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.

Local and regional dynamics of chikungunya virus transmission in Colombia: the role of mismatched spatial heterogeneity.

BACKGROUND: Mathematical models of transmission dynamics are routinely fitted to epidemiological time series, which must inevitably be aggregated at some spatial scale. Weekly case reports of chikungunya have been made available nationally for numerous countries in the Western Hemisphere since late 2013, and numerous models have made use of this data set for forecasting and inferential purposes. Motivated by an abundance of literature suggesting that the transmission of this mosquito-borne pathogen is localized at scales much finer than nationally, we fitted models at three different spatial scales to weekly case reports from Colombia to explore limitations of analyses of nationally aggregated time series data. METHODS: We adapted the recently developed Disease Transmission Kernel (DTK)-Dengue model for modeling chikungunya virus (CHIKV) transmission, given the numerous similarities of these viruses vectored by a common mosquito vector. We fitted versions of this model specified at different spatial scales to weekly case reports aggregated at different spatial scales: (1) single-patch national model fitted to national data; (2) single-patch departmental models fitted to departmental data; and (3) multi-patch departmental models fitted to departmental data, where the multiple patches refer to municipalities within a department. We compared the consistency of simulations from fitted models with empirical data. RESULTS: We found that model consistency with epidemic dynamics improved with increasing spatial granularity of the model. Specifically, the sum of single-patch departmental model fits better captured national-level temporal patterns than did a single-patch national model. Likewise, multi-patch departmental model fits better captured department-level temporal patterns than did single-patch departmental model fits. Furthermore, inferences about municipal-level incidence based on multi-patch departmental models fitted to department-level data were positively correlated with municipal-level data that were withheld from model fitting. CONCLUSIONS: Our model performed better when posed at finer spatial scales, due to better matching between human populations with locally relevant risk. Confronting spatially aggregated models with spatially aggregated data imposes a serious structural constraint on model behavior by averaging over epidemiologically meaningful spatial variation in drivers of transmission, impairing the ability of models to reproduce empirical patterns.

Temperature and population density determine reservoir regions of seasonal persistence in highland malaria.

A better understanding of malaria persistence in highly seasonal environments such as highlands and desert fringes requires identifying the factors behind the spatial reservoir of the pathogen in the low season. In these 'unstable' malaria regions, such reservoirs play a critical role by allowing persistence during the low transmission season and therefore, between seasonal outbreaks. In the highlands of East Africa, the most populated epidemic regions in Africa, temperature is expected to be intimately connected to where in space the disease is able to persist because of pronounced altitudinal gradients. Here, we explore other environmental and demographic factors that may contribute to malaria's highland reservoir. We use an extensive spatio-temporal dataset of confirmed monthly Plasmodium falciparum cases from 1995 to 2005 that finely resolves space in an Ethiopian highland. With a Bayesian approach for parameter estimation and a generalized linear mixed model that includes a spatially structured random effect, we demonstrate that population density is important to disease persistence during the low transmission season. This population effect is not accounted for in typical models for the transmission dynamics of the disease, but is consistent in part with a more complex functional form of the force of infection proposed by theory for vector-borne infections, only during the low season as we discuss. As malaria risk usually decreases in more urban environments with increased human densities, the opposite counterintuitive finding identifies novel control targets during the low transmission season in African highlands.

Expected endpoints from future chikungunya vaccine trial sites informed by serological data and modeling.

In recent decades, there has been an increased interest in developing a vaccine for chikungunya. However, due to its unpredictable transmission, planning for a chikungunya vaccine trial is challenging. To inform decision making on the selection of sites for a vaccine efficacy trial, we developed a new framework for projecting the expected number of endpoint events at a given site. In this framework, we first accounted for population immunity using serological data collated from a systematic review and used it to estimate parameters related to the timing and size of past outbreaks, as predicted by an SIR transmission model. Then, we used that model to project the infection attack rate of a hypothetical future outbreak, in the event that one were to occur at the time of a future trial. This informed projections of how many endpoint events could be expected if a trial were to take place at that site. Our results suggest that some sites may have sufficient transmission potential and susceptibility to support future vaccine trials, in the event that an outbreak were to occur at those sites. In general, we conclude that sites that have experienced outbreaks within the past 10 years may be poorer targets for chikungunya vaccine efficacy trials in the near future. Our framework also generates projections of the numbers of endpoint events by age, which could inform study participant recruitment efforts.

The New Astronomical Frontier of Interstellar Objects.

The upcoming commencement of the Vera C. Rubin Observatory's Legacy Survey of Space and Time (LSST) will greatly enhance the discovery rate of interstellar objects (ISOs). 'Oumuamua and Borisov were the first two ISOs confirmed in the Solar System, although the first interstellar meteor was detected earlier. We explore the intriguing mass budget of ejected planetesimals implied by the detections of 'Oumuamua and Borisov and explore the expected abundance of ISOs as a function of size in the solar neighborhood. Specifically, we find that a significant fraction of stellar mass must go toward producing ISOs and that ISOs outnumber Solar System objects in the Oort cloud. We consider signatures of ISOs colliding with Earth, the Moon, and neutron stars, as well as the possibility of differentiating ISOs from Solar System objects in stellar occultation surveys, and we show that these methods are observationally feasible. We introduce a test for dynamical anisotropy that is capable of determining the typical ejection speed of ISOs from their parent stars. Finally, we predict a new population of dynamically distinct ISOs originating from stars in the Galactic halo. One of the two branches of the newly established Galileo Project1 seeks to learn more about the nature of ISOs like 'Oumuamua by performing new searches and designing follow-up observations.

Risk factors for mortality among hospitalized COVID-19 patients in Northern Ethiopia: A retrospective analysis.

BACKGROUND: COVID-19 is a deadly pandemic caused by an RNA virus that belongs to the family of CORONA virus. To counter the COVID-19 pandemic in resource limited settings, it is essential to identify the risk factors of COVID-19 mortality. This study was conducted to identify the social and clinical determinants of mortality in COVID-19 patients hospitalized in four treatment centers of Tigray, Northern Ethiopia. METHODS: We reviewed data from 6,637 COVID-19 positive cases that were reported from May 7, 2020 to October 28, 2020. Among these, 925 were admitted to the treatment centers because of their severity and retrospectively analyzed. The data were entered into STATA 16 version for analysis. The descriptive analysis such as median, interquartile range, frequency distribution and percentage were used. Binary logistic regression model was fitted to identify the potential risk factors of mortality of COVID-19 patients. The adjusted odds ratio (AOR) with 95% confidence interval was used to determine the magnitude of the association between the outcome and predictor variables. RESULTS: The median age of the patients was 30 years (IQR, 25-44) and about 70% were male patients. The patients in the non-survivor group were much older than those in the survivor group (median 57.5 years versus 30 years, p-value < 0.001). The overall case fatality rate was 6.1% (95% CI: 4.5% - 7.6%) and was increased to 40.3% (95% CI: 32.2% - 48.4%) among patients with critical and severe illness. The proportions of severe and critical illness in the non-survivor group were significantly higher than those in the survivor group (19.6% versus 5.1% for severe illness and 80.4% versus 4.5% for critical illness, all p-value < 0.001). One or more pre-existing comorbidities were present in 12.5% of the patients: cardiovascular diseases (42.2%), diabetes mellitus (25.0%) and respiratory diseases (16.4%) being the most common comorbidities. The comorbidity rate in the non-survivor group (44.6%) was higher than in the survivor group (10.5%). The results from the multivariable binary regression showed that the odds of mortality was higher for patients who had cardiovascular diseases (AOR = 2.49, 95% CI: 1.03-6.03), shortness of breath (AOR = 9.71, 95% CI: 4.73-19.93) and body weakness (AOR = 3.04, 95% CI: 1.50-6.18). Moreover, the estimated odds of mortality significantly increased with patient's age. CONCLUSIONS: Age, cardiovascular diseases, shortness of breath and body weakness were the predictors for mortality of COVID-19 patients. Knowledge of these could lead to better identification of high risk COVID-19 patients and thus allow prioritization to prevent mortality.

Breakup of a long-period comet as the origin of the dinosaur extinction.

The origin of the Chicxulub impactor, which is attributed as the cause of the K/T mass extinction event, is an unsolved puzzle. The background impact rates of main-belt asteroids and long-period comets have been previously dismissed as being too low to explain the Chicxulub impact event. Here, we show that a fraction of long-period comets are tidally disrupted after passing close to the Sun, each producing a collection of smaller fragments that cross the orbit of Earth. This population could increase the impact rate of long-period comets capable of producing Chicxulub impact events by an order of magnitude. This new rate would be consistent with the age of the Chicxulub impact crater, thereby providing a satisfactory explanation for the origin of the impactor. Our hypothesis explains the composition of the largest confirmed impact crater in Earth's history as well as the largest one within the last million years. It predicts a larger proportion of impactors with carbonaceous chondritic compositions than would be expected from meteorite falls of main-belt asteroids.

Malaria trends in Ethiopian highlands track the 2000 'slowdown' in global warming.

A counterargument to the importance of climate change for malaria transmission has been that regions where an effect of warmer temperatures is expected, have experienced a marked decrease in seasonal epidemic size since the turn of the new century. This decline has been observed in the densely populated highlands of East Africa at the center of the earlier debate on causes of the pronounced increase in epidemic size from the 1970s to the 1990s. The turnaround of the incidence trend around 2000 is documented here with an extensive temporal record for malaria cases for both Plasmodium falciparum and Plasmodium vivax in an Ethiopian highland. With statistical analyses and a process-based transmission model, we show that this decline was driven by the transient slowdown in global warming and associated changes in climate variability, especially ENSO. Decadal changes in temperature and concurrent climate variability facilitated rather than opposed the effect of interventions.

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.

The impact of war on the health system of the Tigray region in Ethiopia: an assessment.

The war in Tigray region of Ethiopia that started in November 2020 and is still ongoing has brought enormous damage to the health system. This analysis provides an assessment of the health system before and during the war. Evidence of damage was compiled from November 2020 to June 2021 from various reports by the interim government of Tigray, and also by international non-governmental organisations. Comparison was made with data from the prewar calendar year. Six months into the war, only 30% of hospitals, 17% of health centres, 11.5% of ambulances and none of the 712 health posts were functional. As of June 2021, the population in need of emergency food assistance in Tigray increased from less than one million to over 5.2 million. While the prewar performance of antenatal care, supervised delivery, postnatal care and children vaccination was 64%, 73%, 63% and 73%, respectively, but none of the services were likely to be delivered in the first 90 days of the war. A conservative estimate places the number of girls and women raped in the first 5 months of the war to be 10 000. These data indicate a widespread destruction of livelihoods and a collapse of the healthcare system. The use of hunger and rape as a weapon of war and the targeting of healthcare facilities are key components of the war. To avert worsening conditions, an immediate intervention is needed to deliver food and supplies and rehabilitate the healthcare delivery system and infrastructure.

Trade-offs between individual and ensemble forecasts of an emerging infectious disease.

Probabilistic forecasts play an indispensable role in answering questions about the spread of newly emerged pathogens. However, uncertainties about the epidemiology of emerging pathogens can make it difficult to choose among alternative model structures and assumptions. To assess the potential for uncertainties about emerging pathogens to affect forecasts of their spread, we evaluated the performance 16 forecasting models in the context of the 2015-2016 Zika epidemic in Colombia. Each model featured a different combination of assumptions about human mobility, spatiotemporal variation in transmission potential, and the number of virus introductions. We found that which model assumptions had the most ensemble weight changed through time. We additionally identified a trade-off whereby some individual models outperformed ensemble models early in the epidemic, but on average the ensembles outperformed all individual models. Our results suggest that multiple models spanning uncertainty across alternative assumptions are necessary to obtain robust forecasts for emerging infectious diseases.

Possible Transfer of Life by Earth-Grazing Objects to Exoplanetary Systems.

Recently, a 30-cm object was discovered to graze the Earth's atmosphere and shift into a Jupiter-crossing orbit. We use the related survey parameters to calibrate the total number of such objects. The number of objects that could have exported terrestrial microbes out of the Solar System is in the range 2 × 10 9 - 3 × 10 11 . We find that 10 7 - 10 9 such objects could have been captured by binary star systems over the lifetime of the Solar System. Adopting the fiducial assumption that one polyextremophile colony is picked up by each object, the total number of objects carrying living colonies on them upon capture could be 10- 10 3 .

Modeling human migration across spatial scales in Colombia.

Human mobility, both short and long term, are important considerations in the study of numerous systems. Economic and technological advances have led to a more interconnected global community, further increasing the need for considerations of human mobility. While data on human mobility are better recorded in many developed countries, availability of such data remains limited in many low- and middle-income countries around the world, particularly at the fine temporal and spatial scales required by many applications. In this study, we used 5-year census-based internal migration microdata for 32 departments in Colombia (i.e., Admin-1 level) to develop a novel spatial interaction modeling approach for estimating migration, at a finer spatial scale, among the 1,122 municipalities in the country (i.e., Admin-2 level). Our modeling approach addresses a significant lack of migration data at administrative unit levels finer than those at which migration data are typically recorded. Due to the widespread availability of census-based migration microdata at the Admin-1 level, our modeling approach opens up for the possibilities of modeling migration patterns at Admin-2 and Admin-3 levels across many other countries where such data are currently lacking.

Leveraging multiple data types to estimate the size of the Zika epidemic in the Americas.

Several hundred thousand Zika cases have been reported across the Americas since 2015. Incidence of infection was likely much higher, however, due to a high frequency of asymptomatic infection and other challenges that surveillance systems faced. Using a hierarchical Bayesian model with empirically-informed priors, we leveraged multiple types of Zika case data from 15 countries to estimate subnational reporting probabilities and infection attack rates (IARs). Zika IAR estimates ranged from 0.084 (95% CrI: 0.067-0.096) in Peru to 0.361 (95% CrI: 0.214-0.514) in Ecuador, with significant subnational variability in every country. Totaling infection estimates across these and 33 other countries and territories, our results suggest that 132.3 million (95% CrI: 111.3-170.2 million) people in the Americas had been infected by the end of 2018. These estimates represent the most extensive attempt to determine the size of the Zika epidemic in the Americas, offering a baseline for assessing the risk of future Zika epidemics in this region.

Early estimates of COVID-19 infections in small, medium and large population clusters.

INTRODUCTION: Since its emergence in late December 2019, COVID-19 has rapidly developed into a pandemic in mid of March with many countries suffering heavy human loss and declaring emergency conditions to contain its spread. The impact of the disease, while it has been relatively low in the sub-Saharan Africa (SSA) as of May 2020, is feared to be potentially devastating given the less developed and fragmented healthcare system in the continent. In addition, most emergency measures practised may not be effective due to their limited affordability as well as the communal way people in SSA live in relative isolation in clusters of large as well as smaller population centres. METHODS: To address the acute need for estimates of the potential impacts of the disease once it sweeps through the African region, we developed a process-based model with key parameters obtained from recent studies, taking local context into consideration. We further used the model to estimate the number of infections within a year of sustained local transmissions under scenarios that cover different population sizes, urban status, effectiveness and coverage of social distancing, contact tracing and usage of cloth face mask. RESULTS: We showed that when implemented early, 50% coverage of contact tracing and face mask, with 33% effective social distancing policies can bringing the epidemic to a manageable level for all population sizes and settings we assessed. Relaxing of social distancing in urban settings from 33% to 25% could be matched by introduction and maintenance of face mask use at 43%. CONCLUSIONS: In SSA countries with limited healthcare workforce, hospital resources and intensive care units, a robust system of social distancing, contact tracing and face mask use could yield in outcomes that prevent several millions of infections and thousands of deaths across the continent.

Heterogeneous local dynamics revealed by classification analysis of spatially disaggregated time series data.

Time series data provide a crucial window into infectious disease dynamics, yet their utility is often limited by the spatially aggregated form in which they are presented. When working with time series data, violating the implicit assumption of homogeneous dynamics below the scale of spatial aggregation could bias inferences about underlying processes. We tested this assumption in the context of the 2015-2016 Zika epidemic in Colombia, where time series of weekly case reports were available at national, departmental, and municipal scales. First, we performed a descriptive analysis, which showed that the timing of departmental-level epidemic peaks varied by three months and that departmental-level estimates of the time-varying reproduction number, R(t), showed patterns that were distinct from a national-level estimate. Second, we applied a classification algorithm to six features of proportional cumulative incidence curves, which showed that variability in epidemic duration, the length of the epidemic tail, and consistency with a cumulative normal density curve made the greatest contributions to distinguishing groups. Third, we applied this classification algorithm to data simulated with a stochastic transmission model, which showed that group assignments were consistent with simulated differences in the basic reproduction number, R0. This result, along with associations between spatial drivers of transmission and group assignments based on observed data, suggests that the classification algorithm is capable of detecting differences in temporal patterns that are associated with differences in underlying drivers of incidence patterns. Overall, this diversity of temporal patterns at local scales underscores the value of spatially disaggregated time series data.

Inter-annual variation in seasonal dengue epidemics driven by multiple interacting factors in Guangzhou, China.

Vector-borne diseases display wide inter-annual variation in seasonal epidemic size due to their complex dependence on temporally variable environmental conditions and other factors. In 2014, Guangzhou, China experienced its worst dengue epidemic on record, with incidence exceeding the historical average by two orders of magnitude. To disentangle contributions from multiple factors to inter-annual variation in epidemic size, we fitted a semi-mechanistic model to time series data from 2005-2015 and performed a series of factorial simulation experiments in which seasonal epidemics were simulated under all combinations of year-specific patterns of four time-varying factors: imported cases, mosquito density, temperature, and residual variation in local conditions not explicitly represented in the model. Our results indicate that while epidemics in most years were limited by unfavorable conditions with respect to one or more factors, the epidemic in 2014 was made possible by the combination of favorable conditions for all factors considered in our analysis.

Spatiotemporal incidence of Zika and associated environmental drivers for the 2015-2016 epidemic in Colombia.

Despite a long history of mosquito-borne virus epidemics in the Americas, the impact of the Zika virus (ZIKV) epidemic of 2015-2016 was unexpected. The need for scientifically informed decision-making is driving research to understand the emergence and spread of ZIKV. To support that research, we assembled a data set of key covariates for modeling ZIKV transmission dynamics in Colombia, where ZIKV transmission was widespread and the government made incidence data publically available. On a weekly basis between January 1, 2014 and October 1, 2016 at three administrative levels, we collated spatiotemporal Zika incidence data, nine environmental variables, and demographic data into a single downloadable database. These new datasets and those we identified, processed, and assembled at comparable spatial and temporal resolutions will save future researchers considerable time and effort in performing these data processing steps, enabling them to focus instead on extracting epidemiological insights from this important data set. Similar approaches could prove useful for filling data gaps to enable epidemiological analyses of future disease emergence events.

Assessing the population at risk of Zika virus in Asia - is the emergency really over?

On November 18, 2016, the WHO ended its designation of the Zika virus (ZIKV) epidemic as a Public Health Emergency of International Concern (PHEIC). At the same time, ZIKV transmission continues in Asia, with the number of Asian countries reporting Zika cases increasing over the last 2 years. Applying a method that combines epidemiological theory with data on epidemic size and drivers of transmission, we characterised the population at risk of ZIKV infection from Aedes aegypti mosquitoes in 15 countries in Asia. Projections made under the assumption of no pre-existing immunity suggest that up to 785 (range: 730-992) million people in Asia would be at risk of ZIKV infection under that scenario. Assuming that 20% of ZIKV infections are symptomatic, this implies an upper limit of 146-198 million for the population at risk of a clinical episode of Zika. Due to limited information about pre-existing immunity to ZIKV in the region, we were unable to make specific numerical projections under a more realistic assumption about pre-existing immunity. Even so, combining numerical projections under an assumption of no pre-existing immunity together with theoretical insights about the extent to which pre-existing immunity may lower epidemic size, our results suggest that the population at risk of ZIKV infection in Asia could be even larger than in the Americas. As a result, we conclude that the WHO's removal of the PHEIC designation should not be interpreted as an indication that the threat posed by ZIKV has subsided.