title: A Cholera Conjugate Vaccine Containing O-specific Polysaccharide (OSP) of V. cholerae O1 Inaba and Recombinant Fragment of Tetanus Toxin Heavy Chain (OSP:rTTHc) Induces Serum, Memory and Lamina Proprial Responses against OSP and Is Protective in Mice.
abstract: BACKGROUND
  Vibrio cholerae is the cause of cholera, a severe watery diarrhea. Protection against cholera is serogroup specific. Serogroup specificity is defined by the O-specific polysaccharide (OSP) component of lipopolysaccharide (LPS).
  
  
  METHODS
  Here we describe a conjugate vaccine for cholera prepared via squaric acid chemistry from the OSP of V. cholerae O1 Inaba strain PIC018 and a recombinant heavy chain fragment of tetanus toxin (OSP:rTTHc). We assessed a range of vaccine doses based on the OSP content of the vaccine (10-50 μg), vaccine compositions varying by molar loading ratio of OSP to rTTHc (3:1, 5:1, 10:1), effect of an adjuvant, and route of immunization.
  
  
  RESULTS
  Immunized mice developed prominent anti-OSP and anti-TT serum IgG responses, as well as vibriocidal antibody and memory B cell responses following intramuscular or intradermal vaccination. Mice did not develop anti-squarate responses. Intestinal lamina proprial IgA responses targeting OSP occurred following intradermal vaccination. In general, we found comparable immune responses in mice immunized with these variations, although memory B cell and vibriocidal responses were blunted in mice receiving the highest dose of vaccine (50 μg). We found no appreciable change in immune responses when the conjugate vaccine was administered in the presence or absence of immunoadjuvant alum. Administration of OSP:rTTHc resulted in 55% protective efficacy in a mouse survival cholera challenge model.
  
  
  CONCLUSIONS
  We report development of an Inaba OSP:rTTHc conjugate vaccine that induces memory responses and protection against cholera in mice. Development of an effective cholera conjugate vaccine that induces high level and long-term immune responses against OSP would be beneficial, especially in young children who respond poorly to polysaccharide antigens.
authors.affiliation: Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Center for Vaccine Sciences, International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh.
authors.forename: Md Abu
authors.initials: MA
authors.lastname: Sayeed
authors.affiliation: Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Meagan Kelly
authors.initials: MK
authors.lastname: Bufano
authors.affiliation: National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), Laboratory of Bioorganic Chemistry (LBC), National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Peng
authors.initials: P
authors.lastname: Xu
authors.affiliation: Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Grace
authors.initials: G
authors.lastname: Eckhoff
authors.affiliation: Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Richelle C
authors.initials: RC
authors.lastname: Charles
authors.affiliation: Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Center for Vaccine Sciences, International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh.
authors.forename: Mohammad Murshid
authors.initials: MM
authors.lastname: Alam
authors.affiliation: Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Center for Vaccine Sciences, International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh.
authors.forename: Tania
authors.initials: T
authors.lastname: Sultana
authors.affiliation: Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Center for Vaccine Sciences, International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh.
authors.forename: Md Rasheduzzaman
authors.initials: MR
authors.lastname: Rashu
authors.affiliation: Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Amanda
authors.initials: A
authors.lastname: Berger
authors.affiliation: Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Gonzalez-Escobedo
authors.affiliation: Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Anjali
authors.initials: A
authors.lastname: Mandlik
authors.affiliation: Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Center for Vaccine Sciences, International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh.
authors.forename: Taufiqur Rahman
authors.initials: TR
authors.lastname: Bhuiyan
authors.affiliation: Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Division of Infectious Disease, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Leung
authors.affiliation: Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Regina C
authors.initials: RC
authors.lastname: LaRocque
authors.affiliation: Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Harris
authors.affiliation: Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Calderwood
authors.affiliation: Center for Vaccine Sciences, International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh.
authors.forename: Firdausi
authors.initials: F
authors.lastname: Qadri
authors.affiliation: Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Laboratory of Bacterial Toxins, Bethesda, Maryland, United States of America.
authors.forename: W F
authors.initials: WF
authors.lastname: Vann
authors.affiliation: Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Pavol
authors.initials: P
authors.lastname: Kováč
authors.affiliation: Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America; Department of Immunology and Infectious Disease, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Ryan
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D002771:Cholera / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D022121:Cholera Vaccines / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007114:Immunization; D007156:Immunologic Memory; D008297:Male; D051379:Mice; D008875:Middle Aged; D009092:Mucous Membrane / Q000276:immunology*; D019081:O Antigens / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D013744:Tetanus Toxin / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D018074:Vaccines, Conjugate / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D041241:Vibrio cholerae O1 / Q000276:immunology; D055815:Young Adult
chemical_list: D000907:Antibodies, Bacterial; D022121:Cholera Vaccines; D019081:O Antigens; D013744:Tetanus Toxin; D018074:Vaccines, Conjugate