Chiyun Lee

In the last decade, there has been substantial progress in vaccine development for malaria, with two WHO-recommended vaccines now available–RTS,S/AS01 (Mosquirix) and R21/Matrix-M. While these vaccines represent significant milestones, their partial efficacy underscores the need to develop next-generation vaccine approaches capable of broader, longer-lasting protection. Peptide vaccines are a promising strategy, as they focus on short, synthetic peptides specifically selected to trigger a T-cell immune response. However, developing effective peptide vaccines for malaria remains challenging, due to the extensive genetic diversity of Plasmodium falciparum. Currently, tools for comparing and prioritising immunogenic targets remain limited, and existing approaches overlook key factors, including genetic variation, lifecycle-stage expression, and peptide-level properties, each of which are critical for vaccine efficacy. To address these gaps, we developed Pf-PeptideFilter, an interactive web-based application and curated database designed for filtering peptide vaccine targets across the P. falciparum genome. By integrating population-scale genomic information (Pf7), liver-stage transcriptomics, and other biological annotations, Pf-PeptideFilter enables users to interactively filter potential vaccine candidates from the P. falciparum genome, based on several criteria relevant to vaccine design. The app allows users to prioritise candidate genes and peptides with immunogenic potential and export shortlists for incorporation into experimental workflows, offering an interactive platform for rational peptide vaccine design in P. falciparum . Author Summary: Malaria vaccines are challenging to design because the parasite responsible for most infections, Plasmodium falciparum , is highly genetically diverse. If a vaccine targets part of the parasite proteome that varies between strains, it may protect against only a subset of parasites and perform poorly across regions. Peptide vaccines offer a promising approach, by focusing immune responses on short, synthetic peptides selected to trigger T-cell immunity. However, identifying which peptides to include in a vaccine is difficult, as the parasite genome contains thousands of genes and huge numbers of potential peptide targets. Here, we introduce Pf-PeptideFilter, an interactive tool that helps researchers prioritise peptide vaccine candidates using a series of biologically relevant filters. We integrate population-scale genome variation from thousands of parasite samples with information on gene expression during liver infection, similarity to human proteins, and conservation across related parasite species. Users can adjust filtering thresholds and immediately see how these choices affect which genes and peptides are retained. Pf-PeptideFilter generates downloadable shortlists designed to support experimental follow-up, providing a robust and transparent platform for the early stages of vaccine design.

Artemisinin partial resistance (ART-R) in Plasmodium falciparum is a major challenge to malaria control globally. Over the last two decades, ART-R has spread widely across Southeast Asia, undermining public health strategies and hindering elimination. As of 2024, ART-R has now emerged in East Africa, with the potential to dramatically impact current efforts to control malaria in the region. Mitigating its spread requires detailed genomic surveillance of point mutations in the kelch13 gene, the primary known determinant of artemisinin resistance. Although extensive surveillance data on these markers is available, it is distributed across many literature studies and open databases. In this review, we aggregate spatiotemporal data for 112,933 P. falciparum samples collected between 1980 and 2023 into a single resource, providing the most comprehensive overview of kelch13 markers to date. We outline the history and current status of these mutations globally, with particular focus on their emergence in Southeast Asia and East/Northeast Africa. Concerningly, we find the recent increases in ART-R in Africa mirror patterns observed in Southeast Asia 10–15 years ago. We examine factors that may influence its spread, including fitness costs, treatment strategies, and local epidemiological dynamics, before discussing potential scenarios for how resistance may spread in Africa in coming years. This review provides a comprehensive account of how the situation of ART-R has unfolded globally so far, highlighting insights for researchers and public health bodies which aim to reduce its negative effects.

Monitoring the genomic evolution of Plasmodium falciparum—the most widespread and deadliest of the human-infecting malaria species—is critical for making decisions in response to changes in drug resistance, diagnostic test failures, and vaccine effectiveness. The MalariaGEN data resources are the world’s largest whole genome sequencing databases for Plasmodium parasites. The size and complexity of such data is a barrier to many potential end users in both public health and academic research. A user-friendly method for accessing and exploring data on the genetic variation of P. falciparum would greatly enable efforts in studying and controlling malaria. We developed Pf-HaploAtlas, a web application enabling exploratory data analysis of genomic variation without requiring advanced technical expertise. The app provides analysis-ready data catalogues and visualisations of amino acid haplotypes for all 5,102 core P. falciparum genes. Pf-HaploAtlas facilitates comprehensive spatial and temporal exploration of genes and variants of interest by using data from 16,203 samples, from 33 countries, and spread between the years 1984 and 2018. The scope of Pf-HaploAtlas will expand with each new MalariaGEN Plasmodium data release. Pf-HaploAtlas is available online for public use at https://apps.malariagen.net/pf-haploatlas, which allows users to download the underlying amino acid haplotype data for further analyses, and its source code is freely available on GitHub under the MIT licence at https://github.com/malariagen/pf-haploatlas.

Artemisinin partial resistance (ART-R) in Plasmodium falciparum is one of the most pressing threats to global malaria control. Over the last two decades, ART-R has spread widely across Southeast Asia, compromising public health strategies and hindering elimination efforts. As of 2024, ART-R has now emerged in East Africa, with the potential to dramatically increase human mortality in the region. Mitigating the spread of ART-R requires detailed genomic surveillance of point mutations in the kelch13 gene, the primary determinant of resistance to artemisinin derivatives. Although extensive surveillance data on these markers is available, it is distributed across many literature studies and open databases. In this literature review, we aggregate publicly available spatiotemporal data for 112,933 P. falciparum samples between 1980 – 2023 into a single resource, providing the most comprehensive overview of kelch13 markers to date. By synthesising insights from these samples over a global scale, we outline the history and current status of kelch13 mutations associated with ART-R, with particular reference to their emergence in Southeast Asia and recent emergence in East and Northeast Africa. Concerningly, we find their recent increases in frequency in these areas of Africa are comparable to those observed in Southeast Asia 10-15 years ago. We review several factors that may influence the spread of ART-R going forwards, such as fitness costs, treatment strategies, and local epidemiological dynamics, before articulating possible scenarios on how resistance may spread in Africa in coming years. In summary, this review provides a unified, comprehensive account of how the situation of ART-R has unfolded globally so far, highlighting insights both for researchers in the field and public health bodies which aim to reduce its negative effects. More broadly, we highlight the critical role genomic surveillance has had, and will continue to have in combating the spread of ART-R.

Tuberculosis (TB) remains a global health emergency, with an estimated 2 billion people infected across the world, and 1.4 million people dying to this disease every year. Many aspects of the causative agent, Mycobacterium tuberculosis, make this disease difficult for healthcare and laboratory researchers to fight against, such as unique pathophysiology, latent infection and long and complex treatment regimens, thus causing patient non-compliance with the treatment. Development of new drugs is critical for tackling these problems. Repurposing drugs is a promising strategy for generating an effective drug treatment whilst circumventing many of the challenges of conventional drug development. In this regard, the incorporation of immunomodulatory drugs into the standard regimen to potentiate frontline drugs is found to be highly appealing. Drugs of diverse chemical classes and drug categories are increasingly being evidenced to possess antitubercular activity, both in vitro and in vivo. This article explores and discusses the molecular entities that have shown promise in being repurposed for use in anti-TB adjunctive therapy and aims to provide the most up-to-date picture of their progress.