The evolution of viruses to escape prevailing host immunity involves selection at multiple integrative scales, from within-host viral and immune kinetics to the host population level. In order to understand how viral immune escape occurs, we develop an analytical framework that links the dynamical nature of immunity and viral variation across these scales. Our epidemiological model incorporates within-host viral evolutionary dynamics for a virus that causes acute infections (e.g. influenza and norovirus) with changes in host immunity in response to genetic changes in the virus population. We use a deterministic description of the within-host replication dynamics of the virus, the pool of susceptible host cells and the host adaptive immune response. We find that viral immune escape is most effective at intermediate values of immune strength. At very low levels of immunity, selection is too weak to drive immune escape in recovered hosts, while very high levels of immunity impose such strong selection that viral subpopulations go extinct before acquiring enough genetic diversity to escape host immunity. This result echoes the predictions of simpler models, but our formulation allows us to dissect the combination of within-host and transmission-level processes that drive immune escape.

Background

Leptospirosis is a zoonotic disease infecting a broad range of mammalian hosts, and is re-emerging globally. California sea lions (Zalophus californianus) have experienced recurrent outbreaks of leptospirosis since 1970, but it is unknown whether the pathogen persists in the sea lion population or is introduced repeatedly from external reservoirs.

Methods

We analyzed serum samples collected over an 11-year period from 1344 California sea lions that stranded alive on the California coast, using the microscopic agglutination test (MAT) for antibodies to Leptospira interrogans serovar Pomona. We evaluated seroprevalence among yearlings as a measure of incidence in the population, and characterized antibody persistence times based on temporal changes in the distribution of titer scores. We conducted multinomial logistic regression to determine individual risk factors for seropositivity with high and low titers.

Results

The serosurvey revealed cyclical patterns in seroprevalence to L. interrogans serovar Pomona, with 4-5 year periodicity and peak seroprevalence above 50%. Seroprevalence in yearling sea lions was an accurate index of exposure among all age classses, and indicated on-going exposure to leptospires in non-outbreak years. Analysis of titer decay rates showed that some individuals probably maintain high titers for more than a year following exposure.

Conclusion

This study presents results of an unprecedented long-term serosurveillance program in marine mammals. Our results suggest that leptospirosis is endemic in California sea lions, but also causes periodic epidemics of acute disease. The findings call into question the classical dichotomy between maintenance hosts of leptospirosis, which experience chronic but largely asymptomatic infections, and accidental hosts, which suffer acute illness or death as a result of disease spillover from reservoir species.

A key question for infectious disease dynamics is the impact of the climate on future burden. Here, we evaluate the climate drivers of respiratory syncytial virus (RSV), an important determinant of disease in young children. We combine a dataset of county-level observations from the US with state-level observations from Mexico, spanning much of the global range of climatological conditions. Using a combination of nonlinear epidemic models with statistical techniques, we find consistent patterns of climate drivers at a continental scale explaining latitudinal differences in the dynamics and timing of local epidemics. Strikingly, estimated effects of precipitation and humidity on transmission mirror prior results for influenza. We couple our model with projections for future climate, to show that temperature-driven increases to humidity may lead to a northward shift in the dynamic patterns observed and that the likelihood of severe outbreaks of RSV hinges on projections for extreme rainfall.

Heterogeneity in transmission is a challenge for infectious disease dynamics and control. An 80-20 "Pareto" rule has been proposed to describe this heterogeneity whereby 80% of transmission is accounted for by 20% of individuals, herein called super-spreaders. It is unclear, however, whether super-spreading can be attributed to certain individuals or whether it is an unpredictable and unavoidable feature of epidemics. Here, we investigate heterogeneous malaria transmission at three sites in Uganda and find that super-spreading is negatively correlated with overall malaria transmission intensity. Mosquito biting among humans is 90-10 at the lowest transmission intensities declining to less than 70-30 at the highest intensities. For super-spreaders, biting ranges from 70-30 down to 60-40. The difference, approximately half the total variance, is due to environmental stochasticity. Super-spreading is thus partly due to super-spreaders, but modest gains are expected from targeting super-spreaders.