Correlation coefficients for correlations between treatment differences at 10 months of age (post-booster).

<p>Correlation coefficients for correlations between treatment differences at 10 months of age (post-booster).</p

Use of weighted multivariate estimates in trials of multi-serotype vaccines to simplify interpretation of treatment differences

<div><p>Background</p><p>Many vaccines contain multiple components. Licensed pneumococcal conjugate vaccines (PCV) contain polysaccharides from 7, 10, or 13 different serotypes of <i>Streptococcus pneumoniae</i>. The main outcomes in randomised trials of pneumococcal vaccines are serotype-specific antibody measures. Comparisons are made between groups for each serotype, resulting in multiple separate comparisons of treatment effects which can be complicated to interpret. We investigated methods for computing the overall difference between vaccine groups across all serotypes.</p><p>Methods</p><p>Pneumococcal antibody concentrations were obtained from a randomised controlled trial of ten-valent pneumococcal vaccine, conducted in Kathmandu, Nepal. Infants received either 2 priming doses of vaccine at 6 and 14 weeks of age followed by a booster (2+1), or 3 priming doses at 6, 10, and 14 weeks of age with no booster (3+0). The overall difference between vaccine schedules across all serotypes was computed at each visit using a multivariate linear model with equal weights for each serotype. Alternative weights were derived from invasive pneumococcal disease cases in Nepal, Bangladesh and Pakistan, and from estimates of the relative invasiveness of each serotype and used in sensitivity analyses.</p><p>Results</p><p>When 10 separate estimates of treatment differences were computed the ratio of antibody responses for each serotype in the 2+1 group compared with the 3+0 group at 10 months of age varied greatly, with serotype-specific GMRs ranging from 2.80 for serotype 14, to 9.14 for serotype 18C. Using equal weights for each serotype, the overall geometric mean ratio (GMR) was 5.02 (95% CI 4.06−6.22) at 10 months of age, and 1.46 (95% CI 1.14−1.88) at 3 years of age. Using weights based on disease incidence gave GMRs ranging from 5.15 to 6.63 at 10 months of age, and 1.47 to 1.78 at 3 years of age. Using weights based on relative invasiveness gave estimates of 6.81 and 1.59, at 10 months and 3 years respectively.</p><p>Conclusion</p><p>PCV clinical trial data have a multivariate structure with correlated outcomes for different serotypes. When analysing each serotype separately, the multiple estimates of the treatment effect can complicate the interpretation of trial results. Reporting a single overall estimate which accounts for the correlation between outcomes can simplify such interpretation. Treatment effects can be weighted equally or alternative weights derived from independent data can be used.</p><p>Many modern vaccines have multiple components, such as quadrivalent meningococcal group ACWY vaccine or four-component group B meningococcal vaccine, thus these methods are widely applicable.</p></div

South Asian estimates of the proportions of vaccine serotype-specific invasive pneumococcal disease due to PCV10 serotypes in unvaccinated populations.

<p>South Asian estimates of the proportions of vaccine serotype-specific invasive pneumococcal disease due to PCV10 serotypes in unvaccinated populations.</p

Serotype-specific geometric mean ratios (2+1 schedule relative to 3+0 schedule) with overall estimates derived using different weighting structures.

<p>Serotype-specific geometric mean ratios (2+1 schedule relative to 3+0 schedule) with overall estimates derived using different weighting structures.</p

Weights derived from estimates of the invasive potential of pneumococcal PCV10 serotypes.

<p>Weights derived from estimates of the invasive potential of pneumococcal PCV10 serotypes.</p

Serotype-specific propensity for isolation as a primary or non-primary isolate.

<p>Pneumococcal serotypes identified from nasopharyngeal swabs of Nepalese children aged 6 weeks to 24 months from the Kathmandu Valley, Nepal, were classified as to whether they occurred as a primary or non-primary isolate (*p<0·05). Specifically for each serotype: 15B, 10A, 35A, 34, 35F, 16F, 20, NT4b, 13, and NT4a p<0.0001; 6A p = 0.0005; 6B, 19A and 6C p = 0.0012; 23A and 33B p = 0.0016; NT2 p = 0.0257; 23F p = 0.0035; 4 p = 0.0101. The serotypes, 9V, 14, 19F, 3, 11D, 17F, 35B, 35C, 39, 7C, 45, 15, 7B, 8, 9N, 18C, 15A, 23B, 29, 22A, 28F, 31, 33C, 6D, 19B, 10F, 24A, 38, 48, 9L, 11A, 11B, 12F, 17A, 18A, 24B, 32F, 33A, 33F, 36, 1, 5, 7F, NT3b, 25F, 28A, 37, 40, 19C, and NT were not labelled and/or had non-significant p-values and/or were isolated on less than five occasions. MGS = Mitis-group Streptococcus.</p

Mean Anti-Hib Antibody Concentrations and Percentage of Participants with Protective Levels.

<p>Only 20% of children under 5 years old have protective (>0.15 µg/ml) antibody levels, rising to 83% of 15–54 year-olds. Geometric mean anti-polyribosylribitol phosphate IgG concentrations for each age group are plotted on the left y-axis (±SE). The percentage of participants with antibody concentrations >0.15 µg/ml (‘short-term protection’: the height of the entire column) and >1 µg/ml (‘long-term’ protection: the height of only the shaded column) are plotted on the right y-axis (±SE). Sample sizes (n): Cord Blood (n = 15); 0.5–4 yrs (n = 15); 5–7 yrs (n = 15); 8–14 yrs (n = 18); 15–54 yrs (n = 12); 55–77 yrs (n = 11).</p

Microarray summary

Summary of microarray detection of pneumococcal serotypes present in nasopharyngeal specimen

Presence of Antibiotic Resistance Genes in Pneumococcal Positive Array Samples.

<p><i>cat</i>—chloramphenicol acetyltransferase, <i>ermB</i>—rRNA adenine N-6-methyltransferase (resistance to erythromycin), <i>tetM</i>—Ribosomal protection protein (conferring resistance to tetracycline), <i>aphA3</i>—kanamycin resistance, <i>sat4</i>—streptothricin, <i>mefA</i>—Macrolide-Lincosamide-Streptogramin B efflux pump, <i>ermC</i>—rRNA adenine N-6-methyltransferase (conferring resistance to erythromycin), <i>tetK</i>—tetracycline efflux pump, <i>tetO</i>—Ribosomal protection protein (conferring resistance to tetracycline).</p><p>Presence of Antibiotic Resistance Genes in Pneumococcal Positive Array Samples.</p

Heat map representation of nasopharyngeal swab isolates from children aged 6 weeks to 24 months from the Kathmandu Valley, Nepal.

<p>Isolates are ordered according to participant number and presence of pneumococcus. The depth of colour is representative of the relative abundance of the isolate identified by microarray. Each isolate was divided into three categories: S—Typeable pneumococci, N– Non-typeable pneumococci and, M—Mitis-group Streptococcus. Subsequent isolates within these categories were then ranked 1–4 according to relative abundance.</p