Microarray analyses reveal strain-specific antibody responses to Plasmodium falciparum apical membrane antigen 1 variants following natural infection and vaccination

Jason A Bailey,Matthew Adams,Shannon Takala-Harrison,Sandeep Dutta ,Andrea A Berry,Sarah Boudová ,Jozelyn Pablo,Emmanuel Y Dotsey,Philip L Felgner,Jigar Patel ,Mahamadou A Théra ,Algis Jasinskas,Rie Nakajima,Amadou Niangaly,Andrew Pike,Matthew B Laurens,Christopher G Jacob ,Ogobara K Doumbo,Amed Ouattara,Ryan M Bannen,Bouréma Kouriba ,Mark A Travassos,Drissa Coulibaly,Kirsten E Lyke,John C Tan,Christopher V Plowe

doi:10.1038/s41598-020-60551-z

Abstract

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.

Highlights

Plasmodium falciparum apical membrane antigen 1 (AMA1) is a malaria parasite surface protein involved in red blood cell invasion[1]
A monovalent AMA1 subunit vaccine tested in a phase 2 clinical trial in Malian children did not provide significant protection against all clinical malaria[21]
Sera were randomly selected from participants in a 3D7-based AMA1 vaccine trial conducted in Bandiagara, Mali to be probed on the whole protein microarray

Summary

Introduction

Plasmodium falciparum apical membrane antigen 1 (AMA1) is a malaria parasite surface protein involved in red blood cell invasion[1]. The AMA1 protein contains a hydrophobic cleft that is the binding site of red blood cell invasion machinery[13,14,15,16]. We previously identified 214 unique ama[1] ectodomain sequences among 506 single or predominant clone P. falciparum infections[9] in Bandiagara, the town in central Mali where the AMA1 vaccine was tested in adults[23] and children[21,24]. A prototype diversity-reflecting protein microarray that included 58 AMA1 variants showed increases in both lifetime and seasonal magnitude and breadth of anti-AMA1 antibodies in malaria-exposed Malian children and adults living in Bandiagara, where malaria transmission is intense but highly seasonal[25]. Our aim was to examine the effects of both natural P. falciparum parasite exposure and AMA1 vaccination on the breadth and magnitude of strain-specific and epitope-specific antibody responses to AMA1

Objectives

Methods

Results

Conclusion