A Phase I, dose-escalation trial in adults of three recombinant attenuated Salmonella Typhi vaccine vectors producing Streptococcus pneumoniae surface protein antigen PspA

• Published in: Vaccine Vol. 31; no. 42; pp. 4874 - 4880
• Main Authors: Frey, Sharon E., Lottenbach, Kathleen R., Hill, Heather, Blevins, Tamara P., Yu, Yinyi, Zhang, Ying, Brenneman, Karen E., Kelly-Aehle, Sandra M., McDonald, Caitlin, Jansen, Angela, Curtiss, Roy
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.10.2013; Elsevier
• Subjects: Administration, Oral; Adult; adults; Allergy and Immunology; Animals; Antibodies, Bacterial - blood; antigens; Applied microbiology; Bacterial Proteins - genetics; Bacterial Proteins - immunology; Bacteriology; Biological and medical sciences; blood; Drug Carriers; Drug-Related Side Effects and Adverse Reactions - epidemiology; Drug-Related Side Effects and Adverse Reactions - pathology; ELISA; ELISPOT; Enzyme-Linked Immunosorbent Assay; Enzyme-Linked Immunospot Assay; Female; Fundamental and applied biological sciences. Psychology; Humans; immune response; immunoglobulin A; Immunoglobulin A - blood; immunoglobulin G; Immunoglobulin G - blood; lipopolysaccharides; Male; Microbiology; Miscellaneous; outer membrane proteins; Pneumococcal surface protein A; Pneumococcal Vaccines - administration & dosage; Pneumococcal Vaccines - adverse effects; Pneumococcal Vaccines - genetics; Pneumococcal Vaccines - immunology; Salmonella enterica; Salmonella Typhi; Salmonella typhi - genetics; Salmonella Typhi vaccine vector; Salmonella typhimurium; Streptococcus pneumoniae; Streptococcus pneumoniae - genetics; Streptococcus pneumoniae - immunology; surface proteins; Typhoid-Paratyphoid Vaccines - administration & dosage; Typhoid-Paratyphoid Vaccines - adverse effects; Typhoid-Paratyphoid Vaccines - genetics; Typhoid-Paratyphoid Vaccines - immunology; vaccination; vaccines; Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects); Vaccines, Attenuated - administration & dosage; Vaccines, Attenuated - adverse effects; Vaccines, Attenuated - genetics; Vaccines, Attenuated - immunology; Vaccines, Synthetic - administration & dosage; Vaccines, Synthetic - adverse effects; Vaccines, Synthetic - genetics; Vaccines, Synthetic - immunology; Young Adult; Salmonella Typhi vaccine vector; Pneumococcal surface protein A; ELISPOT; Streptococcus pneumoniae; ELISA; Salmonella typhi; Vaccine; Protein; Antigen; Streptococcaceae; Phase I trial; Bacteria; Micrococcales; ELISPOT assay; ELISA assay; Vector; Enterobacteriaceae
• ISSN: 0264-410X; 1873-2518; 1873-2518
• DOI: 10.1016/j.vaccine.2013.07.049

•Three live attenuated, recombinant S. Typhi vectors were evaluated as oral vaccines.•The target antigen was pneumococcal surface protein A (PspA) antigen.•IgG and IgA responses were measured using ELISA and ELISPOT assay. 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). 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 (107, 108, 109 or 1010CFU). Adverse events, safety, shedding, and IgG and IgA titers against Salmonella outer membrane proteins (OMPs), lipopolysaccharide (LPS) and PspA were evaluated. 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. 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.