Individual variation in Plasmodium vivax malaria risk: Are repeatedly infected people just unlucky?

Abstract

Extensive research has examined why some people have frequent Plasmodium falciparum malaria episodes in sub-Saharan Africa while others remain free of disease most of the time. In contrast, malaria risk heterogeneity remains little studied in regions where P. vivax is the dominant species. Are repeatedly infected people in vivax malaria settings such as the Amazon just unlucky? Here, we briefly review evidence that human genetic polymorphism and acquired immunity after repeated exposure to parasites can modulate the risk of P. vivax infection and disease in predictable ways. One-fifth of the hosts account for 80% or more of the community-wide vivax malaria burden and contribute disproportionally to onward transmission, representing a priority target of more intensive interventions to achieve malaria elimination. Importantly, high-risk individuals eventually develop clinical immunity, even in areas with very low or residual malaria transmission, and may constitute a large but silent parasite reservoir.

Fig 1. Zero-inflated negative binomial model (purple bars) fitted to overdispersed malaria episode counts per person (dots) over 33 months of follow-up in a population-based cohort in the Amazon Basin of Brazil.

Counts of P. falciparum and P. vivax infections are combined (mean, 0.62 episodes; variance, 1.4). The not-at-risk (green bar segment) and highest-risk (orange arrow) fractions of the population are indicated. Redrawn from [2].

Fig 2. How blood-stage parasite density relates to the risk of clinical manifestations and human-to-mosquito transmission of Plasmodium vivax.

(A) Distribution of parasite densities measured by quantitative PCR in symptomatic (“Symp”) and asymptomatic (“Asymp”) P. vivax infections. (B) Association between P. vivax blood-stage density and the risk of clinical symptoms (fever or headache) within 7 days prior to detection of blood-stage infection, with >50% of the individuals being symptomatic above 1,100 parasites/μL. (C) Association between total P. vivax blood-stage density and the probability of Anopheles darlingi infection in standard membrane feeding assays, with 50% of the mosquitoes being infected at approximately 2,000 parasites/μL, assuming that 15% of circulating parasites are mature gametocytes. (D) Relative infectiousness of infected individuals in the community. We combine individual estimates of relative infectiousness of P. vivax carriers in the community. Most infected people are little infectious (relative infectiousness close to zero), but the top 20% spreaders are estimated to account for nearly 80% of all transmission events. Data from a farming settlement in the Amazon Basin of Brazil [63]. Figures redrawn from [59].

Fig 3. Transmission dynamics of Plasmodium vivax in a heterogeneous population.

(A) SIS-type model used to describe the dynamics of symptomatic and asymptomatic Plasmodium vivax infections across age groups in LR and HR individuals. Compartment S_i,j represents susceptible but uninfected individuals from risk group j who have experienced i prior clinical malaria. At birth, individuals are allocated to compartment S_0,j. Compartment I_i,j represents individuals from risk group j currently experiencing their i^th clinical vivax malaria episode Finally, compartment A_i,j represents individuals from risk group j with i past clinical malaria episodes who are currently experiencing an asymptomatic P. vivax infection. The next panels show the dynamics of the following: (B) Susceptible but uninfected LR individuals; (C) Infected and symptomatic LR individuals; (D) Infected and asymptomatic LR individuals; (E) Susceptible but uninfected HR individuals; (F) Infected and symptomatic HR individuals; and (F) Infected and asymptomatic HR individuals. Redrawn from [68]. HR, high-risk; LR, low-risk; SIS, susceptible-infected-susceptible.