UC Davis

Rabies is a fatal zoonotic neurotropic viral disease estimated to cause nearly 60,000 deathsworldwide each year. Most of these deaths occur in developing nations in Asia and Africa where the virus is maintained in free-roaming dog populations. Some wild carnivore species such as raccoon-dogs and foxes can also be viral reservoirs. Rabies is most-commonly transmitted through a bite and all mammals are susceptible to it. The virus slowly transits from the bite location to the central nervous system where it replicates. After a long incubation, rabies symptoms are typified by neurological disorders and eventual organ failure and death. Although rabies is fatal once symptoms set in, postexposure prophylaxis is highly effective at preventing disease from happening if administered prior to symptom start. Furthermore, mass canine vaccination is a proven tool to control rabies at its source and is considered to most cost-effective way to control the disease in dogs and prevent it in humans. Unfortunately, in countries where rabies is endemic, application of these prevention and control tools is often underwhelming due to limited resources and knowledge to apply them in the comprehensive and sustained way that is necessary to achieve full control. This means PEP accessibility is often limited or too costly for bite victims and vaccination campaigns are not sustained enough to fully control disease in the reservoir. Furthermore, due to the lack of accessibility to care for victims, rabies is often underreported and so does not feature as a key priority in many areas. Thus, epidemiological studies are key to provide knowledge that will both provide evidence of rabies burden and help strategize allocation of limited resources for intervention. In recent years, under the guidance of WHO and OIE there has been a push in many countries to achieve canine rabies eradication by 2030. Cambodia is a nation in Southeast Asia with a human population of 15 million and an estimated dog population of five million. The majority of dogs in Cambodia are owned but allowed to roam freely and are poorly vaccinated. Cambodia is endemic with rabies and has one of the highest mortality rates from the disease worldwide. The main institution in charge of rabies prevention and surveillance in Cambodia is the Pasteur Institute of Cambodia (IPC). Since it’s opening in 1995 it has provided postexposure prophylaxis to bite victim, collected information on bite attack victims and tested animals, the majority of which were dogs, for rabies, providing passive surveillance on rabies. Until 2018, IPC only had one institution in Phnom Penh, meaning access to PEP and surveillance was limited, with most patients and tested animals coming from Phnom Penh and its surroundings. Furthermore, there is no program for widespread canine vaccination in Cambodia with prevention relying solely on PEP. Nevertheless, to meet eradication targets, Cambodia has been expanding control and prevention in recent years. Two new PEP centers have opened in rural provinces in 2018 and 2019. Pilot vaccination studies have also been conducted to help inform future campaigns. Epidemiological studies could help guide future opening of PEP centers and vaccination campaigns in the years to come. These are the goals of the following three chapters. The first chapter investigated the impact of physical accessibility to PEP centers on the rate of PEP patients in the population using Bayesian Poisson regression. The model used geographical accessibility data in the form of travel time to a center or a provincial capital and demographic data in the form of urban proportion of the population as predictors of PEP numbers and rates. Regression models were then used to test PEP expansion scenarios where we measured the impact of opening new centers in specific locations. From 2000 to 2016, 294,000 patients presented to IPC for PEP. The majority of these were in Phnom Penh and the neighboring province of Kandal. We observed strong evidence that travel time to a PEP center had a negative association with PEP rate, with an increase in one hour leading to a PEP rate reduction of 70% to 80%. We identified five provincial capitals in which the opening of a new center would maximize PEP access: Banteay Meanchey, Siem Reap, Takeo, Kampot, and Svay Rieng. Adding a center in every provincial capital would increase the number of people living within 60 minutes of a PEP center from 27% to 65%. The second chapter investigated predictors of rabies positive tests in biting animals. We used patient interview information on the patient, the biting animal and the attack collected by IPC doctors during the first consultation as predictor variables in a Bayesian spatio-temporal logistic regression. From 2000 to 2016, 1.5% (2,500) of PEP patients brought the head of the biting animal for testing. Tested animals, as patients, mostly from Phnom Penh and nearby provinces though not as centrally distributed as PEP patients were. Of the tested animals, 60% tested positive for rabies using direct fluorescent antibody test. A number of variables were predictive of a positive test, notably if a dog was not owned, if the attack was unprovoked and if there was a large number of victims. However, the most predictive variable was a disease suspicion variable assigned by IPC doctors based on behavior and symptoms descriptions from the patient, showing IPC has a strong protocol to identify rabies suspect animals. Finally, we identified three provinces at higher risk of returning positive tests: Kandal, Kampong Cham and Kampong Thom. The third chapter used data collected in the pilot vaccination campaign to build a spatially explicit rabies transmission agent-based model to help study the impact of demographic turnover on vaccination coverage, and the level of vaccination required to prevent rabies spread. The model was conducted at a small spatial scale in five villages of Kandal province. We characterized the contact probabilities within a 100m infection radius that led to basic reproduction number (R0) values within the range of 1 and 2, where most estimates from field observational and mathematical modelling studies lie. Within this range, 70% target vaccination coverage annually was sufficient in all cases to reduce R0 to below one, which theoretically stops disease spread. However, we observed large outbreaks where still possible in up to 8% of simulations with this coverage, in the worst-case infection scenario, and a 90% target vaccination coverage was necessary to reduce these to below 1%. We also observed that one year after vaccination occurred, coverage had reduced by 40% with rapid population turnover, showing the need for sustained annual vaccination to maintain high levels of immunity over time. Through these three chapters, we provide information that could help guide where rabies risk and needs are the greatest in Cambodia, to inform future PEP center opening. We also provide information on the effectiveness of vaccination and the need for vaccination to be sustained over time to be effect