A double-blind, placebo-controlled phase 1/2a trial of the genetically attenuated malaria vaccine PfSPZ-GA1

Roestenberg, Meta; Walk, Jona; Boor, Saskia C van der; Langenberg, Marijke C. C.; Hoogerwerf, Marie-Astrid; Janse, Jacqueline J.; Manurung, Mikhael D.; Yap, Xi Zen; Fabra-García, Amanda; Koopman, J.; Meij, Pauline; Wessels, Els; Teelen, Karina; Waardenburg, Youri M van; Vegte‐Bolmer, Marga van de; Gemert, Geert Jan van; Visser, Leo G.; Ven, A.J.A.M. van der; Mast, Quirijn de; Natasha, K C; Abebe, Yonas; Murshedkar, Tooba; Billingsley, Peter F.; Richie, Thomas L.; Sim, B. Kim Lee; Janse, Chris J.; Hoffman, Stephen L.; Khan, Shahid M.; Sauerwein, Robert W.

doi:10.1126/scitranslmed.aaz5629

Cited by 52 publications

(67 citation statements)

References 31 publications

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“…Sanaria ® PfSPZ Vaccine (Sanaria Inc., Rockville, MD), composed of radiation-attenuated, aseptic, purified, cryopreserved, whole Plasmodium falciparum (Pf) sporozoites (SPZ), is designed to achieve these objectives. PfSPZ Vaccine has been assessed in 21 completed or ongoing trials in the United States, European Union, and Africa, and shown to be safe and well tolerated, 2 – 17 with almost no differences in adverse event (AE) profiles between vaccinees and normal saline (NS) placebo recipients in 12 of the 13 trials among the 21 that used a randomized, double-blind, placebo-controlled design (in one trial conducted in Burkina Faso, there was an increased frequency myalgia in vaccinees—Sirima and Laurens, unpublished). Vaccine efficacy (VE) > 90% against homologous (same parasite strain in vaccine and challenge) controlled human malaria infection (CHMI) at 3–11 weeks after last dose has been shown in the United States, 3 , 5 Tanzania, 11 and Mali, 17 and can last for at least 14 months.…”

Section: Introductionmentioning

confidence: 99%

Multi-Dose Priming Regimens of PfSPZ Vaccine: Safety and Efficacy against Controlled Human Malaria Infection in Equatoguinean Adults

Jongo

Church

Nchama

et al. 2022

The American Journal of Tropical Medicine and Hygiene

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Plasmodium falciparum sporozoites (PfSPZ) Vaccine is composed of radiation-attenuated, aseptic, purified cryopreserved PfSPZ. Multiple clinical trials empirically assessing two to six doses have shown multi-dose priming (—two to four doses the first week) to be optimal for protection in both 4- and 16-week regimens. In this randomized, double-blind, normal saline (NS), placebo-controlled trial, four groups (G) of 18- to 32-year-old Equatoguineans received multi-dose priming regimens with or without a delayed final dose at 4 or 16 weeks (9 × 105 PfSPZ/dose). The regimens were G1: days 1, 3, 5, 7, and 113; G2: days 1, 3, 5, and 7; G3: days 1, 3, 5, 7, and 29; and G4: days 1, 8, and 29). All doses were 9 × 105 PfSPZ. Tolerability, safety, immunogenicity, and vaccine efficacy (VE) against homologous-controlled human malaria infection (CHMI) 6–7 weeks after vaccination were assessed to down-select the best regimen. All four regimens were safe and well tolerated, with no significant differences in adverse events (AEs) between vaccinees (N = 84) and NS controls (N = 20) or between regimens. Out of 19 controls, 13 developed Pf parasitemia by quantitative polymerase chain reaction (qPCR) after CHMI. Only the vaccine regimen administered on study days 1, 8, and 29 gave significant protection (7/21 vaccinees versus 13/19 controls infected, VE 51.3%, P = 0.03, Barnard’s test, two-tailed). There were no significant differences in antibodies against Pf circumporozoite protein (PfCSP), a major SPZ antigen, between protected and nonprotected vaccinees or controls pre-CHMI. The six controls not developing Pf parasitemia had significantly higher antibodies to blood stage antigens Pf exported protein 1 (PfEXP1) and Pf merozoite surface protein 1 (PfMSP1) than the controls who developed parasitemia, suggesting naturally acquired immunity against Pf-limited infections in controls. This study identified a safe, protective, 4-week, multi-dose prime vaccination regimen for assessment in future trials of PfSPZ Vaccine.

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Section: Introductionmentioning

confidence: 99%

Multi-Dose Priming Regimens of PfSPZ Vaccine: Safety and Efficacy against Controlled Human Malaria Infection in Equatoguinean Adults

Jongo

Church

Nchama

et al. 2022

The American Journal of Tropical Medicine and Hygiene

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“… 49 Pf SPZ-GA1 vaccine, a Pf identical double knockout ( b9 - slarp - ), which attenuate early in EEF development, presented safety profile and elicited immune responses. 50 The pre-clinical findings of PfSPZ-GA1 are promising, as they have shown optimal immunogenicity and some indication of protection.…”

Section: Progress With Malaria Pre-erythrocytic Stage Vaccinesmentioning

confidence: 99%

Immune responses to malaria pre‐erythrocytic stages: Implications for vaccine development

Abuga

Jones‐Warner

Hafalla

2020

Parasite Immunology

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Radiation‐attenuated sporozoites induce sterilizing immunity and remain the 'gold standard' for malaria vaccine development. Despite practical challenges in translating these whole sporozoite vaccines to large‐scale intervention programmes, they have provided an excellent platform to dissect the immune responses to malaria pre‐erythrocytic (PE) stages, comprising both sporozoites and exoerythrocytic forms. Investigations in rodent models have provided insights that led to the clinical translation of various vaccine candidates—including RTS,S/AS01, the most advanced candidate currently in a trial implementation programme in three African countries. With advances in immunology, transcriptomics and proteomics, and application of lessons from past failures, an effective, long‐lasting and wide‐scale malaria PE vaccine remains feasible. This review underscores the progress in PE vaccine development, focusing on our understanding of host‐parasite immunological crosstalk in the tissue environments of the skin and the liver. We highlight possible gaps in the current knowledge of PE immunity that can impact future malaria vaccine development efforts.

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“…The development of malaria vaccines has accelerated in recent times. Several types of malaria vaccines [ 6 ], including protein subunit vaccines [ 7 , 8 , 9 , 10 , 11 ], DNA vaccines [ 12 ], viral vector or virus-like particle vaccines [ 13 , 14 ], whole parasite vaccines, and genetically/chemically attenuated parasite vaccines [ 15 , 16 , 17 ] are being developed, and some of these are currently in clinical trials. RTS,S/AS01 malaria vaccine (Mosquirix) [ 8 , 9 , 10 ] is the frontrunner malaria vaccine, and has been administered to 800,000 children in Ghana, Kenya, and Malawi in an ongoing pilot program since 2019.…”

Section: Introductionmentioning

confidence: 99%

“…B9/slarp gene-deficient Pf sporozoites were generated [ 20 ]; these parasites invaded hepatocytes, but although they died during liver-stage parasite development, they made enough antigen to induce anti-liver-stage malaria immunity. A clinical study of controlled human malaria infection using the above genetically attenuated parasite, PfSPZ-GA1, was conducted in the Netherlands [ 17 ]. Usually, sporozoite(s)-based (whole parasite) vaccines have strain specificity.…”

Section: Introductionmentioning

confidence: 99%

Live Vaccination with Blood-Stage Plasmodium yoelii 17XNL Prevents the Development of Experimental Cerebral Malaria

et al. 2022

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In our work, we aim to develop a malaria vaccine with cross-strain (-species) protection. C57BL/6 mice infected with the P. berghei ANKA strain (PbA) develop experimental cerebral malaria (ECM). In contrast, ECM development is inhibited in infected mice depleted of T cells. The clinical applications of immune-cell depletion are limited due to the benefits of host defense against infectious diseases. Therefore, in the present study we attempted to develop a new method for preventing ECM without immune cell depletion. We demonstrated that mice inoculated with a heterologous live-vaccine of P. yoelii 17XNL were able to prevent both ECM and lung pathology and survived longer than control mice when challenged with PbA. Live vaccination protected blood–organ barriers from PbA infection. Meanwhile, live vaccination conferred sterile protection against homologous challenge with the P. yoelii 17XL virulent strain for the long-term. Analysis of the immune response induced by live vaccination showed that cross-reactive antibodies against PbA antigens were generated. IL-10, which has an immunosuppressive effect, was strongly induced in mice challenged with PbA, unlike the pro-inflammatory cytokine IFNγ. These results suggest that the protective effect of heterologous live vaccination against ECM development results from IL-10-mediated host protection.

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A double-blind, placebo-controlled phase 1/2a trial of the genetically attenuated malaria vaccine PfSPZ-GA1

Abstract: The genetically attenuated malaria vaccine PfSPZ-GA1 is safe, immunogenic, and has suboptimal protective efficacy in people.

Cited by 52 publications

References 31 publications

Multi-Dose Priming Regimens of PfSPZ Vaccine: Safety and Efficacy against Controlled Human Malaria Infection in Equatoguinean Adults

Multi-Dose Priming Regimens of PfSPZ Vaccine: Safety and Efficacy against Controlled Human Malaria Infection in Equatoguinean Adults

Immune responses to malaria pre‐erythrocytic stages: Implications for vaccine development

Live Vaccination with Blood-Stage Plasmodium yoelii 17XNL Prevents the Development of Experimental Cerebral Malaria

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