Superinfection and the hypnozoite reservoir for Plasmodium vivax: a general framework

Abstract

A characteristic of malaria in all its forms is the potential for superinfection (that is, multiple concurrent blood-stage infections). An additional characteristic of Plasmodium vivax malaria is a reservoir of latent parasites (hypnozoites) within the host liver, which activate to cause (blood-stage) relapses. Here, we present a model of hypnozoite accrual and superinfection for P. vivax. To couple host and vector dynamics for a homogeneously-mixing population, we construct a density-dependent Markov population process with countably many types, for which disease extinction is shown to occur almost surely. We also establish a functional law of large numbers, taking the form of an infinite-dimensional system of ordinary differential equations that can also be recovered by coupling expected host and vector dynamics (i.e. a hybrid approximation) or through a standard compartment modelling approach. Recognising that the subset of these equations that model the infection status of the human hosts has precisely the same form as the Kolmogorov forward equations for a Markovian network of infinite server queues with an inhomogeneous batch arrival process, we use physical insight into the evolution of the latter process to write down a time-dependent multivariate generating function for the solution. We use this characterisation to collapse the infinite-compartment model into a single integrodifferential equation (IDE) governing the intensity of mosquito-to-human transmission. Through a steady state analysis, we recover a threshold phenomenon for this IDE in terms of a parameter $$R_0$$ R 0 expressible in terms of the primitives of the model, with the disease-free equilibrium shown to be uniformly asymptotically stable if $$R_0<1$$ R 0 < 1 and an endemic equilibrium solution emerging if $$R_0>1$$ R 0 > 1 . Our work provides a theoretical basis to explore the epidemiology of P. vivax, and introduces a strategy for constructing tractable population-level models of malarial superinfection that can be generalised to allow for greater biological realism in a number of directions.

A hybrid transmission model for Plasmodium vivax accounting for superinfection, immunity and the hypnozoite reservoir

“…In Mehra et al. ( 2023 ), for a simpler model structure—accounting only for superinfection and short-latency hypnozoite accrual—we began by constructing a Markov population process (with countably many types) to couple host and vector dynamics. Using the work of Barbour and Luczak ( 2012 ), we then recovered a deterministic (infinite) compartmental model as a functional law of large numbers; that is, we showed that the sample paths of the Markov process converged to a deterministic sample path in the infinite population size limit, when the number of mosquitoes per human was held fixed.…”

“…In Mehra et al. ( 2023 ), we have recently proposed a transmission model for P. vivax that explicitly accounts for superinfection and (short-latency) hypnozoite accrual; both hypnozoite density and the multiplicity of blood-stage infection are specifically included in the state space. Under the deterministic model derived in Mehra et al.…”

“…Under the deterministic model derived in Mehra et al. ( 2023 ), we can recover population-level distributions for various quantities of epidemiological interest without encountering the computational overheads that have curtailed previous efforts to model explicit hypnozoite densities (White 2018a ). The conceptual underpinning of the model detailed in Mehra et al.…”

“…The conceptual underpinning of the model detailed in Mehra et al. ( 2023 ) is the within-host framework we introduced in Mehra et al. ( 2022 ), which captures hypnozoite and superinfection dynamics as a function of mosquito-to-human transmission intensity, or the force of reinfection (FORI), in a general transmission setting.…”

“…In the present paper, we adopt an analogous mathematical construction to Mehra et al. ( 2023 ), extending our previous work to allow for long-latency (temperate) strains and the acquisition of transmission-blocking and antidisease immunity.…”