Biology subjects

Jit, M.

Publications and source records attributed to Jit, M..

4 recordsLinked to original sources

bioRxiv2019

Within-host competition determines vaccine impact on antibiotic resistance

Bacterial vaccines can protect recipients from contracting potentially antibiotic-resistant infections. But by altering the selective balance between sensitive and resistant strains, vaccines may also suppress--or spread--antibiotic resistance among unvaccinated individuals. Predicting the outcome requires knowing what drives selection for resistance in bacterial pathogens, and in particular, what maintains the circulation of both antibiotic-sensitive and resistant strains of bacteria. Using mathematical modelling, we show that the frequency of penicillin resistance in Streptococcus pneumoniae (pneumococcus) across 27 European countries can be explained by between-host diversity in antibiotic use, heritable diversity in pneumococcal carriage duration, or frequency-dependent selection brought about by within-host competition between resistant and sensitive strains. We use our calibrated models to predict the impact of non-serotype-specific pneumococcal vaccination upon the prevalence of carriage, incidence of disease, and frequency of resistance for S. pneumoniae. We find that the relative strength and directionality of competition between resistant and sensitive pneumococcal strains is the most important determinant of whether vaccination promotes, inhibits, or has little effect upon the evolution of antibiotic resistance. Finally, we show that country-specific differences in pathogen transmission substantially alter the predicted impact of vaccination, highlighting that policies for managing resistance with vaccines must be tailored to a specific pathogen and setting. One sentence summaryFrequency-dependent competition and extrinsically-maintained diversity shape selection for antibiotic resistance following vaccination.

evolutionary biology↗

bioRxiv2018

Approximating instantaneous vaccine efficacy from cumulative vaccine efficacy

Few methods exist to estimate vaccine efficacy and its decay following immunisation. Existing methods are largely based on survival analyses such as Poisson or Cox-regression, applied to individual-level data from randomised placebo-controlled trials (RCTs), however, such are often not easily available for analysing pooling evidence across trials. Hence, cumulative vaccine efficacy (VE), the commonly reported endpoint, is implicitly assumed a reasonable proxy for the instantaneous vaccine efficacy (iVE). This assumption is violated if the relative risk (RR) of vaccinated vs unvaccinated is not constant over time, i.e. if vaccine efficacy changes after immunisation. We propose a method to overcome this issue. We use estimates of VE stratified by time since completed immunisation, and estimate time-dependent iVE. We validate the method against simulated data for two forms of vaccine protection: all-or-nothing protection and leaky protection. We illustrate how VE estimates are biased by time-dependent effects in the baseline force of infection and in iVE. Our proposed method improves upon available iVE estimation techniques, particularly if the vaccine induced leaky-like protection and the disease outcome is rare.

epidemiology↗

bioRxiv2017

Within-host dynamics explain the coexistence of antibiotic-sensitive and resistant bacteria

The spread of antibiotic resistance, a major threat to human health, is poorly understood. Empirically, resistant strains gradually increase in prevalence as antibiotic consumption increases, but current mathematical models predict a sharp transition between full sensitivity and full resistance. In other words, we do not understand what drives persistent coexistence between resistant and sensitive strains of disease-causing bacteria in host populations. Without knowing what drives patterns of resistance, we cannot accurately predict the impact of potential strategies for managing resistance. Here, we show that within-host dynamics--bacterial growth, strain competition, and host immune responses--promote frequency-dependent selection for resistant strains, explaining patterns of resistance at the population level. By capturing these processes in a parsimonious mathematical framework, we resolve a long-standing conflict between theory and observation. Our models capture widespread coexistence for multiple bacteria-drug combinations across 30 European countries and explain associations between carriage prevalence and resistance prevalence among bacterial subtypes. A mechanistic understanding of resistance evolution is needed to accurately forecast the impact and effectiveness of resistance-management strategies.

epidemiology↗

bioRxiv2017

Target immunity levels for achieving and maintaining measles elimination

BackgroundVaccination has reduced the global incidence of measles to the lowest rates in history. However, local interruption of measles virus transmission requires sustained high levels of population immunity that can be challenging to achieve and maintain. The herd immunity threshold for measles is typically stipulated at 90-95%. This figure does not easily translate into age-specific immunity levels required to interrupt transmission. Previous estimates of such levels were based on speculative contact patterns based on historical data from high-income countries. The aim of this study was to determine age-specific immunity levels that would ensure elimination of measles when taking into account empirically observed contact patterns.\n\nMethodsWe combined estimated immunity levels from serological data in 17 countries with studies of age-specific mixing patterns to derive contact-adjusted immunity levels. We then compared these to case data from the 10 years following the seroprevalence studies to establish a contact-adjusted immunity threshold for elimination. We lastly combined a range of hypothetical immunity profiles with contact data from a wide range of socioeconomic and demographic settings to determine whether they would be sufficient for elimination.\n\nResultsWe found that contact-adjusted immunity levels were able to predict whether countries would experience outbreaks in the decade following the serological studies in about 70% of countries. The corresponding threshold level of contact-adjusted immunity was found to be 93%, corresponding to an average basic reproduction number of approximately 14. Testing different scenarios of immunity with this threshold level using contact studies from around the world, we found that 95% immunity would have to be achieved by the age of five and maintained across older age groups to guarantee elimination. This reflects a greater level of immunity required in 5-9 year olds than established previously.\n\nConclusionsThe immunity levels we found necessary for measles elimination are higher than previous guidance. The importance of achieving high immunity levels in 5-9 year olds presents both a challenge and an opportunity. While such high levels can be difficult to achieve, school entry provides an opportunity to ensure sufficient vaccination coverage. Combined with observations of contact patterns, further national and sub-national serological studies could serve to highlight key gaps in immunity that need to be filled in order to achieve national and regional measles elimination.

epidemiology↗