Development and preclinical evaluation of safety and immunogenicity of an oral ETEC vaccine containing inactivated E. coli bacteria overexpressing colonization factors CFA/I, CS3, CS5 and CS6 combined with a hybrid LT/CT B subunit antigen, administered alone and together with dmLT adjuvant

• A first-generation oral inactivated whole-cell enterotoxigenic Escherichia coli (ETEC) vaccine, comprising formalin-killed ETEC bacteria expressing different colonization factor (CF) antigens combined with cholera toxin B subunit (CTB), when tested in phase III studies did not significantly reduce overall (generally mild) ETEC diarrhea in travelers or children although it reduced more severe ETEC diarrhea in travelers by almost 80%. We have now developed a novel more immunogenic ETEC vaccine based on recombinant non-toxigenic E. coli strains engineered to express increased amounts of CF antigens, including CS6 as well as an ETEC-based B subunit protein (LCTB. A), and the optional combination with a nontoxic double-mutant heat-labile toxin (LT) molecule (dmLT) as an adjuvant.Two test vaccines were prepared under GMP: (1) A prototype E. coli CFA/I-only formalin-killed whole-cell. +. LCTB. A vaccine, and (2) A "complete" inactivated multivalent ETEC-CF (CFA/I, CS3, CS5 and CS6 antigens) whole-cell. +. LCTB. A vaccine. These vaccines, when given intragastrically alone or together with dmLT in mice, were well tolerated and induced strong intestinal-mucosal IgA antibody responses as well as serum IgG and IgA responses to each of the vaccine CF antigens as well as to LT B subunit (LTB). Both mucosal and serum responses were further enhanced (adjuvanted) when the vaccines were co-administered with dmLT. We conclude that the new multivalent oral ETEC vaccine, both alone and especially in combination with the dmLT adjuvant, shows great promise for further testing in humans. 

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine (hsv//eng)

Nyckelord

Colonization factors

DmLT

ETEC

Immune responses

Mucosal immunity

Vaccine

bacterial antigen

bacterial vaccine

colonization factor CFA/I

colonization factor CS3

colonization factor CS5

colonization factor CS6

double mutant heat labile toxin

enterotoxigenic Escherichia coli vaccine

hybrid protein

immunoglobulin A antibody

toxin

unclassified drug

adjuvant therapy

animal experiment

animal model

antibody blood level

antibody response

antibody titer

article

bacterial colonization

controlled study

drug safety

Escherichia coli

female

immune response

immunization

immunogenicity

immunological memory

mouse

nonhuman

operon

priority journal

protein subunit

Adjuvants

Immunologic

Administration

Oral

Animals

Antibody Formation

Antigens

Bacterial

Bacterial Toxins

Cholera Toxin

Enterotoxigenic Escherichia coli

Enterotoxins

Escherichia coli Infections

Escherichia coli Proteins

Escherichia coli Vaccines

Fimbriae Proteins

Immunity

Mucosal

Immunoglobulin A

Immunoglobulin G

Intestines

Mice

Mice

Inbred BALB C

Mutant Proteins

Vaccines

Inactivated

ETEC

Colonization factors

Vaccine

dmLT

Immune responses

Mucosal immunity

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)