Biology subjects

Hill, A. V. S.

Publications and source records attributed to Hill, A. V. S..

5 recordsLinked to original sources

bioRxiv2024

Repertoire, function, and structure of serological antibodies induced by the R21/Matrix-M malaria vaccine

The World Health Organization recently recommended the programmatic use of R21/Matrix-M vaccine for Plasmodium falciparum malaria prevention in children living in malaria-endemic areas. To determine its effects on humoral immunity, we conducted a proteomic analysis of polyclonal IgG antibodies directed against the NANP tetrapeptide of the circumsporozoite protein (CSP) which comprises the vaccines core immunogen. In ten malaria-naive adult volunteers, R21/Matrix-M induced polarized IgG anti-NANP repertoires, heavily skewed for IGHV3-30/3-33 genes bearing minimal somatic mutation, which remained static in composition following a controlled human malaria infection challenge. Notably, these vaccine-generated antibodies cross-reacted with another protective CSP epitope, the N-terminal junction region, despite its absence from the R21 construct. NANP-specific IGHV3-30/3-33 monoclonal antibodies mined from polyclonal IgG repertoires blocked sporozoite invasion in vitro and prevented parasitemia in vivo. Overall, R21/Matrix-M elicits polarized, minimally mutated, polyclonal IgG responses that can target multiple protective CSP epitopes, offering molecular insight into the serological basis for its demonstrated efficacy against P. falciparum malaria.

immunology↗

bioRxiv2022

Nationwide genomic biobank in Mexico unravels demographic history and complex trait architecture from 6,057 individuals

Latin America continues to be severely underrepresented in genomics research, and fine-scale genetic histories as well as complex trait architectures remain hidden due to the lack of Big Data. To fill this gap, the Mexican Biobank project genotyped 1.8 million markers in 6,057 individuals from 32 states and 898 sampling localities across Mexico with linked complex trait and disease information creating a valuable nationwide genotype-phenotype database. Through a suite of state-of-the-art methods for ancestry deconvolution and inference of identity-by-descent (IBD) segments, we inferred detailed ancestral histories for the last 200 generations in different Mesoamerican regions, unraveling native and colonial/post-colonial demographic dynamics. We observed large variations in runs of homozygosity (ROH) among genomic regions with different ancestral origins reflecting their demographic histories, which also affect the distribution of rare deleterious variants across Mexico. We analyzed a range of biomedical complex traits and identified significant genetic and environmental factors explaining their variation, such as ROH found to be significant predictors for trait variation in BMI and triglycerides.

genomics↗

bioRxiv2020

Dissection-independent production of a protective whole-sporozoite malaria vaccine

Complete protection against human malaria challenge has been achieved using infected mosquitoes as the delivery route for immunization with Plasmodium parasites. Strategies seeking to replicate this efficacy with either a manufactured whole-parasite or subunit vaccine, however, have shown only limited success. A major roadblock to whole parasite vaccine progress and understanding of the human infective sporozoite form in general, is reliance on manual dissection for parasite isolation from infected mosquitoes. We report here the development of a four-step process based on whole mosquito homogenization, slurry and density-gradient filtration, combined with free-flow electrophoresis that is able to rapidly produce a pure, aseptic sporozoite inoculum from hundreds of mosquitoes. Murine P. berghei or human-infective P. falciparum sporozoites produced in this way are 2-3-fold more infective with in vitro hepatocytes and can confer sterile protection when immunized intravenously with subsequent challenge using a mouse malaria model. Critically, we can also demonstrate for the first time 60-70% protection when the same parasites are administered via intramuscular (i.m.) route. In developing a process amenable to industrialisation and demonstrating efficacy by i.m. route these data represent a major advancement in capacity to produce a whole parasite malaria vaccine at scale. One-Sentence SummaryA four-step process for isolating pure infective malaria parasite sporozoites at scale from homogenized whole mosquitoes, independent of manual dissection, is able to produce a whole parasite vaccine inoculum that confers sterilizing protection.

microbiology↗

bioRxiv2018

Characterisation of antigenic MHC Class I-restricted T cell epitopes in the glycoprotein of Ebolavirus

Ebolavirus is a pathogen capable of causing highly lethal haemorrhagic fever in humans. The envelope-displayed viral glycoprotein is the primary target of humoral immunity induced by both natural exposure and vaccination. The epitopes targeted by B cells have been thoroughly characterised by functional and structural analyses of the glycoprotein, GP, yet there is a paucity of information regarding the cellular immune response to Ebolavirus. To date, no T cell epitopes in the glycoprotein have been characterised in detail in humans.\n\nA recent Phase I clinical trial of a heterologous prime-boost vaccination regime with viral vectors encoding filovirus antigens elicited strong humoral and T cell responses in vaccinees. Using samples from this trial, the most frequently recognised peptide pools were studied in more detail to identify the minimal epitopes recognised by antigen-specific T cells and associated HLA-restrictions.\n\nUsing IFN{gamma} ELISPOT and flow cytometry, we characterised nine highly immunogenic T cell epitopes located on both the GP1 and GP2 subunits of the Ebolavirus GP. Epitope mapping revealed the location of these epitopes as presented on the mature virion. HLA-typing on all participants, combined with in silico epitope analysis, determined the likely MHC class I restriction elements. Thirteen HLA-A and -B alleles were predicted to present the identified epitopes, suggesting promiscuous recognition and induction of a broad immune response.\n\nThe glycoprotein of Ebolavirus is highly immunogenic, inducing both CD4+ and CD8+ T cell responses and we have shown here for the first time that these responses are associated with multiple HLA types. Delivery of this antigen using a heterologous prime-boost approach with ChAd3 and MVA is likely to be highly immunogenic in genetically diverse human populations, due to the induction of responses against multiple immunodominant epitopes.\n\nAuthor SummaryThe West African Ebolavirus epidemic in 2013-2016 claimed more than 11,000 lives, eclipsing all previously recorded outbreaks combined. Understanding the mechanisms of host-pathogen interactions informs rational vaccine design. B cell epitopes have been described extensively through the characterisation of monoclonal antibodies from survivors of Ebolavirus disease. Despite a clear role for cellular immunity in survival of Ebolavirus disease, data relating to minimal T cell epitopes in the glycoprotein has so far only been obtained in murine. This study describes the first identification of human T cell epitopes in the surface glycoprotein of the Ebolavirus. These epitopes have been identified using samples from a clinical trial of viral vectored vaccines against the Zaire Ebolavirus undertaken during the 2013-2016 West African outbreak. We also describe the recognition of these epitopes through multiple HLA alleles. As efforts to progress a vaccine against Ebola towards licensure proceed, detailed characterisation of immunity to the virus contribute to our understanding of the potential application of vaccines in diverse populations.

immunology↗

bioRxiv2018

Population Turnover in Remote Oceania Shortly After Initial Settlement

Ancient DNA analysis of three individuals dated to ~3000 years before present (BP) from Vanuatu and one ~2600 BP individual from Tonga has revealed that the first inhabitants of Remote Oceania (\"First Remote Oceanians\") were almost entirely of East Asian ancestry, and thus their ancestors passed New Guinea, the Bismarck Archipelago, and the Solomon Islands with minimal admixture with the Papuan groups they encountered [1]. However, all present-day populations in Near and Remote Oceania harbor 25-100% Papuan ancestry, implying that there must have been at least one later stream of migration eastward from Near Oceania. We generated genome-wide data for 14 ancient individuals from Efate and Epi Islands in Vanuatu ranging from 3,000-150 BP, along with 185 present-day Vanuatu individuals from 18 islands. We show that people of almost entirely Papuan ancestry had arrived in Vanuatu by 2400 BP, an event that coincided with the end of the Lapita cultural period, changes in skeletal morphology, and the cessation of long-distance trade between Near and Remote Oceania [2]. First Remote Oceanian ancestry subsequently increased via admixture but remains at 10-20% in most islands. Through a fine-grained comparison of ancestry profiles in Vanuatu and Polynesia with diverse groups in Near Oceania, we find that Papuan ancestry in Vanuatu is consistent with deriving from the Bismarck Archipelago instead of the geographically closer Solomon Islands. Papuan ancestry in Polynesia also shows connections to the ancestry profiles present in the Bismarck Archipelago but is more similar to Tolai from New Britain and Tutuba from Vanuatu than to the ancient Vanuatu individuals and the great majority of present-day Vanuatu populations. This suggests a third eastward stream of migration from Near to Remote Oceania bringing a different type of Papuan ancestry.

genetics↗