Stronger defense: symptomatic malaria provides durable protection against reinfection

In a recent study published in the PLOS Pathogens Journal, researchers evaluated the immune protection conferred by symptomatic and asymptomatic Plasmodium falciparum (P. falciparum) infections against reinfection.

Study: Symptomatic malaria enhances protection from reinfection with homologous Plasmodium falciparum parasites. Image Credit: JarunOntakrai/Shutterstock.com

Background

The slow rise in naturally developed immunity (NAI) in malaria contributes to global mortality. Because of short-lived immunological responses and Plasmodium falciparum antigenic diversity, NAI provides durable protection against severe P. falciparum infections but does not prevent symptomatic malaria.

It is critical to uncover strong phenotypes of learned protection among naturally exposed individuals to improve vaccine development.

Capturing identical reinfection events and assessing their relationships with host and parasite variables can shed light on anti-parasite immunological memory induction mechanisms.

About the study

In the present community-based, longitudinal study, researchers evaluated the chances of reinfection following symptomatic and asymptomatic P. falciparum infections in Kenya.

The team explored how exposure to different sequences among high-risk regions influences the time to reinfect with Plasmodium falciparum.

They analyzed immunoreactive antigenic segments of the malarial parasites by deep sequencing and the time to reinfection following parasite clearance. Additionally, they classified parasites at the described epitopes within targets of anti-parasite immunity.

The researchers investigated whether symptomaticity affected reinfection risks with parasitic organisms comprising homologous hematological apical membrane antigen 1 (AMA-1) and pre-erythrocytic circumsporozoite protein (CSP) types of epitopes.

From June 2017 to July 2018, the team collected samples from 137 and 902 symptomatic and asymptomatic malaria cases, respectively. Among the samples obtained, pfcsp and pfama could be successfully amplified and sequenced from 861 and 724, respectively.

For all participants, the beginning and end of infection episodes were defined. Subsequently, the time to reinfect was calculated as the period between an index episode’s end and the beginning of the following episode.

Index infection episodes with reinfection times of ≤60.0 days were excluded. As a result, reinfection times were computed following 69 and 275 symptomatic and asymptomatic malaria cases, respectively, which comprised the study dataset.

Multivariable mixed effects Cox proportional hazards regression modeling was performed to calculate the adjusted hazard ratios (aHRs) for reinfection risks following symptomatic and asymptomatic P. falciparum infections.

Results

A median value of 126.0 days was obtained for the time to P. falciparum infection, and the likelihood of being reinfection-free for a year after the index episode was 0.10.

Plasmodium falciparum was identified among 239 individuals who were genotyped at immunoreactive parasitic targets detected during the circumsporozoite proteinaceous and hematological AMA-1 phases and grouped based on variations in CSP’s Th2R, Th3R, and DV10 epitopes and AMA-1’s c1L site.

In comparison to asymptomatic malaria, symptomatic cases were related to a lowered reinfection risk by parasites comprising identical Th2R, Th3R, and c1L epitopes, with aHR values of 0.6, 0.7 and 0.6, respectively.

Symptomatic infections lowered reinfection risks by 30% to 40%, and the association between symptomatic malaria and homologous reinfection risks was most robust for rare epitopes. Assessing the genotypes of the causative infections showed 155 and 209 pfcsp and pfama nucleotide genetic sequences, respectively.

They coded for 145 CSP amino acid sequences with missense mutations in 39 of 95 amino acid positions and 203 AMA-1 amino acid sequences with mutations in 50 of 99 amino acid positions.

The CSP DV10 epitope had a notably lower level of epitope type diversity in relation to Th2R, Th3R, and c1L, with 73% (2,521 of 3,443) of the pfcsp haplotype occurrences identified in 861 samples encoding the main epitope type.

The finding that symptom presence was linked to a lowered risk of reinfections by parasites comprising homologous epitopes is concordant with the increased involvement of immune cells during symptomatic-type infections.

The types of CSP epitopes were described based on polymorphic residues among helper [cluster of differentiation 4-positive (CD4+)] and cytotoxic (CD8+) T lymphocytic epitopes situated within the C-terminal domain (CTD).

The findings indicated that symptomatic P. falciparum infections prime T lymphocytes more efficiently than asymptomatic infections. The functional immunological responses to circumsporozoite protein epitopes increased due to symptomatic P. falciparum infections or decreased during asymptomatic infections.

Symptomaticity reflected the development of immune responses and the acquisition of effective immunity to similar degrees across different effector mechanisms. Within polyclonal infections, the amino acid diversity of CSP was maximized at the Th2R epitope.

Conclusions

Overall, the study findings showed that symptomatic P. falciparum infections lowered the risk of reinfections caused by parasites comprising homologous epitopes with increased immune protection from homologous and symptomatic malaria across diverse AMA-1 and CSP epitopes. However, the immune system responded most to the rare epitopes.

Given that the delay in reinfections by identical parasites is a signature of acquired-type functional immune responses, the findings indicate that, in comparison to asymptomatic P. falciparum infections, which are commonly observed in high-risk zones, symptomatic malaria more effectively induces anti-parasite immunity to protect against P. falciparum reinfections.