Translational Projects
Translational research programs are typically multiyear, multimillion dollar projects for which preclinical immunogenicity/efficacy testing has been completed and the commitment to clinical testing has been made. Most new programs coming into MVI enter as preclinical feasibility studies, and of those, a limited number subsequently advance to full translational programs on a clinical track. This stage of development spans from preclinical studies through Phase 1 to Phase 2 studies. MVI’s translational projects currently include the research areas listed below, followed by descriptions of the individual projects.
- Crucell Ad35.CS/Ad26.CS
- Crucell/GSK Ad35.CS/RTS,S-AS01
- WRAIR-GSK PvCSP/AS01
Transmission-blocking approach
- NIAID Pfs25
India-based product development projects
- Gennova CSP
- ICGEB/MVDP PvDBPII
Prime-boost approaches
Project name: Ad35.CS/Ad26.CS (Crucell)
Partners: Crucell N.V., Seattle BioMed Malaria Clinical Trials Center (MCTC)
Development stage: Phase 1/2a clinical trial
Platform: Replication-incompetent, recombinant human adenovirus serotype 35 and 26 vectors expressing Plasmodium falciparum gene encoding the circumsporozoite (CS) surface antigen.
Antigen: Full-length CS gene
Adjuvant: N/A
Recent events: Completed vaccination and challenge
Project initiation: October 2007
Project end date: Study closeout expected in June 2012
Biological rationale: While recombinant adenoviruses are potent inducers of cell-mediated immunity to heterologous antigens, the ability to boost immune responses is severely impaired by anti-vector immunity. Heterologous prime-boost regimens, in which common antigens are delivered by different adenovirus serotypes, appear to circumvent this restriction. Preclinical studies have shown that both Ad35.CS and Ad26.CS, when independently administered, are immunogenic, eliciting significant CS-specific antibody responses and CS-specific T-cell responses. Humoral and cellular responses showed dose dependency for both candidate vaccines in several animal experiments. A heterologous prime-boost regimen with Ad35.CS/Ad26.CS has been tested in different animal models, including mice and rabbits, and was shown to have more advantages over homologous boosting. Additional analysis of the antibody responses using immunofluorescence assay showed that all tested sera from animals receiving rAd35.CS/rAd26.CS were positive, indicating that the antibodies induced by the prime-boost regimen are able to bind native P. falciparum sporozoites.
Project name: Ad35.CS/RTS,S-AS01 prime boost
Main partners: Crucell NV, GlaxoSmithKline Vaccines
Additional partners: WRAIR Clinical Trials Center, University of Maryland, Baltimore
Development stage: Phase 1/2a clinical trial
Platform: Replication-deficient, recombinant human adenovirus serotype 35 vector expressing Plasmodium falciparum gene encoding the circumsporozoite (CS) surface antigen; hepatitis B surface antigen (HBsAg) expressing sequences of the CS antigen (RTS,S).
Antigen: P. falciparum circumsporozoite (CS protein)
Adjuvant: AS01, formulated at bedside with AS01 adjuvant (liposomal formulation containing QS21 and MPL) manufactured by GSK Vaccines.
Recent events: Completed vaccination and malaria sporozoite challenge of first cohort
Project Initiation: The clinical trial was started in November 2011
Project End-date: Study closeout expected in November 2013
Biological rationale: Heterologous prime-boost strategies involving the sequential administration of an antigen in two different platforms have been shown to increase the magnitude and/or breadth of vaccine-specific immune responses. In a preclinical nonhuman primate study, a prime-boost regimen involving one dose of Ad35.CS followed by two doses of RTS,S/AS01 was shown to enhance immunogenicity when compared to either vaccine candidate given alone. It is hoped that a corresponding enhancement of protection will be achieved when the same prime-boost strategy is tested in the Phase 1/2a clinical trial.
P. vivax
Project name: P. vivax CSP: VMP001/AS01 (WRAIR/GSK)
Partners: Walter Reed Army Institute of Research, GlaxoSmithKline Vaccines
Development stage: Phase 1/2a clinical trial
Platform: Plasmodium vivax Malaria Protein 001 (VMP001) is a chimeric circumsporozoite protein (CSP) produced in Escherichia coli from a construct that incorporates the major domains of the CS protein from both VK210 (type 1) and VK247 (type 2) parasites, but is distinct from the native protein.
Antigen: Chimeric CS protein
Adjuvant: AS01, formulated at bedside with AS01 adjuvant (liposomal formulation containing QS21 and MPL) manufactured by GSK Vaccines.
Recent events: Completion of all tests
Project initiation: July 2010
Project end date: Q2 2012
Biological rationale: The antigen, VMP001, is a synthetic, chimeric recombinant protein based on the circumsporozoite (CS) protein of P. vivax that incorporates the major domains of the CS protein. The CS protein is the most abundant sporozoite protein present on the sporozoites of all Plasmodium species and has been shown to have great potential as a vaccine for P. vivax malaria. In previous studies, the VMP001 vaccine candidate demonstrated strong immunogenicity and also demonstrated high efficacy in Aotus monkeys challenged with infectious P. vivax sporozoites. This recombinant subunit protein is produced in and purified from E. coli bacteria at the Walter Reed bioproduction facility under cGMP. The antigen is adjuvanted with AS01B, a proprietary adjuvant from GSK that has been used in other vaccines.
Transmission-blocking vaccine approach
Project name: Pfs25-EPA
Main partner: US National Institute of Allergy and Infectious Diseases Laboratory of Malaria Immunology and Virology
Additional partner: Johns Hopkins University Center for Immunization Research
Development stage: Phase 1 clinical trial
Platform: Recombinant Pfs25H protein corresponds to Pfs25 on the surface of zygotes and ookinetes of P. falciparum. It is produced in Pichia, purified, and chemically conjugated to the carrier protein EPA. EPA is a recombinant protein produced in E. coli, and corresponds to a mutant detoxified form of Exo Protein A from Pseudomonas aeruginosa.
Antigen: Pfs25
Adjuvant: Alhydrogel®
Recent events: Completion of the third and final vaccination
Project initiation: September 2011
Project end date: Q3 2013
Biological rationale: Animal studies showed that antibodies against Pfs25 elicit transmission-blocking activities, making Pfs25 a target for development of a transmission-blocking vaccine that has the potential to interrupt parasite development in the mosquito. While such a vaccine would not directly protect an immunized individual from developing clinical malaria, it would reduce the chances that other individuals in the community contract malaria by preventing the spread of infection by the mosquito. Studies conducted in animals demonstrated that conjugating Pfs25H to rEPA significantly increased immunogenicity of Pfs25. In order to further stabilize the conjugate and to enhance immunogenicity, Pfs25-EPA has been adsorbed to Alhydrogel®.
India-based product development projects
Gennova CSP
In 2009, a short study was performed that identified Gennova Biopharmaceuticals as a preferred partner for the development and supply of recombinant circumsporozoite protein (CSP), an important protein for P. falciparum vaccine development, that would be used in feasibility studies evaluating novel delivery systems and adjuvants, in addition to prime-boost regimens. Since that time, Gennova has continued process development (PD) activities on the rCSP in partnership with the Research and Development team at MVI. 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.
PvDBP2
PvDBP2 is a blood-stage antigen targeting P. vivax malaria that will likely be combined with pre-erythrocytic antigen in the future. The objectives of the current project with the International Centre for Genetic Engineering and Biotechnology and the Malaria Vaccine Development Program—both based in New Delhi, India—are to:
- Develop a manufacturing process and produce clinical trial vaccine material.
- Develop assays to support product stability as well as assays to measure antibody responses in human trial volunteers.
- Assess safety, tolerability, and immunogenicity of the PvDBPII vaccine approach in a Phase 1 clinical trial.
