Modelling transmission, immunity and disease of Haemophilus influenzae type b in a structured population.

An individual-based stochastic simulation model was constructed to study the epidemiology of Haemophilus influenzae type b (Hib) transmission, immunity and invasive disease. Embedded in a demographic model, the transmission model of Hib carriage employs the most important social mixing patterns with three types of contact sites (family, day-care group, and school class). The model includes immunity against invasive Hib disease, initiated and boosted by Hib carriage and cross-reactive bacterial encounters. The model reproduces the observed age patterns in Hib carriage and disease in Finland before large-scale use of the Hib conjugate vaccines. The model was used to investigate characteristics of Hib transmission. The analysis emphasizes transmission between children and adults in families while pointing out the importance of pre-school and school-aged children in maintaining Hib circulation. Carriage in these age groups is thus identified as being essential to target for sustained effects of interventions by vaccination.

Indirect protection obtained by Haemophilus influenzae type b vaccination: analysis in a structured population model.

We used a structured population model to study factors determining the magnitude of indirect protection in Haemophilus influenzae type b (Hib) vaccination. On a simulation platform mimicking the population of Finland, a Hib transmission and immunity model, including cross-reactive bacterial encounters, was formulated. Utilizing different vaccination coverages and vaccine types we could study how fast the incidence of Hib disease declined due to direct and indirect vaccination effects. With the Finnish vaccination schedule we could reproduce the observed disappearance of Hib cases. Our results show that an indirect effect was already significant with a relatively low vaccine coverage, even with a vaccine only partly reducing carriage acquisition. This suggests that the vaccination schedule and vaccine to be used should be chosen to result, in addition to immunological memory, in high antibody concentrations, sufficient to reduce carriage, the latter being the main factor behind successful elimination of transmission and disease.

Haemophilus influenzae type b and cross-reactive antigens in natural Hib infection dynamics; modelling in two populations.

Natural immunity to Haemophilus influenzae type b (Hib) invasive disease is based on antibodies arising in response to encounters with Hib or cross-reactive (CR) bacteria. The relative importance of Hib and CR contacts is unknown. We applied a statistical model to estimate the total rate of immunizing infections of Hib and CR prior to wide-scale vaccinations in Finland and the UK. The average rates of these contacts were 0.7 and 1.2 per year per child in Finland and the UK, respectively. Using a rough estimate of 0.1 Hib acquisitions per year per child in the UK based on carriage rates, the proportion of Hib among all immunizing contacts was in the order of 10%, suggesting that CR bacteria have a major role. In general, varying frequency of CR contacts may explain some differences in the pre-vaccination incidence and age-distribution of invasive disease in different countries.

Pneumococcal carriage in children during their first two years: important role of family exposure.

BACKGROUND: Close family and day-care contacts have been identified as risk factors for pneumococcal (Pnc) carriage. This study addresses the risk of Pnc carriage by infants 2 to 24 months of age in terms of simultaneous carriage of pneumococcus by family members. METHODS: Nasopharyngeal swabs were collected from 100 Finnish infants and their family members on 10 scheduled visits (when infant was 2, 3, 4, 5, 6, 9, 12, 15, 18 and 24 months of age). The 7 most common pneumococcal serogroups (4, 6, 9, 14, 18, 19, 23), also represented in the new heptavalent Pnc conjugate vaccine, were analyzed. Marginal logistic regression analyses were performed to assess the relative importance of different predictors for carriage. RESULTS: The carriage of the studied Pnc serogroups increased with age, being highest at the age of 18 months (28%). Among children older than 6 months of age, the strongest predictor of carriage was simultaneous carriage of the same serogroup by another family member (odds ratio, 3.8; 95% confidence interval, 2.1 to 6.9). At the age of 6 months or younger, carriage was rare and was not significantly associated with a family carriage. CONCLUSIONS: Young infants (< or =6 months old) were largely protected from pneumococcal carriage. After this age family transmission seemed very important despite the small family size. Contrary to some earlier studies communal day care was not associated with an increased risk of Pnc carriage. This could be partly because of the long parental leave in Finland and thus the late age of starting organized day care.

Do antibodies to pneumococcal surface adhesin a prevent pneumococcal involvement in acute otitis media?

Antibodies to the pneumococcal (Pnc) surface protein PsaA are immunogenic and protective in experimental animal models, but their role in protection from Pnc disease in humans is not known. In the present study, the ability of antibodies to PsaA to prevent the progression of Pnc carriage to Pnc acute otitis media (Pnc AOM) was evaluated. Antibodies to PsaA were measured in acute-phase serum samples of children with AOM and with Streptococcus pneumoniae cultured from the nasopharynx. The risk of Pnc AOM was evaluated by a logistic regression model with anti-PsaA concentration as the predictive variable. Higher concentrations of antibodies to PsaA were associated with lower risk of the Pnc nasopharyngeal carriage progression to Pnc AOM. This was true in children 9-24 months old (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.31-0.78) but not in children <9 months old (OR, 0.81; 95% CI, 0.48-1.35).

Normative values for tympanometry in 7- and 24-month-old children.

The objective was to determine normative values for tympanometric variables for 7- and 24-month-old children and to assess the effect of various factors on these variables. Tympanometry was performed at scheduled health visits at 7 and 24 months of age on children recruited to a prospective vaccine efficacy trial (n=2497 children at enrolment). Tympanograms obtained successfully from healthy ears with no recent otitis media were analysed. Normative values for static acoustic admittance (SAA), tympanometric peak pressure (TPP) and tympanometric width (TW) were calculated. The mean SAA was 0.25 cm3 at the 7-month visit compared to 0.34 cm3 at the 24-month visit. The TW decreased and TPP remained unchanged with age. Higher SAA values were found in boys. A history of recurrent acute otitis media and history of tympanostomy tubes were found to increase SAA and decrease TW at 24 months. In conclusion, age-specific normative values for interpretation of SAA and TW are necessary.

Bacteriology of acute otitis media in a cohort of Finnish children followed for the first two years of life.

BACKGROUND: Timely information on the bacteriology of primary, noncomplicated acute otitis media (AOM) may today be needed more than ever, because of the increasing antimicrobial resistance of its major bacterial causes and because of the potential of new pneumococcal and other bacterial vaccines for prevention of AOM. METHODS: The study followed 329 children from 2 to 24 months of age at scheduled healthy visits and sick visits at the study clinic. Whenever AOM was diagnosed during the follow-up, myringotomy was performed and middle ear fluid was aspirated for bacterial culture. RESULTS: At least one middle ear fluid sample was available from 772 AOM events; Streptococcus pneumoniae (Pnc) was isolated in 201 (26%), Moraxella catarrhalis (Mc) in 177 (23%) and Haemophilus influenzae (Hi) in 174 events (23%). The incidence of Pnc AOM peaked at 12 months of age, whereas the incidence of Mc AOM showed the first peak at 6 months and Hi AOM at 20 months. Pnc AOM showed less prominent seasonality in occurrence than Mc and Hi AOM. Hi was a rare cause of the first 2 AOM episodes (13%) but became increasingly common from the third episode on (32% on average). CONCLUSIONS: Pnc, Mc and Hi were almost equally common findings in AOM. Pnc seems to be the most pathogenic of these three, the role of Mc is increasing and Hi is clearly associated with recurrent AOM.

Nasopharyngeal carriage of Streptococcus pneumoniae in Finnish children younger than 2 years old.

To describe the natural course of nasopharyngeal carriage of Streptococcus pneumoniae and its relationship to acute otitis media (AOM), 329 Finnish children were followed from ages 2 to 24 months. In total, 3024 nasopharyngeal (NP) swabs (obtained at 10 scheduled healthy visits) and 2007 NP aspirates (obtained during respiratory infections) were cultured. Carriage during health increased gradually (9%-43%) with age. Within 4 age intervals, carriage was lower during health (13%-43%) than during respiratory infection without AOM (22%-45%). Higher proportions of positive samples were found during AOM (45%-56%), in particular during pneumococcal AOM (97%-100%). Antimicrobial treatment reduced carriage only temporarily. The most frequent NP serotypes were 6B, 6A, 11, 19F, and 23F. Both age and health status were important determinants of NP carriage of S. pneumoniae and these features should be considered carefully during analysis of carriage rates.

Natural development of antibodies to pneumococcal surface protein A, pneumococcal surface adhesin A, and pneumolysin in relation to pneumococcal carriage and acute otitis media.

Pneumococcal surface protein A (PspA), pneumococcal surface adhesin A (PsaA), and pneumolysin (Ply) are common to virtually all Streptococcus pneumoniae isolates. They are immunogenic and protective against pneumococcal challenge in animals and are the major candidates for a protein-based pneumococcal vaccine for humans. However, little is known of the natural development of antibodies to these proteins in humans. The objective of this study was to evaluate the natural development of antibodies to PspA, PsaA, and Ply in relation to pneumococcal infection and carriage in young children. Serum antibodies to these proteins were measured by EIA in children at ages 6, 12, 18, and 24 months and in their mothers. All age groups were capable of producing antibodies to the 3 proteins. The antibody concentrations increased with age and were strongly associated with pneumococcal exposure, whether by carriage or infection (acute otitis media).

Interrater agreement on tympanometry in infants.

Two-hundred and forty-two tympanograms of infants were interpreted according to a standard operating procedure independently by an audiologist and ten study doctors from the Finnish Otitis Media Vaccine Trial. The interrater agreement among the study doctors according to Kappa index was excellent (kappa = 0.80). The agreement was significantly better on curves taken during pre-scheduled healthy visits than during sick visits due to respiratory infection (p < 0.001). In addition concurrent knowledge of the clinical ear status significantly improved the agreement on abnormal curves (flat B-curves and failed F-curves, p < 0.001). The clinical differences between the groups were minor. The age of the infant had no effect on interpretation. The agreement between the audiologist and the study doctors was also excellent (kappa = 0.77). Excellent agreement can be achieved in infant tympanometry through adequate instruction and training.

Dynamics of natural immunity caused by subclinical infections, case study on Haemophilus influenzae type b (Hib).

Natural immunity to Haemophilus influenzae type b (Hib) is based primarily on antibodies that are thought to develop in response to subclinical infections. Wide use of conjugated Hib vaccines could lead to decreases in circulating Hib bacteria, thereby diminishing antibody levels in the unvaccinated. We applied a statistical model to estimate the duration of natural immunity to Hib under different forces of infection. Prior to the introduction of conjugated Hib vaccines, new Hib infections were estimated to occur once in 4 years and the antibody concentration to stabilize at a level around 1 microg/ml. In the absence of new stimuli, i.e. infection, 57% of the unvaccinated population would become susceptible to invasive disease (antibody levels < 0.15 microg/ml) in 10 years. Due to an interaction between the force of infection and the duration of immunity, in some situations numbers of invasive infections could increase in unvaccinated cohorts. This theoretical scenario has yet to be observed in practice.

Diagnostic value of tympanometry in infants in clinical practice.

One hundred and twenty-one visits of 58 infants (2-11 months of age) were evaluated in the Finnish Otitis Media Vaccine Trial. Infants were examined with tympanometry (Grason-Stadler GSI 38 Autotymp) and pneumatic otoscopy by one study doctor. Diagnosis of otitis media was verified by myringotomy in 74% of cases. Tympanometry was technically successful in 94% of ears. The success rate was statistically significantly higher (P < 0.05) among infants less than 7 months of age than those above 7 months. The sensitivity of tympanometry (type B) to detect ears with middle ear fluid was 0.70 and the specificity 0.98 with a positive predictive value of 0.93 and negative predictive value of 0.94. The sensitivity was somewhat lower in the younger age group (0.61); specificity and positive and negative predictive values were good in both age groups. The high success rate and high negative and positive predictive values of tympanometry make it a useful aid for assuring the correct diagnosis of otitis media in infants in routine clinical practice.

Neonatal group B streptococcal disease in Finland: a ten-year nationwide study.

BACKGROUND: Group B Streptococcus (GBS) is the most common cause of invasive infections in newborns. GBS bacteria are typed on the basis of capsular polysaccharides or surface-localized proteins. Both polysaccharides and protein antigens have been suggested as potential vaccine candidates. METHODS: A prospective nationwide laboratory-based study of invasive GBS infections in children younger than 3 months of age was conducted in 1985 through 1994. Isolates were serotyped by immunodiffusion in agar gel with HCl extracts and rabbit antisera. Clinical diagnoses and case fatalities were verified from the patient records or the national hospital discharge register. RESULTS: There were 485 cases registered during the 10-year period. The incidence of disease was 0.76/1000 live births. The case fatality rate was 8.0%. Of the 485 cases 398 (83%) were early onset and 87 (17%) late onset infections. The most common clinical diagnosis was bacteremia (77%) without an identified focus of infection. Other diagnoses included meningitis (17%), pneumonia (3%), osteomyelitis or septic arthritis (2%), pyelonephritis or cellulitis. Serotyping of 395 isolates revealed that 47% were of serotype III or III/R, 23% of Ia/c, 11% of Ib, 6% of II/R, 8% of IV, 1% of V and 7% were nontypable. CONCLUSIONS: The clinical picture of GBS disease and serotype distribution are similar to what has been reported from other countries. Serotypes III and III/R dominated (47% of all infections), especially in late onset disease. On the basis of these results a GBS vaccine including at least the Ia, Ib, II and III components would provide coverage against 88% of GBS serotypes causing neonatal disease in Finland.

A hierarchical Bayesian model to predict the duration of immunity to Haemophilus influenzae type b.

A hierarchical Bayesian regression model is fitted to longitudinal data on Haemophilus influenzae type b (Hib) serum antibodies. To estimate the decline rate of the antibody concentration, the model accommodates the possibility of unobserved subclinical infections with Hib bacteria that cause increasing concentrations during the study period. The computations rely on Markov chain Monte Carlo simulation of the joint posterior distribution of the model parameters. The model is used to predict the duration of immunity to subclinical Hib infection and to a serious invasive Hib disease.

Clinical evaluation of new pneumococcal vaccines: the Finnish approach.

Clinical evaluation of a new vaccine should be based on information about the epidemiology and pathogenesis of the infection to be prevented, the protective immunity to this infection, and the immunological properties of the vaccine to be evaluated. In this review we describe one approach to evaluate a new vaccine, using our experience with pneumococcal conjugates as an example. Information on the epidemiology, pathogenesis and host responses was collected mainly during 1987-1992, improvement in diagnostic methods was carried out during 1990-1995, and the immunogenicity of vaccine candidates was tested during 1992-1995. Based on these factors, a randomized, controlled, blinded efficacy trial of two pneumococcal conjugate vaccines against acute otitis media was started in Finland in 1995. Enrolment of 2,497 infants has now been completed by April 1997, and the follow-up phase will continue until 1999.

Economic evaluation of rotavirus vaccinations in Finland: randomized, double-blind, placebo-controlled trial of tetravalent rhesus rotavirus vaccine.

The cost-benefit ratio of tetravalent rhesus rotavirus vaccine (RRV-TV) in Finland for prevention of rotavirus gastroenteritis was assessed in a randomized, double-blind, placebo-controlled trial. Costs related to vaccination, side effects, and gastroenteritis were identified. Children received RRV-TV (n = 1,191) or placebo (n = 1,207) at 2, 3, and 5 months of age with other infant vaccinations. Prospective follow-up averaged 1.0 years per child. An intention-to-treat analysis was performed from the perspective of society. Nine cases of severe rotavirus gastroenteritis occurred in the RRV-TV group, versus 100 in the placebo group (P < .0001); mean cost per vaccinated child was 4 Finnish marks (FIM) in the RRV-TV group, versus 203 FIM in the placebo group. Side effects with related costs occurred after 11% and 7% of doses in the RRV-TV group and placebo group, respectively (P < .001); mean cost per child was 89 FIM vs. 75 FIM. The break-even cost (i.e., net benefit, excluding cost of vaccine) of RRV-TV in prevention of severe rotavirus gastroenteritis was 109 FIM (U.S. $19.60) per child.

Comparison of four different sampling methods for detecting pharyngeal carriage of Streptococcus pneumoniae and Haemophilus influenzae in children.

Samples from 96 children with acute respiratory infection were obtained simultaneously with nasal, nasopharyngeal, and oropharyngeal swabs and by nasopharyngeal aspiration and were cultured on chocolate and blood agar plates. The rates of isolation of Streptococcus pneumoniae and Haemophilus influenzae detected by the four sampling methods were compared. Nasopharyngeal aspirates were optimal for the detection of both S. pneumoniae (isolation rate, 33%) and H. influenzae (isolation rate, 31%). When a nasopharyngeal aspirate is not available, such as for healthy children or children with no obtainable secretions, the nasopharyngeal swab seems optimal for the detection of both S. pneumoniae and H. influenzae among children younger than 13 months of age. Among older children, similarly, the nasopharyngeal swab seems optimal for the detection of S. pneumoniae; however, for H. influenzae, the oropharyngeal swab seems optimal.

Pneumococcal capsular antigen detection after enrichment culture: an alternative to culture methods in epidemiologic research.

Bacterial culture of Streptococcus pneumoniae followed by serotyping is not always feasible under field conditions. Antigen detection methods could be an alternative, but they are associated with sensitivity problems. In an effort to improve their sensitivity, we introduced an enrichment phase before antigen detection and compared the results with direct bacterial culture, using nasopharyngeal swabs from 95 children with symptoms of acute respiratory infection. Antigen detection was performed by latex agglutination and counterimmunoelectrophoresis. Streptococcus pneumoniae was found in 29 (30%) of the samples by culture, and in 42 (44%) by antigen detection after enrichment, an excess of 45% over culture findings. This excess was shown to represent true positive samples since pneumococcal DNA could be detected by polymerase chain reaction in all 15 antigen-positive, culture-negative samples. Two culture-positive samples were antigen-negative; in one of these the bacteria were nonencapsulated. We conclude that for type-specific demonstration of S. pneumoniae, detection of pneumococcal antigen after an enrichment step is a sensitive method that can be applied for epidemiologic study purposes, e.g., in vaccine trials, in areas without ready access to a good microbiology laboratory.

A statistical model of transmission of Hib bacteria in a family.

The simultaneous estimation of family and community transmission rates as well as cure rates from panel data in a recurrent Hib (Haemophilus influenzae type b bacteria) infection is considered. An individual-based stationary Markov process model with constant hazards in two age groups is applied to describe recurrent asymptomatic Hib infection in a family with small children. The problem of estimation is solved in terms of the Bayesian posterior of the model parameters. The model is used to predict prevalence and incidence of Hib carriage in families as a function of the family size and age structure.

Subtyping of common pediatric pneumococcal serotypes from invasive disease and pharyngeal carriage in Finland.

Ninety-nine penicillin-sensitive Streptococcus pneumoniae strains of common pediatric serogroups/types (6, 7, 14, 19, and 23) cultured from the blood of children with invasive disease (n = 49) or asymptomatic oropharyngeal carriage (n = 50) were analyzed by multilocus enzyme electrophoresis and ribotyping; 53 distinctive multilocus enzyme genotypes (ETs) and 53 ribotypes were identified. Multilocus enzyme electrophoresis showed good correlation with ribotying. ETs and ribotypes among invasive and carriage isolates were similar. Within different S. pneumoniae serogroups/types, both clonal (7 and 14) and heterogenous (6, 19, and 23) ET and rRNA hybridization patterns were observed. Greatest diversity was observed among serotypes 6A, 6B, and 19F. Use of 12 additional restriction enzymes besides PvuII and BglII did not increase ribotype discrimination within serotype 7 and 14 isolates. Serotype 7 and 14 strains, which appear clonal by subtyping, are rare among carriers but common causes of invasive disease. Characteristics associated with their clonality may represent an advantage for invasiveness.