Abstract:Immunization with Plasmodium falciparum (Pf) sporozoites under chemoprophylaxis (PfSPZ-CVac) is the most efficacious approach to malaria vaccination. Implementation is hampered by a complex chemoprophylaxis regimen and missing evidence for efficacy against heterologous infection. We report the results of a double-blinded, randomized, placebo-controlled trial of a simplified, condensed immunization regimen in malaria-naive volunteers (EudraCT-Nr: 2018-004523-36). Participants are immunized by direct venous inoc… Show more
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.
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.
“…To estimate the concentration of the IgG antibodies in the saliva, a dilution series of highly pure human IgG (#31154, ThermoFisher) was in parallel coated on the ELISA plates and quantified using the secondary antibodies. A four-parameter logistic curve using MARS Data Analysis Software Version 3.31 was fitted to the respective OD values and the antibody concentrations in the sample specimen calculated 46 .…”
SARS-CoV-2 is evolving with mutations in the receptor binding domain (RBD) being of particular concern. It is important to know how much cross-protection is offered between strains following vaccination or infection. Here, we obtain serum and saliva samples from groups of vaccinated (Pfizer BNT-162b2), infected and uninfected individuals and characterize the antibody response to RBD mutant strains. Vaccinated individuals have a robust humoral response after the second dose and have high IgG antibody titers in the saliva. Antibody responses however show considerable differences in binding to RBD mutants of emerging variants of concern and substantial reduction in RBD binding and neutralization is observed against a patient-isolated South African variant. Taken together our data reinforce the importance of the second dose of Pfizer BNT-162b2 to acquire high levels of neutralizing antibodies and high antibody titers in saliva suggest that vaccinated individuals may have reduced transmission potential. Substantially reduced neutralization for the South African variant further highlights the importance of surveillance strategies to detect new variants and targeting these in future vaccines.
“…5 ). The array comprises 262 Pf protein fragments representing 228 unique proteins as described before 18 . Fig.…”
Section: Resultsmentioning
confidence: 99%
“…The technical challenges of manufacturing and preserving billions of pharmaceutical-grade sporozoites for human use were overcome by the company Sanaria Inc. 22 and clinical development was led by an international effort, including institutions from America, Europe, Asia, and Africa. In this framework, clinical trials have used whole sporozoites that were physically (PfSPZ Vaccine) 23 – 27 , chemically (PfSPZ–CVac) 10 , 18 , 28 , 29 or genetically (PfSPZ–GAP1) 30 attenuated in both malaria-naive and lifelong malaria-exposed human subjects.…”
Section: Discussionmentioning
confidence: 99%
“…A subsequent trial conducted in Tübingen, allowed us to study a PfSPZ–CVac regimen partially inspired by the 10-day regimen with three immunizations of 1.1 × 10 5 PfSPZ given at days 1, 6, and 29 under similar chloroquine dosage. Of interest, we achieved a high degree of heterologous protection (77% VE) challenging the vaccinees immunized using parasite strain PfSPZ NF54 of African origin with the genetically distant Pf 7G8 strain, which was isolated in South America 18 .…”
Repeated direct venous inoculation of Plasmodium falciparum sporozoites (PfSPZ) together with antimalarial chemoprophylaxis (PfSPZ–CVac) is the most potent way to induce sterile immunity against P. falciparum infection in malaria-naive volunteers. However, established schedules are complex and long. Here, we tested two accelerated three-dose schedules (28- and 10-day regimen) assessing efficacy by controlled human malaria infection (CHMI) against placebo, comparing vaccine-specific T cell and antibody responses by antigen-reactive T cell enrichment (ARTE) and protein microarray, respectively. Both regimens were similarly efficacious (67 and 63% vaccine efficacy) but different in the induction of vaccine-specific T cells and antibodies. The 10-day regimen resulted in higher numbers of antigen-specific CD4+ effector memory pro-inflammatory T cells and a broader antibody response compared with the 28-day regimen. Usually in nature, P. falciparum liver stage lasts about 6.5 days. The short vaccination-interval of the 10-day regimen prolongs the time of continuous exposure to liver-stage parasites, which may explain the stronger response. Besides dose and number of vaccinations, duration of liver-stage exposure is a factor to optimize PfSPZ–CVac immunogenicity.
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