RTS,S/AS01 malaria vaccine mismatch observed among Plasmodium falciparum isolates from southern and central Africa and globally

Julia C Pringle,Mike Chaponda,William J Moss,Douglas E Norris,Sha Joe Zhu,Thierry Bobanga,Giovanna Carpi,Tamaki Kobayashi,Jacob Almagro-Garcia,Modest Mulenga

doi:10.1038/s41598-018-24585-8

Abstract

The RTS,S/AS01 malaria vaccine encompasses the central repeats and C-terminal of Plasmodium falciparum circumsporozoite protein (PfCSP). Although no Phase II clinical trial studies observed evidence of strain-specific immunity, recent studies show a decrease in vaccine efficacy against non-vaccine strain parasites. In light of goals to reduce malaria morbidity, anticipating the effectiveness of RTS,S/AS01 is critical to planning widespread vaccine introduction. We deep sequenced C-terminal Pfcsp from 77 individuals living along the international border in Luapula Province, Zambia and Haut-Katanga Province, the Democratic Republic of the Congo (DRC) and compared translated amino acid haplotypes to the 3D7 vaccine strain. Only 5.2% of the 193 PfCSP sequences from the Zambia-DRC border region matched 3D7 at all 84 amino acids. To further contextualize the genetic diversity sampled in this study with global PfCSP diversity, we analyzed an additional 3,809 Pfcsp sequences from the Pf3k database and constructed a haplotype network representing 15 countries from Africa and Asia. The diversity observed in our samples was similar to the diversity observed in the global haplotype network. These observations underscore the need for additional research assessing genetic diversity in P. falciparum and the impact of PfCSP diversity on RTS,S/AS01 efficacy.

Highlights

Indoor residual spraying (IRS) and insecticide treated bednets (ITNs) have dramatically decreased malaria transmission, the global impact of malaria remains high with an estimated 216 million cases reported in 20161,2
The RTS,S/AS01 vaccine is a recombinant protein vaccine containing a portion of the NANP repeats (B-cell epitopes) and the C-terminal region (B-cell and T-cell epitopes) of the Plasmodium falciparum circumsporozoite protein (PfCSP) fused with hepatitis B surface antigen (HBsAg) and is administered with a novel adjuvant, AS018,9
Of the 103 Dried blood spot (DBS) samples extracted from our collections in Zambia and the Democratic Republic of the Congo (DRC), 77 yielded suitable Pfcsp amplicons for sequencing

Summary

Introduction

Indoor residual spraying (IRS) and insecticide treated bednets (ITNs) have dramatically decreased malaria transmission, the global impact of malaria remains high with an estimated 216 million cases reported in 20161,2. Because the gene encoding P. falciparum CSP (Pfcsp) is globally diverse[13,14,15], multiple studies were conducted during the RTS,S/AS01 Phase II clinical trials to monitor Pfcsp haplotypes from vaccine and placebo recipients for signals of allele-specific vaccine-induced immunity. Four studies conducted in The Gambia, Kenya, and Mozambique found no evidence of allele-specific vaccine-induced immunity[16,17,18,19] These genetic surveillance analyses relied either on Sanger sequencing[16,18] or oligonucleotide hybridization assays to assign genotypes to P. falciparum isolates[17,19]. While state of the art assays at the time, the advent of affordable and scalable generation sequencing technologies with the capacity to rapidly analyze larger sample sets has rendered both methods outdated

Methods

Results

Conclusion