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

Covalent Carbene Functionalization of Graphene: Toward Chemical Band-Gap Manipulation

In this work, we employ dibromocarbene (DBC) radicals to covalently functionalize solution exfoliated graphene via the formation of dibromocyclopropyl adducts. This is achieved using a basic aqueous/organic biphasic reaction mixture to decompose the DBC precursor, bromoform, in conjunction with a phase-transfer catalyst to facilitate ylide formation and carbene migration to graphene substrates. DBC-functionalized graphene (DBC-graphene) was characterized using a range of spectroscopic and analytical techniques to confirm the covalent nature of functionalization. Modified optical and electronic properties of DBC-graphene were investigated using UV–vis spectroscopy, analysis of electrical <i>I</i>–<i>V</i> transport properties, and noncontact terahertz time-domain spectroscopy. The implications of carbene functionalization of graphene are considered in the context of scalable radical functionalization methodologies for bulk-scale graphene processing and controlled band-gap manipulation of graphene

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

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

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

Studies of the effects of Opa proteins on CD4⁺ T cell proliferation.

<p>Studies of the effects of Opa proteins on CD4⁺ T cell proliferation.</p

Serum bactericidal antibody titres of pooled murine sera against 4 target strains, following immunisation with wild-type and mutant recombinant OpaA and OpaD proteins.

<p>Serum bactericidal antibody titres of pooled murine sera against 4 target strains, following immunisation with wild-type and mutant recombinant OpaA and OpaD proteins.</p

CD4⁺ T cell proliferation following incubation of PBMCs ex vivo with different antigens.

<p>Proliferation of each antigen relative to media only control. Each coloured dot represents the value for a single individual (control antigens—blue; recombinant proteins—purple, liposomal proteins—green, outer membrane vesicles—yellow, inactivated bacteria—red). Black dots represent mean value for each antigen, with 95% confidence intervals shown. Number in parentheses after each antigen represents number on individuals in that group. CEACAM = carcinoembryonic antigen-related cell adhesion molecule; SEB = Staphylococcal enterotoxin B; PBS = phosphate-buffered saline; LDAO = llauryldimethylamine-oxide; wt = wild-type. PHA (phytohaemagglutinin) result not shown for clarity, to confine y-axis to relevant range for other antigens.</p

CD4⁺ T cell proliferation following incubation of PBMCs with different antigens, plus IL-2.

<p>CD4⁺ T cell proliferation following incubation of PBMCs with different antigens, plus IL-2.</p