Vaccine value profile for enterotoxigenic Escherichia coli (ETEC).

Enterotoxigenic Escherichia coli (ETEC) is one of the leading bacterial causes of diarrhoea, especially among children in low-resource settings, and travellers and military personnel from high-income countries. WHO's primary strategic goal for ETEC vaccine development is to develop a safe, effective, and affordable ETEC vaccine that reduces mortality and morbidity due to moderate-to-severe diarrhoeal disease in infants and children under 5 years of age in LMICs, as well as the long-term negative health impact on infant physical and cognitive development resulting from infection with this enteric pathogen. An effective ETEC vaccine will also likely reduce the need for antibiotic treatment and help limit the further emergence of antimicrobial resistance bacterial pathogens. The lead ETEC vaccine candidate, ETVAX, has shown field efficacy in travellers and has moved into field efficacy testing in LMIC infants and children. A Phase 3 efficacy study in LMIC infants is projected to start in 2024 and plans for a Phase 3 trial in travellers are under discussion with the U.S. FDA. Licensing for both travel and LMIC indications is projected to be feasible in the next 5-8 years. Given increasing recognition of its negative impact on child health and development in LMICs and predominance as the leading etiology of travellers' diarrhoea (TD), a standalone vaccine for ETEC is more cost-effective than vaccines targeting other TD pathogens, and a viable commercial market also exists. In contrast, combination of an ETEC vaccine with other vaccines for childhood pathogens in LMICs would maximize protection in a more cost-effective manner than a series of stand-alone vaccines. This 'Vaccine Value Profile' (VVP) for ETEC is intended to provide a high-level, holistic assessment of available data to inform the potential public health, economic and societal value of pipeline vaccines and vaccine-like products. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public private partnerships, and multi-lateral organizations. All contributors have extensive expertise on various elements of the ETEC VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

Vaccine value profile for Shigella.

Shigella is the leading bacterial cause of diarrhoea and the second leading cause of diarrhoeal mortality among all ages. It also exhibits increasing levels of antibiotic resistance. The greatest burden is among children under five in low- and middle-income countries (LMICs). As such, a priority strategic goal of the World Health Organization (WHO) is the development of a safe, effective and affordable vaccine to reduce morbidity and mortality from Shigella-attributable dysentery and diarrhea, including long term outcomes associated with chronic inflammation and growth faltering, in children under 5 years of age in LMICs. In addition, a safe and effective Shigella vaccine is of potential interest to travellers and military both to prevent acute disease and rarer, long-term sequelae. An effective Shigella vaccine is also anticipated to reduce antibiotic use and thereby help diminish further emergence of enteric pathogens resistant to antimicrobials. The most advanced vaccine candidates are multivalent, parenteral formulations in Phase 2 and Phase 3 clinical studies. They rely on O-antigen-polysaccharide protein conjugate technologies or, alternatively, outer membrane vesicles expressing penta-acylated lipopolysaccharide that has been detoxified. Other parenteral and oral formulations, many delivering a broader array of Shigella antigens, are at earlier stages of clinical development. These formulations are being assessed in alignment with the WHO Preferred Product Characteristics, which call for a 1 to 2 dose primary immunization series given during the first 12 months of life, ideally starting at 6 months of age. This 'Vaccine Value Profile' (VVP) for Shigella is intended to provide a high-level, holistic assessment of the information and data that are currently available to inform the potential public health, economic and societal value of pipeline vaccines and vaccine-like products. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, government agencies and multi-lateral organizations. All contributors have extensive expertise on various elements of the Shigella VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

Heterogeneity in enterotoxigenic Escherichia coli and shigella infections in children under 5 years of age from 11 African countries: a subnational approach quantifying risk, mortality, morbidity, and stunting.

BACKGROUND: Diarrhoea, a global cause of child mortality and morbidity, is linked to adverse consequences including childhood stunting and death from other diseases. Few studies explore how diarrhoeal mortality varies subnationally, especially by cause, which is important for targeting investments. Even fewer examine indirect effects of diarrhoeal morbidity on child mortality. We estimated the subnational distribution of mortality, morbidity, and childhood stunting attributable to enterotoxigenic Escherichia coli (ETEC) and shigella infection in children younger than 5 years from 11 eastern and central African countries. These pathogens are leading causes of diarrhoea in young children and have been linked to increased childhood stunting. METHODS: We combined proxy indicators of morbidity and mortality risk from the most recent Demographic and Health Surveys with published relative risks to estimate the potential distribution of diarrhoeal disease risk. To estimate subnational burden, we used country-specific or WHO region-specific morbidity and mortality estimates and distributed them subnationally by three indices that integrate relevant individual characteristics (ie, underweight, probability of receiving oral rehydration treatment of diarrhoea, and receiving vitamin A supplementation) and household characteristics (ie, type of drinking water and sanitation facilities). FINDINGS: Characterising ETEC and shigella subnational estimates of indirect morbidity (infection-attributable stunting) and indirect mortality (stunting-related deaths from other infectious diseases) identified high-risk areas that could be missed by traditional metrics. Burundi and Democratic Republic of the Congo had the highest ETEC-associated and shigella-associated mortality and stunting rates. Mozambique, Democratic Republic of the Congo, and Zimbabwe had the greatest subnational heterogeneity in most ETEC and shigella mortality measures. Inclusion of indirect ETEC and shigella mortality in burden estimates resulted in a 20-30% increase in total ETEC and shigella mortality rates in some subnational areas. INTERPRETATION: Understanding the indirect mortality and morbidity of diarrhoeal pathogens on a subnational level will strengthen disease control strategies and could have important implications for the relative impact and cost-effectiveness of new enteric vaccines. Because our methods rely on publicly available data, they could be employed for national planning. FUNDING: Bill & Melinda Gates Foundation.

Reduction in lower-alpha power during Ganzfeld flicker stimulation is associated with the production of imagery and trait positive schizotypy.

Light-flicker Ganzfeld (LFG) induces a lower to upper-alpha frequency shift. However, it is unclear how this neurophysiological response might relate to LFG-induced pseudo-hallucinatory phenomena. It is also unknown whether emotional states (e.g., fear) or traits associated with risk for psychosis (e.g., proneness to perceptual anomalies, ability to produce vivid mental imagery) affect such neurophysiological and/or perceptual responses to LFG. The present study investigated alpha sub-bands during LFG across several flicker frequencies, in relation to individual differences in propensity for Ganzfeld-induced imagery (GI), positive schizotypy and trait mental imagery, and in relation to manipulations of affective state. Given previously reported sex differences in risk for psychosis and response to Ganzfeld, the effect of sex on GI was also studied. Forty-six healthy adults (16 men) completed psychometric measures of trait mental imagery and positive schizotypy before undergoing three LFG (20 min each) conditions. In each condition, participants wore white-out goggles and listened to either mood-inducing soundscapes (fear, serenity) or pink noise (control) through headphones. Greatest propensity for GI arose between 13.1 and 16.0 Hz flicker, with a peak at 16.0 Hz flicker. Occipital lower-alpha was reduced for lower flicker frequencies (13.1-16.0 Hz) and was inversely associated with GI. Upper-alpha power was not significantly related to GI or to other measures. Fear-induction was associated with reduction in alpha power, but did not significantly affect GI. Men reported more GI than women. Findings support a role for cortical destabilisation, as reflected in reduced lower-alpha, in perceptual anomalies; and, by extension, LFG as an experimental model of liability for psychosis.