» Articles » PMID: 24958881

Immunization with a Functional Protein Complex Required for Erythrocyte Invasion Protects Against Lethal Malaria

Overview
Specialty Science
Date 2014 Jun 25
PMID 24958881
Citations 50
Authors
Affiliations
Soon will be listed here.
Abstract

An essential step in the invasion of red blood cells (RBCs) by Plasmodium falciparum (Pf) merozoites is the binding of rhoptry neck protein 2 (RON2) to the hydrophobic groove of apical membrane antigen 1 (AMA1), triggering junction formation between the apical end of the merozoite and the RBC surface to initiate invasion. Vaccination with AMA1 provided protection against homologous parasites in one of two phase 2 clinical trials; however, despite its ability to induce high-titer invasion-blocking antibodies in a controlled human challenge trial, the vaccine conferred little protection even against the homologous parasite. Here we provide evidence that immunization with an AMA1-RON2 peptide complex, but not with AMA1 alone, provided complete protection against a lethal Plasmodium yoelii challenge in mice. Significantly, IgG from mice immunized with the complex transferred protection. Furthermore, IgG from PfAMA1-RON2-immunized animals showed enhanced invasion inhibition compared with IgG elicited by AMA1 alone. Interestingly, this qualitative increase in inhibitory activity appears to be related, at least in part, to a switch in the proportion of IgG specific for certain loop regions in AMA1 surrounding the binding site of RON2. Antibodies induced by the complex were not sufficient to block the FVO strain heterologous parasite, however, reinforcing the need to include multiallele AMA1 to cover polymorphisms. Our results suggest that AMA1 subunit vaccines may be highly effective when presented to the immune system as an invasion complex with RON2.

Citing Articles

PfSPZ Vaccine induces focused humoral immune response in HIV positive and negative Tanzanian adults.

Tumbo A, Lorenz F, Yang A, Sefried S, Schindler T, Mpina M EBioMedicine. 2024; 108:105364.

PMID: 39353279 PMC: 11464252. DOI: 10.1016/j.ebiom.2024.105364.


A broadly cross-reactive i-body to AMA1 potently inhibits blood and liver stages of Plasmodium parasites.

Angage D, Chmielewski J, Maddumage J, Hesping E, Caiazzo S, Lai K Nat Commun. 2024; 15(1):7206.

PMID: 39174515 PMC: 11341838. DOI: 10.1038/s41467-024-50770-7.


The Need for Novel Asexual Blood-Stage Malaria Vaccine Candidates for .

Takashima E, Otsuki H, Morita M, Ito D, Nagaoka H, Yuguchi T Biomolecules. 2024; 14(1).

PMID: 38254700 PMC: 10813614. DOI: 10.3390/biom14010100.


Structure guided mimicry of an essential P. falciparum receptor-ligand complex enhances cross neutralizing antibodies.

Yanik S, Venkatesh V, Parker M, Ramaswamy R, Diouf A, Sarkar D Nat Commun. 2023; 14(1):5879.

PMID: 37735574 PMC: 10514071. DOI: 10.1038/s41467-023-41636-5.


Hiding in plain sight: an epitope-based strategy for a subunit malaria vaccine.

Good M, Yanow S Trends Parasitol. 2023; 39(11):929-935.

PMID: 37684152 PMC: 10592166. DOI: 10.1016/j.pt.2023.08.006.


References
1.
Miura K, Herrera R, Diouf A, Zhou H, Mu J, Hu Z . Overcoming allelic specificity by immunization with five allelic forms of Plasmodium falciparum apical membrane antigen 1. Infect Immun. 2013; 81(5):1491-501. PMC: 3648006. DOI: 10.1128/IAI.01414-12. View

2.
Wallner B, Elofsson A . Can correct protein models be identified?. Protein Sci. 2003; 12(5):1073-86. PMC: 2323877. DOI: 10.1110/ps.0236803. View

3.
Ouattara A, Takala-Harrison S, Thera M, Coulibaly D, Niangaly A, Saye R . Molecular basis of allele-specific efficacy of a blood-stage malaria vaccine: vaccine development implications. J Infect Dis. 2012; 207(3):511-9. PMC: 3537449. DOI: 10.1093/infdis/jis709. View

4.
Murray C, Rosenfeld L, Lim S, Andrews K, Foreman K, Haring D . Global malaria mortality between 1980 and 2010: a systematic analysis. Lancet. 2012; 379(9814):413-31. DOI: 10.1016/S0140-6736(12)60034-8. View

5.
Vulliez-Le Normand B, Tonkin M, Lamarque M, Langer S, Hoos S, Roques M . Structural and functional insights into the malaria parasite moving junction complex. PLoS Pathog. 2012; 8(6):e1002755. PMC: 3380929. DOI: 10.1371/journal.ppat.1002755. View