title: A Phase I, dose-escalation trial in adults of three recombinant attenuated Salmonella Typhi vaccine vectors producing Streptococcus pneumoniae surface protein antigen PspA.
abstract: BACKGROUND
  Live, attenuated, orally-administered Salmonella strains are excellent vectors for vaccine antigens and are attractive as vaccines based on previous use of S. Typhimurium in animals. A Phase I dose escalation trial was conducted to evaluate the safety and immunogenicity of three newly constructed recombinant attenuated Salmonella enterica serovar Typhi vaccine (RASV) vectors synthesizing Streptococcus pneumoniae surface protein A (PspA).
  
  
  METHODS
  The 3 S. Typhi strains used as vectors to deliver PspA were S. Typhi ISP1820; S. Typhi Ty2 RpoS(-); and S. Typhi Ty2 RpoS(+). Sixty healthy adults (median age 25.2 years) were enrolled into 4 Arms (total 15 subjects per Arm); within each Arm, subjects were randomized 1:1:1 into 3 Groups of 5. All subjects in the same Group received the same vaccine vector, and all subjects in the same Arm received the same titer of vaccine (10(7), 10(8), 10(9) or 10(10)CFU). Adverse events, safety, shedding, and IgG and IgA titers against Salmonella outer membrane proteins (OMPs), lipopolysaccharide (LPS) and PspA were evaluated.
  
  
  RESULTS
  In the highest dose group, no subject experienced severe reactions or serious adverse events. Most adverse events were mild; one subject had a positive blood culture. No subject shed vaccine in stool. No statistically significant differences for post vaccination ELISA or ELISPOT results between Groups were detected. However, a limited number of ≥ 4 fold increases from baseline for IgA anti-OMPs, IgA and IgG anti-LPS, and IgA anti-PspA occurred for a few individuals as measured by ELISA, and IgA anti-OMPs as measured by ELISPOT assay.
  
  
  CONCLUSIONS
  All three S. Typhi vectored pneumococcal vaccines were safe and well-tolerated. Immunogenicity was limited possibly due to pre-existing high antibody titers prior to vaccination. Increases in IgA were most often observed.
authors.affiliation: Saint Louis University, School of Medicine, Center for Vaccine Development, St. Louis, MO, USA. Electronic address: freyse@slu.edu.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Frey
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Lottenbach
authors.forename: Heather
authors.initials: H
authors.lastname: Hill
authors.forename: Tamara P
authors.initials: TP
authors.lastname: Blevins
authors.forename: Yinyi
authors.initials: Y
authors.lastname: Yu
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Karen E
authors.initials: KE
authors.lastname: Brenneman
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Kelly-Aehle
authors.forename: Caitlin
authors.initials: C
authors.lastname: McDonald
authors.forename: Angela
authors.initials: A
authors.lastname: Jansen
authors.forename: Roy
authors.initials: R
authors.lastname: Curtiss
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D004337:Drug Carriers; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D022242:Pneumococcal Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology*; D012485:Salmonella typhi / Q000235:genetics; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000276:immunology*; D014436:Typhoid-Paratyphoid Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology*; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D055815:Young Adult
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D004337:Drug Carriers; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D022242:Pneumococcal Vaccines; D014436:Typhoid-Paratyphoid Vaccines; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic; C051592:pneumococcal surface protein A
keywords: ELISA; ELISPOT; Pneumococcal surface protein A; Salmonella Typhi vaccine vector; Streptococcus pneumoniae