Biology subjects

Minassian, A. M.

Publications and source records attributed to Minassian, A. M..

4 recordsLinked to original sources

bioRxiv2024

Evaluation of Precision of the Plasmodium knowlesi Growth Inhibition Assay for Plasmodium vivax Duffy-Binding Protein-based Malaria Vaccine Development

Recent data indicate increasing disease burden and importance of Plasmodium vivax (Pv) malaria. A robust assay will be essential for blood-stage Pv vaccine development. Results of the in vitro growth inhibition assay (GIA) with transgenic P. knowlesi (Pk) parasites expressing the Pv Duffy-binding protein region II (PvDBPII) correlate with in vivo protection in the first PvDBPII controlled human malaria infection (CHMI) trials, making the PkGIA an ideal selection tool once the precision of the assay is defined. To determine the precision in percentage of inhibition in GIA (%GIA) and in GIA50 (antibody concentration that gave 50 %GIA), ten GIAs with transgenic Pk parasites were conducted evaluating four different anti-PvDBPII human monoclonal antibodies (mAbs) at different concentrations, and three GIAs were conducted testing eighty anti-PvDBPII human polyclonal antibodies (pAbs) at 10 mg/mL. A significant assay-to-assay variation was observed, and the analysis revealed a standard deviation (SD) of 13.1 in the mAb and 5.94 in the pAb dataset for %GIA, with a LogGIA50 SD of 0.299 (for mAbs). Moreover, the ninety-five percent confidence interval (95%CI) for %GIA or GIA50 in repeat assays was calculated in this investigation. These results will support the development of future blood-stage malaria vaccines, specifically second generation PvDBPII-based formulations.

immunology↗

bioRxiv2024

Preclinical Development of a Stabilized RH5 Virus-Like Particle Vaccine that Induces Improved Anti-Malarial Antibodies

The development of a highly effective vaccine against the pathogenic blood-stage infection of human malaria will require a delivery platform that can induce an antibody response of both maximal quantity and functional quality. One strategy to achieve this includes presenting antigens to the immune system on virus-like particles (VLPs). Here we sought to improve the design and delivery of the blood-stage Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) antigen, which is currently in a Phase 2 clinical trial as a full-length soluble protein-in-adjuvant vaccine candidate called RH5.1/Matrix-M. We identify disordered regions of the full-length RH5 molecule induce non-growth inhibitory antibodies in human vaccinees, and a re-engineered and stabilized immunogen that includes just the alpha-helical core of RH5 induces a qualitatively superior growth-inhibitory antibody response in rats vaccinated with this protein formulated in Matrix-M adjuvant. In parallel, bioconjugation of this new immunogen, termed "RH5.2", to hepatitis B surface antigen VLPs using the "plug-and-display" SpyTag-SpyCatcher platform technology also enabled superior quantitative antibody immunogenicity over soluble antigen/adjuvant in vaccinated mice and rats. These studies identify a new blood-stage malaria vaccine candidate that may improve upon the current leading soluble protein vaccine candidate RH5.1/Matrix-M. The RH5.2-VLP/Matrix-M vaccine candidate is now under evaluation in Phase 1a/b clinical trials.

immunology↗

bioRxiv2023

Natural malaria infection elicits rare but potent neutralizing antibodies to the blood-stage antigen RH5

Plasmodium falciparum RH5 is the most advanced blood-stage malaria vaccine candidate and is under evaluation for efficacy in endemic regions, emphasizing the need to study the underlying antibody response to RH5 during natural infection. Here, we found that RH5-reactive B cells were rare in malaria-exposed individuals despite repeated infections over multiple years. RH5-specific monoclonal antibodies isolated from these individuals were extensively mutated but mostly targeted non-neutralizing epitopes, in contrast to antibodies from RH5-vaccinated, malaria-naive individuals. However, infection-derived MAD8-151 and MAD8-502 were among the most potent neutralizers out of 186 antibodies isolated from both cohorts and target the same epitopes as the most effective vaccine-induced antibodies. Binding to basigin receptor-proximal epitopes was the primary factor governing the potency of RH5-specific antibodies from both natural infection and vaccination, followed by the strength of binding. These results indicate a clear strategy for the development of next-generation RH5 vaccines for use in malaria-endemic regions.

immunology↗

bioRxiv2023

Analysis of the Diverse Antigenic Landscape of the Malaria Invasion Protein RH5 Identifies a Potent Vaccine-Induced Human Public Antibody Clonotype

The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines that seek to protect against the disease-causing blood-stage of malaria. However, the features of the human vaccine-induced antibody response that confer highly potent inhibition of malaria parasite invasion into red blood cells are not well defined. Here we characterize over 200 human IgG monoclonal antibodies induced by the most advanced PfRH5 vaccine. We define the antigenic landscape of this molecule, and establish epitope specificity, antibody association rate and intra-PfRH5 antibody interactions are key determinants of functional anti-parasitic potency. In addition, we identify a germline gene combination that results in an exceptionally potent class of antibody and demonstrate its prophylactic potential to protect against P. falciparum parasite challenge in vivo. This comprehensive dataset provides a framework to guide rational design of next-generation vaccines and prophylactic antibodies to protect against blood-stage malaria.

immunology↗