An In Silico Analysis of Malaria Pre-Erythrocytic-Stage Antigens Interpreting Worldwide Genetic Data to Suggest Vaccine Candidate Variants and Epitopes

Abstract

Failure to account for genetic diversity of antigens during vaccine design may lead to vaccine escape. To evaluate the vaccine escape potential of antigens used in vaccines currently in development or clinical testing, we surveyed the genetic diversity, measured population differentiation, and performed in silico prediction and analysis of T-cell epitopes of ten such Plasmodium falciparum pre-erythrocytic-stage antigens using whole-genome sequence data from 1010 field isolates. Of these, 699 were collected in Africa (Burkina Faso, Cameroon, Guinea, Kenya, Malawi, Mali, and Tanzania), 69 in South America (Brazil, Colombia, French Guiana, and Peru), 59 in Oceania (Papua New Guinea), and 183 in Asia (Cambodia, Myanmar, and Thailand). Antigens surveyed include cell-traversal protein for ookinetes and sporozoites, circumsporozoite protein, liver-stage antigens 1 and 3, sporozoite surface proteins P36 and P52, sporozoite asparagine-rich protein-1, sporozoite microneme protein essential for cell traversal-2, and upregulated-in-infectious-sporozoite 3 and 4 proteins. The analyses showed that a limited number of these protein variants, when combined, would be representative of worldwide parasite populations. Moreover, predicted T-cell epitopes were identified that could be further explored for immunogenicity and protective efficacy. Findings can inform the rational design of a multivalent malaria vaccine.

Malaria prevention in children: an update

“…While RTS,S and R21 protect the youngest children from severe malaria, concerns exist that the burden of severe malaria may be pushed to older children. Also, the RTS,S and R21 vaccines are based on a single laboratory adapted strain, NF54 [44,73], and CSP sequences that match it are relatively rare (<5-40% depending on which region of CSP is sequenced, study location, and target population) [74][75][76]. As widespread vaccine rollout occurs, monitoring for continued vaccine effectiveness and for potential selection for vaccine-resistant strains will be important.…”

Designing a conjugate vaccine targeting Klebsiella pneumoniae ST258 and ST11

“…Linear B-cell epitopes are effective antigenic peptide sequences for stimulating B-cell immune responses [ 64 ]. Most B-cell epitopes are discontinuous, and these conformational B-cell epitopes represent more than 90% of functional B-cell epitopes [ 65 ]. Linear B cell epitopes were used in conjunction with conformational B cell epitopes to maximize the humoral immune response by the construct [ 66 ].…”

Diversity and selection analyses identify transmission-blocking antigens as the optimal vaccine candidates inPlasmodium falciparum

“…We identified the following percent of unique haplotypes across all countries for individual full-length genes: 41 (32/131) for CelTOS full-length. The 3D7 vaccine strain haplotype was dominant for antigens Pfs48/45 (full-length and partial), and Pfs25 and Pfs28 (both full-length) (Fig.…”

“…With the release of thousands of publicly available P. falciparum whole genome sequences (WGS), it is possible to study the natural genetic and functional variation of targets for malaria vaccine candidate antigens, yet, to date few studies have done so 34,[38][39][40] . Two recent studies reported comprehensive analyses of vaccine candidate antigens 25,41 , but were focused primarily on pre-erythrocytic and bloodstage antigens, with limited inclusion of transmission-blocking antigens. Here, we aimed to characterize the natural genetic and structural variation of ten P. falciparum vaccine antigens spanning the three different vaccine classes, including transmission-blocking antigens.…”