Author(s): Thalib Aditya Hakim, Annissa Retno Arimdayu, Ilma Fauziah Ma’ruf, Wulan Mayasari, Hesti Lina Wiraswati


DOI: 10.52711/0974-360X.2023.00655   

Address: Thalib Aditya Hakim1, Annissa Retno Arimdayu2, Ilma Fauziah Ma’ruf5, Wulan Mayasari3, Hesti Lina Wiraswati2,3,4*
1Post Graduate Student of Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
2Oncology and Stem Cell Working Group, Faculty of Medicine, Universitas Padjadjaran.
3Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Sumedang 45363, Indonesia.
4Infection Working Group, Faculty of Medicine, Universitas Padjadjaran, Sumedang 45363, Indonesia.
5Research Center for Climate and Atmosphere, National Research and Innovation Agency, Bandung 40135, Indonesia.
*Corresponding Author

Published In:   Volume - 16,      Issue - 8,     Year - 2023

Variant surface antigen 2- chondroitin sulfate A (VAR2CSA) is a protein belonging to the Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) family. Since the discovery of the protein, various studies have been carried out to utilize VAR2CSA in the clinical field. The typical application is the development of malaria vaccines and anticancer drug carriers based on VAR2CSA. Will anticancer drugs (with VAR2CSA vehicle) work effectively in patients who have already received the VAR2CSA-based malaria vaccine? Given that theoretically, the presence of antibodies triggered by the VAR2CSA vaccine might be against anticancer drugs delivered by VAR2CSA. Therefore, a review regarding the development of research on VAR2CSA, especially as a vaccine or anticancer drug vehicle, is needed. This paper provides an overview of current knowledge about VAR2CSA including its structure and function, biochemical aspects, research approaches both in vitro, ex vivo and in vivo, and the development of potential studies of VAR2CSA in the field of medicine. The literature search was carried out systematically from the PubMed database with the keywords “VAR2CSA”, “VAR2CSA” AND “vaccine”, "VAR2CSA" AND "drug delivery", "VAR2CSA" AND "cancer", "VAR2CSA" AND "placental malaria", "VAR2CSA" AND "review". A Study of VAR2CSA shows promising results, especially in the development of VAR2CSA as the main candidate for the placental malaria vaccine and anticancer drug carrier. Current findings reveal that both studies will carry out clinical trials soon. However, limitations of the study should be considered in future clinical applications for more effective cancer treatment, such as the administration of anticancer drugs by VAR2CSA vehicles on patients who have already received VAR2CSA-based antimalarial vaccines. Furthermore, an example of promising future research is leveraging other domains of VAR2CSA that have not been explored yet.

Cite this article:
Thalib Aditya Hakim, Annissa Retno Arimdayu, Ilma Fauziah Ma’ruf, Wulan Mayasari, Hesti Lina Wiraswati. VAR2CSA protein for malaria vaccine or anticancer drug delivery? A review of preclinical and clinical research. Research Journal of Pharmacy and Technology. 2023; 16(8):3990-8. doi: 10.52711/0974-360X.2023.00655

Thalib Aditya Hakim, Annissa Retno Arimdayu, Ilma Fauziah Ma’ruf, Wulan Mayasari, Hesti Lina Wiraswati. VAR2CSA protein for malaria vaccine or anticancer drug delivery? A review of preclinical and clinical research. Research Journal of Pharmacy and Technology. 2023; 16(8):3990-8. doi: 10.52711/0974-360X.2023.00655   Available on:

1.    Suruse PB. Duragkar NJ. Shivhare UD. Raut SY. Warokar AS. Contribution of Traditional Medicines to the Development of Modern Medicine for Malaria. Research J. Pharmacology and Pharmacodynamics. 2011; 3(1): 1-4.
2.    Amadi OK. Otuokere IE. Bartholomew CF. Synthesis, Characterization, in vivo Antimalarial Studies and Geometry Optimization of Lumefantrine/Artemether Mixed Ligand Complexes. Res. J. Pharm. Dosage Form. & Tech. 2015;7(1):59-68. doi: 10.5958/0975-4377.2015.00009.9
3.    Thillainayagam M. Ramaiah S. Mosquito, Malaria and Medicines – A Review. Research J. Pharm. and Tech. 2016; 9(8):1268-1276. doi: 10.5958/0974-360X.2016.00241.9
4.    Mutiah R. Badiah R. Hayati EK. Widyawaruyanti A. Activity of Antimalarial Compounds from Ethyl Acetate Fraction of Sunflower Leaves (Helianthus annuus L.) against Plasmodium falciparum Parasites 3D7 Strain. Asian J. Pharm. Tech. 2017; 7(2): 86-90. doi: 10.5958/2231-5713.2017.00015.0
5.    Dubey S. Bhardwaj S. Parbhakaran P. Singh E. In silico Prediction of Pyrazoline Derivatives as Antimalarial agents. Asian Journal of Pharmaceutical Research. 2022; 12(2):119-4. doi: 10.52711/2231-5691.2022.00018
6.    Amari MR, Wiraswati HL, Fauziah N, Ma’ruf IF. Antimalarial Effect of Doxorubicin on Plasmodium Falciparum: An in Vitro Study in FCR-3 Strain. Biomed Pharmacol J. 2022;15(1).
7.    Khairani S, Fauziah N, Wiraswati HL, Panigoro R, Setyowati EY, Berbudi A. Oral Administration of Piperine as Curative and Prophylaxis Reduces Parasitaemia in Plasmodium berghei ANKA-Infected Mice. J Trop Med. 2022;2022:5721449. doi: 10.1155/2022/5721449.
8.    Khairani S, Fauziah N, Wiraswati HL, Panigoro R, Setyowati EY, Berbudi A. The Potential use of a Curcumin-Piperine Combination as an Antimalarial Agent: A Systematic Review. J Trop Med. 2021;2021:9135617. doi: 10.1155/2021/9135617.
9.    Khairani S, Fauziah N, Wiraswati HL, Panigoro R, Salleh A, Setyowati EY, Berbudi A. Piperine Enhances the Antimalarial Activity of Curcumin in Plasmodium berghei ANKA-Infected Mice: A Novel Approach for Malaria Prophylaxis. Evidence-Based Complementary and Alternative Medicine.Volume 2022, Article ID 7897163,
10.    Chaniad P, Techarang T, Phuwajaroanpong A, Horata N, Septama AW, Punsawad C. Exploring Potential Antimalarial Candidate from Medicinal Plants of Kheaw Hom Remedy. Tropical Medicine and Infectious Disease. 2022; 7(11):368.
11.    Wiraswati HL, Fauziah N, Pradini GW, Kurnia D, Kodir RA, Berbudi A, Arimdayu AR, Laelalugina A, Supandi, Ma'ruf IF. Breynia cernua: Chemical Profiling of Volatile Compounds in the Stem Extract and Its Antioxidant, Antibacterial, Antiplasmodial and Anticancer Activity In Vitro and In Silico. Metabolites. 2023;13(2):281. doi: 10.3390/metabo13020281.
12.    Rasti N, Wahlgren M, Chen Q. Molecular aspects of malaria pathogenesis. FEMS Immunol Med Microbiol. 200441(1):9-26. doi: 10.1016/j.femsim.2004.01.0
13.    Rogerson SJ. Desai M. Mayor A. Sicuri E. Taylor SM. van Eijk AM. Burden, pathology, and costs of malaria in pregnancy: new     developments for an old problem. Lancet Infect Dis. 2018;18(4):e107–18.
14.    Theander TG. Turner L. Marsh K. Nielsen MA. Ofori MF. Barfod L et al. Evidence for the Involvement of VAR2CSA in Pregnancy-associated Malaria. J Exp Med. 2004;200(9):1197–203.
15.    Cutts JC. Agius PA. Zaw Lin. Powell R. Moore K. Draper B et al. Pregnancy-specific malarial immunity and risk of malaria in pregnancy and adverse birth outcomes: A systematic review. BMC Med. 2020;18(1):1–21.
16.    Maestre A. Carmona-Fonseca J. Immune responses during gestational malaria: A review of the current knowledge and future trend of research. J Infect Dev Ctries. 2014;8(4):391–402.
17.    Fried M. Duffy PE. Designing a VAR2CSA-based vaccine to prevent placental malaria. Vaccine. 2015;33(52):7483–8.
18.    Hommel M. Chan JA. Umbers AJ. Langer C. Rogerson SJ. Smith JD et al. Evaluating antibody functional activity and strain-specificity of vaccine candidates for malaria in pregnancy using in vitro phagocytosis assays. Parasites and Vectors. 2018;11(1):1–7.
19.    Sungwa M. Susan T. Mikkel JC. Adolph KR. Boniface MS. Grundtvig TT et al. A VAR2CSA:CSP conjugate capable of inducing dual specificity antibody responses. Afr Health Sci. 2017;17(2):373–81.
20.    Srivastava A. Gangnard S. Dechavanne S. Amirat F. Lewit Bentley A. Bentley GA et al. Var2CSA Minimal CSA Binding Region Is Located within the N-Terminal Region. PLoS One [Internet]. 2011;6(5):e20270.
21.    Khunrae P. Higgins MK. Structural insights into chondroitin sulfate binding in pregnancy-associated malaria. Biochem Soc Trans. 2010;38(5):1337–41.
22.    Tuikue-Ndam N. Deloron P. Developing vaccines to prevent malaria in pregnant women. Expert Opin Biol Ther. 2015;15(8):1173–82.
23.    Takem EN. D’Alessandro U. Malaria in pregnancy. Mediterr J Hematol Infect Dis. 2013;5(1).
24.    Andersen D. Christoffersen S. Clausen TM. Dahlbäck M. Agerbæk MØ. Jensen KE et al.  Structural and Functional Insight into How the Plasmodium falciparum VAR2CSA Protein Mediates Binding to Chondroitin Sulfate A in Placental Malaria . J Biol Chem. 2012;287(28):23332–45.
25.    Salanti A. Clausen TM. Agerbæk MO. Al Nakouzi N. Dahlbäck M. Oo HZ et al. Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein. Cancer Cell. 2015; 28(4): 500–14.
26.    Pati NB. Jyothi TS. Thakur GS. ReddyS., Meghna G. Tapentadol in Cancer Pain. Asian J. Res. Pharm. Sci. 2017; 7(4):183-188. doi: 10.5958/2231-5659.2017.00028.5
27.    Balaji EV. Selvan AT. Cancer-A Historical Status, Government Regulation and Current Scenario of Socio-Economic Impact – Retrospective Study. Asian J. Pharm. Res. 2018; 8(3): 133-135. doi: 10.5958/2231-5691.2018.00023.0
28.    Sawant R. BaghkarA. Jagtap S. Harad L. Chavan A. Khan NA. Yevale RP. Kale MK. A Review on - Herbs in Anticancer. Asian J. Res. Pharm. Sci. 2018; 8(4):179-184. doi: 10.5958/2231-5659.2018.00031.0
29.    Raju CP. Babu GR. Sowjanya M. Ramayyappa M Evaluation of Cancer Bio-markers through Hyphenated Analytical Techniques. Asian Journal of Pharmaceutical Analysis. 2021; 11(3):235-2. doi: 10.52711/2231-5675.2021.00041
30.    Azzam MH, Fauziah N, Wiraswati HL, The Anticancer Effect of Phytochemicals and Potential of Breynia cernua: An overview. Biomed Pharmacol J 2022;15(4).
31.    WHO. Cancer. World Health Organization. 2018.
32.    Wiraswati HL, Hangen E, Sanz AB, Lam NV, Reinhardt C, Sauvat A, Mogha A, Ortiz A, Kroemer G, Modjtahedi N. Apoptosis inducing factor (AIF) mediates lethal redox stress induced by menadione. Oncotarget. 2016;7(47):76496-76507. doi: 10.18632/oncotarget.12562.
33.    Wiraswati HL, Martoprawiro MA, Akhmaloka, Warganegara FM. Apoptosis Inducing Factor (AIF) Stabilizes Menadione-Conjugate Product in Programmed Cell Death. International Journal of Pharm Tech Research. 2017; 10(4):237-245. 10.20902/IJPTR.2017.10430
34.    Zugazagoitia J. Guedes C. Ponce S. Ferrer I. Molina-Pinelo S. Paz-Ares L. Current Challenges in Cancer Treatment. Clin Ther. 2016;38(7):1551–66.
35.    Madhusudhanan J., Indumathi M. Ammu S. A Novel System for Drug Delivery Using Nanoparticle. Asian J. Pharm. Tech. 2013;  3(4):137-141.
36.    Madhusudhanan J. Monika P. Monica K. Drug Delivery using Nanoparticle along with ssDNA. Asian J. Pharm. Tech. 2013; 3(4):161-164.
37.    Swapnil K. Vijay S. Chandrakant M.. Targeted Drug Delivery: A Backbone for Cancer Therapy. Asian J. Pharm. Res. 2016; 3(1): 40-46.
38.    Sahu K. Pathak R. Agrawal N, Pinkesh Banjare, Harish Sharma, Gyanesh Sahu. A Review of the Novel Drug Delivery System used in the Treatment of Cancer. Res. J. Pharma. Dosage Forms and Tech. 2019; 11(3):199-205. doi: 10.5958/0975-4377.2019.00035.1
39.    Kegade P.  Gade A. Sawant R. Parkar S. Liposomal drug delivery in Cancer. Asian J. Pharm. Res. 2020; 10(4):293-298. doi: 10.5958/2231-5691.2020.00050.7
40.    Sirima SB. Richert L. Chêne A. Konate AT. Campion C. Dechavanne S et al. PRIMVAC vaccine adjuvanted with Alhydrogel or GLA-SE to prevent placental malaria: a first-in-human, randomised, double-blind, placebo-controlled study. Lancet Infect Dis. 2020; 20(5): 585–97.
41.    Thrane S. Janitzek CM. Agerbæk M. Ditlev SB. Resende M. Nielsen MA et al. A novel virus-like particle based vaccine platform displaying the placental malaria antigen VAR2CSA. PLoS One. 2015; 10(11): 1–16.
42.    Zhao K. Li D. Cheng G. Zhang B. Han J. Chen J et al. Targeted delivery prodigiosin to choriocarcinoma by peptide-guided dendrigraft poly-l-lysines nanoparticles. Int J Mol Sci. 2019; 20(21).
43.    Bang-Christensen SR. Pedersen RS. Pereira MA. Clausen TM. Løppke C. Sand NT et al. Capture and Detection of Circulating Glioma Cells Using the Recombinant VAR2CSA Malaria Protein. Cells. 2019; 8(9):1–21.
44.    Tomlinson A. Semblat J-P. Gamain B. Chêne A. VAR2CSA-Mediated Host Defense Evasion of Plasmodium falciparum Infected Erythrocytes in Placental Malaria. Front Immunol [Internet]. 2021 Feb 9;11.
45.    Khunrae P. Dahlbäck M. Nielsen MA. Andersen G. Ditlev SB. Resende M et al. Full-Length Recombinant Plasmodium falciparum VAR2CSA Binds Specifically to CSPG and Induces Potent Parasite Adhesion-Blocking Antibodies. J Mol Biol. 2010;397(3):826–34.
46.    Salanti A. An Affinity-Chromatography and Glycoproteomics Workflow to Profile the Chondroitin Sulfate Proteoglycans that interact with malarial VAR2CSA in the Placenta and in Cancer. Oxford Univ Press. 2020;
47.    Agerbæk M. Bang-Christensen S. Salanti A. Fighting Cancer Using an Oncofetal Glycosaminoglycan-Binding Protein from Malaria Parasites. Trends Parasitol. 2019;35(3):178–81.
48.    Doritchamou J. Teo A. Morrison R. Arora G. Kwan J. Manzella-Lapeira J et al. Functional Antibodies against Placental Malaria Parasites Are Variant Dependent and Differ by Geographic Region. Infect Immun. 2019;87(7).
49.    Dahlbäck M. Jørgensen LM. Nielsen MA. Clausen TM. Ditlev SB. Resende M et al. The Chondroitin Sulfate A-binding Site of the VAR2CSA Protein Involves Multiple N-terminal Domains. J Biol Chem. 2011; 286(18): 15908–17.
50.    Andersen P. Nielsen MA. Resende M. Rask TS. Dahlbäck M. Theander T et al. Structural insight into epitopes in the pregnancy-associated malaria protein VAR2CSA. PLoS Pathog. 2008;4(2).
51.    Fried M. Kurtis JD. Swihart B. Morrison R. Pond-Tor S. Barry A et al. Antibody levels to recombinant VAR2CSA domains vary with Plasmodium falciparum parasitaemia, gestational age, and gravidity, but do not predict pregnancy outcomes. Malar J. 2018; 17(1): 106.
52.    Ayres Pereira M. Mandel Clausen T. Pehrson C. Mao Y. Resende M. Daugaard M et al. Placental Sequestration of Plasmodium falciparum Malaria Parasites Is Mediated by the Interaction Between VAR2CSA and Chondroitin Sulfate A on Syndecan-1.  PLOS Pathog. 2016; 12(8): e1005831.
53.    Pehrson C. Heno KK. Adams Y. Resende M. Mathiesen L. Soegaard M et al. Comparison of functional assays used in the clinical development of a placental malaria vaccine. Vaccine. 2017; 35(4): 610–8.
54.    Gbédandé K. Fievet N. Viwami F. Ezinmegnon S., Issifou S. Chippaux JP et al. Clinical development of a VAR2CSA-based placental malaria vaccine PAMVAC: Quantifying vaccine antigen-specific memory B & T cell activity in Beninese primigravidae. Vaccine. 2017; 35(27): 3474–81.
55.    Mitran CJ. Higa LM. Good MF. Yanow SK. Generation of a peptide vaccine candidate against falciparum placental malaria based on a discontinuous epitope. Vaccines. 2020; 8(3): 1–13.
56.    Chêne A. Gangnard S. Dechavanne C. Dechavanne S. Srivastava A. Tétard M et al. Down-selection of the VAR2CSA DBL1-2 expressed in E. coli as a lead antigen for placental malaria vaccine development. npj Vaccines. 2018; 3(1): 1–11.
57.    Dahlback M. Salanti A. Nielsen M A. Can any lessons be learned from the ambiguous glycan binding of PfEMP1 domains?. Trends in Parasitol. 2010; 26(5):230-235.
58.    Dechavanne S. Srivastava A. Gangnard S. Nunes-Silva S. Dechavanne C. Fievet N et al. Parity-Dependent Recognition of DBL1X-3X Suggests an Important Role of the VAR2CSA High-Affinity CSA-Binding Region in the Development of the Humoral Response against Placental Malaria. Infect Immun. 2015; 83(6): 2466–74.
59.    Salanti A. Resende M. Ditlev SB. Pinto V V. Dahlbäck M. Andersen G et al. Several domains from VAR2CSA can induce Plasmodium falciparum adhesion-blocking antibodies. Malar J . 2010 Dec 11; 9(1):11.
60.    Pinto V V. Ditlev SB. Jensen KE. Resende M. Dahlbäck M. Andersen G et al. Differential Induction of Functional IgG Using the Plasmodium falciparum Placental Malaria Vaccine Candidate VAR2CSA. Langsley G, editor. PLoS One. 2011; 6(3):e17942.
61.    Zhao K. Cheng G. Zhang B. Li D. Han J. Chen J et al. Targeting delivery of partial VAR2CSA peptide guided N-2-Hydroxypropyl trimethyl ammonium chloride chitosan nanoparticles for multiple cancer types. Mater Sci Eng C. 2020; 106: 110171.
62.    Zhang B. Tan L. Yu Y. Wang B. Chen Z. Han J et al. Placenta-specific drug delivery by trophoblast-targeted nanoparticles in mice. Theranostics. 2018; 8(10): 2765–81.
63.    Sharma S. Propper D. Salanti A. Ditlev SB. Aicher A. Bang-Christensen SR et al. The VAR2CSA malaria protein efficiently retrieves circulating tumor cells in an EpCAM-independent manner. Nat Commun. 2018; 9(1).

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