Projecting vaccine demand and impact for emerging zoonotic pathogens.

BACKGROUND: Despite large outbreaks in humans seeming improbable for a number of zoonotic pathogens, several pose a concern due to their epidemiological characteristics and evolutionary potential. To enable effective responses to these pathogens in the event that they undergo future emergence, the Coalition for Epidemic Preparedness Innovations is advancing the development of vaccines for several pathogens prioritized by the World Health Organization. A major challenge in this pursuit is anticipating demand for a vaccine stockpile to support outbreak response. METHODS: We developed a modeling framework for outbreak response for emerging zoonoses under three reactive vaccination strategies to assess sustainable vaccine manufacturing needs, vaccine stockpile requirements, and the potential impact of the outbreak response. This framework incorporates geographically variable zoonotic spillover rates, human-to-human transmission, and the implementation of reactive vaccination campaigns in response to disease outbreaks. As proof of concept, we applied the framework to four priority pathogens: Lassa virus, Nipah virus, MERS coronavirus, and Rift Valley virus. RESULTS: Annual vaccine regimen requirements for a population-wide strategy ranged from > 670,000 (95% prediction interval 0-3,630,000) regimens for Lassa virus to 1,190,000 (95% PrI 0-8,480,000) regimens for Rift Valley fever virus, while the regimens required for ring vaccination or targeting healthcare workers (HCWs) were several orders of magnitude lower (between 1/25 and 1/700) than those required by a population-wide strategy. For each pathogen and vaccination strategy, reactive vaccination typically prevented fewer than 10% of cases, because of their presently low R0 values. Targeting HCWs had a higher per-regimen impact than population-wide vaccination. CONCLUSIONS: Our framework provides a flexible methodology for estimating vaccine stockpile needs and the geographic distribution of demand under a range of outbreak response scenarios. Uncertainties in our model estimates highlight several knowledge gaps that need to be addressed to target vulnerable populations more accurately. These include surveillance gaps that mask the true geographic distribution of each pathogen, details of key routes of spillover from animal reservoirs to humans, and the role of human-to-human transmission outside of healthcare settings. In addition, our estimates are based on the current epidemiology of each pathogen, but pathogen evolution could alter vaccine stockpile requirements.

Catalytic Oxidative Cyclization of 2'-Arylbenzaldehyde Oxime Ethers under Photoinduced Electron Transfer Conditions.

A series of 2'-arylbenzaldehyde oxime ethers were synthesized and shown to generate the corresponding phenanthridines upon irradiation in the presence of 9,10-dicyanoanthracene in acetonitrile. Mechanistic studies suggest that the oxidative cyclization reaction sequence is initiated by an electron transfer step followed by nucleophilic attack of the aryl ring onto the nitrogen of the oxime ether. A concave downward Hammett plot is presumably the result of a change in charge distribution in the radical cation species with strongly electron-donating substituents that yields a less electrophilic nitrogen atom and a decreased amount of cyclized product. The reaction is selective (no nitrile byproduct is formed unlike other photochemical reactions involving aldoxime ethers) as well as regiospecific when using 2'-aryl groups with meta-substituents, making this reaction a useful alternative for preparing substituted phenanthridines.

A domain-knowledge modeling of hospital-acquired infection risk in Healthcare personnel from retrospective observational data: A case study for COVID-19.

INTRODUCTION: Hospital-acquired infections of communicable viral diseases (CVDs) have been posing a tremendous challenge to healthcare workers globally. Healthcare personnel (HCP) is facing a consistent risk of viral infections, and subsequently higher rates of morbidity and mortality. MATERIALS AND METHODS: We proposed a domain-knowledge-driven infection risk model to quantify the individual HCP and the population-level risks. For individual-level risk estimation, a time-variant infection risk model is proposed to capture the transmission dynamics of CVDs. At the population-level, the infection risk is estimated using a Bayesian network model constructed from three feature sets, including individual-level factors, engineering control factors, and administrative control factors. For model validation, we investigated the case study of the Coronavirus disease, in which the individual-level and population-level infection risk models were applied. The data were collected from various sources such as COVID-19 transmission databases, health surveys/questionaries from medical centers, U.S. Department of Labor databases, and cross-sectional studies. RESULTS: Regarding the individual-level risk model, the variance-based sensitivity analysis indicated that the uncertainty in the estimated risk was attributed to two variables: the number of close contacts and the viral transmission probability. Next, the disease transmission probability was computed using a multivariate logistic regression applied for a cross-sectional HCP data in the UK, with the 10-fold cross-validation accuracy of 78.23%. Combined with the previous result, we further validated the individual infection risk model by considering six occupations in the U.S. Department of Labor O*Net database. The occupation-specific risk evaluation suggested that the registered nurses, medical assistants, and respiratory therapists were the highest-risk occupations. For the population-level risk model validation, the infection risk in Texas and California was estimated, in which the infection risk in Texas was lower than that in California. This can be explained by California's higher patient load for each HCP per day and lower personal protective equipment (PPE) sufficiency level. CONCLUSION: The accurate estimation of infection risk at both individual level and population levels using our domain-knowledge-driven infection risk model will significantly enhance the PPE allocation, safety plans for HCP, and hospital staffing strategies.

Burden is in the eye of the beholder: Sensitivity of yellow fever disease burden estimates to modeling assumptions.

Estimates of disease burden are important for setting public health priorities. These estimates involve numerous modeling assumptions, whose uncertainties are not always well described. We developed a framework for estimating the burden of yellow fever in Africa and evaluated its sensitivity to modeling assumptions that are often overlooked. We found that alternative interpretations of serological data resulted in a nearly 20-fold difference in burden estimates (range of central estimates, 8.4 × 104 to 1.5 × 106 deaths in 2021­2030). Uncertainty about the vaccination status of serological study participants was the primary driver of this uncertainty. Even so, statistical uncertainty was even greater than uncertainty due to modeling assumptions, accounting for a total of 87% of variance in burden estimates. Combined with estimates that most infections go unreported (range of 95% credible intervals, 99.65 to 99.99%), our results suggest that yellow fever's burden will remain highly uncertain without major improvements in surveillance.