Nasopharyngeal Carriage of Streptococcus pneumoniae Shortly before Vaccination with a Pneumococcal Conjugate Vaccine Causes Serotype-Specific Hyporesponsiveness in Early Infancy

Background. The antibody response to pneumococcal conjugate vaccines (PCVs) in infants is variable. Factors responsible for this variability have not been fully elucidated. The objective of this study was to investigate whether pneumococcal carriage around the time of the first dose of 7-valent PCV (PCV7) affects serotype-specific immunologic response. Methods. Healthy 2-month old infants were randomized to receive 2 (at the ages of 4 and 6 months) or 3 (at the ages of 2, 4, and 6 months) PCV7 doses and a booster dose (at the age of 12 months). Nasopharyngeal or oropharyngeal specimens were obtained for culture shortly before the first PCV7 dose. Serotype-specific immunoglobulin (Ig) G levels were measured at ages 2, 7, and 13 months. Results. Of 545 children studied, 332 received a booster dose. The most common serotypes carried around the time of the first PCV7 dose were 6B (n = 37), 19F (n = 22), and 23F (n = 14). In carriers before the first dose, the IgG response to the carried serotype after 2 or 3 doses was significantly lower than in noncarriers. In contrast, response to the noncarried serotypes was not affected. Although all children responded to the booster dose, the response to the originally carried serotype was generally lower. Conclusions. Serotype-specific hyporesponsiveness to PCV7 after pneumococcal carriage in infants is demonstrated for the first time. This phenomenon was common, lasted for at least several months, and was only partially overcome by the 12-month booster. Trial registration. isrctn.org identifier: ISRCTN2844584

A toddler PCV booster dose following 3 infancy priming doses increases circulating serotype-specific IGG levels but does not increase protection against carriage

Background: We compared PCV7 serological response and protection against carriage in infants receiving 3 doses (2, 4, 6 months; 3+0 schedule) to those receiving a booster (12 months; 3+1). Methods: A prospective, randomized controlled study, conducted between 2005 and 2008, before PCVs were implemented in Israel. Healthy infants were randomized 1:1:1 to receive 3+1, 3+0 and 0+2 (control group; 12, 18 months doses). Nasopharyngeal/oropharyngeal swabs were obtained at all visits. Serum serotype-specific IgG concentrations and opsonic activities (OPA) were measured at 2, 7, 13 and 19 months. This study was registered with Current Controlled Trials, Ltd. ISRCTN28445844. Results: Overall, 544 infants were enrolled: 3+1 (n = 178), 3+0 (n = 178) and 0+2 (n = 188). Post-priming (7 months), antibody concentrations were similar in both groups, except for serotype 18C (higher in 3+0). Post-booster (13, 19 months), ELISA and OPA levels were significantly higher in 3+1 than in 3+0 group. Nasopharyngeal/oropharyngeal cultures were positive for Streptococcus pneumoniae in 2673 (543%) visits. Acquisition rates (vaccine and non-vaccine serotypes) were similar for 3+1 and 3+0 groups at 7-30 months and for 0+2 group at 19-30 months. Conclusions: PCV7 booster after 3 priming doses increased substantially IgG concentrations but did not further reduced vaccine-serotype nasopharyngeal acquisition, suggesting that protection from pneumococcal carriage does not depend primarily on serum IgG. (C) 2018 Elsevier Ltd. All rights reserved.Peer reviewe

Pneumococcal Phenotype and Interaction with Nontypeable Haemophilus influenzae as Determinants of Otitis Media Progression

All-cause otitis media (OM) incidence has declined in numerous settings following introduction of pneumococcal conjugate vaccines (PCVs) despite increases in carriage of nonvaccine pneumococcal serotypes escaping immune pressure. To understand the basis for the declining incidence, we assessed the intrinsic capacity of pneumococcal serotypes to cause OM independently and in polymicrobial infections involving nontypeable Haemophilus influenzae (NTHi) using samples obtained from middle ear fluid and nasopharyngeal cultures before PCV7/13 rollout. Data included samples from OM episodes (11,811) submitted for cultures during a 10-year prospective study in southern Israel and nasopharyngeal samples (1,588) from unvaccinated asymptomatic children in the same population. We compared data representing pneumococcal serotype diversity across carriage and disease isolates with and without NTHi coisolation. We also measured associations between the pneumococcal phenotype and the rate of progression from colonization to OM in the presence and absence of NTHi. Whereas pneumococcal serotype diversity was lower in single-species OM than in single-species colonization, levels of serotype diversity did not differ significantly between colonization and OM in mixed-species episodes. Serotypes differed roughly 100-fold in progression rates, and those differences were attenuated in polymicrobial episodes. Vaccine serotype pneumococci had higher rates of progression than nonvaccine serotypes. While serotype invasiveness was a weak predictor of the OM progression rate, efficient capsular metabolic properties-traditionally thought to serve as an advantage in colonization-predicted an enhanced rate of progression to complex OM. The lower capacity of nonvaccine serotypes to cause OM may partially account for reductions in all-cause OM incidence despite serotype replacement in carriage following rollout of PCVs

Influence of age, social patterns and nasopharyngeal carriage on antibodies to three conserved pneumococcal surface proteins (PhtD, PcpA and PrtA) in healthy young children

The acquisition of specific antibodies is paramount to protect children against pneumococcal diseases, and a better understanding of how age, ethnicity and/or Streptococcus pneumoniae (Spn) nasopharyngeal carriage influence the acquisition of antibodies to pneumococcal surface proteins (PSP) is important for the development of novel serodiagnostic and immunisation strategies. IgG antibody titres against three conserved PSP (PhtD, PcpA and PrtA) in the sera of 451 healthy children aged 1 to 24months from Israel [Jewish (50.1%) and Bedouin (49.9%)] were measured by enzyme-linked immunosorbent assay (ELISA), while nasopharyngeal swabs from these children were assessed for the presence of Spn. Globally, anti-PhtD and anti-PrtA geometric mean concentrations (GMC; EU/ml) were high at <2.5months of age [PhtD: 35.3, 95% confidence interval (CI) 30.6-40.6; PrtA: 71.2, 95 % CI 60-84.5], was lower at 5-7months of age (PhtD: 10, 95 % CI 8-12.4; PrtA: 17.9, 95 % CI 14.4-22.1) and only increased after 11months of age. In contrast, an increase in anti-PcpA was observed at 5-7months of age. Anti-PcpA and anti-PrtA, but not anti-PhtD, were significantly higher in Bedouin children (PcpA: 361.6 vs. 226.3, p = 0.02; PrtA: 67.2 vs. 29.5, p < 0.001) in whom Spn nasopharyngeal carriage was identified earlier (60% vs. 38% of carriers <6months of age, p = 0.002). Spn carriage was associated with significantly higher anti-PSP concentrations in carriers than in non-carriers (p < 0.001 for each PSP). Thus, age, ethnicity and, essentially, nasopharyngeal carriage exert distinct cumulative influences on infant responses to PSP. These specific characteristics are worthwhile to include in the evaluation of pneumococcal seroresponses and the development of new PSP-based vaccine

What is the mechanism for persistent coexistence of drug-susceptible and drug-resistant strains of Streptococcus pneumoniae?

The rise of antimicrobial resistance in many pathogens presents a major challenge to the treatment and control of infectious diseases. Furthermore, the observation that drug-resistant strains have risen to substantial prevalence but have not replaced drug-susceptible strains despite continuing (and even growing) selective pressure by antimicrobial use presents an important problem for those who study the dynamics of infectious diseases. While simple competition models predict the exclusion of one strain in favour of whichever is ‘fitter’, or has a higher reproduction number, we argue that in the case of Streptococcus pneumoniae there has been persistent coexistence of drug-sensitive and drug-resistant strains, with neither approaching 100 per cent prevalence. We have previously proposed that models seeking to understand the origins of coexistence should not incorporate implicit mechanisms that build in stable coexistence ‘for free’. Here, we construct a series of such ‘structurally neutral’ models that incorporate various features of bacterial spread and host heterogeneity that have been proposed as mechanisms that may promote coexistence. We ask to what extent coexistence is a typical outcome in each. We find that while coexistence is possible in each of the models we consider, it is relatively rare, with two exceptions: (i) allowing simultaneous dual transmission of sensitive and resistant strains lets coexistence become a typical outcome, as does (ii) modelling each strain as competing more strongly with itself than with the other strain, i.e. self-immunity greater than cross-immunity. We conclude that while treatment and contact heterogeneity can promote coexistence to some extent, the in-host interactions between strains, particularly the interplay between coinfection, multiple infection and immunity, play a crucial role in the long-term population dynamics of pathogens with drug resistance

Clustering of serotypes in a longitudinal study of Streptococcus pneumoniae carriage in three day care centres

<p>Abstract</p> <p>Background</p> <p><it>Streptococcus pneumoniae </it>(pneumococcus) causes a wide range of clinical manifestations that together constitute a major burden of disease worldwide. The main route of pneumococcal transmission is through asymptomatic colonisation of the nasopharynx. Studies of transmission are currently of general interest because of the impact of the new conjugate-polysaccharide vaccines on nasopharyngeal colonisation (carriage). Here we report the first longitudinal study of pneumococcal carriage that records serotype specific exposure to pneumococci simultaneously within the two most important mixing groups, families and day care facilities.</p> <p>Methods</p> <p>We followed attendees (N = 59) with their family members (N = 117) and the employees (N = 37) in three Finnish day care centres for 9 months with monthly sampling of nasopharyngeal carriage. Pneumococci were cultured, identified and serotyped by standard methods.</p> <p>Results</p> <p>Children in day care constitute a core group of pneumococcal carriage: of the 36 acquisitions of carriage with documented exposure to homologous pneumococci, the attendee had been exposed in her/his day care centre in 35 cases and in the family in 9 cases. Day care children introduce pneumococci to the family: 66% of acquisitions of a new serotype in a family were associated with simultaneous or previous carriage of the same type in the child attending day care. Consequently, pneumococcal transmission was found to take place as micro-epidemics driven by the day care centres. Each of the three day care centres was dominated by a serotype of its own, accounting for 100% of the isolates of that serotype among all samples from the day care attendees.</p> <p>Conclusion</p> <p>The transmission of pneumococci is more intense within than across clusters defined by day care facilities. The ensuing micro-epidemic behaviour enhances pneumococcal transmission.</p

Nasopharyngeal Carriage of Streptococcus pneumoniae in Healthy Children: Implications for the Use of Heptavalent Pnemococcal Conjugate Vaccine

We assessed the prevalence of Streptococcus pneumoniae serotypes in the nasopharynx of healthy children, antimicrobial susceptibility patterns, risk factors for carriage, and the coverage of heptavalent pneumococcal conjugate vaccine. In 2,799 healthy infants and children, the S. pneumoniae carrier rate was 8.6% (serotypes 3, 19F, 23F, 19A, 6B, and 14 were most common). Most pneumococci (69.4%) were resistant to one or more antimicrobial classes. The rate of penicillin resistance was low (9.1%); macrolide resistance was high (52.1%). Overall, 63.2% of the isolates belonged to strains covered by the heptavalent pneumococcal vaccine. This percentage was higher in children <2 years old (73.1%) and in those >2-5 years old(68.9%). Sinusitis in the previous 3 months was the only risk factor for carrier status; acute otitis media was the only risk factor for the carriage of penicillin-resistant S. pneumoniae. Most the isolated strains are covered by the heptavalent conjugate vaccine, especially in the first years of life, suggesting that its use could reduce the incidence of pneumococcal disease

Between-Strain Competition in Acquisition and Clearance of Pneumococcal Carriage—Epidemiologic Evidence From a Longitudinal Study of Day-Care Children

The state of pneumococcal carriage—that is, pneumococcal colonization in the nasopharynx of healthy persons—represents a reservoir for the spread of pneumococci among individuals. In light of the introduction of new pneumococcal conjugate vaccines, further knowledge on the dynamics of pneumococcal carriage is important. Different serotypes (strains) of pneumococcus are known to compete with each other in colonizing human hosts. Understanding the strength and mode of between-serotype competition is important because of its implications for vaccine-induced changes in the ecology of pneumococcal carriage. Competition may work through reduced acquisition of new serotypes, due to concurrent carriage in the individual, or through enhanced clearance of serotypes in carriers who harbor more than 1 serotype simultaneously. The authors employed longitudinal data (1999–2001) on pneumococcal carriage in Danish day-care children to analyze between-serotype competition. The data included observations of carriage in children who had not been vaccinated against pneumococcus, and the level of pneumococcal antibiotic resistance and antibiotic usage in the community was very low. Clearance of any single serotype was not affected by simultaneous carriage of other serotypes. In contrast, acquisition of other serotypes in already-colonized hosts was weak (relative rate of acquisition = 0.09, 95% credible interval: 0.05, 0.15)

Fluoroquinolone and Other Antimicrobial Resistance in Invasive Pneumococci, Hong Kong, 1995–2001

Fluoroquinolone resistance among invasive pneumococci in Hong Kong was high and a result of clonal expansion and spread