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1.
Vaccine ; 41(10): 1657-1667, 2023 03 03.
Article in English | MEDLINE | ID: mdl-36746739

ABSTRACT

BACKGROUND: Inactivated trivalent poliovirus vaccine (IPV) induces humoral immunity, which protects against paralytic poliomyelitis but does not induce sufficient mucosal immunity to block intestinal infection. We assessed the intestinal immunity in healthy adults in Belgium conferred by a co-formulation of IPV with the mucosal adjuvant double mutant Labile Toxin (dmLT) derived from Escherichia coli. METHODS: Healthy fully IPV-vaccinated 18-45-year-olds were randomly allocated to three groups: on Day 1 two groups received one full dose of IPV (n = 30) or IPV + dmLT (n = 30) in a blinded manner, and the third received an open-label dose of bivalent live oral polio vaccine (bOPV types 1 and 3, n = 20). All groups received a challenge dose of bOPV on Day 29. Participants reported solicited and unsolicited adverse events (AE) using study diaries. Mucosal immune responses were measured by fecal neutralization and IgA on Days 29 and 43, with fecal shedding of challenge viruses measured for 28 days. Humoral responses were measured by serum neutralizing antibody (NAb). RESULTS: Solicited and unsolicited AEs were mainly mild-to-moderate and transient in all groups, with no meaningful differences in rates between groups. Fecal shedding of challenge viruses in both IPV groups exceeded that of the bOPV group but was not different between IPV and IPV + dmLT groups. High serum NAb responses were observed in both IPV groups, alongside modest levels of fecal neutralization and IgA. CONCLUSIONS: Addition of dmLT to IPV administered intramuscularly neither affected humoral nor intestinal immunity nor decreased fecal virus shedding following bOPV challenge. The tolerability of the dose of dmLT used in this study may allow higher doses to be investigated for impact on mucosal immunity. Registered on ClinicalTrials.gov - NCT04232943.


Subject(s)
Poliomyelitis , Poliovirus Vaccine, Inactivated , Humans , Adult , Poliomyelitis/prevention & control , Hot Temperature , Poliovirus Vaccine, Oral , Adjuvants, Immunologic , Antibodies, Neutralizing , Immunoglobulin A
2.
Microorganisms ; 9(7)2021 Jun 25.
Article in English | MEDLINE | ID: mdl-34202102

ABSTRACT

The global diarrheal disease burden for Shigella, enterotoxigenic Escherichia coli (ETEC), and Campylobacter is estimated to be 88M, 75M, and 75M cases annually, respectively. A vaccine against this target trio of enteric pathogens could address about one-third of diarrhea cases in children. All three of these pathogens contribute to growth stunting and have demonstrated increasing resistance to antimicrobial agents. Several combinations of antigens are now recognized that could be effective for inducing protective immunity against each of the three target pathogens in a single vaccine for oral administration or parenteral injection. The vaccine combinations proposed here would result in a final product consistent with the World Health Organization's (WHO) preferred product characteristics for ETEC and Shigella vaccines, and improve the vaccine prospects for support from Gavi, the Vaccine Alliance, and widespread uptake by low- and middle-income countries' (LMIC) public health stakeholders. Broadly protective antigens will enable multi-pathogen vaccines to be efficiently developed and cost-effective. This review describes how emerging discoveries for each pathogen component of the target trio could be used to make vaccines, which could help reduce a major cause of poor health, reduced cognitive development, lost economic productivity, and poverty in many parts of the world.

3.
Vaccine ; 37(34): 4768-4774, 2019 08 07.
Article in English | MEDLINE | ID: mdl-31358236

ABSTRACT

PATH hosted the second Vaccines Against Shigella and Enterotoxigenic Escherichia coli (VASE) Conference in Mexico City in June 2018, again providing experts from around the world an opportunity to participate in a highly collaborative forum to discuss progress in the development of new enteric vaccines. Through a combination of plenary sessions and posters, keynote presentations, and workshops, the 2018 VASE Conference aimed to accelerate communication and progress among those working to achieve the goal of licensed vaccines against these two bacterial pathogens. Many presentations recognized the importance of diarrheal disease and long-term sequelae caused by infections with Shigella and enterotoxigenic E. coli (ETEC). Other presentations explored new strategies for vaccine development, including the search for novel, possibly conserved, antigens for more effective vaccines. Much progress is being made as some vaccine candidates are now moving through clinical trials. Research presented in oral and poster presentations at the VASE Conference covered a range of topics, including: the global burden of disease, epidemiology, and health economics; host parameters and genomics that predict responses to infection and disease; preclinical evaluations of vaccine antigens and models of enteric diseases; and vaccine candidates in clinical trials and human challenge studies. This article reviews key points and highlighted research presented in each of the plenary conference sessions and poster presentations at the 2018 VASE Conference.


Subject(s)
Diarrhea/prevention & control , Dysentery, Bacillary/prevention & control , Enterotoxigenic Escherichia coli/immunology , Escherichia coli Infections/prevention & control , Escherichia coli Vaccines/biosynthesis , Shigella Vaccines/biosynthesis , Shigella/immunology , Animals , Antigens, Bacterial/chemistry , Antigens, Bacterial/immunology , Clinical Trials as Topic , Congresses as Topic , Diarrhea/epidemiology , Diarrhea/immunology , Diarrhea/microbiology , Disease Models, Animal , Dysentery, Bacillary/epidemiology , Dysentery, Bacillary/immunology , Dysentery, Bacillary/microbiology , Enterotoxigenic Escherichia coli/drug effects , Enterotoxigenic Escherichia coli/pathogenicity , Escherichia coli Infections/epidemiology , Escherichia coli Infections/immunology , Escherichia coli Infections/microbiology , Escherichia coli Vaccines/administration & dosage , Host-Pathogen Interactions/immunology , Humans , Immunization/methods , Macaca mulatta , Mice , Shigella/drug effects , Shigella/pathogenicity , Shigella Vaccines/administration & dosage
4.
Infect Immun ; 74(2): 994-1000, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16428745

ABSTRACT

A vaccine against enterotoxigenic Escherichia coli (ETEC) is needed to prevent diarrheal illness among children in developing countries and at-risk travelers. Two live attenuated ETEC strains, PTL002 and PTL003, which express the ETEC colonization factor CFA/II, were evaluated for safety and immunogenicity. In a randomized, double-blind, placebo-controlled trial, 19 subjects ingested one dose, and 21 subjects ingested two doses (days 0 and 10) of PTL-002 or PTL-003 at 2 x 10(9) CFU/dose. Anti-CFA/II mucosal immune responses were determined from the number of antibody-secreting cells (ASC) in blood measured by enzyme-linked immunospot assay, the antibody in lymphocyte supernatants (ALS) measured by enzyme-linked immunosorbent assay (ELISA), and fecal immunoglobulin A (IgA) levels determined by ELISA. Time-resolved fluorescence (TRF) ELISA was more sensitive than standard colorimetric ELISA for measuring serum antibody responses to CFA/II and its components, CS1 and CS3. Both constructs were well tolerated. Mild diarrhea occurred after 2 of 31 doses (6%) of PTL-003. PTL-003 produced more sustained intestinal colonization than PTL-002 and better IgA response rates: 90% versus 55% (P = 0.01) for anti-CFA/II IgA-ASCs, 55% versus 30% (P = 0.11) for serum anti-CS1 IgA by TRF, and 65% versus 25% (P = 0.03) for serum anti-CS3 IgA by TRF. Serum IgG response rates to CS1 or CS3 were 55% in PTL-003 recipients and 15% in PTL-002 recipients (P = 0.02). Two doses of either strain were not significantly more immunogenic than one. Based on its superior immunogenicity, which was comparable to that of a virulent ETEC strain and other ETEC vaccine candidates, PTL-003 will be developed further as a component of a live, oral attenuated ETEC vaccine.


Subject(s)
Escherichia coli Vaccines/adverse effects , Escherichia coli Vaccines/immunology , Escherichia coli/immunology , Vaccines, Attenuated/adverse effects , Vaccines, Attenuated/immunology , Adolescent , Adult , Antibodies, Bacterial/analysis , Antibodies, Bacterial/blood , Antibody-Producing Cells , Double-Blind Method , Enterotoxins/metabolism , Escherichia coli Infections/prevention & control , Escherichia coli Vaccines/administration & dosage , Feces/microbiology , Humans , Immunoglobulin A/analysis , Immunoglobulin A/blood , Immunoglobulin G/blood , Middle Aged , Vaccines, Attenuated/administration & dosage
5.
Infect Immun ; 73(1): 258-67, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15618162

ABSTRACT

An invasive strain of Shigella flexneri 2a (SC608) has been developed as a vector for the expression and delivery of heterologous antigens. SC608 is an aspartate semialdehyde dehydrogenase (asd) derivative of SC602 (icsA iuc), a well-characterized live attenuated vaccine strain which has undergone several clinical trials in human volunteers. When administered orally at a single 10(4) (CFU) dose, SC602 is both immunogenic and efficacious against shigellosis. Using asd-based plasmid vectors, we designed SC608 to express the enterotoxigenic Escherichia coli (ETEC) fimbrial subunit CfaB (CFA/I structural subunit) alone or in combination with the E. coli B subunit of heat-labile enterotoxin (LTB). The expression of each heterologous protein in SC608 was verified by immunoblot analysis. Each strain was comparable to the parent strain, SC602, in a HeLa cell invasion assay. After intranasal immunizations of guinea pigs, serum and mucosal immune responses were detected against both Shigella lipopolysaccharide and heterologous ETEC antigens by enzyme-linked immunosorbent assay and ELISPOT analysis. All immunized animals were subsequently protected against a challenge with wild-type S. flexneri 2a in a keratoconjunctivitis Sereny test. Serum antibodies generated against LTB and CfaB demonstrated antitoxin and agglutination activities, respectively. These results suggest that CfaB and LTB expressed in SC608 retain important conformational epitopes that are required for the generation of antibodies that have functional activities. These initial experiments demonstrate that a fully invasive Shigella vaccine strain can be engineered to deliver antigens from other diarrheal pathogens.


Subject(s)
Bacterial Toxins/immunology , Enterotoxins/immunology , Escherichia coli Proteins/immunology , Escherichia coli/immunology , Fimbriae Proteins/immunology , Shigella Vaccines/immunology , Shigella flexneri/immunology , Vaccines, Synthetic/immunology , Animals , Bacterial Toxins/genetics , Enterotoxins/genetics , Escherichia coli Proteins/genetics , Fimbriae Proteins/genetics , Guinea Pigs , HeLa Cells , Humans , Male , Plasmids , Shigella flexneri/genetics , Vaccination
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