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Neutralizing and interfering human antibodies define the structural and mechanistic basis for antigenic diversion

Palak N. Patel, Thayne H. Dickey, Christine S. Hopp, Ababacar Diouf, Wai Kwan Tang, Carole A. Long, Kazutoyo Miura, Peter D. Crompton and Niraj H. Tolia ()
Additional contact information
Palak N. Patel: National Institutes of Health
Thayne H. Dickey: National Institutes of Health
Christine S. Hopp: National Institutes of Health
Ababacar Diouf: National Institutes of Health
Wai Kwan Tang: National Institutes of Health
Carole A. Long: National Institutes of Health
Kazutoyo Miura: National Institutes of Health
Peter D. Crompton: National Institutes of Health
Niraj H. Tolia: National Institutes of Health

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Defining mechanisms of pathogen immune evasion and neutralization are critical to develop potent vaccines and therapies. Merozoite Surface Protein 1 (MSP-1) is a malaria vaccine antigen and antibodies to MSP-1 are associated with protection from disease. However, MSP-1-based vaccines performed poorly in clinical trials in part due to a limited understanding of the protective antibody response to MSP-1 and of immune evasion by antigenic diversion. Antigenic diversion was identified as a mechanism wherein parasite neutralization by a MSP-1-specific rodent antibody was disrupted by MSP-1-specific non-inhibitory blocking/interfering antibodies. Here, we investigated a panel of MSP-1-specific naturally acquired human monoclonal antibodies (hmAbs). Structures of multiple hmAbs with diverse neutralizing potential in complex with MSP-1 revealed the epitope of a potent strain-transcending hmAb. This neutralizing epitope overlaps with the epitopes of high-affinity non-neutralizing hmAbs. Strikingly, the non-neutralizing hmAbs outcompete the neutralizing hmAb enabling parasite survival. These findings demonstrate the structural and mechanistic basis for a generalizable pathogen immune evasion mechanism through neutralizing and interfering human antibodies elicited by antigenic diversion, and provides insights required to develop potent and durable malaria interventions.

Date: 2022
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DOI: 10.1038/s41467-022-33336-3

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