Sporozoite Immunization: Innovative Translational Science to Support the Fight Against Malaria

Introduction: Malaria, a devastating febrile illness caused by protozoan parasites, sickened 247,000,000 people in 2021 and killed 619,000, mostly children and pregnant women in sub-Saharan Africa. A highly effective vaccine is urgently needed, especially for (Pf), the deadliest human malaria parasite.

Areas Covered: Sporozoites (SPZ), the parasite stage transmitted by mosquitoes to humans, are the only vaccine immunogen achieving >90% efficacy against Pf infection. This review describes >30 clinical trials of PfSPZ vaccines in the U.S.A., Europe, Africa, and Asia, based on first-hand knowledge of the trials and PubMed searches of 'sporozoites,' 'malaria,' and 'vaccines.'

Expert Opinion: First generation (radiation-attenuated) PfSPZ vaccines are safe, well tolerated, 80-100% efficacious against homologous controlled human malaria infection (CHMI) and provide 18-19 months protection without boosting in Africa. Second generation chemo-attenuated PfSPZ are more potent, 100% efficacious against stringent heterologous (variant strain) CHMI, but require a co-administered drug, raising safety concerns. Third generation, late liver stage-arresting, replication competent (LARC), genetically-attenuated PfSPZ are expected to be both safe and highly efficacious. Overall, PfSPZ vaccines meet safety, tolerability, and efficacy requirements for protecting pregnant women and travelers exposed to Pf in Africa, with licensure for these populations possible within 5 years. Protecting children and mass vaccination programs to block transmission and eliminate malaria are long-term objectives.

Citing Articles

Liver stage P. falciparum antigens highly targeted by CD4+ T cells in malaria-exposed Ugandan children.

Acevedo G, Samiee S, Ilala M, Levan J, Olive M, Hunter R PLoS Pathog. 2025; 21(2):e1012943.

PMID: 39993000 PMC: 11906071. DOI: 10.1371/journal.ppat.1012943.

Setting sights on a single-shot malaria vaccine.

Goswami D, Kappe S Nat Med. 2025; 31(1):33-34.

PMID: 39753973 DOI: 10.1038/s41591-024-03427-3.

Single immunization with genetically attenuated Pf∆mei2 (GA2) parasites by mosquito bite in controlled human malaria infection: a placebo-controlled randomized trial.

Roozen G, van Schuijlenburg R, Hensen A, Koopman J, Lamers O, Geurten F Nat Med. 2025; 31(1):218-222.

PMID: 39753962 PMC: 11750698. DOI: 10.1038/s41591-024-03347-2.

Identifying Plasmodium P36 and P52 antigens for coadministration with circumsporozoite protein to enhance vaccine efficacy.

Yadav N, Kalata A, Reynolds R, Raappana A, Sather D, Murphy S NPJ Vaccines. 2024; 9(1):241.

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A Plasmodium late liver stage arresting GAP provides superior protection in mice.

Mishra A, Paul P, Srivastava M, Mishra S NPJ Vaccines. 2024; 9(1):193.

PMID: 39424860 PMC: 11489731. DOI: 10.1038/s41541-024-00975-0.

References

Spring M, Murphy J, Nielsen R, Dowler M, Bennett J, Zarling S . First-in-human evaluation of genetically attenuated Plasmodium falciparum sporozoites administered by bite of Anopheles mosquitoes to adult volunteers. Vaccine. 2013; 31(43):4975-83. DOI: 10.1016/j.vaccine.2013.08.007. View

Regules J, Cicatelli S, Bennett J, Paolino K, Twomey P, Moon J . Fractional Third and Fourth Dose of RTS,S/AS01 Malaria Candidate Vaccine: A Phase 2a Controlled Human Malaria Parasite Infection and Immunogenicity Study. J Infect Dis. 2016; 214(5):762-71. DOI: 10.1093/infdis/jiw237. View

Sulyok Z, Fendel R, Eder B, Lorenz F, Kc N, Karnahl M . Heterologous protection against malaria by a simple chemoattenuated PfSPZ vaccine regimen in a randomized trial. Nat Commun. 2021; 12(1):2518. PMC: 8097064. DOI: 10.1038/s41467-021-22740-w. View

Casares S, Richie T . Immune evasion by malaria parasites: a challenge for vaccine development. Curr Opin Immunol. 2009; 21(3):321-30. DOI: 10.1016/j.coi.2009.05.015. View

Matthias D, Robertson J, Garrison M, Newland S, Nelson C . Freezing temperatures in the vaccine cold chain: a systematic literature review. Vaccine. 2007; 25(20):3980-6. DOI: 10.1016/j.vaccine.2007.02.052. View

Gueirard P, Tavares J, Thiberge S, Bernex F, Ishino T, Milon G . Development of the malaria parasite in the skin of the mammalian host. Proc Natl Acad Sci U S A. 2010; 107(43):18640-5. PMC: 2972976. DOI: 10.1073/pnas.1009346107. View

Datoo M, Natama H, Some A, Bellamy D, Traore O, Rouamba T . Efficacy and immunogenicity of R21/Matrix-M vaccine against clinical malaria after 2 years' follow-up in children in Burkina Faso: a phase 1/2b randomised controlled trial. Lancet Infect Dis. 2022; 22(12):1728-1736. DOI: 10.1016/S1473-3099(22)00442-X. View

Sulyok M, Ruckle T, Roth A, Murbeth R, Chalon S, Kerr N . DSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infection. Lancet Infect Dis. 2017; 17(6):636-644. PMC: 5446410. DOI: 10.1016/S1473-3099(17)30139-1. View

Wang R, Doolan D, Le T, Hedstrom R, Coonan K, Charoenvit Y . Induction of antigen-specific cytotoxic T lymphocytes in humans by a malaria DNA vaccine. Science. 1998; 282(5388):476-80. DOI: 10.1126/science.282.5388.476. View

10.

Wahid R, Fresnay S, Levine M, Sztein M . Immunization with Ty21a live oral typhoid vaccine elicits crossreactive multifunctional CD8+ T-cell responses against Salmonella enterica serovar Typhi, S. Paratyphi A, and S. Paratyphi B in humans. Mucosal Immunol. 2015; 8(6):1349-59. PMC: 4607552. DOI: 10.1038/mi.2015.24. View

11.

Schafer C, Dambrauskas N, Reynolds L, Trakhimets O, Raappana A, Flannery E . Partial protection against P. vivax infection diminishes hypnozoite burden and blood-stage relapses. Cell Host Microbe. 2021; 29(5):752-756.e4. DOI: 10.1016/j.chom.2021.03.011. View

12.

Krzych U, Dalai S, Zarling S, Pichugin A . Memory CD8 T cells specific for plasmodia liver-stage antigens maintain protracted protection against malaria. Front Immunol. 2012; 3:370. PMC: 3517952. DOI: 10.3389/fimmu.2012.00370. View

13.

Zarling S, Berenzon D, Dalai S, Liepinsh D, Steers N, Krzych U . The survival of memory CD8 T cells that is mediated by IL-15 correlates with sustained protection against malaria. J Immunol. 2013; 190(10):5128-41. PMC: 3646969. DOI: 10.4049/jimmunol.1203396. View

14.

Roestenberg M, Bijker E, Sim B, Billingsley P, James E, Bastiaens G . Controlled human malaria infections by intradermal injection of cryopreserved Plasmodium falciparum sporozoites. Am J Trop Med Hyg. 2012; 88(1):5-13. PMC: 3541746. DOI: 10.4269/ajtmh.2012.12-0613. View

15.

Nyirenda T, Nyirenda J, Tembo D, Storm J, Dube Q, Msefula C . Loss of Humoral and Cellular Immunity to Invasive Nontyphoidal Salmonella during Current or Convalescent Plasmodium falciparum Infection in Malawian Children. Clin Vaccine Immunol. 2017; 24(7). PMC: 5498726. DOI: 10.1128/CVI.00057-17. View

16.

Horne-Debets J, Faleiro R, Karunarathne D, Liu X, Lineburg K, Poh C . PD-1 dependent exhaustion of CD8+ T cells drives chronic malaria. Cell Rep. 2013; 5(5):1204-13. DOI: 10.1016/j.celrep.2013.11.002. View

17.

Olotu A, Urbano V, Hamad A, Eka M, Chemba M, Nyakarungu E . Advancing Global Health through Development and Clinical Trials Partnerships: A Randomized, Placebo-Controlled, Double-Blind Assessment of Safety, Tolerability, and Immunogenicity of PfSPZ Vaccine for Malaria in Healthy Equatoguinean Men. Am J Trop Med Hyg. 2017; 98(1):308-318. PMC: 5928718. DOI: 10.4269/ajtmh.17-0449. View

18.

Warburg A, MILLER L . Sporogonic development of a malaria parasite in vitro. Science. 1992; 255(5043):448-50. DOI: 10.1126/science.1734521. View

19.

Bastiaens G, van Meer M, Scholzen A, Obiero J, Vatanshenassan M, van Grinsven T . Safety, Immunogenicity, and Protective Efficacy of Intradermal Immunization with Aseptic, Purified, Cryopreserved Plasmodium falciparum Sporozoites in Volunteers Under Chloroquine Prophylaxis: A Randomized Controlled Trial. Am J Trop Med Hyg. 2015; 94(3):663-673. PMC: 4775905. DOI: 10.4269/ajtmh.15-0621. View

20.

Seder R, Chang L, Enama M, Zephir K, Sarwar U, Gordon I . Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine. Science. 2013; 341(6152):1359-65. DOI: 10.1126/science.1241800. View