Designing an effective malaria vaccine targeting Plasmodium vivax Duffy-binding protein

Dickey, Thayne H.; Tolia, Niraj H.

doi:10.1016/j.pt.2023.06.011

Cited by 9 publications

(2 citation statements)

References 98 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Plasmodium parasites utilize a variety of DBL domain-containing proteins [15,16] to bind to host receptors [17,18]. The structural and mechanistic basis [19] for some of these interactions in erythrocyte invasion [20][21][22][23][24][25][26][27], cytoadherence [28,29] and placental sequestration [11][12][13] have been defined. Insights from antibody neutralization of parasite proteins [30][31][32][33][34][35][36][37] have enabled vaccine design for some antigens [38][39][40][41].…”

Section: Introductionmentioning

confidence: 99%

Structure-guided design of VAR2CSA-based immunogens and a cocktail strategy for a placental malaria vaccine

Ma,

Salinas,

Orr-Gonzalez

et al. 2024

PLoS Pathog

Self Cite

View full text Add to dashboard Cite

Placental accumulation of Plasmodium falciparum infected erythrocytes results in maternal anemia, low birth weight, and pregnancy loss. The parasite protein VAR2CSA facilitates the accumulation of infected erythrocytes in the placenta through interaction with the host receptor chondroitin sulfate A (CSA). Antibodies that prevent the VAR2CSA-CSA interaction correlate with protection from placental malaria, and VAR2CSA is a high-priority placental malaria vaccine antigen. Here, structure-guided design leveraging the full-length structures of VAR2CSA produced a stable immunogen that retains the critical conserved functional elements of VAR2CSA. The design expressed with a six-fold greater yield than the full-length protein and elicited antibodies that prevent adhesion of infected erythrocytes to CSA. The reduced size and adaptability of the designed immunogen enable efficient production of multiple variants of VAR2CSA for use in a cocktail vaccination strategy to increase the breadth of protection. These designs form strong foundations for the development of potent broadly protective placental malaria vaccines.

show abstract

Section: Introductionmentioning

confidence: 99%

Structure-guided design of VAR2CSA-based immunogens and a cocktail strategy for a placental malaria vaccine

Ma,

Salinas,

Orr-Gonzalez

et al. 2024

PLoS Pathog

Self Cite

View full text Add to dashboard Cite

show abstract

“…Malaria symptoms are caused by the blood stage of the parasite, and a vaccine targeting this stage would reduce morbidity and mortality. Duffy‐binding protein (DBP) is an essential extracellular parasite protein and is therefore a leading vaccine candidate (Dickey & Tolia, 2023 ; Haynes et al, 1988 ; Singh et al, 2005 ). DBP mediates invasion by binding to the Duffy antigen receptor for chemokines (DARC), which is located on the surface of immature red blood cells known as reticulocytes (Haynes et al, 1988 ).…”

Section: Introductionmentioning

confidence: 99%

Structure‐based design of a Plasmodium vivax Duffy‐binding protein immunogen focuses the antibody response to functional epitopes

Dickey,

McAleese,

Salinas

et al. 2024

Protein Science

Self Cite

View full text Add to dashboard Cite

The Duffy‐binding protein (DBP) is a promising antigen for a malaria vaccine that would protect against clinical symptoms caused by Plasmodium vivax infection. Region II of DBP (DBP‐II) contains the receptor‐binding domain that engages host red blood cells, but DBP‐II vaccines elicit many non‐neutralizing antibodies that bind distal to the receptor‐binding surface. Here, we engineered a truncated DBP‐II immunogen that focuses the immune response to the receptor‐binding surface. This immunogen contains the receptor‐binding subdomain S1S2 and lacks the immunodominant subdomain S3. Structure‐based computational design of S1S2 identified combinatorial amino acid changes that stabilized the isolated S1S2 without perturbing neutralizing epitopes. This immunogen elicited DBP‐II‐specific antibodies in immunized mice that were significantly enriched for blocking activity compared to the native DBP‐II antigen. This generalizable design process successfully stabilized an integral core fragment of a protein and focused the immune response to desired epitopes to create a promising new antigen for malaria vaccine development.

show abstract

Subunit protein-based vaccines

Apostolopoulos,

Chavda

2024

Advanced Vaccination Technologies for Infectious and Chronic Diseases

View full text Add to dashboard Cite

Designing an effective malaria vaccine targeting Plasmodium vivax Duffy-binding protein

Cited by 9 publications

References 98 publications

Structure-guided design of VAR2CSA-based immunogens and a cocktail strategy for a placental malaria vaccine

Structure-guided design of VAR2CSA-based immunogens and a cocktail strategy for a placental malaria vaccine

Structure‐based design of a Plasmodium vivax Duffy‐binding protein immunogen focuses the antibody response to functional epitopes

Subunit protein-based vaccines

Contact Info

Product

Resources

About