tetanus toxoid were determined in 146 Swedish infants; 75 of them received PRP conjugated to tetanus toxoid (PRP-T) concurrently with diphtheria toxoid vaccine, and 71 received PRP conjugated to an outer membrane complex of Neisseria meningitidis (PRP-OMP) concurrently with diphtheria-tetanus toxoid vaccine. Injections were given subcutaneously at ages 3, 5 and 12 months. One month after the second injection, the PRP-T recipients had a geometric mean (GM) concentration of 0.38 microgram/ml and only 69% had PRP antibodies > or = 0.15 microgram/ml (considered a protective level). In the PRP-OMP group the GM concentration was 0.44 microgram/ml and 85% had PRP antibodies > or = 0.15 microgram/ml. One month after the third injection, 99% of the infants in both groups had PRP antibodies > or = 0.15 microgram/ml, but PRP-T recipients had significantly higher GM concentration than infants vaccinated with PRP-OMP, 10.21 micrograms/ml vs. 1.90 micrograms/ml (P < 0.001). After all three injections the diphtheria-tetanus toxoid vaccine elicited higher GM concentrations of tetanus toxoid antibodies than did the PRP-T vaccine, but both vaccines induced antibodies above the proposed protective level, 0.01 IU/ml. The reason for the lower than expected immunogenicity of the two Haemophilus influenzae type b conjugate vaccines has yet not been established. For PRP-OMP the most probable explanation is the use of a lot of low immunogenicity, but the route of administration also has to be considered.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibody response to outer membrane of noncapsulated Haemophilus influenzae isolated from the nasopharynx of children with pneumonia

In a prospective study aimed at determining the etiology of community-acquired pneumonia in children nasopharyngeal cultures and paired serum samples were obtained from 336 consecutive children ages 6 weeks to 15 years with pneumonia, 167 hospitalized and 169 outpatients. Results regarding Haemophilus influenzae are reported here. Blood cultures obtained from 127 of the hospitalized patients did not yield growth of H. influenzae. H. influenzae was isolated from the nasopharynx of 88 children. Seventy-three strains were noncapsulated, 2 were type b, 2 were type f and 11 were not serotyped. Paired serum samples were available.