Feasibility studies
New initiatives aim to combine several approaches to developing highly efficacious clinical and transmission-blocking vaccines
MVI is working with a range of partners to evaluate antigens and delivery systems using specialized assays and animal models. These preclinical feasibility studies represent the early stages in vaccine development. Feasibility studies are generally short (typically 6 to 18 months) and require lower levels of investment. Successful outcomes of some of these programs will lead to their advancement to translational programs. By supporting these studies, MVI ensures that any projects that may transition into the portfolio are effectively aligned with our long-term strategic goals.
Some feasibility studies are part of existing and ongoing research collaborations with key partners. A few are represented below.
New initiatives answer R&D questions
MVI expects that our vaccine portfolio and our efforts to accelerate development of malaria vaccines will benefit from the following key collaborations:
Adjuvants/formulations
Antigens
Delivery platforms
Evaluation technologies
Macromolecule and Vaccine Stabilization Center (MVSC)
Type of project: Formulation development of vaccine antigens
Description: The University of Kansas is working to develop stable vaccine formulations that are safe and effective. The scope of work includes the following:
- Biophysical characterization and construction of empirical phase diagrams as a function of pH and temperature.
- Development of high throughput excipient screening assays.
- Excipient screening to identify potential stabilizers that could shield the antigens from environmental stresses.
Project initiation: May 2009
Length of project: 5 years
PfCSP
Type of project: Antigen evaluation
Description: In 2009, a comprehensive immunogenicity and process development analysis of multiple full-length or near-full-length recombinant circumsporozoite proteins (CSP) identified Gennova as a partner for the development and supply of recombinant CSP. CSP is an important target for Plasmodium falciparum vaccine development. The availability of full-length, recombinant CSP has enabled feasibility studies evaluating novel delivery systems and adjuvants, in addition to prime-boost regimens. Since that time, Gennova has continued process development (PD) activities in partnership with several other partners, including the laboratories of Carole Long at Laboratory of Malaria and Vector Research/National Institutes of Health (NIH), Fidel Zavala at Johns Hopkins University, and Bob Seder at Vaccine Research Center/NIH. The next goal for Gennova, after completing PD, is to manufacture rCSP that can be used in early phase clinical trials using technology platforms (e.g., delivery systems and/or adjuvants) being developed by other partners.
Project initiation: 2009
Length of project: Ongoing
Novel pre-erythrocytic antigen discovery
Type of project: Identification and screening of potential novel P. falciparum vaccine targets
Description: The purpose of two ongoing collaborations (Seattle BioMed, Naval Medical Research Center [NMRC]) is to identify targets of CD8+ cell mediated immunity against P. falciparum with the potential to confer protection from infection. Work includes assessment of capacity to protect rodents against P. berghei and/or P. yoelii and of recall responses in human volunteers exposed to P. falciparum.
Project initiation: Seattle BioMed 2009; NMRC 2010
Length of project: 3–4 years
AnAPN1
Type of project: Antigen evaluation
Description: The purpose of this project is to evaluate the feasibility of developing a process to manufacture AnAPN1 as a recombinant protein expressed in E. coli and assess its ability to induce antibodies that block the development of oocysts in the mosquito, thereby indicating that transmission from humans to mosquitoes may be interrupted following immunization.
Syngene International Ltd., India, will:
- Perform process development to include E. coli expression of recombinant AnAPN1 at the 5- to 10-liter fermentation scale as well as purification of the recombinant protein.
- Develop analytical methods to analyze the drug substance and final drug product.
- Perform cGMP manufacturing of the drug substance and final formulation of the drug product, and QA release of clinical trial material.
- Perform real-time and accelerated stability studies on the drug substance and final drug product.
- Prepare the chemistry, manufacturing, and controls section for manufacture of the drug substance and drug product to enable regulatory submission.
Johns Hopkins University Bloomberg School of Public Health will:
- Perform animal immunogenicity experiments, immunizing with various lots of protein (interim and final) to demonstrate consistency in the transmission-blocking activity of the vaccine antigen.
- Conduct epitope mapping, mechanism of action, and structure-function studies to provide further biological insights.
- Perform experiments using antibodies raised to the recombinant AnAPN1 protein to determine if the antibodies have an impact on various life history traits in the mosquito vector, and may therefore affect vaccine efficacy.
Project initiation: Syngene: 2012; Johns Hopkins: 2009
Length of project: Syngene: 1 year; Johns Hopkins: 3 years
EBA/Rh combination blood-stage vaccine
Type of project: Antigen evaluation
Description: Scientists at the Walter and Eliza Hall Institute (WEHI) have demonstrated that immunizing with a combination of merozoite invasion ligands expressed as recombinant proteins induces antibodies that potently block merozoite invasion into erythrocytes. The goal of this project is to identify the optimal minimum combination of antigens to include in a vaccine that can elicit a high level of parasite-growth-inhibitory antibodies against multiple parasite strains of diverse geographical origin.
Gennova Biopharmaceuticals will:
- Perform a feasibility study of small-scale expression and purification of EBA-175, PfRipr, and PfRh5.
- Following protein expression and purification, perform protein characterization and stability studies.
- Provide to WEHI proteins of sufficient quality to meet specified criteria to proceed to further optimization of lead antigens.
- Produce the adjuvant GLA-SE and provide it to WEHI for use in animal immunization studies.
WEHI will:
- Perform preliminary animal immunogenicity experiments using recombinant proteins produced in-house, and confirmatory studies using proteins provided by Gennova.
- Perform initial expression studies of PfRh5 and PfRipr in E. coli and baculovirus. Immunize animals with PfRh5 and PfRipr antigen combinations and assess immunogenicity by performing growth inhibitory assays (GIA).
- Immunize animals with protein combinations produced and characterized by Gennova using GLA-SE adjuvant; perform GIAs against a panel of 30 parasite isolates of diverse origin.
- Perform DNA sequence analysis of all putative vaccine antigens on parasite DNA extracted from a panel of 30 diverse isolates.
- Leverage resources from an ongoing cohort study of children in Papua New Guinea and determine whether associations exist between antibody titer, GIA, and protection from clinical disease.
- Develop a multi-cycle GIA to measure the effect of ongoing exposure to antibodies and identify whether any parasite escape lines arise.
Project initiation: WEHI: 2009; Gennova: 2009
Length of project: 5 years
pDNA with electroporation
Type of project: Plasmid DNA delivery by electroporation
Description: This project focuses on the delivery of plasmids encoding PfCSP, LSA-1, CelTOS, TRAP, and AMA-1. All plasmids were designed to improve expression, consisting of codon and RNA optimization, and the addition of a highly efficient IgE leader sequence. Delivery of plasmids occurs by intramuscular or intradermal injection and electroporation. Initial attention is given to immunogenicity studies in mice and non-human primates using both homologous and heterologous prime-boost regimens. Further, the adjuvant effect of cytokine plasmids such as IL-28B DNA is being evaluated. Inovio Pharmaceuticals and the University of Pennsylvania are collaborating on this project.
Project initiation: March 2009 (extended in September 2010)
Length of project: 4 years
pDNA and VSV prime-boost
Type of project: Delivery of CSP by heterologous prime-boost
Description: The purpose of this study is to generate and test recombinant plasmid DNA (pDNA) and vesicular stomatitis virus (VSV) expressing P. falciparum CSP, as combinations of these two vectors have previously demonstrated strong T- and B-cell responses in preclinical HIV vaccine development. T- and B-cell responses to PfCSP induced by these constructs when administered in homologous and heterologous pDNA-VSV prime-boost regimens will be measured first in mice; if successful, a follow-on immunogenicity study in non-human primates will take place. Profectus Biosciences is performing this study.
Project initiation: July 2009 (extended in October 2011)
Length of project: 3 years
Pre-erythrocytic functional assays
Type of project: Assay optimization
Description: In this study, serum from patients immunized with RTS,S and subsequently challenged will be evaluated using a selection of humoral functional assays performed in different laboratories. The study will involve an initial assessment of assay robustness using standardized reagents provided by MVI followed by downselection of the number of assays used to evaluate the RTS,S serum. Assays that reveal a correlation between antibody activity and protection status in a sporozoite challenge study may then undergo qualification/validation efforts.
Project initiation: 2010
Length of project: Approximately 2.5 years for the initial phase
