Comprehensive Data Integration Approach to Assess Immune Responses and Correlates of RTS,S/AS01-Mediated Protection From Malaria Infection in Controlled Human Malaria Infection Trials.

RTS,S/AS01 (GSK) is the world's first malaria vaccine. However, despite initial efficacy of almost 70% over the first 6 months of follow-up, efficacy waned over time. A deeper understanding of the immune features that contribute to RTS,S/AS01-mediated protection could be beneficial for further vaccine development. In two recent controlled human malaria infection (CHMI) trials of the RTS,S/AS01 vaccine in malaria-naïve adults, MAL068 and MAL071, vaccine efficacy against patent parasitemia ranged from 44% to 87% across studies and arms (each study included a standard RTS,S/AS01 arm with three vaccine doses delivered in four-week-intervals, as well as an alternative arm with a modified version of this regimen). In each trial, RTS,S/AS01 immunogenicity was interrogated using a broad range of immunological assays, assessing cellular and humoral immune parameters as well as gene expression. Here, we used a predictive modeling framework to identify immune biomarkers measured at day-of-challenge that could predict sterile protection against malaria infection. Using cross-validation on MAL068 data (either the standard RTS,S/AS01 arm alone, or across both the standard RTS,S/AS01 arm and the alternative arm), top-performing univariate models identified variables related to Fc effector functions and titer of antibodies that bind to the central repeat region (NANP6) of CSP as the most predictive variables; all NANP6-related variables consistently associated with protection. In cross-study prediction analyses of MAL071 outcomes (the standard RTS,S/AS01 arm), top-performing univariate models again identified variables related to Fc effector functions of NANP6-targeting antibodies as highly predictive. We found little benefit-with this dataset-in terms of improved prediction accuracy in bivariate models vs. univariate models. These findings await validation in children living in malaria-endemic regions, and in vaccinees administered a fourth RTS,S/AS01 dose. Our findings support a "quality as well as quantity" hypothesis for RTS,S/AS01-elicited antibodies against NANP6, implying that malaria vaccine clinical trials should assess both titer and Fc effector functions of anti-NANP6 antibodies.

Effect of Subject-Specific Vertebral Position and Head and Neck Size on Calculation of Spine Musculoskeletal Moments.

Spine musculoskeletal models used to estimate loads and displacements require many simplifying assumptions. We examined how assumptions about subject size and vertebral positions can affect the model outcomes. Head and neck models were developed to represent 30 subjects (15 males and 15 females) in neutral posture and in forward head postures adopted while using tablet computers. We examined the effects of (1) subject size-specific parameters for head mass and muscle strength; and (2) vertebral positions obtained either directly from X-ray or estimated from photographs. The outcome metrics were maximum neck extensor muscle moment, gravitational moment of the head, and gravitational demand, the ratio between gravitational moment and maximum muscle moment. The estimates of maximum muscle moment, gravitational moment and gravitational demand were significantly different when models included subject-specific vertebral positions. Outcome metrics of models that included subject-specific head and neck size were not significantly different from generic models on average, but they had significant sex differences. This work suggests that developing models from X-rays rather than photographs has a large effect on model predictions. Moreover, size-specific model parameters may be important to evaluate sex differences in neck musculoskeletal disorders.

Gravitational demand on the neck musculature during tablet computer use.

Tablet computer use requires substantial head and neck flexion, which is a risk factor for neck pain. The goal of this study was to evaluate the biomechanics of the head-neck system during seated tablet computer use under a variety of conditions. A physiologically relevant variable, gravitational demand (the ratio of gravitational moment due to the weight of the head to maximal muscle moment capacity), was estimated using a musculoskeletal model incorporating subject-specific size and intervertebral postures from radiographs. Gravitational demand in postures adopted during tablet computer use was 3-5 times that of the neutral posture, with the lowest demand when the tablet was in a high propped position. Moreover, the estimated gravitational demand could be correlated to head and neck postural measures (0.48 < R(2) < 0.64, p < 0.001). These findings provide quantitative data about mechanical requirements on the neck musculature during tablet computer use and are important for developing ergonomics guidelines. Practitioner Summary: Flexed head and neck postures occur during tablet computer use and are implicated in neck pain. The mechanical demand on the neck muscles was estimated to increase 3-5 times during seated tablet computer use versus seated neutral posture, with the lowest demand in a high propped tablet position but few differences in other conditions.