Evaluation of Novel Preerythrocytic Anti-infection Malaria Vaccine Candidates

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

From our collaborative publication this year, we report the following advances in FY2023: Chavtur C, Staubus WJ, Ho M, Hergott DEB, Seilie AM, Healy SA, Duffy PE, Jackson L, Talley A, Kappe SHI, Hoffman SL, Richie TL, Kublin JG, Chang M, Murphy SC. Plasmodium 18S Ribosomal RNA Biomarker Clearance After Food and Drug Administration-Approved Antimalarial Treatment in Controlled Human Malaria Infection Trials. 2023. Open Forum Infect Dis. Apr 13;10(5):ofad202. doi: 10.1093/ofid/ofad202. Sensitive molecular assays, such as quantitative reverse-transcription polymerase chain reaction (qRT-PCR) of Plasmodium 18S ribosomal RNA (rRNA), are increasingly the primary method of detecting infections in controlled human malaria infection (CHMI) trials. However, thick blood smears (TBSs) remain the main method for confirming clearance of parasites after curative treatment, in part owing to uncertainty regarding biomarker clearance rates. This collaborative project led by University of Washington compiled 18S rRNA qRT-PCR data from 127 Plasmodium falciparuminfected participants treated with chloroquine or atovaquone-proguanil in 6 CHMI studies conducted in Seattle, Washington, over the past decade. We used a survival analysis approach to compare biomarker and TBS clearance times among studies. The effect of the parasite density at which treatment was initiated on clearance time was estimated using linear regression. The median time to biomarker clearance was 3 days (interquartile range, 35 days), while the median time to TBS clearance was 1 day (12 days). Time to biomarker clearance increased with the parasite density at which treatment was initiated. Parasite density did not have a significant effect on TBS clearance. We concluded the Plasmodium 18S rRNA biomarker clears quickly and can be relied on to confirm the adequacy of Food and Drug Administrationapproved treatments in CHMI studies at nonendemic sites. Richie TL, Church LWP, Murshedkar T, Billingsley PF, James ER, Healy SA, Diawara H, Sissoko MS, Sagara I, Cook DM, Mordmller B, Chakravarty S, Kapulu M, Kreidenweiss A, Vaughan A, Kublin J, Murphy S, Jongo S, Tanner M, Sirima S, Laurens M, Daubenberger C, Silva J, Lyke KE, Abdulla S, Dicko A, Kappe S, Sim BKL, Kremsner PG, Duffy PE, Hoffman SL. Sporozoite Immunization: Innovative Translational Science to Support the Fight Against Malaria. 2023. Expert Review of Vaccines. In press. doi:10.1080/14760584.2023.2245890 A highly effective malaria vaccine is urgently needed, especially for Plasmodium falciparum (Pf), the deadliest human malaria parasite. Sporozoites (SPZ), the parasite stage transmitted by Anopheles mosquitoes to humans, are the only vaccine immunogen achieving > 90% efficacy against Pf infection. We and our partners in the PfSPZ Consortium reviewed > 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.' 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. These studies conducted in humans have generated data and samples that can now be exploited for discovery of novel sporozoite/liver-stage antigens targeted by protective immune responses. Our unpublished progress during this reporting period includes the following advances: In FY2023, we continued our work on the 2 PfPEVA candidates PfSHMT and PfTBP. Efforts to make full-length PfTBP proved to be quite challenging, so a novel approach was taken. We employed in silico and structural prediction to design an N-terminal construct that improves recombinant expression and may focus B cell responses. PfTBP N-terminus was produced in E. coli and purified to a high level using mixed mode chromatography. Immunization with PfTBP N-terminus demonstrated low antibody titers suggesting the immunogenicity of the construct was low. Efforts to improve immunogenicity are underway. Since the PfPEVA candidates are partnered with PfCSP we tested if co-immunization with PfSHMT interfered with PfCSP titers or functional activity. Mice were immunized with 3 doses of either PfCSP-EPA conjugate vaccine alone or PfCSP-EPA+PfSHMT, with a high and a low dose of PfSHMT. Animals that received the high dose of PfSHMT had a small reduction in the PfCSP titers suggesting slight interference, however, this did not manifest in a reduction in sterile protection with challenge of the Pb PfCSP chimeric parasite. Finally, we sought a model in which to test the efficacy of our PfPEVA candidates. In collaboration with Leiden University Medical Center we successfully generated double transgenic Plasmodium berghei parasites that expressed both PfCSP and PfSHMT or PfCSP and PfTBP.