title: Development of a Pfs25-EPA malaria transmission blocking vaccine as a chemically conjugated nanoparticle.
abstract: Successful efforts to control infectious diseases have often required the use of effective vaccines. The current global strategy for control of malaria, including elimination and eradication will also benefit from the development of an effective vaccine that interrupts malaria transmission. To this end, a vaccine that disrupts malaria transmission within the mosquito host has been investigated for several decades targeting a 25 kDa ookinete specific surface protein, identified as Pfs25. Phase 1 human trial results using a recombinant Pfs25H/Montanide ISA51 formulation demonstrated that human Pfs25 specific antibodies block parasite infectivity to mosquitoes; however, the extent of blocking was likely insufficient for an effective transmission blocking vaccine. To overcome the poor immunogenicity, processes to produce and characterize recombinant Pfs25H conjugated to a detoxified form of Pseudomonas aeruginosa exoprotein A (EPA) have been developed and used to manufacture a cGMP pilot lot for use in human clinical trials. The Pfs25-EPA conjugate appears as a nanoparticle with an average molar mass in solution of approximately 600 kDa by static light scattering with an average diameter 20 nm (range 10-40 nm) by dynamic light scattering. The molar ratio of Pfs25H to EPA is about 3 to 1 by amino acid analysis, respectively. Outbred mice immunized with the Pfs25-EPA conjugated nanoparticle formulated on Alhydrogel(®) had a 75-110 fold increase in Pfs25H specific antibodies when compared to an unconjugated Pfs25H/Alhydrogel(®) formulation. A phase 1 human trial using the Pfs25-EPA/Alhydrogel(®) formulation is ongoing in the United States.
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Rockville, MD 20852, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Shimp
authors.forename: Christopher
authors.initials: C
authors.lastname: Rowe
authors.forename: Karine
authors.initials: K
authors.lastname: Reiter
authors.forename: Beth
authors.initials: B
authors.lastname: Chen
authors.forename: Vu
authors.initials: V
authors.lastname: Nguyen
authors.forename: Joan
authors.initials: J
authors.lastname: Aebig
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Rausch
authors.forename: Krishan
authors.initials: K
authors.lastname: Kumar
authors.forename: Yimin
authors.initials: Y
authors.lastname: Wu
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Jin
authors.forename: David S
authors.initials: DS
authors.lastname: Jones
authors.forename: David L
authors.initials: DL
authors.lastname: Narum
mesh_terms: D036002:ADP Ribose Transferases / Q000737:chemistry / Q000276:immunology; D000536:Aluminum Hydroxide; D000818:Animals; D001427:Bacterial Toxins / Q000737:chemistry / Q000276:immunology; D005098:Exotoxins / Q000737:chemistry / Q000276:immunology; D005260:Female; D006801:Humans; D017780:Malaria Vaccines / Q000737:chemistry / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology / Q000517:prevention & control* / Q000635:transmission; D051379:Mice; D053758:Nanoparticles; D010963:Plasmodium falciparum / Q000276:immunology*; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000737:chemistry / Q000276:immunology*; D011550:Pseudomonas aeruginosa; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology*; D014611:Vaccination; D018074:Vaccines, Conjugate / Q000737:chemistry / Q000276:immunology; D037521:Virulence Factors / Q000737:chemistry / Q000276:immunology; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D000536:Aluminum Hydroxide; D001427:Bacterial Toxins; D005098:Exotoxins; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D018074:Vaccines, Conjugate; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C099774:transmission-Blocking Vaccine based on Pfs25