Human Health

Infant pneumonia and otitis media

Our objective is to design, construct and evaluate an RASV delivering multiple protective pneumococcal protein antigens to be delivered orally to newborns and infants to confer protective immunity to all pneumococcal serotypes. The vaccine prototype has been demonstrated to be totally safe in newborn, pregnant, malnourished and immunodeficient mice and the collective preclinical data led to FDA approval and the granting of an IND license. Human clinical dose escalation trials with doses up to 1010 CFU have been completed with no adverse reactions, essentially no bacteremias and no shedding of viable vaccine cells in stools. Although totally safe, the RASV constructs were not as immunogenic as desired but strains with the RpoS+  phenotype gave better results than the vaccine strain that was RpoS. A selected strain has been further improved to significantly enhance immunogenicity without compromising safety attributes. This isolate will be evaluated in human trials. The vaccine is also designed to confer protective immunity to diverse Salmonella serotypes causing diarrheal disease.

For more information see:

Kang, H. Y., J. Srinivasan, and R. Curtiss III. 2002. Immune responses to recombinant pneumococcal PspA antigen delivered by live attenuated Salmonella enterica serovar Typhimurium vaccine. Infect. Immun. 70:1739-1749.

Xin, W., S. Y. Wanda, Y. Li, S. Wang, H. Mo, and R. Curtiss III. 2008. Analysis of type II secretion of recombinant pneumococcal PspA and PspC in aSalmonella enterica serovar Typhimurium vaccine with regulated delayed antigen synthesis. Infect. Immun. 76:3241-3254.

Li, Y., S. Wang, G. Scarpellini, B. Gunn, W. Xin, S. Y. Wanda, K. L. Roland, and R. Curtiss III. 2009. Evaluation of new generation Salmonella enterica serovar Typhimurium vaccines with regulated delayed attenuation to induce immune responses against PspA. Proc. Natl. Acad. Sci. USA 106:593-598.

Xin, W., Y. Li, H. Mo, K. L. Roland, and R. Curtiss III. 2009. PspA family fusion proteins delivered by attenuated Salmonella enterica serovar Typhimurium extend and enhance protection against Streptococcus pneumoniae. Infect. Immun. 77:4518-4528.

Gunn, B. M., S. Y. Wanda, D. Burshell, C. Wang, and R. Curtiss III. 2010. Construction of recombinant attenuated Salmonella enterica serovar Typhimurium vaccine vector strains for safety in newborn and infant mice. Clin. Vaccine Immunol. 17:354-362.

Shi, H., S. Wang, K. L. Roland, B. M. Gunn, and R. Curtiss III. 2010. Immunogenicity of a live recombinant Salmonella enterica serovar Typhimurium vaccine expressing pspA in neonates and infant mice born from naïve and immunized mothers. Clin. Vaccine Immunol. 17:363-371

Shi, H., J. Santander, K. Brenneman, S. Y. Wanda, S. Wang, P. Senechal, W. Sun, K. Roland, and R. Curtiss III. 2010. Live recombinant Salmonella Typhi vaccines constructed to investigate the role of rpoS in eliciting immunity to a heterologous antigen. PLoS ONE 8:e11142.

Wang, S., Y. Li, H. Shi, G. Scarpellini, A. Torres-Escobar, K. L. Roland, and R. Curtiss III. 2010. Immune responses to recombinant pneumococcal PsaA antigen delivered by a live attenuated Salmonella vaccine. Infect. Immun.78:3258-3271.

Brenneman, K. E., C. McDonald, S. M. Kelly, K. L. Roland, and R. Curtiss III. 2012. Use of RapidChek® SELECT™ Salmonella to detect shedding of live attenuated Salmonella enterica serovar Typhi vaccine strains. J. Microbiol. Methods 89:137-147.

Shi, H., S. Wang, and R. Curtiss III. 2013. Evaluation of regulated delayed attenuation strategies for Salmonella enterica serovar Typhi vaccine vectors in neonatal and infant mice. Clin. Vaccine Immunol. 20:931-944.

Lottenbach, K. R., S. M. Kelly-Aehle, K. E. Brenneman, R. Curtiss III, and S. E. Frey. 2013. Rapid, sensitive recovery of recombinant attenuated Salmonella enterica serovar Typhi vaccine strains from human blood. Clin. Vaccine Immunol. 20:1473-1478.

Frey, S. E., K. R. Lottenbach, H. Hill, T. P. Blevins, Y. Yu, Y. Zhang, K. E. Brenneman, S. M. Kelly-Aehle, C. McDonald, A. Jansen, and R. Curtiss III. 2013. A Phase I, dose-escalation trial in adults of three recombinant attenuated Salmonella Typhi vaccine vectors producing Streptococcus pneumoniae surface protein antigen PspA. Vaccine 31:4874-4880.

Brenneman, K.E., A. Gonzales, K.L. Roland and R. Curtiss III. 2015. Use of Ensure® Nutrition Shakes as an alternative formulation method for live recombinant attenuated Salmonella Typhi vaccines. BMC Microbiol. 15:76.

Dysentery

Shigella dysentery is an extreme diarrheal disease with bloody stools and some 50,000 to 100,000 deaths per year. Our objective is to design, construct and evaluate a RASV platform antigen delivery system to induce protective immunity to diverse  Salmonella serotypes and other enteric bacteria in theEnterobacteriaceae and will also deliver several conserved protective Shigella antigens to augment induction of protective immunity to diverse Shigella species and serotypes.

Diarrheal diseases

ETEC is a common cause of “traveler’s” diarrhea and a leading cause of bacterially induced diarrhea in children in the developing world. Our objective is to design, construct and evaluate a RASV platform antigen delivery system to induce protective immunity to diverse Salmonella serotypes and other enteric bacteria in the Enterobacteriaceae family and will also deliver several conserved protective ETEC antigens to augment induction of protective immunity to prevent ETEC-induced diarrheal disease.

We are using our RASV platform antigen delivery system to induce protective immunity to diverse Salmonella serotypes and other enteric bacteria in theEnterobacteriaceae family (which includes Yersinia species) and will also deliver several conserved protective Yersinia antigens to augment induction of protective immunity to both Y. entercolitica and Y. pseudotuberculosis  that are responsible for some diarrheal disease. We are also developing a recombinant attenuated Y. psuedotuberculosis vaccine to immunize zoonotic rodent reservoirs carrying Y. pestis to hopefully decrease these reservoirs.

Bubonic plague, Pneumonic plague

Plague is endemic in rodent populations in many areas of the world, including the western United States.  It is also a potential bioweapon. We are using our RASV platform antigen delivery system to induce protective immunity to diverse Salmonella serotypes and other enteric bacteria in the Enterobacteriaceae family (which includes Yersinia species) and will also deliver several conserved protective Y. pestis antigens to augment induction of protective immunity to Y. pestis. We have had considerable success and will soon propose to evaluate these RASVs in human volunteers. We may also use these vector systems as part of a program to vaccinate wild rodents to reduce zoonotic reservoirs. We are also constructing an attenuated Y. pestis vaccine strain.

For more information see:

Branger, C., J. Fetherston, R. Perry, and R. Curtiss III. 2007. Oral vaccination with different antigens from Yersinia pestis KIM delivered by live attenuatedSalmonella Typhimurium elicits a protective immune response against plague. Adv. Exp. Med. Biol. 603:387-399.

Sun, W., K. Roland, X. Kuang, C. G. Branger, and R. Curtiss III. 2010. Yersinia pestis with regulated delayed attenuation as a vaccine candidate to induce protective immunity against plague. Infect. Immun. 78:1304-1313.

Torres-Escobar, A., M. D. Juarez-Rodriguez, B. M. Gunn, C. G. Branger, S. A. Tinge, and R. Curtiss III. 2010. Fine tuning synthesis of Yersinia pestis LcrV from runaway-like replication balanced-lethal plasmid in a Salmonella enterica serovar Typhimurium vaccine induces protection against a lethal Y. pestischallenge in mice. Infect. Immun. 78:2529-2543.

Torres-Escobar, A., M. D. Juarez-Rodriguez, C. G. Branger, and R. Curtiss III. 2010. Evaluation of the humoral immune response in mice orally vaccinated with live recombinant attenuated Salmonella enterica delivering a secreted form of Yersinia pestis PsaA. Vaccine 28:5810-5816.

Branger, C. G., W. Sun, A. Torres-Escobar, R. Perry, K. L. Roland, J. Fetherston, and R. Curtiss III. 2010. Evaluation of Psn, HmuR and a modified LcrV protein delivered to mice by live attenuated Salmonella as a vaccine against bubonic and pneumonic Yersinia pestis challenge. Vaccine 29:274-282.

Sun, W, D. Six, X. Kuang, K. L. Roland, C. R. Raetz, and R. Curtiss III. 2011. A live attenuated strain of Yersinia pestis KIM as a vaccine against plague. Vaccine 29:2986-2998.

Sun, W., K. L. Roland, and R. Curtiss III. 2011. Developing live vaccines against plague. J. Infect. Dev. Countries 5:614-627.

Sun, W. and R. Curtiss III. 2012. Amino acid substitutions in LcrV at putative sites of interaction with toll-like receptor II do not affect the virulence of Yersinia pestis. Microb. Pathog. 53:198-206.

Sun, W., J. Olinzock, S. Wang, S. Sanapala and R. Curtiss III. 2014. Evaluation of YadC protein delivered by live attenuated Salmonella as a vaccine against plague. Pathog. Dis. 70:119-131.

Sun, W., S. Sanapala, J.C. Henderson, S. Sam, J. Olinzock, M. S. Trent and R. Curtiss III. 2014. LcrV delivered via Type III secretion system of live attenuated Yersinia tuberculosis enhances immunogenicity against pneumonic plague. Infect. Immun. 82:4390-4404.

Tuberculosis

A scourge to humankind throughout recorded history, tuberculosis (TB) continues to have a devastating impact even today. The World Health Organization has estimated that one-third of the world’s population is infected with M. tuberculosis, with approximately 8 million new cases diagnosed annually. Although not everyone who is infected develops active disease, of those who do, nearly two million die each year. We are employing the recombinant attenuatedSalmonella vaccine systems with regulated delayed lysis in vivo to synthesize M. tuberculosis antigens and to deliver them to optimal sites within immunized individuals to generate protective mucosal, systemic and cellular immune responses against the tubercle bacilli.

For more information see:

Kong, W., S. Y. Wanda, X. Zhang, W. Bollen, S. A. Tinge, K. L. Roland, and R. Curtiss III. 2008. Regulated programmed lysis of recombinant Salmonella in host tissues to release protective antigens and confer biological containment. Proc. Natl. Acad. Sci. USA 105:9361-9366.

Juárez-Rodríguez, M. D., L. T. Arteaga-Cortés, R. Kader, R. Curtiss III, and J. E. Clark-Curtiss. 2012. Live attenuated Salmonella vaccines againstMycobacterium tuberculosis with antigen delivery via the type III secretion system. Infect. Immun. 80:798-814.

Juárez-Rodríguez, M. D., J. Yang, R. Kader, P. Alamuri, R. Curtiss III, and J. E. Clark-Curtiss. 2012. Live attenuated Salmonella vaccines displaying regulated delayed lysis and delayed antigen synthesis to confer protection against Mycobacterium tuberculosis. Infect. Immun. 80:815-831.

Enteric and typhoid fevers

Although not formal vaccine programs, we are using S. Paratyphi A and S. Typhi as attenuated vectors for RASVs to deliver multiple protective antigens from pneumococcal strains, ShigellaYersinia species, M. tuberculosis and influenza virus to prevent infections by these pathogens.  Enteric fever is similar to typhoid fever, but is a much milder disease. Since the incidence of enteric fever is increasing globally, we may use some of our attenuated strains as vaccines against enteric fever and possibly against typhoid fever.

Cancer

S. Typhimurium strains have been extensively modified as therapeutic vaccines to destroy solid tumors or induce clearance of other cancers. Many of these strains exhibit the regulated delayed lysis in vivo phenotype and deliver antigens to cause tumor cell death or augment immune responses to induce cancer cell elimination.

For more information see:

Saltzman, D. A., C. P. Heise, D. E. Hasz, M. Zebede, S. M. Kelly, R. Curtiss III, A. S. Leonard, and P. M. Anderson. 1996. Attenuated Salmonella typhimuriumcontaining interleukin-2 decreases MC-38 hepatic metastases: a novel anti-tumor agent. Cancer Biother. Radiopharm. 11:145-153.

Saltzman, D. A., E. Katsanis, C. P. Heise, D. Hasz, S. M. Kelly, R. Curtiss III, A. S. Leonard, and P. M. Anderson. 1997. Patterns of hepatic and splenic colonization by an attenuated strain of Salmonella typhimurium containing the gene for human interleukin-2: A novel anti-tumoragent. Cancer Biother. Radiopharm. 12:37-45.

Frahm, M., S. Felgner, D. Kocijancic, M. Rohde, M. Hensel, R. Curtiss 3rd, M. Erhardt, S. Weiss. 2015. Efficiency of conditionally attenuated Salmonella enterica serovar Typhimurium in bacterium-mediate tumor therapy. MBio 6: e00254-15.

Felgner S, Kocijancic D, Frahm M, Curtiss R III, Erhardt M, Weiss S. 2016. Optimizing Salmonella enterica serovar Typhimurium for bacteria-mediated tumor therapy. Gut Microbes. 7:171-7.

Influenza virus

We are using extensively modified RASVs with the regulated delayed lysis in vivo phenotype to deliver (i) conserved M2e sequences fused to the woodchuck hepatitis virus core, (ii) the conserved NP antigen with fusion to additional conserved T-cell epitopes to the cytosol for class I presentation and (iii) DNA vaccines delivered to the cell nucleus for synthesis of variable HA antigens. In all cases, high-level protective immunity has been induced to challenge with influenza virus in mice.

For more information see:

Zhang X, Kong W, Ashraf S, Curtiss R III. 2009. A one-plasmid system to generate influenza virus in cultured chicken cells for potential use in influenza vaccine. J Virol. 83:9296-303.

Ameiss, K., S. Ashraf, W. Kong, A. Pekosz, W. H. Wu, D. Milich, J. N. Billaud, and Roy Curtiss III. 2010. Delivery of woodchuck hepatitis virus-like particle presented influenza M2e by recombinant attenuated Salmonella displaying a delayed lysis phenotype. Vaccine 28:6704-6713.

Ashraf, S., W. Kong, S. Wang, J. Yang, and R. Curtiss III. 2011. Protective cellular responses elicited by vaccination with influenza nucleoprotein delivered by a live recombinant attenuated Salmonella vaccine. Vaccine 29:3990-4002.

Kong, W., M. Brovold, B. A. Koneneman, J. Clark-Curtiss, and R. Curtiss III. 2012. Turning self-destructing Salmonella into a universal DNA vaccine delivery platform. Proc. Natl. Acad. USA 109:19414-19419. *Recommended by Faculty of 1000 Biology

Zhang, X., W. Kong, SY. Wanda, W. Xin, P. Alamuri and R. Curtiss III. 2015. Generation of influenza virus from avian cells infected by Salmonella carrying the viral genome. PloS One 10:e0229041.

Zhang X, Curtiss R III. 2015. Efficient generation of influenza virus with a mouse RNA polymerase I-driven all-in-one plasmid. Virol J. 12:95