title: Vaccine platforms combining circumsporozoite protein and potent immune modulators, rEA or EAT-2, paradoxically result in opposing immune responses.
abstract: BACKGROUND
  Malaria greatly impacts the health and wellbeing of over half of the world's population. Promising malaria vaccine candidates have attempted to induce adaptive immune responses to Circumsporozoite (CS) protein. Despite the inclusion of potent adjuvants, these vaccines have limited protective efficacy. Conventional recombinant adenovirus (rAd) based vaccines expressing CS protein can induce CS protein specific immune responses, but these are essentially equivalent to those generated after use of the CS protein subunit based vaccines. In this study we combined the use of rAds expressing CS protein along with rAds expressing novel innate immune response modulating proteins in an attempt to significantly improve the induction of CS protein specific cell mediated immune (CMI) responses.
  
  
  RESULTS
  BALB/cJ mice were co-vaccinated with a rAd vectors expressing CS protein simultaneous with a rAd expressing either TLR agonist (rEA) or SLAM receptors adaptor protein (EAT-2). Paradoxically, expression of the TLR agonist uncovered a potent immunosuppressive activity inherent to the combined expression of the CS protein and rEA. Fortunately, use of the rAd vaccine expressing EAT-2 circumvented CS protein's suppressive activity, and generated a fivefold increase in the number of CS protein responsive, IFNγ secreting splenocytes, as well as increased the breadth of T cells responsive to peptides present in the CS protein. These improvements were positively correlated with the induction of a fourfold improvement in CS protein specific CTL functional activity in vivo.
  
  
  CONCLUSIONS
  Our results emphasize the need for caution when incorporating CS protein into malaria vaccine platforms expressing or containing other immunostimulatory compounds, as the immunological outcomes may be unanticipated and/or counter-productive. However, expressing the SLAM receptors derived signaling adaptor EAT-2 at the same time of vaccination with CS protein can overcome these concerns, as well as significantly improve the induction of malaria antigen specific adaptive immune responses in vivo.
authors.affiliation: Genetics Program, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Nathaniel J
authors.initials: NJ
authors.lastname: Schuldt
authors.forename: Yasser A
authors.initials: YA
authors.lastname: Aldhamen
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Appledorn
authors.forename: Sergey S
authors.initials: SS
authors.lastname: Seregin
authors.forename: Youssef
authors.initials: Y
authors.lastname: Kousa
authors.forename: Sarah
authors.initials: S
authors.lastname: Godbehere
authors.forename: Andrea
authors.initials: A
authors.lastname: Amalfitano
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000918:Antibody Specificity; D017951:Antigen Presentation / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D007111:Immunity, Cellular / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D007155:Immunologic Factors / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists; D014612:Vaccines / Q000235:genetics* / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007155:Immunologic Factors; D015800:Protozoan Proteins; D051193:Toll-Like Receptors; D014612:Vaccines; C041595:circumsporozoite protein, Protozoan