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.

Serotypes and clinical manifestations of group B streptococcal infections in western Sweden.

OBJECTIVES: To study the serotype distributions of group B streptococci (GBS) isolated from blood and cerebrospinal fluid and from the genital tract of pregnant women and to investigate any possible relation between serotype, age and clinical manifestation. METHODS: Invasive strains were collected from 1988 to 1997 and genital strains from 1995 to 1996. Strains of GBS were serotyped with coagglutination. Clinical data were obtained from hospital notes. RESULTS: A total of 144 invasive strains, 78 from neonates and infants and 66 from adults, were serotyped. The most common isolates from neonates and infants were types III (62%), Ia (18%), and V (9%). The most common isolates from adults were types III (29%), Ib (23%), V (21%) and II (15%). A majority of the adults (94%) had an underlying medical condition. The most common serotypes of the 114 strains isolated from the genital tract of pregnant women were types III (32%), V (22%), Ia (13%), Ib (13%) and II (11%). CONCLUSIONS: Serotype III was the single most frequent GBS isolate from infants and adults. Serotype V, which appeared first in 1992, was the third most frequent isolate. A vaccine containing five GBS capsular polysaccharides appears to be appropriate for the Swedish population.

Studies on a Hib-tetanus toxoid conjugate vaccine: effects of co-administered tetanus toxoid vaccine, of administration route and of combined administration with an inactivated polio vaccine.

A freeze-dried tetanus toxoid (T) conjugated Haemophilus influenzae type b (Hib) vaccine, was reconstituted in either diphtheria toxoid (D), DT or a combined DT and inactivated polio vaccine (IPV), and administered in an open randomized trial either intramuscularly (i.m. ) or subcutaneously (s.c.) to 287 Swedish infants at three, five and 12 months of age. When not included in the mixture, IPV was administered s.c. at a separate site. The geometric mean concentrations of Hib antibodies after primary and booster vaccinations were 1.0 and 11.6 microg/ml, respectively, with no differences related to co-administration of the carrier protein T. Antibodies against T were induced by the T conjugated Hib vaccine (Hib-T) alone in 69/95 infants aged six months, and in 87/93 children aged 13 months, although infants receiving both Hib-T and T had significantly higher concentrations. Antibody responses to Hib, D, T or polio were not negatively influenced by administration route or by mixing with IPV, except that the mixed vaccine DT-IPV induced lower anti-polio GM titers after primary vaccination than did separate IPV. More local reactions were induced by the s.c. than by the i.m. route (P-values from 0.001 to 0.01). Slight increases in rates of local reactions and febrile events (>/=38 degrees C) occurred by order of dose. The low Hib antibody concentrations after the first two doses in this and other Swedish studies are unlikely to be of clinical relevance. The tetanus antibody response from T as a carrier protein alone was not sufficient for basic tetanus immunization, but should be considered in future use of additional T conjugated vaccines.

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.

Incidence and prognosis of meningitis due to Haemophilus influenzae, Streptococcus pneumoniae and Neisseria meningitidis in Sweden.

The incidence, concomitant conditions and case fatality rate of Haemophilus influenzae (Hi) and pneumococcal meningitis and of invasive meningococcal infections were studied retrospectively in Sweden (population 8.4 million) for the years 1987-89, the period before vaccination against Hi type b started. A total of 1,019 cases with culture-verified infection were found. The incidence rates per 100,000 per year were 1.8 for Hi meningitis, 1.2 for pneumococcal meningitis and 1.0 for invasive meningococcal infections. The age-specific incidence was highest in the 3-23 months age group for the 3 bacterial species. Pneumococcal meningitis was common in individuals > or = 60 years and meningococcal infections in the age-group 10-24 years. A serious concomitant condition was known in 57% of all patients with pneumococcal meningitis while this was uncommon for the other organisms. The case fatality rate was 2% for Hi meningitis, 24% for pneumococcal meningitis and 10% for meningococcal infections. All 81 pneumococcal isolates which had been serotyped belonged to serotypes in the 23-valent pneumococcal vaccine. Of the meningococcal isolates, 65% belonged to serogroup B. In conclusion, the high incidence of Hib meningitis justifies general Hib vaccination. Development of a vaccine against N. meningitidis group B should have high priority. Furthermore, improved pneumococcal vaccines are needed for patients with predisposing conditions. The currently available pneumococcal polysaccharide vaccine seems to be underused.

Serum antibodies against haemophilus influenzae type b and tetanus at 2.5 years of age: a follow-up of 2 different regimens of infant vaccination.

In 1990-91 we compared 2 Haemophilus influenzae type b (Hib) conjugate vaccines and 2 different regimens of tetanus vaccination, by vaccinating 142 Swedish infants at ages 3, 5, and 12 months, with either PRP-T (the capsular polysaccharide of Hib conjugated to tetanus toxoid) + D (diphtheria toxoid), or with PRP-OMP (PRP conjugated to an outer membrane complex of meningococcus group B) + DT (diphtheria-tetanus toxoid). In this follow-up, antibodies against Hib and tetanus were analyzed in sera from 133 of the children at the age of 2.5 years. Hib antibodies (> or = 0.06 micrograms/ml) were found in 99% of the children of both groups, but 93% of the PRP-T vaccinees had maintained Hib antibodies > or = 0.15 micrograms/ml, as compared with 80% of the PRP-OMP vaccinees (p < 0.05). In 1992, the batch of PRP-OMP was reported to have questionable immunogenicity. Tetanus toxoid (T) antibodies (> or = 0.01 IU/ml) were found in all sera from both groups. All sera with T antibodies < 0.1 IU/ml showed tetanus toxin neutralizing activity. However, only 75% of children vaccinated with PRP-T had T antibodies > or = 0.1 IU/ml, as compared to 97% of children vaccinated with DT (p < 0.001). In conclusion, Hib and tetanus antibodies were well maintained 18 months after primary vaccination, also in the group vaccinated with the batch of PRP-OMP of somewhat low immunogenicity and in the group of infants receiving their primary tetanus vaccination only by the carrier protein of PRP-T.

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.

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)

Epidemiology of invasive Haemophilus influenzae type b disease in Scandinavia.

In all Scandinavian countries, most invasive Haemophilus influenzae type b (Hib) infections occur before the age of 5 years. The age-specific incidence of Hib meningitis in this age group is 26-35/100,000 per year in Denmark, Norway, Finland and Sweden and about 43/100,000 per year in Iceland. Of the meningitis patients, approximately 60% are younger than 2 years but Hib meningitis also occurs in older children and adults. The case fatality rate is low (1-3%) in children but the rate of neurological sequelae is considerable. The incidence of acute epiglottitis, the other main manifestation of Hib disease, varies considerably. In Sweden, four studies have shown a very high incidence in the age group 0-4 years, 21-34 cases/100,000 population per year compared to only 5-17 in the other Nordic countries. Epiglottitis is more common than Hib meningitis in older children and adults. In Scandinavia the age-specific incidence of all invasive Hib infections could be estimated to be about 50-65/100,000 per year in the most susceptible age group and the risk of contracting invasive Hib disease before the age of 15 years would be about 1/200-300 children.

Dose response study of an inactivated hepatitis A virus vaccine.

In this dose-response study evaluating 3 different doses and 2 time schedules, the highest dose, 25 units of viral protein antigen, induced a seroconversion antibody response against hepatitis A virus (anti-HAV) over 10 mIU in all vaccinees by week 3 after one dose, indicating rapid onset of protective antibody levels. Following the second dose, given 4 weeks later, rising titers were observed for 20 weeks, when the third and final dose of 25 units was given. The GMT of anti-HAV at 24 weeks (before the third vaccine injection) was 398 mIU/ml for the 25-unit dose, compared to 42 and 65 mIU/ml, respectively, for the 12.5 unit and 6.25 unit doses. The third vaccine dose at 24 weeks gave a booster response in all vaccinees, but the increase in titers was most pronounced in the 25 unit group, which had reached a GMT of 6593 mIU/ml when tested 4 weeks later. Side-effects included mainly local reactions and a few cases of mild diarrhoea, and did not differ for the 3 doses studied. In Scandinavia, hepatitis A vaccines will probably be used mainly for vaccination of foreign travellers. This category usually requires a rapid immunization schedule with few doses. Two doses approximately 3-4 weeks apart will probably be accepted by most travellers, and a single dose may provide short-term protection for most individuals. The need and timing for a booster dose will have to be further studied.

Characterization of the serum antibody response to the capsular polysaccharide of Haemophilus influenzae type b in children with invasive infections.

The serum antibody response to the capsular polysaccharide of Haemophilus influenzae type b (Hib) was studied in 30 children aged 1 day-5 years with invasive Hib infections. From each child, serum was obtained 0-2 days, 5-11 days, 1 month, and 6-12 months after onset of symptoms. Total antibodies were determined with RIA and isotypes with ELISA. Only 2 children had antibody levels above the estimated protective level (0.15 microgram/mL) in the first serum sample. The antibody response was age dependent with wide individual variations. Children > or = 2 years had increases in IgG, IgM, and IgA antibodies with predominance of IgG. The initial IgG response was IgG1 and IgG2 with predominance of IgG1. In the last serum sample, IgG1 antibodies had decreased while IgG2 antibodies remained unchanged. Only 2 of 7 children < 1 year had a detectable antibody response. The correlation coefficient for total antibodies compared with the sum of IgG, IgM, and IgA was .88 (P < .0001) and for IgG compared with the sum of IgG1 and IgG2 was .97 (P < .0001).

Determination of neutralizing antibodies and specific immunoglobulin isotype levels in infants after vaccination against diphtheria.

Serum samples were obtained from 44 infants vaccinated against diphtheria at the ages of 3, 5 and 12 months with an aluminium-adsorbed diphtheria-tetanus toxoid vaccine containing 15 Lf units of diphtheria toxoid. Toxin-neutralizing antibodies (antitoxin) were measured by the Vero cell assay and IgG, IgM and IgA antibodies against diphtheria toxoid by enzyme-linked immunosorbent assay. A neutralizing antibody titer of 10 corresponded to 0.01 IU/ml, the level considered necessary for short-term protection. Geometric mean neutralizing antibody titers at 3, 5, 6, 12, 13 and 30 months were 28, 21, 173, 61, 1076 and 61. All children had titers of greater than or equal to 10 (greater than or equal to 0.01 IU/ml) between 6 and 30 months of age. At 30 months only 48% had titers of greater than or equal to 100 (greater than or equal to 0.01 IU/ml), the level considered necessary for long-term protection. Geometric mean IgG antibody levels were 13, 36, 216, 64, 649 and 57. IgG antibodies significantly correlated with neutralizing titers and predicted neutralizing antibodies above or below 10 and 100 with an accuracy of 96 and 82%, respectively. IgG antibodies could not, however, be used to predict individual neutralizing antibody titers with great accuracy. IgM antibodies were only detected after the third vaccination. IgA antibodies were not detected in any serum sample from ten infants tested. In conclusion, the Swedish vaccination schedule results in protective antibody levels in infants until at least 30 months of age. The decline of the antibody titers indicates a need for further studies to establish the duration of protection.

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.

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 from 38 children with growth of noncapsulated H. influenzae in the nasopharynx as the only potential pathogen. Sixteen of them responded with significant increases in serum antibodies against outer membrane preparations prepared from their own nasopharyngeal isolates. Thirty-eight age- and sex-matched control children with pneumonia without growth of H. influenzae in the nasopharynx served as controls. Sera from each control patient were tested for antibodies against two strains of noncapsulated H. influenzae. Of those, 4 had significant increases in antibodies against one or both outer membrane preparations. The increases in serum antibodies against the outer membrane of noncapsulated strains of H. influenzae indicate that this organism might be a cause of pneumonia in some children.

Etiology of community-acquired pneumonia in children based on antibody responses to bacterial and viral antigens.

The serologic responses to bacterial and viral antigens were determined in paired serum samples from 336 children, ages 1 month to 15 years, with roentgenographically verified community-acquired pneumonia. Significant increases in antibodies against one agent were found in 40% and against two or more agents in 8% of the children. There were significant increases in antibodies against respiratory syncytial virus in 20%, viruses of the influenza-parainfluenza group in 6% and adenovirus in 3%. A serologic response to one or more of the pneumococcal antigens used (type-specific capsular polysaccharide, C-polysaccharide and pneumolysin) was demonstrated in 13% of the patients. Ten percent of the children had significant increases in antibodies against Mycoplasma pneumoniae. Only three patients had increases against Haemophilus influenzae type b and one each against Legionella pneumophila and Chlamydia. Respiratory syncytial virus was the predominant etiologic agent in young children whereas M. pneumoniae was more frequent in the older age group.

Development of serum antibodies of the immunoglobulin G class and subclasses against the capsular polysaccharide of Haemophilus influenzae type b in children and adults with invasive infections.

The development of total immunoglobulin G (IgG) antibodies and antibodies of the four IgG subclasses in serum against Haemophilus influenzae type b capsular polysaccharide (CPS) was studied in 24 children and 11 adults with invasive Haemophilus influenzae type b infections, by using an enzyme-linked immunosorbent assay. None of the 8 children aged 10 months or younger had increases in the IgG class or in any of the IgG subclasses. In contrast, 14 of 16 children between 10 months and 6 years of age and 10 of 11 adults had significant increases in total IgG, IgG1, or IgG2 antibodies in various combinations, but none of them had increases in IgG3 or IgG4 antibodies. The increases in IgG1 and IgG2 antibodies in the children were of similar magnitudes. Of 11 adult patients, 9 had significant increases in IgG2 antibodies, while only 4 had increases in IgG1 antibodies. In conclusion, this study shows that children younger than approximately 1 year have no IgG response to H. influenzae type b CPS, while individuals above this age have a mixed IgG1 and IgG2 response.