Epidemiological consequences of enduring strain-specific immunity requiring repeated episodes of infection

Abstract

Group A Streptococcus (GAS) skin infections are caused by a diverse array of strain types and are highly prevalent in disadvantaged populations. The role of strain-specific immunity in preventing GAS infections is poorly understood, representing a critical knowledge gap in vaccine development. A recent GAS murine challenge study showed evidence that sterilising strain-specific and enduring immunity required two skin infections by the same GAS strain within three weeks. This mechanism of developing enduring immunity may be a significant impediment to the accumulation of immunity in populations. We used an agent-based mathematical model of GAS transmission to investigate the epidemiological consequences of enduring strain-specific immunity developing only after two infections with the same strain within a specified interval. Accounting for uncertainty when correlating murine timeframes to humans, we varied this maximum inter-infection interval from 3 to 420 weeks to assess its impact on prevalence and strain diversity, and considered additional scenarios where no maximum inter-infection interval was specified. Model outputs were compared with longitudinal GAS surveillance observations from northern Australia, a region with endemic infection. We also assessed the likely impact of a targeted strain-specific multivalent vaccine in this context. Our model produced patterns of transmission consistent with observations when the maximum inter-infection interval for developing enduring immunity was 19 weeks. Our vaccine analysis suggests that the leading multivalent GAS vaccine may have limited impact on the prevalence of GAS in populations in northern Australia if strain-specific PLOS COMPUTATIONAL BIOLOGY

Global and local epidemiology of Group A Streptococcus indicates that naturally-acquired immunity is enduring and strain-specific

“…Our agent-based model allowed us to compare three alternate hypotheses for the immune response to GAS infection: an SIR-type response [18] (where one infection leads to permanent immunity), an SIRS-type response [19] (where one infection leads to temporary immunity), and an SIS-type response (where infection does not lead to protective immunity). We used a previously proposed model to explore a fourth hypothesis for the immune response: an SIRIRtype response [8,9] (where enduring immunity requires two skin infections by the same GAS strain within a short-time frame). We conducted in silico experiments to identify infection-and immune-parameter regions in both models where changes to population-specific parameters, specifically, the basic reproduction number R 0 and population size N , were sufficient to explain global epidemiological trends of GAS.…”

“…S7C). The analogous parameter exploration was then repeated using the SIRIR-type model described in [9], which assumes that lasting strain-specific immunity to GAS requires two infections by the same strain within a specific time interval, the so-called inter-infection interval, w. In this analysis, scenario sets (within which R 0 and N were varied, as above) were characterised by a specific value of the inter-infection interval (3 or 19 weeks, which were determined to be possible values in [9]) and level of resistance to co-infection (x ∈ {10, 100}). Both the mean endemic D(t) and P (t) were insensitive to changes in R 0 (as well as x and w), but both were found to be increasing functions of N (SI Appendix, Fig.…”

“…A murine challenge study showed evidence that sterilising strain-specific and enduring immunity requires two skin infections by the same GAS strain within a short-time frame [8]. Although this model of immune development has not been directly assessed in humans, we have previously shown that it can lead to patterns of transmission that are consistent with GAS epidemiology in at least one hyper-endemic population [9].…”

“…Although there is currently no consensus on the immune response to GAS infection, it is likely contributing to the observed relationship between disease prevalence, strain diversity and population context. Mathematical modelling studies of other multi-strain infectious disease systems have provided valuable insight into how the strain-specific immune response relates to epidemiology, particularly strain diversity [9,18,23,24]. However, existing models have not addressed the interaction between immunity, diversity, prevalence and population context.…”

“…Here, the number of observed infections of each strain (emm sequence type) is shown for each month of the study. (C) Candidate models of the immune response to GAS infection with respect to a single strain -of SIRIR-type (enduring strain-specific immunity requires two infections by the same strain in quick succession [8,9]), SIR-type (one infection leads to enduring immunity [18]), SIRS-type (one infection leads to temporary immunity [19]), and SIS-type (infection does not lead to immunity). the characteristics of the immune response that underlie the marked variation in GAS epidemiology across different population settings remain unknown.…”