Research programs

Also referred to as translational programs, these are typically multi-year, multi-million 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 portfolio, translational programs on a clinical track. This stage of development spans from preclinical studies through Phase 1 to Phase 2 studies.

 

Crucell adenovirus-based malaria vaccine candidate

Project Name: Crucell Holland Ltd. Ad35.CS/Ad26.CS Prime Boost

Partner: Crucell N.V.

Development stage: Preclinical; cGMP manufacturing

Platform: Replication-incompetent, recombinant human adenovirus serotype 35 and 26 vectors expressing P. falciparum gene encoding the circumsporozoite (CS) surface antigen

Antigen: Full-length CS gene

Adjuvant: N/A

Recent events: Completed release of Ad26.CS.01 Master Virus Seed and manufacture of Ad26.CS.01 drug substance (clinical trial material). Stability of Ad35.CS.01 drug product continues.

Project Initiation: October 2007

Project End-date: Current agreement with Crucell continues through July 2012. There is no project end-date identified for the clinical trial portion of the project.

Biological rationale: While recombinant adenoviruses are potent inducers of cell-mediated immunity (CMI) to heterologous antigens, the ability to boost immune responses is severely impaired by vector immunity induced following the primary immunization. Prime boost regimens, in which common antigens are delivered by different adenovirus serotypes, appear to circumvent this restriction and therefore hold significant promise for vaccine development using this delivery platform. Preclinical studies for assessment of the humoral and cellular responses to the prime boost of Ad35.CS.01/Ad26.CS.01 were completed in December 2008. The prime boost regimen was studied in mice with a group of 6-8 week old BALB/c mice immunized intramuscularly with Ad35.CS.01 (prime) at a dose of 1x109 vp followed by a boost with Ad26.CS.01 at a dose of 1x1010 vp. Significant IFN-g responses were measured by means of ELISPOT in groups of mice. Analysis of the CS antibody responses by ELISA showed that Ad35.CS.01/Ad26.CS.01 (prime boost) regimen-induced antibody responses that were significantly higher than responses induced by Ad35.CS.01/Ad26.Empty (prime only). Additional analysis of the antibody responses using immunofluorescence assay (IFA) on sera samples from Ad35.CS.01/Ad26.CS.01 groups of mice showed positive, indicating that antibodies induced by the prime boost regimen were able to bind to P. falciparum sporozoites. Poole sera from naïve mice were negative.

Read project fact sheet (34 KB PDF)

ICGEB/PvRII

Project Name: Plasmodium vivax Duffy Binding Protein, Region II (PvRII)

Partners:The International Centre for Genetic Engineering and Biotechnology (ICGEB)

Development Stage: cGMP Manufacture

Platform: Recombinant protein expressed in E. coli.

Antigens: Region II of the Duffy Binding Protein (DBP) of Plasmodium vivax, which is the obligate ligand for merozoite invasion of host erythrocytes.

Adjuvant: N/A

Recent Events: N/A

Project Initiation: N/A

Biological Rationale: Plasmodium vivax and the related simian malaria parasite P. knowlesi are completely dependent on interaction with the Duffy antigen for invasion of human erythrocytes. The receptor binding domain (RII) of DBP mediates this binding and allows the merozoite to invade the red blood cell. Because P. vivax infection does not occur in Duffy negative individuals, and naturally acquired antibodies against the binding domains are developed, PvRII has strong potential as a P. vivax vaccine candidate.P. knowlesi has a Duffy binding protein (PkDBP), which contains a binding domain that is homologous to PvRII, and it has been demonstrated that antibodies to the binding domain of PkDBP block invasion of human erythrocytes by P. knowlesi.Moreover, chemokines, including IL-8 have been shown to inhibit invasion of erythrocytes by P. knowlesi with 50 percent inhibition at nanomolar concentrations of chemokines, thus potentially contributing to functional capacity of the immune response to block erythrocyte invasion.Taken together, this evidence suggests PvRII may be an effective blood-stage vaccine candidate antigen.Indeed, rabbit serum raised against PvRII completely blocks binding of human erythrocytes to COS cells expressing PvRII on their surface up to a dilution of 1:2500.Naturally occurring antibodies directed against PvRII block binding completely only up to a dilution of 1:20 in similar binding assays. Finally, it is predicted that the majority of the polymorphisms found in PvRII in field isolates map to the side opposite to the receptor-binding site, which is good news for a vaccine based on PvRII. Thus, PvRII demonstrates strong potential as a candidate vaccine by eliciting a potent, potentially conserved, merozoite invasion-blocking immune response.

Sanaria PfSPZ

Project Name: Sanaria Inc. Plasmodium falciparum sporozoites

Main Partner: Sanaria Inc.

Additional Partners: US Navy Medical Research Center; Center for Vaccine Development, University of Maryland

Development Stage: Biodistribution study and preparation for Investigational New Drug (IND) ongoing

Platform: Live attenuated sporozoites extracted from the salivary glands of irradiated P. falciparum-infected mosquitoes

Antigen: Sporozoite and liver-stage complex

Adjuvant: N/A

Recent events: Clinical development plan meeting held July 21, 2008

Project initiation: October 2006

Project end date: December 2009

Biological rationale: An estimated 5,000 to 10,000 irradiated sporozoites, delivered by the feeding of more than 1,000 irradiated, infected mosquitoes, protected volunteers from subsequent feeding of unirradiated, infected mosquitoes.

Read project fact sheet (34 KB PDF)

WRAIR/GSK (PvCSP/AS01)

Project Name: Phase 1/2a Study of VMP001 and AS01B in Healthy Malaria-Naïve Adults

Partners: Walter Reed Army Institute of Research (WRAIR) and GlaxoSmithKline (GSK)

Development Stage: Phase 1/2a clinical

Platform: Soluble recombinant protein

Antigens: Chimeric P. vivax CSP containing repeat regions from multiple alleles, expressed in E.coli (VMP001)

Adjuvant: AS01B adjuvant system (liposomes + 3-O-desacyl-4’-20 monophosphoryl lipid A + QS21), GSK (Rixensart, Belgium)

Recent Events: Completed toxicology studies of VMP001/AS01B

Project Initiation: May 2010

Biological Rationale: The P.falciparum vaccine candidate RTS,S, expressing the central and C-terminal regions of CSP protein from Plasmodium falciparum, and fused to hepatitis B surface protein VLPs and formulated with AS01 and AS02 adjuvants, has proven successful in Phase 2a and 2b clinical trials. Targeting other Plasmodium species, such as P. vivax, using a similar approach, is logical. However, unlike for P.falciparum, the CSP protein from P.vivax is associated with allelic variation within the CSP repeats, which represents an important site for B cell epitopes that elicit neutralizing antibody responses. Investigators at WRAIR have developed a novel synthetic “immunologically optimal” chimeric CSP construct. This synthetic construct includes the N- and C-terminal parts of the CS protein and a truncated repeat region that contains repeat sequences from both the VK210 (type 1) and the VK247 (type 2) parasites. The construct is expressed in E. coli as a soluble protein and termed VMP001. It is formulated with GSK’s AS01B adjuvant system, which is known to induce antigen-specific antibody response and Th1 type T cell responses.