Understanding the traits underlying vaccine-driven virulence evolution in malaria parasites.

Background: Vaccine-driven evolution can erode the beneficial effects of vaccination and is a concern, especially for newly introduced vaccines. While obvious candidates for vaccine-driven evolution are the precise parasite antigens that are the targets of vaccine-induced immunity, traits underlying parasite virulence may also evolve. Previous experimental work in rodent malaria demonstrated that evolution in vaccinated hosts resulted in increased parasite virulence, as measured by anemia (minimum red blood cell density). However, no genetic changes were detected at vaccine target sites, leaving the underlying traits or their interactions with host responses unclear. Using a hierarchical Bayesian framework, we fitted a mathematical model of within-host malaria infection dynamics to experimental time series data from infections in mice inoculated with parasites that had evolved in either vaccinated mice or sham-vaccinated (control) mice. We compared parameter estimates across treatments to understand which parasite traits could plausibly explain differences in infection dynamics and virulence.

Results: Vaccine-evolved parasites elicited lower targeted immune killing and anemia-driven erythropoiesis, differences that were observed at the level of treatment means and when accounting for individual-level variation. We validated our model by calculating early-infection parasite multiplication rates, finding no differences across treatments (either experimental or simulated)-differences that would be expected if the vaccine target antigen (AMA-1) had evolved.

Conclusions: Our results emphasize the complexity of virulence, showing that parasite modulation of host responses can influence disease severity. We also highlight the important role for evolution of parasite traits beyond target antigens in response to vaccination.