Limited impact of neonatal or early infant schedules of 7-valent pneumococcal conjugate vaccination on nasopharyngeal carriage of Streptococcus pneumoniae in Papua New Guinean children: A randomized controlled trial

Streptococcus pneumoniae is a leading cause of pneumonia, the most common cause of childhood death. Papua New Guinean children experience high rates of nasopharyngeal pneumococcal colonization within weeks of birth, predisposing them to pneumococcal disease. In a trial to determine the safety and immunogenicity of early infant vaccination with 7-valent pneumococcal conjugate vaccine (7vPCV), we investigated the impact of early schedules on pneumococcal carriage. Infants were randomized at birth to receive 7vPCV in a 0–1–2-month (n = 101) or a 1–2–3-month (n = 105) schedule or no 7vPCV (n = 106). All children received 23-valent pneumococcal polysaccharide vaccine at age 9 months. We cultured nasopharyngeal swabs (NPS) collected at ages 1, 2, 3, 4 weeks and 3, 9, 18 months, and middle ear discharge if present. Pneumococcal serotypes were identified by the Quellung reaction. A total of 1761 NPS were cultured. The prevalence of pneumococcal carriage was 22% at 1 week of age, rising to 80% by age 3 months and remained >70% thereafter, with high-density carriage in 42% of pneumococcuspositive samples. We identified 63 different serotypes; 43% of isolates from controls were 13vPCV serotypes. There were no significant differences in 7vPCV serotype carriage between 7vPCV recipients and controls at any age (22% vs. 31% at 9 months, p = 0.2). At age 9 months the prevalence of non-7vPCV carriage was 17% higher in 7vPCV recipients (48%) than in controls (25%, p = 0.02). More non-7vPCV serotypes were isolated from ear discharge in 16 7vPCV recipients than from 4 controls (48% vs. 25%, p = 0.13). The limited impact of neonatal or accelerated infant 7vPCV schedules on vaccine serotype carriage is probably due to the early onset of dense carriage of a broad range of pneumococcal serotypes. While serotype-independent pneumococcal vaccines are needed in high-risk populations, the underlying environmental factors and sources of infection must be investigated

The effects of swaddling on oxygen saturation and respiratory rate of healthy infants in Mongolia.

BACKGROUND: Infant swaddling is common practice in some developing countries where infant respiratory morbidity is also prevalent. Little is known about the effect of swaddling on respiratory variables in healthy infants. Such information could have important implications for respiratory diseases. AIMS: To compare respiratory rates (RR) and arterial oxygen saturations (SaO2) of healthy swaddled infants and non-swaddled infants during different conditions of sleep and arousal. SETTING: Community based, nested case control study in Ulaanbaatar, Mongolia. SUBJECTS AND METHODS: Habitually swaddled and non-swaddled infants aged 9-10 weeks taking part in a randomised controlled trial of swaddling. Respiratory rate and SaO2 were measured during quiet wakefulness, feeding, quiet and active sleep. Habitually swaddled infants were studied in swaddled and non-swaddled conditions. Habitually non-swaddled infants were studied only in the non-swaddled state. RESULTS: SaO2 was higher during awake states compared with sleep states in all groups of infants. Habitually swaddled infants had lower mean SaO2 in the swaddled compared with non-swaddled condition (96.5% vs. 96.9%, p < 0.01) but these were not significantly different from the mean SaO2 of non-swaddled infants (96.9%, minimum p = 0.22). Habitually swaddled infants in the swaddled and non-swaddled states had similar respiratory rates, but these were, in both cases, significantly lower than in habitually non-swaddled infants. CONCLUSION: Swaddling has little or no clinical effect on SaO2 or respiratory rates in healthy 9-10-week-old infants in Mongolia

Generalised estimating equations studying associations between change in serotype-specific antibody titers in response to challenge and pneumococcal vaccine history and pre-challenge antibody titers.

<p>Generalised estimating equations studying associations between change in serotype-specific antibody titers in response to challenge and pneumococcal vaccine history and pre-challenge antibody titers.</p

Flowchart for children in the study.

<p>A flowchart of the completed preceding neonatal PCV7 trial is published elsewhere [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0185877#pone.0185877.ref008" target="_blank">8</a>]. A total of 132 of 259 children who participated in the previous PCV7 study and who were vaccinated with PPV23 at 9 months of age were included in this study. One hundred and twenty seven children could not be enrolled for reasons summarized in Fig 1, including death; being too old according to pre-defined inclusion criteria; illness; migration to an area outside the study’s reach capacities; not located; and refusal. A total of 121 of 136 potential community controls who were assented to participate in the study were included in the final analysis: of the 15 not included, three children were over age; three did not consent; three could not be relocated and blood collection pre-challenge was not successful for six children. Post-challenge data were not available for 41 children for reasons summarized. <i>N</i> is Neonatal PCV7 group; <i>I</i> is Infant PCV7 group; <i>C</i> is control group (no PCV7).</p

Rationale and methods of a randomized controlled trial of immunogenicity, safety and impact on carriage of pneumococcal conjugate and polysaccharide vaccines in infants in Papua New Guinea

Abstract Background Children in third-world settings including Papua New Guinea (PNG) experience early onset of carriage with a broad range of pneumococcal serotypes, resulting in a high incidence of severe pneumococcal disease and deaths in the first 2 years of life. Vaccination trials in high endemicity settings are needed to provide evidence and guidance on optimal strategies to protect children in these settings against pneumococcal infections. Methods This report describes the rationale, objectives, methods, study population, follow-up and specimen collection for a vaccination trial conducted in an endemic and logistically challenging setting in PNG. The trial aimed to determine whether currently available pneumococcal conjugate vaccines (PCV) are suitable for use under PNG’s accelerated immunization schedule, and that a schedule including pneumococcal polysaccharide vaccine (PPV) in later infancy is safe and immunogenic in this high-risk population. Results This open randomized-controlled trial was conducted between November 2011 and March 2016, enrolling 262 children aged 1 month between November 2011 and April 2014. The participants were randomly allocated (1:1) to receive 10-valent PCV (10vPCV) or 13-valent PCV (13vPCV) in a 1-2-3-month schedule, with further randomization to receive PPV or no PPV at age 9 months, followed by a 1/5th PPV challenge at age 23 months. A total of 1229 blood samples were collected to measure humoral and cellular immune responses and 1238 nasopharyngeal swabs to assess upper respiratory tract colonization and carriage load. Serious adverse events were monitored throughout the study. Of the 262 children enrolled, 87% received 3 doses of PCV, 79% were randomized to receive PPV or no PPV at age 9 months, and 67% completed the study at 24 months of age with appropriate immunization and challenge. Conclusion Laboratory testing of the many samples collected during this trial will determine the impact of the different vaccine schedules and formulations on nasopharyngeal carriage, antibody production and function, and immune memory. The final data will inform policy on pneumococcal vaccine schedules in countries with children at high risk of pneumococcal disease by providing direct comparison of an accelerated schedule of 10vPCV and 13vPCV and the potential advantages of PPV following PCV immunization. Trial registration ClinicalTrials.gov CTN NCT01619462 , retrospectively registered on May 28, 201

Individual pneumococcal serotype-specific IgG antibody titers before and after challenge.

<p>Graphs present scatterplots of pneumococcal serotype-specific IgG antibody titers pre- and 1 month post-challenge with a low dose of PPV23 for individual children in the groups not vaccinated with any pneumococcal vaccines (grey triangles), vaccinated with PCV7 and PPV23 (black circles), and vaccinated with PPV23 only (open squares). Serotypes with an asterisk (*) are included in PPV23 only, while other serotypes are included in both PCV7 and PPV23. For children whose antibody titers are higher post- than pre-challenge (increase in antibody titer) data points lie above the line; for children with similar titers before and after challenge data points cluster around the reference line; and for children whose antibody titers were lower 1month after challenge than before data points lie under the reference line. The p-values included in the graphs correspond with non-parametric analysis of paired pre- and post-challenge responses within the treatment groups (Wilcoxon Signed Rank Test).</p

Proportion of 3-5-year-old children with pneumococcal serotype IgG antibody titers ≥ 0.35 μg/ml and ≥ 1 μg/ml before challenge.

<p>Proportion of 3-5-year-old children with pneumococcal serotype IgG antibody titers ≥ 0.35 μg/ml and ≥ 1 μg/ml before challenge.</p

Individual pneumococcal serotype-specific IgG antibody titers following PPV23 vaccination at 9 months versus low-dose challenge at 3–5 years of age.

<p>Graphs present scatterplots of pneumococcal serotype-specific IgG antibody titers measured in individual children 1 month after PPV23 vaccination (vaccinated at 9 months of age) (x axis) and 1 month after challenge with a low dose of PPV23 at 3–5 years of age (y axis), in those who had received 3 doses of PCV7 before the PPV23 vaccine (primed; grey circles), or only received PPV23 (unprimed; black diamonds). Serotypes with an asterisk (*) are included in PPV23 only, while the other serotypes are included in both PCV7 and PPV23. The p-values included in the graphs correspond with non-parametric analysis of paired responses within the treatment groups (Wilcoxon Signed Rank Test).</p

Proportion of 3-5-year-old children with pneumococcal serotype IgG antibody titers ≥ 0.35 μg/ml and ≥ 1 μg/ml one month after low-dose PPV23 challenge.

<p>Proportion of 3-5-year-old children with pneumococcal serotype IgG antibody titers ≥ 0.35 μg/ml and ≥ 1 μg/ml one month after low-dose PPV23 challenge.</p

Pneumococcal serotype-specific IgG antibody titers before and after challenge.

<p>Serum antibody titers were assessed in 3-5-year-old children who had received PCV7 and PPV23 as infants (white bars; n = 100 /n = 86), who had received only PPV23 as infants (grey bars; n = 32 /n = 28), or who had not received pneumococcal vaccines (striped bars; n = 121 pre-challenge/ n = 98 post-challenge) (A) before and (B) after challenge with a low dose of PPV23. Data are presented as geometric mean titers and 95% confidence intervals. Serotype-specific geometric mean titers before or after challenge were compared between each group using Mann-Whitney U test. * p < 0.05.</p