Antimalarial drug resistance is a substantial impediment to malaria control. The spread of resistance has been described using genetic markers, which are important epidemiological tools. We carried out a temporal analysis of changes in allele frequencies of 12 drug resistance markers over 2 decades of changing antimalarial drug policy in Kenya.

Artemisinin resistance (AR) emerged in South East Asia 13 years ago and the identification of the resistance conferring molecular marker, Plasmodium falciparum Kelch 13 ( Pfk13) , 7 years ago has provided an invaluable tool for monitoring AR in malaria endemic countries. Molecular Pfk13 surveillance revealed the resistance foci in the Greater Mekong Subregion, an independent emergence in Guyana, South America, and a low frequency of mutations in Africa. The recent identification of the R561H Pfk1 3 AR associated mutation in Tanzania, Uganda and in Rwanda, where it has been associated with delayed parasite clearance, should be a concern for the continent. In this review, we provide a summary of Pfk13 resistance associated propeller domain mutation frequencies across Africa from 2012 to 2020, to examine how many other countries have identified these mutations. Only four African countries reported a recent identification of the M476I, P553L, R561H, P574L, C580Y and A675V Pfk13 mutations at low frequencies and with no reports of clinical treatment failure, except for Rwanda. These mutations present a threat to malaria control across the continent, since the greatest burden of malaria remains in Africa. A rise in the frequency of these mutations and their spread would reverse the gains made in the reduction of malaria over the last 20 years, given the lack of new antimalarial treatments in the event artemisinin-based combination therapies fail. The review highlights the frequency of Pfk13 propeller domain mutations across Africa, providing an up-to-date perspective of Pfk13 mutations, and appeals for an urgent and concerted effort to monitoring antimalarial resistance markers in Africa and the efficacy of antimalarials by re-establishing sentinel surveillance systems.

Abstract Background Plasmodium falciparum infections lead to febrile illness unless the host has sufficient immunity, in which case infection may cause no immediate symptoms (ie, “asymptomatic parasitemia”). Previous studies are conflicting on the role of asymptomatic parasitemia in determining the risk of developing febrile malaria. Methods We monitored 2513 children (living in Kilifi, Kenyan Coast) by blood smears in 17 cross-sectional surveys to identify asymptomatic parasitemia and used active surveillance over 11325 child-years of follow-up to detect febrile malaria. We evaluated the interaction between transmission intensity, age, and asymptomatic parasitemia in determining the risk of developing febrile malaria. Results In the moderate and high transmission intensity settings, asymptomatic parasitemia was associated with a reduced risk of febrile malaria in older children (> 3 years), while in the lower transmission setting, asymptomatic parasitemia was associated with an increased risk of febrile malaria in children of all ages. Additionally, the risk associated with asymptomatic parasitemia was limited to the first 90 days of follow-up. Conclusions Asymptomatic parasitemia is modified by transmission intensity and age, altering the risk of developing febrile episodes and suggesting that host immunity plays a prominent role in mediating this process.

Malaria is still a significant public health burden in the tropics. Infection with malaria causing parasites results in a wide range of clinical disease presentations, from severe to uncomplicated or mild, and in the poorly understood asymptomatic infections. The complexity of asymptomatic infections is due to the intricate interplay between factors derived from the human host, parasite, and environment. Asymptomatic infections often go undetected and provide a silent natural reservoir that sustains malaria transmission. This creates a major obstacle for malaria control and elimination efforts. Numerous studies have tried to characterize asymptomatic infections, unanimously revealing that host immunity is the underlying factor in the maintenance of these infections and in the risk of developing febrile malaria infections. An in-depth understanding of how host immunity and parasite factors interact to cause malaria disease tolerance is thus required. This review primarily focuses on understanding anti-inflammatory and pro-inflammatory responses to asymptomatic infections in malaria endemic areas, to present the view that it is potentially the shift in host immunity toward an anti-inflammatory profile that maintains asymptomatic infections after multiple exposures to malaria. Conversely, symptomatic infections are skewed toward a pro-inflammatory immune profile. Moreover, we propose that these infections can be better interrogated using next generation sequencing technologies, in particular RNA sequencing (RNA-seq), to investigate the immune system using the transcriptome sampled during a clearly defined asymptomatic infection.

Background The invasion of the red blood cells by Plasmodium falciparum merozoites involves the interplay of several proteins that are also targets for vaccine development. The proteins PfRh5-PfRipr-PfCyRPA-Pfp113 assemble into a complex at the apical end of the merozoite and are together essential for erythrocyte invasion. They have also been shown to induce neutralizing antibodies and appear to be less polymorphic than other invasion-associated proteins, making them high priority blood-stage vaccine candidates. Using available whole genome sequencing data (WGS) and new capillary sequencing data (CS), this study describes the genetic polymorphism in the Rh5 complex in P. falciparum isolates obtained from Kilifi, Kenya. Methods 162 samples collected in 2013 and 2014 were genotyped by capillary sequencing (CS) and re-analysed WGS from 68 culture-adapted P. falciparum samples obtained from a drug trial conducted from 2005 to 2007. The frequency of polymorphisms in the merozoite invasion proteins, PfRh5, PfRipr, PfCyRPA and PfP113 were examined and where possible polymorphisms co-occurring in the same isolates. Results From a total 70 variants, including 2 indels, 19 SNPs [27.1%] were identified by both CS and WGS, while an additional 15 [21.4%] and 36 [51.4%] SNPs were identified only by either CS or WGS, respectively. All the SNPs identified by CS were non-synonymous, whereas WGS identified 8 synonymous and 47 non-synonymous SNPs. CS identified indels in repeat regions in the p113 gene in codons 275 and 859 that were not identified in the WGS data. The minor allele frequencies of the SNPs ranged between 0.7 and 34.9% for WGS and 1.1–29.6% for CS. Collectively, 12 high frequency SNPs (> 5%) were identified: four in Rh5 codon 147, 148, 203 and 429, two in p113 at codons 7 and 267 and six in Ripr codons 190, 259, 524, 985, 1003 and 1039. Conclusion This study reveals that the majority of the polymorphisms are rare variants and confirms a low level of genetic polymorphisms in all proteins within the Rh5 complex.