Vaccine Strain-Specificity of Protective HLA-Restricted Class 1 P. falciparum Epitopes

Martha Sedegah; Bjoern Peters; Michael R Hollingdale; Harini D Ganeshan; Jun Huang; Fouzia Farooq; Maria N Belmonte; Arnel D Belmonte; Keith J Limbach; Carter Diggs; Lorraine Soisson; Ilin Chuang; Eileen D Villasante

doi:10.1371/journal.pone.0163026

Vaccine Strain-Specificity of Protective HLA-Restricted Class 1 P. falciparum Epitopes

PLoS One. 2016 Oct 3;11(10):e0163026. doi: 10.1371/journal.pone.0163026. eCollection 2016.

Authors

Martha Sedegah¹, Bjoern Peters², Michael R Hollingdale^{1

3}, Harini D Ganeshan^{1

3}, Jun Huang^{1

3}, Fouzia Farooq^{1

3}, Maria N Belmonte^{1

3}, Arnel D Belmonte^{1

3}, Keith J Limbach^{1

3}, Carter Diggs⁴, Lorraine Soisson⁴, Ilin Chuang¹, Eileen D Villasante¹

Affiliations

¹ Malaria Department, Naval Medical Research Center, Silver Spring, MD, 20910, United States of America.
² La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, United States of America.
³ Henry M. Jackson Foundation for the Advancement of Military Medicine, Rockville, MD, 20817, United States of America.
⁴ USAID, Washington, DC, 20523, United States of America.

Abstract

A DNA prime/adenovirus boost malaria vaccine encoding Plasmodium falciparum strain 3D7 CSP and AMA1 elicited sterile clinical protection associated with CD8+ T cell interferon-gamma (IFN-γ) cells responses directed to HLA class 1-restricted AMA1 epitopes of the vaccine strain 3D7. Since a highly effective malaria vaccine must be broadly protective against multiple P. falciparum strains, we compared these AMA1 epitopes of two P. falciparum strains (7G8 and 3D7), which differ by single amino acid substitutions, in their ability to recall CD8+ T cell activities using ELISpot and flow cytometry/intracellular staining assays. The 7G8 variant peptides did not recall 3D7 vaccine-induced CD8+ T IFN-γ cell responses in these assays, suggesting that protection may be limited to the vaccine strain. The predicted MHC binding affinities of the 7G8 variant epitopes were similar to the 3D7 epitopes, suggesting that the amino acid substitutions of the 7G8 variants may have interfered with TCR recognition of the MHC:peptide complex or that the 7G8 variant may have acted as an altered peptide ligand. These results stress the importance of functional assays in defining protective epitopes. Clinical Trials Registrations: NCT00870987, NCT00392015.

MeSH terms

Antigens, Protozoan / immunology
CD8-Positive T-Lymphocytes / drug effects
CD8-Positive T-Lymphocytes / immunology
Epitopes / immunology*
Flow Cytometry
HLA Antigens / immunology*
HLA-B Antigens / immunology
Humans
Interferon-gamma / pharmacology
Malaria Vaccines / immunology*
Malaria, Falciparum / immunology
Malaria, Falciparum / prevention & control
Membrane Proteins / immunology
Plasmodium falciparum / immunology*
Protozoan Proteins / immunology

Substances

Antigens, Protozoan
Epitopes
HLA Antigens
HLA-B Antigens
HLA-B58
Malaria Vaccines
Membrane Proteins
Protozoan Proteins
apical membrane antigen I, Plasmodium
Interferon-gamma

Associated data

ClinicalTrials.gov/NCT00870987
ClinicalTrials.gov/NCT00392015

Grants and funding

This study was supported by the United States Agency for International Development "Development of Adenovirus-Vectored Malaria Vaccines" interagency agreement # GHA-P-00-03-00006-01, project number 936–3118, www.usaid.gov, recipient EV; Congressionally Directed Medical Research Program (https://cdmrp.org) "Development of Recombinant Adenoviral-based Vaccines against Malaria", grant # W81XWH-05-2-0041, recipient EV; Military Infectious Research Program "Phase 1/2a clinical trials assessing the safety, tolerability, immunogenicity & protective efficacy of Ad5-CA, a two-antigen, adenovirus-vectored Plasmodium falciparum malaria vaccine, in healthy, malaria-naive adults", work unit number 62787A 870 F 1432, https://midrp.amedd.army.mil, recipient EV. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.