Evaluation of new generation Salmonella enterica serovar Typhimurium vaccines with regulated delayed attenuation to induce immune responses against PspA

Yuhua Li, Shifeng Wang, Giorgio Scarpellini, Bronwyn Gunn, Wei Xin, Soo Young Wanda, Kenneth L. Roland, Roy Curtiss

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

Increasing the immunogenicity to delivered antigens by recombinant attenuated Salmonella vaccines (RASV) has been the subject of intensive study. With this goal in mind, we have designed and constructed a new generation of RASV that exhibit regulated delayed attenuation. These vaccine strains are phenotypically wild type at the time of immunization and become attenuated after colonization of host tissues. The vaccine strains are grown under conditions that allow expression of genes required for optimal invasion and colonization of host tissues. Once established in the host, these virulence genes are turned off, fully attenuating the vaccine strain. In this study, we compared 2 of our newly developed regulated delayed attenuation Salmonella enterica serovar Typhimurium strains χ9088 and χ9558 with the Δcya Δcrp Δasd strain χ8133, for their abilities to express and present a secreted form of the α-helical region of pneumococcal surface protein A (PspA) to the mouse immune system. All 3 strains induced high levels of serum antibodies specific for PspA as well as to Salmonella antigens in orally immunized mice. However, both RASVs expressing delayed attenuation elicited significantly greater anti-PspA immune responses, including serum IgG and T cell secretion of IL-4 and IFN-γ, than other groups. Also, vaccination with delayed attenuation strains resulted in a greater degree of protection against Streptococcus pneumoniae challenge than in mice vaccinated with χ8133 (71-86% vs. 21% survival, P ≤ 0.006). Together, the results demonstrate that the regulated attenuation strategy results in highly immunogenic antigen delivery vectors for oral vaccination.

Original languageEnglish (US)
Pages (from-to)593-598
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number2
DOIs
StatePublished - Jan 13 2009

Keywords

  • Bacterial vectors
  • Streptococcus pneumoniae

ASJC Scopus subject areas

  • General

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