Antigen-Displaying Lipid-Enveloped PLGA Nanoparticles as Delivery Agents for a Plasmodium vivax Malaria Vaccine

The parasite Plasmodium vivax is the most frequent cause of malaria outside of sub-Saharan Africa, but efforts to develop viable vaccines against P. vivax so far have been inadequate. We recently developed pathogen-mimicking polymeric vaccine nanoparticles composed of the FDA-approved biodegradable polymer poly(lactide-co-glycolide) acid (PLGA) “enveloped” by a lipid membrane. In this study, we sought to determine whether this vaccine delivery platform could be applied to enhance the immune response against P. vivax sporozoites. A candidate malaria antigen, VMP001, was conjugated to the lipid membrane of the particles, and an immunostimulatory molecule, monophosphoryl lipid A (MPLA), was incorporated into the lipid membranes, creating pathogen-mimicking nanoparticle vaccines (VMP001-NPs). Vaccination with VMP001-NPs promoted germinal center formation and elicited durable antigen-specific antibodies with significantly higher titers and more balanced Th1/Th2 responses in vivo, compared with vaccines composed of soluble protein mixed with MPLA. Antibodies raised by NP vaccinations also exhibited enhanced avidity and affinity toward the domains within the circumsporozoite protein implicated in protection and were able to agglutinate live P. vivax sporozoites. These results demonstrate that these VMP001-NPs are promising vaccines candidates that may elicit protective immunity against P. vivax sporozoites.

[1]  D. Irvine,et al.  Robust IgG responses to nanograms of antigen using a biomimetic lipid-coated particle vaccine. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[2]  D. Irvine,et al.  Enhancing humoral responses to a malaria antigen with nanoparticle vaccines that expand Tfh cells and promote germinal center induction , 2012, Proceedings of the National Academy of Sciences.

[3]  D. Irvine,et al.  In situ engineering of the lymph node microenvironment via intranodal injection of adjuvant-releasing polymer particles , 2011, Proceedings of the National Academy of Sciences.

[4]  D. Irvine,et al.  Membrane Anchored Immunostimulatory Oligonucleotides for In Vivo Cell Modification and Localized Immunotherapy** , 2011, Angewandte Chemie.

[5]  S. Nutt,et al.  Germinal center B and follicular helper T cells: siblings, cousins or just good friends? , 2011, Nature Immunology.

[6]  Wah Chiu,et al.  Interbilayer-Crosslinked Multilamellar Vesicles as Synthetic Vaccines for Potent Humoral and Cellular Immune Responses , 2011, Nature materials.

[7]  John Steel,et al.  Programming the magnitude and persistence of antibody responses with innate immunity , 2010, Nature.

[8]  E. Fikrig,et al.  TLR9-Targeted Biodegradable Nanoparticles as Immunization Vectors Protect against West Nile Encephalitis , 2010, The Journal of Immunology.

[9]  G. Vogel.  Infectious disease. New map illustrates risk from the 'other' malaria. , 2010, Science.

[10]  W. Ballou.  The development of the RTS,S malaria vaccine candidate: challenges and lessons , 2009, Parasite immunology.

[11]  J. Baird,et al.  Key gaps in the knowledge of Plasmodium vivax, a neglected human malaria parasite. , 2009, The Lancet. Infectious diseases.

[12]  Burton E. Barnett,et al.  Bcl6 and Blimp-1 Are Reciprocal and Antagonistic Regulators of T Follicular Helper Cell Differentiation , 2009, Science.

[13]  Richard A Flavell,et al.  Inflammasome-activating nanoparticles as modular systems for optimizing vaccine efficacy. , 2009, Vaccine.

[14]  Wei Xu,et al.  Enhanced resistance to coxsackievirus B3-induced myocarditis by intranasal co-immunization of lymphotactin gene encapsulated in chitosan particle. , 2009, Virology.

[15]  C. Ockenhouse,et al.  Process development for the production of an E. coli produced clinical grade recombinant malaria vaccine for Plasmodium vivax. , 2009, Vaccine.

[16]  J. Tschopp,et al.  Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome , 2009, Proceedings of the National Academy of Sciences.

[17]  D. Irvine,et al.  Polymer-supported lipid shells, onions, and flowers. , 2008, Soft matter.

[18]  A. Salem,et al.  A comparative study of the antigen-specific immune response induced by co-delivery of CpG ODN and antigen using fusion molecules or biodegradable microparticles. , 2007, Journal of pharmaceutical sciences.

[19]  Nicholas J White,et al.  Vivax malaria: neglected and not benign. , 2007, The American journal of tropical medicine and hygiene.

[20]  Sai T Reddy,et al.  Exploiting lymphatic transport and complement activation in nanoparticle vaccines , 2007, Nature Biotechnology.

[21]  J. Sattabongkot,et al.  A Novel Chimeric Plasmodium vivax Circumsporozoite Protein Induces Biologically Functional Antibodies That Recognize both VK210 and VK247 Sporozoites , 2006, Infection and Immunity.

[22]  Roger Le Grand,et al.  Surfactant-free anionic PLA nanoparticles coated with HIV-1 p24 protein induced enhanced cellular and humoral immune responses in various animal models. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[23]  Manmohan J. Singh,et al.  Encapsulation of the immune potentiators MPL and RC529 in PLG microparticles enhances their potency. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[24]  Ying-hua Chen,et al.  High epitope density in a single protein molecule significantly enhances antigenicity as well as immunogenicity: a novel strategy for modern vaccine development and a preliminary investigation about B cell discrimination of monomeric proteins , 2005, European journal of immunology.

[25]  L. McHeyzer-Williams,et al.  Antigen-specific memory B cell development. , 2005, Annual review of immunology.

[26]  Jie Li,et al.  Size-Dependent Immunogenicity: Therapeutic and Protective Properties of Nano-Vaccines against Tumors1 , 2004, The Journal of Immunology.

[27]  U. Frevert,et al.  Intravital microscopy demonstrating antibody-mediated immobilisation of Plasmodium berghei sporozoites injected into skin by mosquitoes. , 2004, International journal for parasitology.

[28]  Russell J Mumper,et al.  Strong T cell type-1 immune responses to HIV-1 Tat (1-72) protein-coated nanoparticles. , 2004, Vaccine.

[29]  J. Ulmer,et al.  Induction of Broad and Potent Anti-Human Immunodeficiency Virus Immune Responses in Rhesus Macaques by Priming with a DNA Vaccine and Boosting with Protein-Adsorbed Polylactide Coglycolide Microparticles , 2003, Journal of Virology.

[30]  G. Lipowsky,et al.  Regulation of IgG antibody responses by epitope density and CD21‐mediated costimulation , 2002, European journal of immunology.

[31]  Federica Sallusto,et al.  Follicular B Helper T Cells Express Cxc Chemokine Receptor 5, Localize to B Cell Follicles, and Support Immunoglobulin Production , 2000, The Journal of experimental medicine.

[32]  D. Jue,et al.  Immunogenicity of Plasmodium falciparum and Plasmodium vivax circumsporozoite protein repeat multiple antigen constructs (MAC). , 1998, Vaccine.

[33]  K. Rock,et al.  Efficient major histocompatibility complex class I presentation of exogenous antigen upon phagocytosis by macrophages. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[34]  S. Hoffman,et al.  Low immunogenicity of a Plasmodium vivax circumsporozoite protein epitope bound by a protective monoclonal antibody. , 1992, American Journal of Tropical Medicine and Hygiene.

[35]  S. Hoffman,et al.  Inability of malaria vaccine to induce antibodies to a protective epitope within its sequence. , 1991, Science.