Modelling the public health impact of second-generation malaria vaccines

Despite significant progress in the control and elimination of malaria over the past two decades, the global burden remains high. The COVID-19 pandemic has seen malaria cases and deaths increase markedly over 2019 resulting in 241 million malaria cases and 627,000 malaria deaths worldwide in 2020, an increase of 14 million cases and 69,000 deaths. Around 47,000 of these additional deaths were linked to pandemic-related disruptions in the provision of malaria prevention, diagnosis and treatment. The need for a highly efficacious childhood malaria vaccine has never felt more pertinent and in 2021, after 30 years of research and development, the World Health Organization recommended the first ever childhood vaccine against P. falciparum malaria, RTS,S/AS01E (RTS,S) for widespread use. The development of RTS,S, its deployment and continued evaluation has facilitated the synthesis of knowledge and data from across a wide range of different disciplines involved in malaria vaccine research. This depth of data has enhanced the development of mathematical modelling frameworks that combine immunological insights with epidemiological transmission models to address public health questions. These frameworks have formed a core part of the evaluation and policy recommendations surrounding RTS,S. The work presented in this thesis builds upon these modelling frameworks to provide insights into the potential impact of alternative RTS,S vaccination approaches. The two RTS,S approaches examined in this thesis are a delayed-fractional primary series and a seasonally targeted vaccination schedule, both of which have demonstrated promising efficacy in human challenge studies and field trials respectively. Drawing on data from the delayed-fractional RTS,S human challenge study I used a Bayesian framework to investigate immunological correlates of vaccine induced protection. I estimate that improvements to the quality, measured as antibody avidity, and not the quantity, measured as antibody titre, of the vaccine induced antibody response is critical to the increased efficacy against infection observed with this schedule. Next, I utilised data from seasonal malaria chemoprevention and seasonal RTS,S vaccination clinical trials to fit and validate an updated efficacy profile of the drug combination Sulfadoxine-pyrimethamine plus amodiaquine (SP+AQ) used for seasonal malaria chemoprevention using a Bayesian survival analysis framework. This approach enabled me to capture uncertainty in the protection provided by seasonal malaria chemoprevention over time. I then use this updated efficacy profile along with the existing RTS,S vaccine efficacy profile to replicate trial cohorts in a transmission model in order to validate the intervention models against clinical trial data. I found that the existing RTS,S model underestimated the protection provided by the seasonal vaccination schedule and explored several biologically motivated alterations to the model that brought results in line with those of the trial. These results combined with the trial reported antibody data suggest that efficacy improvements with this regime were not driven by increases in antibody quantity. Further model results suggest that when vaccination and chemoprevention were combined this resulted in potential synergistic interactions that enhanced the efficacy of SP+AQ in particular. This work resulted therefore in several updated versions of RTS,S and SP+AQ efficacy models that capture the current uncertainty in intervention effects. Finally extending these updated efficacy models from the validation exercise, I used a model of malaria transmission to investigate the long-term public health impact of novel RTS,S vaccination schedules compared to the original age-based RTS,S dosing schedule in seasonal settings. I considered the impact both in the presence and absence of seasonal malaria chemoprevention. I examined impact by degree of seasonality, transmission intensity and by wider health system and operational factors. RTS,S vaccination in seasonal malaria transmission settings could be a valuable additional tool to existing seasonal interventions, with seasonal delivery maximising impact relative to an age-based approach. Decisions surrounding deployment strategies of RTS,S in such settings will need to consider the local and regional variations in seasonality, current levels of other interventions and potential achievable RTS,S coverage.Open Acces

Colorectal Cancer Brochure Development for African Americans

Introduction: African Americans are more likely to die from colorectal cancer (CRC) than any other racial/ethnic group in the United States. Unfortunately, African Americans are also less likely to undergo screening for CRC than their White counterparts. Focus groups methodology was used to refine educational brochures designed to increase CRC screening among African Americans. Methods: Two series of focus groups were completed, with a total of seven groups and 39 participants. Six different brochures (stage-matched and culturally sensitive) designed to promote CRC screening among African Americans were evaluated. Results: All participants thought that the brochures motivated them to talk with their health care providers about screening. Cost, pain, medical mistrust and fear were identified as major barriers and the brochures were modified to address these concerns. Conclusions: Focus groups methodology with African Americans can be used to inform brochures designed to increase African Americans CRC screening that addresses their major concerns

Chinese American Immigrant Breast Cancer Survivors and Their Experiences with Post-Treatment Care

This study examined the experiences of Chinese American immigrant breast cancer survivors with post-treatment breast cancer care and surveillance in New York City. As part of a mixed methods approach, in-depth interviews were conducted with 11 Chinese American immigrant breast cancer survivors treated in a public hospital setting regarding their final breast cancer treatment visit, perceived risk of breast cancer recurrence, and experiences with social and family networks following the completion of treatment. Several salient and shared themes emerged from the interviews including two areas of particular concern regarding the transition from the treatment to post-treatment setting: survivors’ lack of access to information regarding post-treatment cancer surveillance and resources for psychosocial and health system support. Findings provide insight into the complex ways in which health system and sociocultural factors intersect and shape Chinese American immigrant women’s experiences with post-treatment care and point to the importance of patient-centered information exchange. Oncology treatment specialists should take into consideration specific sociocultural factors and contexts, including communication and available social support of their patients, in the practice of post-treatment care for Chinese American immigrant breast cancer survivors

Copy number variation burden does not predict severity of neurodevelopmental phenotype in children with a sex chromosome trisomy

Sex chromosome trisomies (SCTs) (XXX, XXY, and XYY karyotypes) are associated with an elevated risk of neurodevelopmental disorders. The range of severity of the phenotype is substantial. We considered whether this variable outcome was related to the presence of copy number variants (CNVs)—stretches of duplicated or deleted DNA. A sample of 125 children with an SCT were compared with 181 children of normal karyotype who had been given the same assessments. First, we compared the groups on measures of overall CNV burden: number of CNVs, total span of CNVs, and likely functional impact (probability of loss‐of‐function intolerance, pLI, summed over CNVs). Differences between groups were small relative to within‐group variance and not statistically significant on overall test. Next, we considered whether a measure of general neurodevelopmental impairment was predicted by pLI summed score, SCT versus comparison group, or the interaction between them. There was a substantial effect of SCT/comparison status but the pLI score was not predictive of outcomes in either group. We conclude that variable presence of CNVs is not a likely explanation for the wide phenotypic variation in children with SCTs. We discuss methodological challenges of testing whether CNVs are implicated in causing neurodevelopmental problems

Uncultured members of the oral microbiome

Around one-third of oral bacteria cannot be cultured using conventional methods. Some bacteria have specific requirements for nutrients while others may be inhibited by substances in the culture media or produced by other bacteria. Oral bacteria have evolved as part of multispecies biofilms, and many thus require interaction with other bacterial species to grow. In vitro models have been developed that mimic these interactions and have been used to grow previously uncultivated organisms

Variability of quasilinear diffusion coefficients for plasmaspheric hiss

In the Outer Radiation Belt, the acceleration and loss of high-energy electrons is largely controlled by wave-particle interactions. Quasilinear diffusion coefficients are an efficient way to capture the small-scale physics of wave-particle interactions due to magnetospheric wave modes such as plasmaspheric hiss. The strength of quasilinear diffusion coefficients as a function of energy and pitch-angle depends on both wave parameters and plasma parameters such as ambient magnetic field strength, plasma number density and composition. For plasmaspheric hiss in the magnetosphere, observations indicate large variations in the wave intensity and wavenormal angle, but less is known about the simultaneous variability of the magnetic field and number density. We use in-situ measurements from the Van Allen Probe mission to demonstrate the variability of selected factors that control the size and shape of pitch-angle diffusion coefficients: wave intensity, magnetic field strength and electron number density. We then compare with the variability of diffusion coefficients calculated individually from co-located and simultaneous groups of measurements. We show that the distribution of the plasmaspheric hiss diffusion coefficients is highly non-Gaussian with large variance, and that the distributions themselves vary strongly across the three phase-space bins studied. In most bins studied, the plasmaspheric hiss diffusion coefficients tend to increase with geomagnetic activity, but our results indicate that new approaches that include natural variability may yield improved parameterizations. We suggest methods like stochastic parameterization of wave-particle interactions could use variability information to improve modelling of the Outer Radiation Belt

Changing the story: an alternative approach to system change in public service innovation

Storytelling is a powerful instrument for system change. Telling stories of lived experience, listening to them, and sharing them contributes to a culture of trust based on dignity, mutual respect and shared values. In this paper we draw attention to public service innovation and co-creation with the people the service is meant for. In the past years, public service innovation was result and output driven, targeting technological and managerial innovation. Stories of service users revealed the unintended negative consequences of such innovation policies and opened new perspectives for conversations of change based on shared values leading to innovations based on human development and dignity

In vitro culture of previously uncultured oral bacterial phylotypes

Around a third of oral bacteria cannot be grown using conventional bacteriological culture media. Community profiling targeting 16S rRNA and shotgun metagenomics methods have proved valuable in revealing the complexity of the oral bacterial community. Studies investigating the role of oral bacteria in health and disease require phenotypic characterizations that are possible only with live cultures. The aim of this study was to develop novel culture media and use an in vitro biofilm model to culture previously uncultured oral bacteria. Subgingival plaque samples collected from subjects with periodontitis were cultured on complex mucin-containing agar plates supplemented with proteose peptone (PPA), beef extract (BEA), or Gelysate (GA) as well as on fastidious anaerobe agar plus 5% horse blood (FAA). In vitro biofilms inoculated with the subgingival plaque samples and proteose peptone broth (PPB) as the growth medium were established using the Calgary biofilm device. Specific PCR primers were designed and validated for the previously uncultivated oral taxa Bacteroidetes bacteria HOT 365 and HOT 281, Lachnospiraceae bacteria HOT 100 and HOT 500, and Clostridiales bacterium HOT 093. All agar media were able to support the growth of 10 reference strains of oral bacteria. One previously uncultivated phylotype, Actinomyces sp. HOT 525, was cultivated on FAA. Of 93 previously uncultivated phylotypes found in the inocula, 26 were detected in in vitro-cultivated biofilms. Lachnospiraceae bacterium HOT 500 was successfully cultured from biofilm material harvested from PPA plates in coculture with Parvimonas micra or Veillonella dispar/parvula after colony hybridization-directed enrichment. The establishment of in vitro biofilms from oral inocula enables the cultivation of previously uncultured oral bacteria and provides source material for isolation in coculture

Children\u27s and Adolescent Literature: A Roundtable Discussion

Chairs: Khimen Cooper, Collin College; Searn Ferrier-Watson, Collin College; Susan Stewart, Texas A&M -- Commerce; Michelle Tvete, Texas A&M -- Commerc