• Children with cerebral malaria or severe malarial anaemia lack immunity to distinct variant surface antigen subsets

      Travassos, M.A.; Niangaly, A.; Bailey, J.A. (Nature Publishing Group, 2018)
      Variant surface antigens (VSAs) play a critical role in severe malaria pathogenesis. Defining gaps, or "lacunae", in immunity to these Plasmodium falciparum antigens in children with severe malaria would improve our understanding of vulnerability to severe malaria and how protective immunity develops. Using a protein microarray with 179 antigen variants from three VSA families as well as more than 300 variants of three other blood stage P. falciparum antigens, reactivity was measured in sera from Malian children with cerebral malaria or severe malarial anaemia and age-matched controls. Sera from children with severe malaria recognized fewer extracellular PfEMP1 fragments and were less reactive to specific fragments compared to controls. Following recovery from severe malaria, convalescent sera had increased reactivity to certain non-CD36 binding PfEMP1s, but not other malaria antigens. Sera from children with severe malarial anaemia reacted to fewer VSAs than did sera from children with cerebral malaria, and both of these groups had lacunae in their seroreactivity profiles in common with children who had both cerebral malaria and severe malarial anaemia. This microarray-based approach may identify a subset of VSAs that could inform the development of a vaccine to prevent severe disease or a diagnostic test to predict at-risk children. Copyright 2018 The Author(s).
    • COVID-19, quarantines, sheltering-in-place, and human rights: The developing crisis

      Openshaw, J.J.; Travassos, M.A. (American Society of Tropical Medicine and Hygiene, 2020)
      As COVID-19 has spread across the globe, quarantines and sheltering-in-place orders have become important public health tools but, as currently implemented, have eroded human rights, particularly for the marginalized, including essential workers, detainees, women, and children. Quarantines and sheltering-in-place orders must include explicit guarantees of human rights protections. We outline protections for the quarantined that communities and governments should strive to guarantee.
    • Microarray analyses reveal strain-specific antibody responses to Plasmodium falciparum apical membrane antigen 1 variants following natural infection and vaccination

      Bailey, J.A.; Berry, A.A.; Travassos, M.A.; Ouattara, A.; Boudova, S.; Dotsey, E.Y.; Pike, A.; Jacob, C.G.; Adams, M.; Takala-Harrison, S.; et al. (Nature Research, 2020)
      Vaccines based on Plasmodium falciparum apical membrane antigen 1 (AMA1) have failed due to extensive polymorphism in AMA1. To assess the strain-specificity of antibody responses to malaria infection and AMA1 vaccination, we designed protein and peptide microarrays representing hundreds of unique AMA1 variants. Following clinical malaria episodes, children had short-lived, sequence-independent increases in average whole-protein seroreactivity, as well as strain-specific responses to peptides representing diverse epitopes. Vaccination resulted in dramatically increased seroreactivity to all 263 AMA1 whole-protein variants. High-density peptide analysis revealed that vaccinated children had increases in seroreactivity to four distinct epitopes that exceeded responses to natural infection. A single amino acid change was critical to seroreactivity to peptides in a region of AMA1 associated with strain-specific vaccine efficacy. Antibody measurements using whole antigens may be biased towards conserved, immunodominant epitopes. Peptide microarrays may help to identify immunogenic epitopes, define correlates of vaccine protection, and measure strain-specific vaccine-induced antibodies. Copyright 2020, The Author(s).
    • A "Natural Death": The Political Battlefield of Infections and Migrant Children's Bodies

      Travassos, M.A. (Oxford University Press, 2020)
      Before September 2018, no child had died in United States Border Patrol custody in a decade. Since then, 7 detained children have died in the past 10 months. Migrant children's bodies have become the latest political battlefield, and these children have been caught in the crossfire. This piece focuses on the recent deaths of several migrant children from overwhelming infections in United States detainment centers. The circumstances surrounding these illnesses bring to the fore concerns about the care of these children, suggesting infectious disease outbreaks in these detainment centers, delays in bringing children to medical attention, and inadequate medical expertise in their care. There is an urgent need for advocacy by clinicians and professional societies to resolve this crisis. Copyright The Author(s) 2019.
    • Strains used in whole organism Plasmodium falciparum vaccine trials differ in genome structure, sequence, and immunogenic potential

      Moser, K.A.; Dwivedi, A.; Stucke, E.M.; Crabtree, J.; Dara, A.; Shah, Z.; Adams, M.; Munro, J.B.; Ouattara, A.; Sparklin, B.C.; et al. (BioMed Central Ltd., 2020)
      Background: Plasmodium falciparum (Pf) whole-organism sporozoite vaccines have been shown to provide significant protection against controlled human malaria infection (CHMI) in clinical trials. Initial CHMI studies showed significantly higher durable protection against homologous than heterologous strains, suggesting the presence of strain-specific vaccine-induced protection. However, interpretation of these results and understanding of their relevance to vaccine efficacy have been hampered by the lack of knowledge on genetic differences between vaccine and CHMI strains, and how these strains are related to parasites in malaria endemic regions. Methods: Whole genome sequencing using long-read (Pacific Biosciences) and short-read (Illumina) sequencing platforms was conducted to generate de novo genome assemblies for the vaccine strain, NF54, and for strains used in heterologous CHMI (7G8 from Brazil, NF166.C8 from Guinea, and NF135.C10 from Cambodia). The assemblies were used to characterize sequences in each strain relative to the reference 3D7 (a clone of NF54) genome. Strains were compared to each other and to a collection of clinical isolates (sequenced as part of this study or from public repositories) from South America, sub-Saharan Africa, and Southeast Asia. Results: While few variants were detected between 3D7 and NF54, we identified tens of thousands of variants between NF54 and the three heterologous strains. These variants include SNPs, indels, and small structural variants that fall in regulatory and immunologically important regions, including transcription factors (such as PfAP2-L and PfAP2-G) and pre-erythrocytic antigens that may be key for sporozoite vaccine-induced protection. Additionally, these variants directly contributed to diversity in immunologically important regions of the genomes as detected through in silico CD8+ T cell epitope predictions. Of all heterologous strains, NF135.C10 had the highest number of unique predicted epitope sequences when compared to NF54. Comparison to global clinical isolates revealed that these four strains are representative of their geographic origin despite long-term culture adaptation; of note, NF135.C10 is from an admixed population, and not part of recently formed subpopulations resistant to artemisinin-based therapies present in the Greater Mekong Sub-region. Conclusions: These results will assist in the interpretation of vaccine efficacy of whole-organism vaccines against homologous and heterologous CHMI. Copyright 2020 The Author(s).