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Principal Investigator: Patrick Duffy
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2020
Award: $3,037,907
Funding agency: National Institute of Allergy and Infectious Diseases
In FY2020, LMIV scientists contributed to 1 publication on conjugate or particle vaccines, and we describe progress reported in those manuscripts here:
1. In published work, we observed that alternate carriers increase antibody titers of Pfs25 & Pfs230 above benchmark EPA carrier; TBV antigens conjugated to TT and CRM197 induce highest functional activity; liposomal GLA-LSQ adjuvant further enhances titers and Th1 isotype switching. Scaria PV, et al. Vaccine. 2020;38(34):5480-5489.) Based on the enhanced immune response observed in these studies, we selected an E. Coli produced CRM197 (EcoCRM from FinaBiosolutions) as an alternate carrier for Pfs230. Currently working on establishing a collaborative agreement with FinaBiosolutions for the use of EcoCRM, process development for scaled up synthesis of Pfs230-EcoCRM conjugate, evaluation of the conjugate in NHP studies and product development activities that enable its clinical testing.
In unpublished work, we report below our progress on other ongoing projects:
Further evaluation of OMPC as a delivery platform for Transmission Blocking Vaccine antigens:
In FY2020, we continued the evaluation of OMPC as a delivery platform for TBV antigens. In our previous report, we described a qualitatively different, Th1-biased immune response was observed for OMPC conjugates as opposed to a Th2 response of EPA conjugates. Based on these findings, we have initiated evaluation of OMPC conjugates of Pfs25 and Pfs230 in nonhuman primates to determine their efficacy in this model and to evaluate the duration of immune response. In these studies, Pfs230 conjugates showed superior transmission blocking activity compared to Pfs25 conjugates. In addition, Pfs230 - OMPC conjugates in Alum adjuvant showed a durable immune response with high antibody titer and functional activity, equivalent to EPA conjugate of Pfs230 formulated in a potent liposomal adjuvant.
Evaluation of mRNA technology for malaria antigens:
In FY2020, we continued the collaboration with CureVac, Germany to test the immunogenicity of LMIVs malaria antigens in CureVacs RNActive technology platform. Antigen delivery using mRNA has generated considerable excitement in the vaccine field as a technology that can rapidly generate vaccine candidates for clinical testing. This technology is now being tested in a number of clinical trials by CureVac and Moderna Therapeutics; both have their proprietary technologies for designing and manufacturing potent mRNAs for vaccine. We worked with CureVac to construct mRNA for our TBV and PMV antigens. In FY2019, CureVac generated a series of mRNA constructs for LMIVs TBV and pregnancy malaria antigens and tested their expression in mammalian cells. As part of this continuing collaboration, mouse immunogenicity studies have been initiated at LMIV to test the immunogenicity and functional activity of these mRNA constructs.
Needle-free vaccine delivery:
In FY2020, we completed the collaboration established with Takeda Pharmaceuticals, Japan to evaluate their proprietary Microneedle Patch delivery technology for delivery of our conjugate immunogens for transmission blocking vaccine. Takedas dissolving microneedle is a technology for vaccine delivery that has a number of attractive features useful for malaria vaccines. Administration of microneedle patches do not require a skilled medical professional or can be self-administered. It avoids needle use by eliminating accidental needle injuries and pain associated with needle delivery. It also does not require cold-chain transport and storage, thereby reducing the cost of mass immunization campaigns. These patches were evaluated in mouse immunogenicity studies at LMIV and showed a poor performance based on antibody responses. Based on these results, Takeda is considering manufacturing issues that may have contributed to poor immunogenicity.
Terms: <Adjuvant><Agreement><Al element><Alum Adjuvant><Aluminum><Antibody Response><Antibody titer measurement><Antigens><Area><Benchmarking><Best Practice Analysis><CRM-197><CRM197><Class Switching><Class Switchings><Clinical Evaluation><Clinical Testing><Clinical Trials><Cold Chains><Collaborations><Development><E coli><E. coli><Escherichia coli><Evaluation><Formulation><Germany><Gestation><Glycans><Goals><Immune response><Immunoglobulin Class Switching><Immunoglobulin Class Switchings><Immunological response><Injury><Isotype Switching><Isotype Switchings><Japan><Liposomal><Liposomes><Malaria><Malaria Vaccines><Malarial Vaccines><Mammalian Cell><Manuscripts><Mass Immunization><Medical><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Meningococcus><Messenger RNA><Mice><Mice Mammals><Modeling><Murine><Mus><N meningitidis><N. meningitidis><Needles><Neisseria meningitidis><P vivax><P. vivax><Pain><Painful><Paludism><Parasites><Performance><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Plasmodium Infections><Plasmodium vivax><Polysaccharides><Pregnancy><Process><Progress Reports><Proteins><Publications><Publishing><RNA vaccine><Recombinant Proteins><Reporting><S enterica serovar Typhi><S typhi><S typhosa><S. enterica serovar Typhi><S. typhi><S. typhosa><Salmonella enterica serovar Typhi><Salmonella typhi><Salmonella typhosa><Scientific Publication><Scientist><Self Administration><Self-Administered><Series><Sexual Development><Surface><Surface Proteins><Technology><Testing><Tetanus Toxoid><Therapeutic><Transmission><Vaccine Antigen><Vaccines><Work><alum><aluminum sulfate><antibody titering><base><burden of disease><burden of illness><clinical test><cost><cross reacting material 197><design><designing><developmental><disease burden><host response><immunogen><immunogenicity><immunoresponse><injuries><mRNA><mRNA vaccine><malaria transmission><malaria transmission-blocking vaccine><non-human primate><nonhuman primate><particle><product development><protein complex><research clinical testing><response><scale up><sex development><transmission process><transmission-blocking vaccine><unpublished works><vaccine candidate><vaccine delivery><vaccines against malaria><years of life lost to disability><years of life lost to disease>