A new malaria vaccine achieves an unprecedented 89% efficacy by targeting late-stage liver antigens, unlocking new horizons in the fight against the global disease.
Study: Safety and Efficacy of Vaccination with Attenuated Liver Malaria Parasite. Image credit: Corona Borealis Studio / Shutterstock
In a recent study published in The New England Journal of Medicineresearchers in the Netherlands evaluated the safety, immune response and protective efficacy of a second generation genetically attenuated (GA) Plasmodium falciparum parasite in healthy adults.
Background
Efforts to eradicate malaria have slowed, highlighting the need for more effective tools. Current malaria vaccines, such as the recombinant protein-based RTS, S/AS01 (Mosquirix), and the modified recombinant R21, target the circumsporozoite protein (CSP), but provide only modest, short-lived protection, particularly in infants. Whole parasite inoculation strategies using GA sporozoites offer a promising alternative. These sporozoites invade liver cells but fail to progress to blood-stage infection, allowing the immune system to safely confront a wide range of parasite antigens and mount humoral and cellular immune responses. Delayed-arrest GA parasites show potential for improved efficacy over early-arrest models. Further research is needed to optimize these strategies and evaluate their effectiveness in malaria endemic areas.
About the Study
A clinical trial was conducted at two centers in the Netherlands, Leiden University Medical Center and Radboud University Medical Center, to evaluate the safety, immunogenicity and efficacy of genetically impaired Plasmodium falciparum parasites. The trial included two phases: phase A, an open-label, dose-escalation phase where participants received 15 or 50 mosquito bites carrying the GA2 parasite, and phase B, a double-blind, placebo-controlled phase comparing the effectiveness of GA2 with GA1 . and placebo. Participants underwent three vaccination sessions at 28-day intervals, each with 50 mosquito bites. Due to COVID-19 restrictions, the trial was conducted with fewer participants than originally planned.
Three weeks after the final inoculation, all participants were subjected to controlled human malaria infection (CHMI) via five mosquito bites infected with non-attenuated P. falciparum strain 3D7 (Pf3D7). Primary outcomes included incidence of adverse events and blood-stage parasitemia, assessed by quantitative polymerase chain reaction (qPCR). Secondary outcomes measured humoral and cellular immune responses using enzyme-linked immunosorbent assay (ELISA) and spectral flow cytometry. Eligible participants, aged 18–35 years, provided informed consent and were randomized by an independent statistician, ensuring blinding of the trial. Statistical analyzes included paired and unpaired t-tests, chi-square tests, and Mann-Whitney tests, with a significance level of 5%.
Study Results
From 13 September 2021 to 28 January 2022, 75 malaria-free adults were screened for participation in the trial, with 43 participants enrolled. No participants withdrew during stage A, while three withdrew before controlled human malaria infection in stage B. Among the participants, 51% were female, with a median age of 23 years and a median body mass index (BMI) of 24.1.
The trial reported no serious adverse events or novel infections following exposure to GA2-infected mosquitoes as confirmed by qPCR. Adverse events, mainly erythema (redness of the skin) and pruritus (itching sensation) at the bite sites, occurred similarly in the GA2, GA1 and placebo groups. Most events were mild and managed with antihistamines or topical corticosteroids. Systemic side effects, such as myalgia and headache, were rare. Two cases of elevated troponin T were assessed as unrelated to the intervention, while elevated liver function test results were attributed to antihistamine use.
In phase B, GA2 immunization provided 89% protection against CHMI, with 8 of 9 participants not developing parasitaemia. In contrast, protection was seen in 1 of 8 GA1 recipients (12%) and none in the placebo group. Time to parasitaemia differed significantly between groups, highlighting the superior efficacy of GA2.
Immunogenicity assay revealed increased antibodies against Plasmodium falciparum CSP (PfCSP) in GA2 and GA1 groups compared to baseline and placebo. However, antibody titers were similar between the GA2 and GA1 groups and did not correlate with protection. Cellular immunoassay showed higher frequencies P. falciparum-specific Cluster of Differentiation 4 Positive T cells (CD4+) and V-Delta-2 Positive Gamma Delta (Vδ2+ γδ) T cells in GA2-immunized participants. These cells displayed a proinflammatory signature, expressing interferon-γ, tumor necrosis factor alpha (TNF-α), and interleukin-2, with GA2 inducing more pluripotent T cells compared to GA1.
GA2-immunized participants showed higher levels of multifunctional CD4+ and Vδ2+ γδ T cells with an effector memory phenotype, indicating a strong immune response. This response was absent in the placebo group and less pronounced in the GA1 group.
conclusions
In summary, this trial showed that late-catch parasites (GA2) induced stronger protective immunity (89%) against malaria than early-catch parasites (GA1, 12%). GA2-induced immunity was associated with multifunctional CD4+ T cells and Vδ2+ γδ T cells, suggesting a central role for late liver stage antigens. Unlike antibodies, these cellular responses were critical for protection. GA2 showed a favorable safety profile, with no significant blood stage infections or serious adverse events.
Further studies are needed to confirm these findings in larger populations, assess durability of immunity, and assess efficacy in malaria endemic areas.
