Pneumococcal carriage in sub-Saharan Africa--a systematic review.

BACKGROUND: Pneumococcal epidemiology varies geographically and few data are available from the African continent. We assess pneumococcal carriage from studies conducted in sub-Saharan Africa (sSA) before and after the pneumococcal conjugate vaccine (PCV) era. METHODS: A search for pneumococcal carriage studies published before 2012 was conducted to describe carriage in sSA. The review also describes pneumococcal serotypes and assesses the impact of vaccination on carriage in this region. RESULTS: Fifty-seven studies were included in this review with the majority (40.3%) from South Africa. There was considerable variability in the prevalence of carriage between studies (I-squared statistic = 99%). Carriage was higher in children and decreased with increasing age, 63.2% (95% CI: 55.6-70.8) in children less than 5 years, 42.6% (95% CI: 29.9-55.4) in children 5-15 years and 28.0% (95% CI: 19.0-37.0) in adults older than 15 years. There was no difference in the prevalence of carriage between males and females in 9/11 studies. Serotypes 19F, 6B, 6A, 14 and 23F were the five most common isolates. A meta-analysis of four randomized trials of PCV vaccination in children aged 9-24 months showed that carriage of vaccine type (VT) serotypes decreased with PCV vaccination; however, overall carriage remained the same because of a concomitant increase in non-vaccine type (NVT) serotypes. CONCLUSION: Pneumococcal carriage is generally high in the African continent, particularly in young children. The five most common serotypes in sSA are among the top seven serotypes that cause invasive pneumococcal disease in children globally. These serotypes are covered by the two PCVs recommended for routine childhood immunization by the WHO. The distribution of serotypes found in the nasopharynx is altered by PCV vaccination

Interleukin 7 from Maternal Milk Crosses the Intestinal Barrier and Modulates T- Cell Development in Offspring

Background Breastfeeding protects against illnesses and death in hazardous environments, an effect partly mediated by improved immune function. One hypothesis suggests that factors within milk supplement the inadequate immune response of the offspring, but this has not been able to account for a series of observations showing that factors within maternally derived milk may supplement the development of the immune system through a direct effect on the primary lymphoid organs. In a previous human study we reported evidence suggesting a link between IL-7 in breast milk and the thymic output of infants. Here we report evidence in mice of direct action of maternally-derived IL-7 on T cell development in the offspring. Methods and Findings  We have used recombinant IL-7 labelled with a fluorescent dye to trace the movement in live mice of IL-7 from the stomach across the gut and into the lymphoid tissues. To validate the functional ability of maternally derived IL- 7 we cross fostered IL-7 knock-out mice onto normal wild type mothers. Subsets of thymocytes and populations of peripheral T cells were significantly higher than those found in knock-out mice receiving milk from IL-7 knock-out mothers. Conclusions/Significance Our study provides direct evidence that interleukin 7, a factor which is critical in the development of T lymphocytes, when maternally derived can transfer across the intestine of the offspring, increase T cell production in the thymus and support the survival of T cells in the peripheral secondary lymphoid tissue

Pneumococcal Antibody Concentrations and Carriage of Pneumococci more than 3 Years after Infant Immunization with a Pneumococcal Conjugate Vaccine

BACKGROUND: A 9-valent pneumococcal conjugate vaccine (PCV-9), given in a 3-dose schedule, protected Gambian children against pneumococcal disease and reduced nasopharyngeal carriage of pneumococci of vaccine serotypes. We have studied the effect of a booster or delayed primary dose of 7-valent conjugate vaccine (PCV-7) on antibody and nasopharyngeal carriage of pneumococci 3-4 years after primary vaccination. METHODOLOGY/PRINCIPAL FINDINGS: We recruited a subsample of children who had received 3 doses of either PCV-9 or placebo (controls) into this follow-up study. Pre- and post- PCV-7 pneumococcal antibody concentrations to the 9 serotypes in PCV-9 and nasopharyngeal carriage of pneumococci were determined before and at intervals up to 18 months post-PCV-7. We enrolled 282 children at a median age of 45 months (range, 38-52 months); 138 had received 3 doses of PCV-9 in infancy and 144 were controls. Before receiving PCV-7, a high proportion of children had antibody concentrations >0.35 µg/mL to most of the serotypes in PCV-9 (average of 75% in the PCV-9 and 66% in the control group respectively). The geometric mean antibody concentrations in the vaccinated group were significantly higher compared to controls for serotypes 6B, 14, and 23F. Antibody concentrations were significantly increased to serotypes in the PCV-7 vaccine both 6-8 weeks and 16-18 months after PCV-7. Antibodies to serotypes 6B, 9V and 23F were higher in the PCV-9 group than in the control group 6-8 weeks after PCV-7, but only the 6B difference was sustained at 16-18 months. There was no significant difference in nasopharyngeal carriage between the two groups. CONCLUSIONS/SIGNIFICANCE: Pneumococcal antibody concentrations in Gambian children were high 34-48 months after a 3-dose primary infant vaccination series of PCV-9 for serotypes other than serotypes 1 and 18C, and were significantly higher than in control children for 3 of the 9 serotypes. Antibody concentrations increased after PCV-7 and remained raised for at least 18 months

Acquisition of pneumococci specific effector and regulatory Cd4+ T cells localising within human upper respiratory-tract mucosal lymphoid tissue

The upper respiratory tract mucosa is the location for commensal Streptococcus (S.) pneumoniae colonization and therefore represents a major site of contact between host and bacteria. The CD4(+) T cell response to pneumococcus is increasingly recognised as an important mediator of immunity that protects against invasive disease, with data suggesting a critical role for Th17 cells in mucosal clearance. By assessing CD4 T cell proliferative responses we demonstrate age-related sequestration of Th1 and Th17 CD4(+) T cells reactive to pneumococcal protein antigens within mucosal lymphoid tissue. CD25(hi) T cell depletion and utilisation of pneumococcal specific MHCII tetramers revealed the presence of antigen specific Tregs that utilised CTLA-4 and PDL-1 surface molecules to suppress these responses. The balance between mucosal effector and regulatory CD4(+) T cell immunity is likely to be critical to pneumococcal commensalism and the prevention of unwanted pathology associated with carriage. However, if dysregulated, such responses may render the host more susceptible to invasive pneumococcal infection and adversely affect the successful implementation of both polysaccharide-conjugate and novel protein-based pneumococcal vaccines

The dynamics of nasopharyngeal streptococcus pneumoniae carriage among rural Gambian mother-infant pairs

<p>Abstract</p> <p>Background</p> <p><it>Streptococcus pneumoniae </it>is an important cause of community acquired pneumonia, sepsis, meningitis and otitis media globally and has been incriminated as a major cause of serious childhood bacterial infections in The Gambia. Better understanding of the dynamics of transmission and carriage will inform control strategies.</p> <p>Methods</p> <p>This study was conducted among 196 mother-infant pairs recruited at birth from six villages in the West Kiang region of The Gambia. Nasopharyngeal swabs were collected from mother-infant pairs at birth (within 12 hours of delivery), 2, 5 and 12 months. Standard techniques of culture were used to identify carriage and serotype <it>S. pneumoniae</it>.</p> <p>Results</p> <p>Of 46 serotypes identified, the 6 most common, 6A, 6B, 14, 15, 19F and 23F, accounted for 67.3% of the isolates from infants. Carriage of any serotype among infants rose from 1.5% at birth to plateau at approximately 80% by 2 m (prevalence at 2 m = 77%; 5 m = 86%; 12 m = 78%). Likewise, maternal carriage almost doubled in the first 2 months post-partum and remained elevated for the next 10 m (prevalence at birth = 13%; 2 m = 24%; 5 m = 22%; 12 m = 21%). Carriage was significantly seasonal in both infants and mothers with a peak in December and lowest transmission in August. The total number of different serotypes we isolated from each infant varied and less than would be expected had the serotypes assorted independently. In contrast, this variability was much as expected among mothers. The half-life of a serotype colony was estimated to be 1.90 m (CI_95%: 1.66-2.21) in infants and 0.75 m (CI_95%: 0.55-1.19) in mothers. While the odds for a serotype to be isolated from an infant increased by 9-fold if it had also been isolated from the mother, the population attributable fraction (PAF) of pneumococcal carriage in infants due to maternal carriage was only 9.5%. Some marked differences in dynamics were observed between vaccine and non-vaccine serotypes.</p> <p>Conclusions</p> <p>Colonisation of the nasopharynx in Gambian infants by <it>S. pneumoniae </it>is rapid and highly dynamic. Immunity or inter-serotype competition may play a role in the dynamics. Reducing mother-infant transmission would have a minimal effect on infant carriage.</p

Safety and immunogenicity of three doses of an eleven-valent diphtheria toxoid and tetanus protein – conjugated pneumococcal vaccine in Filipino infants

BACKGROUND: An 11-valent pneumococcal conjugate vaccine could provide significantly larger reduction in pneumococcal disease burden than the currently available 7-valent vaccine formulation in many countries. METHODS: In total, 50 infants were enrolled to this open, uncontrolled study, which evaluated the safety and immunogenicity of an aluminium adjuvanted 11-valent mixed-carrier diphtheria toxoid or tetanus protein-conjugated vaccine (11-PncTD) when administered in three doses at 6, 10 and 14 weeks of age simultaneously with DTwP//PRP-T and OPV vaccines in Filipino infants. RESULTS: The rates of local reactions between the two injection sites, those associated with the 11-PncTD vaccine and those with the DTwP//PRP-T were almost of equal frequency for all three vaccine doses except for induration, which was significantly more common in the DTP//PRP-T injection site. Fever was present in 39%, 22% and 21% of infants following each of the three doses. Antibody responses were determined by an enzyme immunoassay method before the first vaccination and after the three doses. The vaccine elicited a significant anti-pneumococcal polysaccharide antibody response against all serotypes included in the vaccine, except for type 14, for which the pre-vaccination geometric mean antibody concentration (GMC) was high (1.61 μg/ml). The GMCs one month after the vaccination series ranged from 1.1 micrograms/ml for type 6B to 23.4 μg/ml for type 4. CONCLUSION: The 11-PncTD vaccine is safe, well-tolerated and immunogenic. The effectiveness of the non-adjuvanted formulation of the vaccine in preventing pneumonia is currently being evaluated in the Philippines

S. pneumoniae transmission according to inclusion in conjugate vaccines: Bayesian analysis of a longitudinal follow-up in schools

BACKGROUND: Recent trends of pneumococcal colonization in the United States, following the introduction of conjugate vaccination, indicate that non-vaccine serotypes tend to replace vaccine serotypes. The eventual extent of this replacement is however unknown and depends on serotype-specific carriage and transmission characteristics. METHODS: Here, some of these characteristics were estimated for vaccine and non-vaccine serotypes from the follow-up of 4,488 schoolchildren in France in 2000. A Bayesian approach using Markov chain Monte Carlo data augmentation techniques was used for estimation. RESULTS: Vaccine and non-vaccine serotypes were found to have similar characteristics: the mean duration of carriage was 23 days (95% credible interval (CI): 21, 25 days) for vaccine serotypes and 22 days (95% CI: 20, 24 days) for non-vaccine serotypes; within a school of size 100, the Secondary Attack Rate was 1.1% (95% CI: 1.0%, 1.2%) for both vaccine and non-vaccine serotypes. CONCLUSION: This study supports that, in 3–6 years old children, no competitive advantage exists for vaccine serotypes compared to non-vaccine serotypes. This is an argument in favour of important serotype replacement. It would be important to validate the result for infants, who are known to be the main reservoir in maintaining transmission. Overall reduction in pathogenicity should also be taken into account in forecasting the future burden of pneumococcal colonization in vaccinated populations

Epidemiology of nasopharyngeal carriage of respiratory bacterial pathogens in children and adults: cross-sectional surveys in a population with high rates of pneumococcal disease

<p>Abstract</p> <p>Background</p> <p>To determine the prevalence of carriage of respiratory bacterial pathogens, and the risk factors for and serotype distribution of pneumococcal carriage in an Australian Aboriginal population.</p> <p>Methods</p> <p>Surveys of nasopharyngeal carriage of <it>Streptococcus pneumoniae</it>, non-typeable <it>Haemophilus influenzae</it>, and <it>Moraxella catarrhalis </it>were conducted among adults (≥16 years) and children (2 to 15 years) in four rural communities in 2002 and 2004. Infant seven-valent pneumococcal conjugate vaccine (7PCV) with booster 23-valent pneumococcal polysaccharide vaccine was introduced in 2001. Standard microbiological methods were used.</p> <p>Results</p> <p>At the time of the 2002 survey, 94% of eligible children had received catch-up pneumococcal vaccination. 324 adults (538 examinations) and 218 children (350 examinations) were enrolled. Pneumococcal carriage prevalence was 26% (95% CI, 22-30) among adults and 67% (95% CI, 62-72) among children. Carriage of non-typeable <it>H. influenzae </it>among adults and children was 23% (95% CI, 19-27) and 57% (95% CI, 52-63) respectively and for <it>M. catarrhalis</it>, 17% (95% CI, 14-21) and 74% (95% CI, 69-78) respectively. Adult pneumococcal carriage was associated with increasing age (p = 0.0005 test of trend), concurrent carriage of non-typeable <it>H. influenzae </it>(Odds ratio [OR] 6.74; 95% CI, 4.06-11.2) or <it>M. catarrhalis </it>(OR 3.27; 95% CI, 1.97-5.45), male sex (OR 2.21; 95% CI, 1.31-3.73), rhinorrhoea (OR 1.66; 95% CI, 1.05-2.64), and frequent exposure to outside fires (OR 6.89; 95% CI, 1.87-25.4). Among children, pneumococcal carriage was associated with decreasing age (p < 0.0001 test of trend), and carriage of non-typeable <it>H. influenzae </it>(OR 9.34; 95% CI, 4.71-18.5) or <it>M. catarrhalis </it>(OR 2.67; 95% CI, 1.34-5.33). Excluding an outbreak of serotype 1 in children, the percentages of serotypes included in 7, 10, and 13PCV were 23%, 23%, and 29% (adults) and 22%, 24%, and 40% (2-15 years). Dominance of serotype 16F, and persistent 19F and 6B carriage three years after initiation of 7PCV is noteworthy.</p> <p>Conclusions</p> <p>Population-based carriage of <it>S. pneumoniae</it>, non-typeable <it>H. influenzae</it>, and <it>M. catarrhalis </it>was high in this Australian Aboriginal population. Reducing smoke exposure may reduce pneumococcal carriage. The indirect effects of 10 or 13PCV, above those of 7PCV, among adults in this population may be limited.</p