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High-throughput mapping of human antibody sequences to PfEMP1 malaria antigen specificity

Award Number: R21AI164147
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/07/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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High-throughput mapping of human antibody sequences to PfEMP1 malaria antigen specificity - Project Summary. Monoclonal antibodies are approved as therapeutics for a number of diseases. Antibody development in the infectious disease setting typically starts with pathogen-specific antigen (PSAg) discovery, followed by raising of PSAg-specific antibodies in animal models. Fully human, PSAg-specific antibodies encoded by circulating memory B cells from clinically immune donors present many advantages over antibodies raised in animals. There is no need for antibody humanization and it enables isolation of affinity- matured antibodies co-evolved with their native target antigens. In the case of Plasmodium falciparum, the malaria parasite studied here, antibody discovery is associated with several important additional challenges. Members of the antigen family PfEMP1 have been identified as key targets of acquired protective antibody- mediated immunity to malaria, but are fraught with substantial intra-clonal and inter-clonal variation. This greatly complicates identification of broadly cross-reactive and neutralizing antibodies. Furthermore, there is no practical animal model for the study of PfEMP1-specific acquired immunity (P. falciparum only infects humans). Finally, the low-throughput technologies so far available for interrogating the functionality of PfEMP1-specific antibodies have severely hampered the identification of broadly reactive, neutralizing antibodies. Human monoclonal antibodies (huMabs) therefore remain a largely unexplored tool in malaria antigen discovery. To address these challenges, we propose to explore the utility of a new technology for the discovery of BCR sequences encoding PSAg-specific antibodies (Specific Aim 1) and to assess the cross-reactivity and functionality of such antibodies in vitro (Specific Aim 2). Specifically, we will apply the recently described LIBRA-seq technology, which enables high-throughput mapping of antibody sequence to antigen specificity, using a specific type of PfEMP1 (VAR2CSA) that is centrally involved in the pathogenesis of a specific and severe complication to P. falciparum infection, called placental malaria. Correspondingly, VAR2CSA-specific antibodies have been identified as the key mechanism of naturally acquired protection from placental malaria. Subsequently, we will generate VAR2CSA-specific recombinant huMabs with the sequences identified by LIBRA-seq to verify their cross-reactivity and assess the functionality of the recombinant antibodies in a range of in vitro assays. The reason that we focus the initial studies proposed here on placental malaria is that the target antigen of acquired protective immunity to placental malaria (VAR2CSA-type PfEMP1) is well established, and because placental malaria is a major cause of malaria-related mortality and severe morbidity among pregnant women and their offspring in areas where transmission of P. falciparum occurs. These initial efforts will show the utility of our proposed approaches for identification of broadly neutralizing PfEMP1-specific antibodies. They will therefore provide a framework for antibody discovery efforts in other severe forms of P. falciparum malaria, e.g., cerebral malaria, and therefore will have a broad impact.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	KOBENHAVNS UNIVERSITET	NORREGADE 10	KOBENHAVN				DNK	Allergy and Infectious Diseases Research	000	2	2/4/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $176,108 )
2022	2022	KOBENHAVNS UNIVERSITET	NORREGADE 10	KOBENHAVN K				DNK	Allergy and Infectious Diseases Research	000	2	6/21/2022	NON-COMPETING CONTINUATION	$176,108
														Subtotal = $176,108

Issue Date FY: 2021 ( Subtotal = $184,291 )
2021	2021	KOBENHAVNS UNIVERSITET	NORREGADE 10	KOBENHAVN K				DNK	Allergy and Infectious Diseases Research	000	1	7/7/2021	NEW	$184,291
														Subtotal = $184,291

Grand Total All Awards = $360,399

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High-throughput mapping of human antibody sequences to PfEMP1 malaria antigen specificity

Award Number: R21AI164147

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/07/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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