Group sequential design for randomized trials using “first hitting time” model
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Mathematical & Computational Biology↗
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A Multi-Armed Bayesian Ordinal Outcome Utility-Based Sequential Trial with a Pairwise Null Clustering Prior
A multi-armed trial based on ordinal outcomes is proposed that leverages a flexible non-proportional odds cumulative logit model and numerical utility scores for each outcome to determine treatment optimality. This trial design uses a Bayesian clustering prior on the treatment effects that encourages the pairwise null hypothesis of no differences between treatments. A group sequential design is proposed to determine which treatments are clinically different with an adaptive decision boundary that becomes more aggressive as the sample size or clinical significance grows, or the number of active treatments decreases. A simulation study is conducted for 3 and 5 treatment arms, which shows that the design has superior operating characteristics (family wise error rate, generalized power, average sample size) compared to utility designs that do not allow clustering, a frequentist proportional odds model, or a permutation test based on empirical mean utilities.
97 MATHEMATICS AND COMPUTING↗
Structural characterization of influenza group 1 chimeric hemagglutinins as broad vaccine immunogens
Chimeric hemagglutinins (cHA) appear to be promising for the design and development of universal influenza vaccines. Influenza A group 1 cHAs, cH5/1, cH8/1, and cH11/1, comprising an H1 stem attached to either an H5, H8, or H11 globular head, have been used sequentially as vaccine immunogens in human clinical trials and induced high levels of broadly protective antibodies. Using X-ray crystallography and negative-stain electron microscopy, we determined structures of cH5/1, cH8/1, and cH11/1 HAs in their apo (unliganded) and antibody Fab-bound states. Stem-reactive antibodies 3E1 and 31.b.09 recognize their cognate epitopes in cH5/1, cH8/1, and cH11/1 HAs. However, with cH5/1, the head domains are rotated by 35 to 45° around the threefold axis of the HA trimer compared to native HA with a more splayed-open conformation at the stem base. cH11/1 with 3E1 is structurally more native-like but resembles cH5/1 with 31.b.09, whereas cH8/1 with 31.b.09 exhibited a range of closed-to-open stem configurations with some separation of head and stem domains. Furthermore, all of these group 1 cHAs effectively bound a broad head trimer interface antibody and other broad stem antibodies. Thus, the cHAs exhibit structural plasticity without compromising the stem and head trimer interface epitopes for elicitation of influenza A group 1 cross-reactive antibodies.
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