VACCINES AGAINST HUMAN
PATHOGENIC BACTERIA
Rachel Schneerson, M.D., Senior Investigator
Audrey Stone, Ph.D., Senior Investigator
Shousun C. Szu, Ph.D., Staff Scientist
Goran Ekborg, Ph.D., Senior Research Fellow
Jianping Li, M.D., Research Fellow
Changfu Cui, M.D., Postdoctoral Fellow
Chunyan Guo, B.Sc., Biologist
Li Zhang, B.Sc., Technical Specialist
Zhongdong Dai, M.D., Guest Researcher
Dai, Zhang, Schneerson, Robbins; in collabora-tion with Morris, Muller, Collins, Schulz
Tuberculosis remains a serious and common disease throughout the world. Worldwide emergence of multi-antibiotic–resistant strains, accelerated by the passage of M. tuberculosis in patients with AIDS, poses a public health problem. Despite the absence of evidence demonstrating that the BCG vaccine prevents primary pulmonary tuberculosis (the most common disease caused by M. tuberculosis), BCG remains the most frequently used vaccine in the world. The protective effect of BCG vaccination against meningitis in children has not been related to an antigen/s or a host immune component.
Research into a new vaccine is based on the similarity of primary infection caused by Mycobacterium tuberculosis with that of capsulated bacterial respiratory pathogens, viz: tuberculous meningitis has a similar age distribution as meningitis caused by meningococci, pneumococci, and Haemophilus influenzae type b; M. tuberculosis and other mycobacteria have a polysaccharide (PS) capsule in vitro and in vivo; and protein components prolonged the survival of but do not protect animals against challenge with wild-type M. tuberculosis. We purified a glucan and an arabinomannan from a saline extract of M. tuberculosis. The PSs were conjugated to P. aeruginosa recombinant protein A and shown to be immunogenic in mice and rabbits. Antibodies induced by these conjugates, whether actively induced or passively administered, did not protect mice against pulmonary challenge with M. tuberculosis. Antibodies to both PSs in adults, measured by ELISA, showed that patients with tuberculosis had much higher levels than did normal individuals. A standardized and quantitative assay for diagnosis of tuberculosis with these PS antigens is under way. In collaboration with CBER (FDA), both the glucan and arabinomannan conjugates are undergoing evaluation for their protective activity in mice.
Vaccines against Enteric Pathogens
Szu, Bryla, Li, Kossaczka, Cui, Hunt, Nguyen, Schneerson, Robbins; in collaboration with Shiloach, Lin, Bohach, Parke, Ahmed
Surface PSs of Gram-negative enteric pathogens, in the form of capsule (CPS) or lipopolysaccharide (LPS), are both essential virulence factors and protective antigens. We enhanced the immunogenicity of these PSs binding to carrier proteins. Sequential clinical studies in adults and in children in Vietnam, an area with a high attack rate of typhoid fever, showed that the capsular PS (Vi) of Salmonella typhi conjugated to the recombinant Pseudomonas aeruginosa exoprotein A (rEPA) elicited high responses against S. typhi. In a Phase III trial, about 12,000 two- to five-year-old children injected with the conjugate vaccine showed no significant side reaction. The efficacy of Vi-rEPA was 91 percent after 27 months of active surveillance and 88 percent after 28 to 40 months of passive surveillance. A conjugate vaccine against Salmonella paratyphi A, the second most common cause of enteric fever in Southeast Asia, was found to be safe and immunogenic in adults, teenagers, and then in two- to four-year-old children.
Escherichia coli O157, an emerging pathogen, causes hemolytic uremic syndrome in young children. A Phase I study of an O157 O-specific PS-rEPA conjugate vaccine demonstrated safety and immunogenicity in adult volunteers. A Phase II study in two- to five-year-old children is planned. To produce a bivalent vaccine, nontoxic shiga toxin I purified from mutant E. coli O157 will be conjugated with O-specific PS (O-PS). The major reservoir of E. coli O157 is cattle. A LPS-protein conjugate was shown to be immunogenic in mice and cattle, and a challenge study is planned to demonstrate the clearance of the carriage state in cattle.
Vibrio cholerae O1 and O139 are the major serotypes in cholera infections. Conjugates synthesized with CPS of O139 and O-PS of LPS elicited vibriocidal antibodies in mice. Clinical trials of these conjugates are planned.
PUBLICATIONS
- Lin FY, Ho VA, Khiem HB, Trach DD, Bay PV, Thanh TC, Kossaczka Z,
Bryla DA, Shiloach J, Robbins JB, Schneerson R, Szu SC. The efficacy
of a Salmonella typhi Vi conjugate vaccine in two-to-five-year-old
children. N Engl J Med. 2001;344:1263-1269.
- Schwebach JR, Casadevall A, Schneerson R, Dai Z, Wang X, Robbins
JB, Glatman-Freedman A. Expression of a Mycobacterium tuberculosis
arabinomannan antigen in vitro and in vivo. Infect Immun. 2001;69:5671-5678.
- Schwebach JR, Glatman-Freedman A, Gunther-Cummins L, Dai Z, Robbins JB, Schneerson R, Casadevall A. Glucan is a component of the Mycobacterium tuberculosis surface that is expressed in vitro and in vivo. Infect Immun. 2002;70:2566-2575.
Amina Ahmed, M.D., Carolinas Medical Center, Charlotte, NC
Carolyn H. Bohach, Ph.D., University of Idaho, Moscow, ID
Frank Collins, Ph.D., CBER, FDA, Bethesda, MD
Pavol Kovac, Ph.D., Laboratory of Medicinal Chemistry, NIDDK, Bethesda, MD
Kimi Lin, M.D., Epidemiology Branch, NICHD, Bethesda, MD
Sheldon L. Morris, Ph.D., CBER, FDA, Bethesda, MD
Jacqueline Muller, Ph.D., CBER, FDA, Bethesda, MD
James C. Parke, M.D., Carolinas Medical Center, Charlotte, NC
Joseph Shiloach, Ph.D., Laboratory of Cellular and Developmental Biology, NIDDK, Bethesda, MD