Modelling multi-type transmission of pneumococcal carriage in Bangladeshi families.

The burden of pneumococcal carriage is largest in developing countries from which, however, detailed studies on pneumococcal transmission are missing. In this study we followed nasopharyngeal carriage in Bangladeshi infants (n=99) from birth, with 2-week sampling intervals until age 4 months, and monthly thereafter until age 1 year, and also their family members at the same intervals. We assessed the dependence of pneumococcal acquisition rates on age, serotype, serotype-specific exposure (i.e. transmission) and current state of carriage (yes/no). A statistical model of pneumococcal transmission, taking into account incompletely observed data, was applied to estimate rates of acquisition and clearance for a large number of serotypes at the same time. Serotypes that were common in the study population were more often acquired from the community than rarer serotypes. However, when conditioning on serotype-specific exposure within the family, transmission rates were similar between different serotypes. Exposure within families signified more than tenfold increase in the rate of acquisition.

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.

Predicting meningococcal disease outbreaks in structured populations.

Rational decision making on whether some form of intervention would be necessary to control the spread of a meningococcal epidemic is based on predictions concerning its potential natural progression. Unfortunately, reliable predictions are difficult to make during the early stages of an outbreak. A stochastic discrete time epidemic model was applied to adaptively predict the development of outbreaks of meningococcal disease in 'closed' populations such as military garrisons or boarding schools, which are further divided into subgroups called 'units'. The performance of the adaptive method was assessed by using 3 simulated epidemics representing substantially different realizations in a 'garrison' of 20 units, with 68 men in each. Predictions of the weekly number of disease cases, of the number of carriers, and of the number of new infections were computed. Simulations suggest that predictions based only on the observed numbers of disease cases are generally inaccurate. These predictions can be improved if temporal observations on asymptomatic carriers in different units are utilized together with observed time series of the disease. A sample of 15 per cent from all units can be sufficient for a major improvement if the alternative is to obtain a full sample of only some units. Exploiting fully such information requires computer intensive Markov chain Monte Carlo methods.

Maternal immunization with pneumococcal polysaccharide vaccine in the Philippines.

A randomized, controlled study was conducted to evaluate the immunogenicity and reactogenicity of the 23-valent pneumococcal (Pnc) polysaccharide (PS) vaccine among pregnant women and to ascertain the transfer of anti-Pnc antibody (Ab) from mother to infant. One hundred and sixty women received either one dose of Pnc PS vaccine, Haemophilus influenzae type b conjugate vaccine and tetanus toxoid (TT) (Pnc vaccine group, N=106) or TT only (control group, N=54). Sera were obtained from all mothers prior to vaccination and 4 weeks after from the vaccinated group. Cord blood was obtained in 75% of deliveries. Anti-Pnc Ab for serotypes 1, 5, 6B, 14, 18C and 19F was determined using enzyme immunoassay. The Pnc vaccine and control groups were comparable in terms of age, parity, gravidity, prior doses of TT, and pre-vaccination geometric mean concentration (GMC in microg/ml) of anti-Pnc Ab. Between 66 and 87% of the mothers had type-specific Ab prior to vaccination. There was a significant rise in anti-Pnc Ab (varying from 3.3- to 9.1-fold for the individual serotypes) between the pre and post-vaccination samples. Adverse reactions were mild and required no treatment. The level of anti-Pnc Ab in cord blood was significantly lower in the control group compared to the Pnc vaccine group. Vaccination of pregnant women with Pnc Ps vaccine induces good immune response and Ab can be transferred to their infants via cord blood thus providing enhanced protection.

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.

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).

Antibody response to the pneumococcal proteins pneumococcal surface adhesin A and pneumolysin in children with acute otitis media.

BACKGROUND: Pneumococcal surface adhesin A (PsaA) and pneumolysin (Ply) are common to virtually all Streptococcus pneumoniae isolates, and they are immunogenic and protective against pneumococcal challenge in experimental animals. We have recently shown production of antibodies to PsaA and Ply in young children, but data on the immune response to these antigens during culture-confirmed pneumococcal infection are lacking. OBJECTIVES: To evaluate whether young children respond to S. pneumoniae by producing antibodies to PsaA and Ply during acute otitis media (AOM). SUBJECTS AND METHODS: A cohort of 329 children was followed prospectively from the age of 2 months to the age of 2 years. Paired sera were obtained during episodes of AOM and used to measure antibodies to PsaA and Ply by enzyme-linked immunosorbent assay. S. pneumoniae cultured from the middle ear fluid was taken as evidence of pneumococcal AOM. The presence of S. pneumoniae in the nasopharyngeal aspirate collected in connection of AOM or any other respiratory infection or in the nasopharyngeal swab collected at scheduled visits was taken to indicate pneumococcal carriage and thus a history of previous contact with S. pneumoniae. RESULTS: Children with previous pneumococcal contacts had high anti-PsaA and anti-Ply concentrations in the acute phase sera regardless of the nature (AOM or carriage) of the current pneumococcal contact. Of the children with no previous pneumococcal contact, those with current pneumococcal AOM had lower antibody concentrations than those with current pneumococcal carriage only. Anti-PsaA and anti-Ply responses were found in children with current pneumococcal contact. The antibody response was strongly associated with low acute phase antibody concentration, but not significantly with age and the nature of the current pneumococcal contact. CONCLUSIONS: We showed that infants are capable of developing a specific antibody response to the pneumococcal proteins PsaA and Ply during AOM.

Microbial etiology of community-acquired pneumonia in the adult population of 4 municipalities in eastern Finland.

To determine the etiology of community-acquired pneumonia in the adult population of a defined area, specific antibody responses in paired serum samples, levels of circulating pneumococcal immune complexes in serum samples, and pneumococcal antigen in urine were measured. Samples (304 paired serum samples and 300 acute urine samples) were obtained from 345 patients > or =15 years old with community-acquired, radiologically confirmed pneumonia, which comprised all cases in the population of 4 municipalities in eastern Finland during 1 year. Specific infecting organisms were identified in 183 patients (including 49 with mixed infection), as follows: Streptococcus pneumoniae, 125 patients; Haemophilus influenzae, 12; Moraxella catarrhalis, 8; chlamydiae, 37 (of which, Chlamydia pneumoniae, 30); Mycoplasma pneumoniae, 30; and virus species, 27. The proportion of patients with pneumococcal infections increased and of those with Mycoplasma infections decreased with age, but for each age group, the etiologic profile was similar among inpatients and among outpatients. S. pneumoniae was the most important etiologic agent. The annual incidence of pneumococcal pneumonia per 1000 inhabitants aged > or =60 years was 8.0.

Efficacy of a pneumococcal conjugate vaccine against acute otitis media.

BACKGROUND: Ear infections are a common cause of illness during the first two years of life. New conjugate vaccines may be able to prevent a substantial portion of cases of acute otitis media caused by Streptococcus pneumoniae. METHODS: We enrolled 1662 infants in a randomized, double-blind efficacy trial of a heptavalent pneumococcal polysaccharide conjugate vaccine in which the carrier protein is the nontoxic diphtheria-toxin analogue CRM197. The children received either the study vaccine or a hepatitis B vaccine as a control at 2, 4, 6, and 12 months of age. The clinical diagnosis of acute otitis media was based on predefined criteria, and the bacteriologic diagnosis was based on a culture of middle-ear fluid obtained by myringotomy. RESULTS: Of the children who were enrolled, 95.1 percent completed the trial. With the pneumococcal vaccine, there were more local reactions than with the hepatitis B vaccine but fewer than with the combined whole-cell diphtheria-tetanus-pertussis and Haemophilus influenzae type b vaccine that was administered simultaneously. There were 2596 episodes of acute otitis media during the follow-up period between 6.5 and 24 months of age. The vaccine reduced the number of episodes of acute otitis media from any cause by 6 percent (95 percent confidence interval, -4 to 16 percent [the negative number indicates a possible increase in the number of episodes]), culture-confirmed pneumococcal episodes by 34 percent (95 percent confidence interval, 21 to 45 percent), and the number of episodes due to the serotypes contained in the vaccine by 57 percent (95 percent confidence interval, 44 to 67 percent). The number of episodes attributed to serotypes that are cross-reactive with those in the vaccine was reduced by 51 percent, whereas the number of episodes due to all other serotypes increased by 33 percent. CONCLUSIONS: The heptavalent pneumococcal polysaccharide-CRM197 conjugate vaccine is safe and efficacious in the prevention of acute otitis media caused by the serotypes included in the vaccine.

Acquired immunity to Chlamydia pneumoniae is dependent on gamma interferon in two mouse strains that initially differ in this respect after primary challenge.

The role of gamma interferon (IFN-gamma) in a Chlamydia pneumoniae mouse model was studied by in vivo neutralization in two inbred mouse strains. During primary C. pneumoniae infection, neutralization of IFN-gamma increased both the numbers of bacteria and the pneumonia score in the lungs of C57BL/6 mice but not BALB/c mice. During reinfection, the bacterial counts in the lungs were increased by IFN-gamma neutralization in both mouse strains. Thus, the effect of IFN-gamma neutralization was dependent on the genetic background in primary infection. However, IFN-gamma appeared to be equally important in both mouse strains during reinfection.

Vaccines, coming of age after 200 years.

An overview on the short, only 200 years, past history and future expectations in the field of vaccines is presented. The focus is on development trends and potential rather than individual vaccines. While the first vaccines were a result of keen observation, the further development has been tightly dependent on the development of microbiology to provide both the knowledge basis and the technology for new vaccines for new purposes. The post-genomic era just starting therefore promises an exponential increase of vaccine research and new vaccines, both improved vaccines with a greater efficacy and less adverse effects to replace old ones and vaccines for prevention of diseases for which no vaccines exist. Furthermore, fully new applications to prevention or treatment of chronic diseases not traditionally associated with infections are expected.

Immunity to Chlamydia pneumoniae induced by vaccination with DNA vectors expressing a cytoplasmic protein (Hsp60) or outer membrane proteins (MOMP and Omp2).

Immune responses induced by intramuscular DNA immunization with Chlamydia pneumoniae genes coding for the major outer membrane protein (MOMP), cysteine-rich outer membrane protein 2 (Omp2) or the heat shock protein 60 (Hsp60) were studied. BALB/c mice were vaccinated intramuscularly three times at 3-week intervals and challenged intranasally 2 weeks after the last injection. Immunization with pmomp or phsp60 showed 1.2-1.5 log reduction in the mean lung bacterial counts after the challenge. Specific antibodies were detected only in sera of the mice immunized with pomp2 and phsp60. Although immunization with pomp2 resulted in a strong serum antibody response against Omp2 protein, it failed to protect the mice. Immunization with any of the three vaccines did not reduce the severity of histologically assessed pneumonia, but resulted in significantly higher lymphoid reaction in the lung indicating immunological memory.

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.

Depletion of CD8+ cells abolishes memory in acquired immunity against Chlamydia pneumoniae in BALB/c mice.

The importance of T cells in Chlamydia pneumoniae infection in mice was assessed by comparing wild-type BALB/c mice with nude mice and mice depleted in vivo of either CD4+ or CD8+ T cells. Whereas wild-type mice cleared the primary infection in 3 weeks, nude mice were only able to restrict the infection and could not clear it during the observation period of 56 days. Nude mice exhibited a greater number of macrophages in their lungs and the pulmonary cells secreted a higher level of tumour necrosis factor-alpha (TNF-alpha) than wild-type mice. Depletion of CD4+ cells did not change the overall infection kinetics of the primary infection. However, depletion of CD8+ cells resulted in a slightly impaired clearance of the bacteria in the late stages of primary infection. To assess the role of the two T-cell subsets in the acquired immunity that develops during primary infection in wild-type BALB/c mice, in vivo depletions were performed during reinfection. Prior to reinfection, immunocompetent wild-type mice were infected and natural immunity was allowed to form. During reinfection, depletion of CD4+ cells did not have any effect on infection kinetics, whereas depletion of CD8+ cells abolished the protection, reverting the infection kinetics and bacterial load to the same levels found in wild-type mice during primary infection. These results show that T cells are necessary for clearing C. pneumoniae infection in mice. Furthermore, whereas neither of the two main T-cell subsets, separately, were essential for clearance of primary infection, the induced protective immunity was strongly CD8 dependent.

Prognosis after community-acquired pneumonia in the elderly: a population-based 12-year follow-up study.

BACKGROUND: Only a few studies have investigated the long-term effects of community-acquired pneumonia (CAP). These studies have focused on cases treated in the hospital, and, to our knowledge, no long-term survival studies that include all cases of CAP are available. METHODS: A prospective observational study on the survival rates in a population-based cohort of elderly inhabitants aged 60 years or older at baseline in 1 township in eastern Finland in 1983. A total of 4167 (99% of the total elderly population), 122 of whom survived CAP during a prospective pneumonia surveillance period from 1983 to 1985, were followed up for mortality from 1983 to 1994 for a median of 9.2 years. The relative risk (RR) of death in patients who survived CAP was compared with that in elderly inhabitants without CAP by Cox multivariate regression analysis. Data on causes of death were obtained from a central register based on death certificates. RESULTS: The long-term survival rate was significantly lower in persons who had survived CAP or pneumococcal CAP (PCAP) than in the rest of the study population. The RR of pneumonia-related mortality was 2.1 (95% confidence interval [CI], 1.3-3.4; P = .004) in all patients with CAP and 2.8 (95% CI, 1.5-5.3; P = .001) in patients with PCAP. The respective numbers for total mortality were 1.5 (95% CI, 1.2-1.9; P = .001) in all patients with CAP and 1.6 (95% CI, 1.1-2.2; P= .01) in those with PCAP. Also the risk of cardiovascular mortality was increased in persons with CAP (RR, 1.4; 95% CI, 1.0-1.9; P = .02) and in those with PCAP (RR, 1.6; 95% CI, 1.0-2.4; P= .04). CONCLUSIONS: The present results indicate that elderly patients treated for CAP are at high risk of subsequent mortality for several years. Based on the high incidence and negative long-term effects of pneumonia, it can be concluded that there is a clear need for prevention, eg, by influenza and pneumococcal immunization.

Incremental effectiveness of pneumococcal vaccine on simultaneously administered influenza vaccine in preventing pneumonia and pneumococcal pneumonia among persons aged 65 years or older.

The effectiveness of simultaneously administered influenza and pneumococcal vaccines vs. influenza vaccine alone in preventing pneumonia, pneumococcal pneumonia and pneumococcal bacteraemia among the elderly was studied. The vaccines were offered to all persons aged 65 years or older (N=43,500) living in 35 administrative districts in Northern Finland. A total of 26,925 persons (62%) decided to participate. Allocation to the vaccination groups took place by year of birth (odd/even). The total follow-up of those vaccinated consisted of 38,037 person years. The incremental effectiveness of the pneumococcal vaccine was -20 (95% CI -50- + 10%) for pneumonia, -20 (95% CI -90- + 20%) for pneumococcal pneumonia and + 60% (95% CI -40- +90%) for pneumococcal bacteraemia. Thus the pneumococcal polysaccharide vaccine did not offer any additional protection from pneumonia among elderly people in Finland although it reduced the incidence of bacteraemia.

The infant rat model adapted to evaluate human sera for protective immunity to group B meningococci.

The infant rat infection model previously developed to evaluate protective ability of passively administered murine antibodies to group B meningococcal (MenB) surface antigens was adapted for human sera. Several challenge doses were tested, aiming at sensitive detection of protection with little interassay variability. Doses of 10(5) and 10(6) colony forming units of strain IH5341 (MenB:15:P1.7,16) injected intraperitoneally gave consistently high levels of bacteremia and meningitis developed in 6 h in 50-100% of the pups. A monoclonal antibody mAb735 to the MenB capsule, injected 1-2 h before bacterial challenge, gave full protection at a dose of 2 microg/pup. Sera from adult volunteers immunized with a MenB outer membrane vesicle vaccine reproducibly reduced bacterial counts in the blood and cerebrospinal fluid, whereas a normal human serum, lacking bactericidal and opsonophagocidal activity, was unprotective.