Human pregnancy-associated malaria-specific B cells target polymorphic, conformational epitopes in VAR2CSA

Area of Science:

• Immunology
• Infectious Diseases
• Parasitology

Background:

• Pregnancy-associated malaria (PAM) is a severe complication caused by Plasmodium falciparum.
• Infected erythrocytes (IEs) adhere to placental chondroitin sulphate A (CSA) via pregnancy-specific variant surface antigens (VSA(PAM)).
• VAR2CSA is a key VSA(PAM) targeted by protective immunity.

Purpose of the Study:

• To investigate the specificity of naturally acquired immunity to PAM.
• To characterize the immune response against VSA(PAM), particularly VAR2CSA.
• To evaluate the diversity of B-cell epitopes on VSA(PAM).

Main Methods:

• Utilized eight human monoclonal IgG1 antibodies reactive with CSA-adhering IEs.
• Employed Western blotting and recombinant VAR2CSA domains (DBL3-X, DBL5-epsilon) for antibody binding assays.
• Analyzed P. falciparum field isolates using recombinant DBL3-X domains and chimeric constructs.

Main Results:

• Seven of eight antibodies recognized VAR2CSA domains (DBL3-X or DBL5-epsilon).
• A high-frequency memory B-cell response to VSA(PAM) was observed.
• Epitope diversity within DBL3-X domains from different isolates was assessed.

Conclusions:

• VAR2CSA is a primary target of naturally acquired protective immunity against PAM.
• Human monoclonal antibodies are valuable tools for characterizing VSA.
• Conformationally intact recombinant antigens are crucial for VSA characterization and vaccine development.