Oral vaccines against cholera: lessons from Vietnam and elsewhere.
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Administration, Oral↗
Biomedical subjects
M M Levine
Publications and source records attributed to M M Levine.
Factors associated with superior antibody responses to a single dose of Haemophilus influenzae type b-tetanus toxoid conjugate vaccine administered to Chilean infants at 2 months of age.
The anticapsular antibody response of Chilean infants to a single dose of Haemophilus influenzae type b capsular polysaccharide-tetanus toxoid conjugate, vaccine is substantially higher than that observed among infants of similar age from the USA. Comparison of selected demographic and environmental factors indicates that low maternal education and a greater number of persons in the home are significantly associated with the superior responder phenotype. High anticapsular antibody responses were associated with high antibody responses to tetanus toxoid, the carrier protein in this conjugate, but not to diphtheria toxoid. These data suggest that environmental factors may enhance the magnitude of the primary antibody response to PRP-T vaccine.
Antibodies, Bacterial↗
A cost-benefit analysis of programmatic use of CVD 103-HgR live oral cholera vaccine in a high-risk population.
BACKGROUND: Cholera spread to Latin America in 1991; subsequently, cholera vaccination was considered as an interim intervention until long-term solutions involving improved water supplies and sanitation could be introduced. Three successive summer cholera outbreaks in northern Argentina and the licensing of the new single-dose oral cholera vaccine, CVD 103-HgR, raised questions of the cost and benefit of using this new vaccine. METHODS: This study explored the potential benefits to the Argentine Ministry of Health of treatment costs averted, versus the costs of vaccination with CVD 103-HgR in the relatively confined population of northern Argentina affected by the cholera outbreaks. Water supplies and sanitation in this area are poor but a credible infrastructure for vaccine delivery exists. RESULTS: In our cost-benefit model of a 3-year period (1992-1994) with an annual incidence of 2.5 case-patients per 1000 population and assumptions of vaccine efficacy of 75% and coverage of 75%, vaccination of targeted high risk groups would prevent 1265 cases. CONCLUSION: Assuming a cost of US$602 per treated case and of US$1.50 per dose of vaccine, the total discounted savings from use of vaccine in the targeted groups would be US$132,100. The projected savings would be altered less by vaccine coverage (range 75-90%) or efficacy (60-85%) changes than by disease incidence changes. Our analysis underestimated the true costs of cholera in Argentina because we included only medical expenditures; Indirect losses to trade and tourism had the greatest economic impact. However, vaccination with CVD 103-HgR was still cost-beneficial in the base case.
Adolescent↗
Vibriocidal antibody responses in North American volunteers exposed to wild-type or vaccine Vibrio cholerae O139: specificity and relevance to immunity.
The emergence of a new agent of cholera, Vibrio cholerae O139, has prompted a reevaluation of the vibriocidal antibody assay. This assay, primarily directed to lipopolysaccharide, is an important correlate of O1 immunity. V. cholerae O139 strains are encapsulated, rendering them relatively resistant to killing by serum. Recent reports suggest that there is strain-to-strain variability in the sensitivity of the vibriocidal assay to fully encapsulated O139 strains. We have assessed a modified vibriocidal assay for fully encapsulated O139 strain AI-1837 and its unencapsulated mutant 2L in sera from 53 volunteers given wild-type AI-1837 or its attenuated derivative CVD 112 and from 48 controls challenged with V. cholerae O1 or strains of the family Enterobacteriaceae. Vibriocidal responses to the AI-1837 and 2L strains were seen in 67 and 89% of volunteers, respectively, following a single exposure to the wild-type strain. However, >50% of all controls had low-level vibriocidal responses to both strains. These nonspecific responses were transient and of the immunoglobulin G isotype. No binding activity against purified O139 lipopolysaccharide (LPS) by immunoblotting was seen in control sera. In contrast, vibriocidal assay and strain 2L LPS responses by immunoblotting were detectable in 91% of tested volunteers following a single exposure to O139. The presence of vibriocidal antibody to AI-1837 or 2L was not associated with protection in rechallenge studies with O139 strain AI-1837. The vibriocidal assay with unencapsulated strain 2L may be used to detect exposure to O139 strain AI-1837 in controlled research trials. However, its lack of specificity does not make it useful for determining exposure to V. cholerae O139 in the field.
Antibodies, Bacterial↗
Safety of live oral Salmonella typhi vaccine strains with deletions in htrA and aroC aroD and immune response in humans.
A single-dose, oral Salmonella typhi vaccine strain has been sought as a carrier or vector of cloned genes encoding protective antigens of other pathogens. Such a hybrid vaccine, administered orally, would stimulate immune responses both at the mucosal surface and in the systemic compartment and would potentially provide protection against multiple pathogens. S. typhi CVD 908 and CVD 906, which harbor deletions in aroC and aroD, were further engineered by deletion in htrA to produce strains CVD 908-htrA and CVD 906-htrA, which are unable to sustain growth and are severely impaired in their ability to survive in host tissues. These strains were fed to humans at doses of 5 x 10(7) to 5 x 10(9) CFU with buffer, and safety and immune responses were assessed. CVD 908-htrA and CVD 906-htrA were well tolerated in volunteers; mild diarrhea in 3 of 36 volunteers and mild fever in 1 volunteer were the only notable adverse responses. The vaccine strains were not detected in blood cultures and only transiently detected in stool. Serum immune responses to S. typhi lipopolysaccharide and H antigens were observed in 75 to 100% of volunteers who received 5 x 10(8) to 5 x 10(9) CFU, and cells secreting S. typhi-specific antibodies were found in all volunteers after ingestion of either strain. Sixty-three percent to 83% of volunteers developed lymphoproliferative responses to S. typhi flagellar and particulate antigens after the higher doses. These studies demonstrate the potential of CVD 908-htrA as a live vector for the delivery of heterologous genes, and a clinical trial of such a construct is planned.
Administration, Oral↗
Safety and immunogenicity in humans of an attenuated Salmonella typhi vaccine vector strain expressing plasmid-encoded hepatitis B antigens stabilized by the Asd-balanced lethal vector system.
Attenuated Salmonella typhi organisms which express genes encoding protective antigens of other pathogens have been developed for use as experimental oral vaccines. A delta asd S. typhi strain attenuated by deletions in cya, crp, and cdt which contains hepatitis B core (HBc) and pre-S genes encoded on an Asd+ pBR-based plasmid vector was constructed. Healthy adult volunteers ingested a single dose of 5 x 10(5) to 5 x 10(8) CFU of strain chi4073 (delta cya delta crp delta cdt S. typhi Ty2), 6 x 10(7) or 1 x 10(9) CFU of strain chi4632(pYA3149), a further derivative of chi4073 deleted in asd and containing the Asd+ vector without the HBc-pre-S fusion, or 3 x 10(7) or 7 x 10(8) CFU of strain X4632(pYA3167), a derivative containing the vector with the HBc-pre-S fusion. Chi4073 was generally well tolerated by 22 volunteers. No volunteer had fever or positive blood cultures; 4 of 22 volunteers shed vaccine organisms in the stool in the first 48 h only. Two of 18 volunteers who received one of the plasmid-containing derivatives of chi4073 developed low-grade fevers on day 10 or 12 after ingestion. One of these volunteers had positive blood cultures on days 7 and 8. Seven of these 18 volunteers had vaccine organisms detected in their stools in the first 48 h only. Most volunteers developed S. typhi-specific serum responses and developed S. typhi-specific antibody-secreting cells. However, no volunteer developed serum antibody to hepatitis pre-S or pre-S-specific antibody-secreting cells. Although the parent strain chi4073 was well tolerated, induced immunoglobulin G seroconversion to S. typhi lipopolysaccharide in 80 to 100% of vaccinees and stimulated specific IgA-secreting lymphocytes in 80 to 100% of vaccinees given a single oral dose of 2 x 10(7) and 5 x 10(8) CFU, chi4073 derivatives containing the Asd+ vector with and without sequences encoding the HBc-pre-S fusion caused occasional febrile reactions at high doses and did not stimulate detectable immune responses to hepatitis B antigens.
Adult↗
Effect of shigella enterotoxin 1 (ShET1) on rabbit intestine in vitro and in vivo.
BACKGROUND: Shigella enterotoxin 1 is a novel enterotoxin elaborated by Shigella flexneri 2a that causes fluid accumulation in rabbit ileal loops and a rise in short circuit current in Ussing chambers. AIMS: To gain insights into the mechanism of action of shigella enterotoxin 1. METHODS: Supernatants from genetically engineered clones either overexpressing shigella enterotoxin 1 or producing deletion mutants of the toxin were tested in rabbit ileum both in vitro and in vivo. RESULTS: In rabbit ileum shigella enterotoxin 1 induced an irreversible rise in short circuit current that was not mediated by any of the recognised intracellular mediators of secretion. Deletion of 90% of the A subunit of the holotoxin ablated its enterotoxicity. In the in vivo perfusion model, the toxin induced a time dependent decrease in water absorption, whereas no changes were detected in the segment perfused with supernatants obtained from the deletion mutant. Finally, partially purified toxin induced a dose dependent increment in short circuit current that reached its plateau at a toxin concentration of 4 x 10(-6) M. CONCLUSIONS: Shigella enterotoxin 1 induces a time and dose dependent intestinal secretion in the rabbit animal model, suggesting that it may be responsible for the watery phase of Shigella flexneri 2a infection.
Animals↗
Volunteer studies investigating the safety and efficacy of live oral El Tor Vibrio cholerae O1 vaccine strain CVD 111.
A live oral cholera vaccine should ideally protect against both classical and El Tor biotypes of Vibrio cholerae O1. An El Tor biotype vaccine strain, therefore, would complement classical cholera vaccine strain CVD 103-HgR, a strain already in use in some countries. In this study, 25 healthy adult volunteers received a single dose of 10s colony-forming units of El Tor vaccine strain CVD 111, a derivative of El Tor Ogawa strain N16117 deleted in the virulence cassette. Three (12%) volunteers developed mild diarrhea (mean stool volume = 813 ml) but no systemic symptoms; 23 (92%) of the 25 volunteers developed serum vibriocidal antibodies (geometric mean titer = 1:2,291). Five weeks after vaccination, 18 vaccines and eight uninimunized control volunteers underwent wild-type challenge with El Tor Ogawa strain 3008. Three (16.7%) of 18 vaccinees and seven (87.5%) of eight controls developed diarrhea (P = 0.001) (vaccine efficacy = 80.9%). Further studies are underway to determine a dosage of CVD 111 that will be more clinically acceptable but equally immunogenic and protective.
Administration, Oral↗
The legacy of Edward Jenner.
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Biotechnology↗
Attenuated Salmonella as live oral vaccines against typhoid fever and as live vectors.
Attenuated Salmonella typhi vaccine strain CVD 908, which harbors deletion mutations in aroC and aroD, has been shown to be well-tolerated and highly immunogenic, eliciting impressive serum antibody, mucosal IgA and cell-mediated immune responses. A further derivative prepared by introducing a deletion in htrA (which encodes a heat-shock protein that also has activity as a serine protease in CVD 908 (Chatfield et al., unpublished data) resulted in CVD 908-htrA. In phase 1 clinical trials, CVD 908-htrA appears very attractive as a live oral vaccine candidate. Both CVD 908 and CVD 908-htrA are useful as live vector vaccines to deliver foreign antigens to the immune system. Conditions that enhance the expression and immunogenicity of foreign antigens carried by CVD 908 and CVD 908-htrA are being investigated.
Administration, Oral↗
Enteroaggregative Escherichia coli heat-stable enterotoxin is not restricted to enteroaggregative E. coli.
Enteroaggregative Escherichia coli (EAggEC) have been implicated as diarrheal pathogens in several settings. Some EAggEC produce a distinct heat-stable enterotoxin named EAST1. The distribution and prevalence of the EAST1 gene in selected groups of bacterial enteropathogens were determined by colony hybridization. One hundred percent of 75 O157:H7 enterohemorrhagic E. coli (EHEC), 41% of 227 EAggEC, 41% of 149 enterotoxigenic E. coli, 22% of 65 enteropathogenic E. coli (EPEC), and 38% of 47 E. coli stool isolates from asymptomatic children hybridized with an EAST1 DNA probe. None of 55 enteroinvasive E. coli, 12 Yersinia enterocolitica, or 20 Vibrio cholerae non-O1 strains were EAST1 probe-positive. Concordance between EAST1 genotype and enterotoxicity was shown in examined strains of EAggEC, EHEC, and EPEC. The gene encoding EAST1 is more broadly distributed among diarrheogenic E. coli than previously known and may represent an additional determinant in the pathogenesis of E. coli diarrhea.
Bacterial Adhesion↗
Pathogenic Escherichia coli in children with and without chronic diarrhea in Tanzania.
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Bacterial Adhesion↗
No adverse impact on protection against pertussis from combined administration of Haemophilus influenza type b conjugate and diphtheria-tetanus toxoid-pertussis vaccines in the same syringe.
To assess whether combining a Haemophilus influenzae type b conjugate vaccine (PRP-T) and diphtheria-tetanus toxoid-pertussis (DTP) vaccine in a single syringe would impact adversely the antibody response and clinical protection conferred by pertussis vaccine, surveillance and a nested serosurvey were conducted among infants in a large-scale evaluation of PRP-T in Santiago. Infants received either combined PRP-T/DTP or DTP only at 2, 4, and 6 months of age. At 8 months, pertussis agglutinin, anti-pertussis toxin, and anti-filamentous hemagglutinin antibody levels in the PRP-T/DTP (137.7, 23.1, and 12.2, respectively) and DTP (142.9, 20.6, and 13.0, respectively) groups were comparable. The incidence of pertussis was similar among infants assigned to health centers administering combined PRP-T/DTP and those administering DTP alone (13.1 vs. 12.2 cases/10(5) child-years). Combined PRP-T/DTP vaccine did not diminish protection against pertussis.
Agglutination Tests↗
Large scale, postlicensure, selective vaccination of Chilean infants with PRP-T conjugate vaccine: practicality and effectiveness in preventing invasive Haemophilus influenzae type b infections.
BACKGROUND: Haemophilus influenzae type b (Hib) conjugate vaccines have demonstrated an impressive impact in diminishing Hib disease in industrialized countries. However, their high cost prompts nonindustrialized countries to corroborate their effectiveness under local conditions before considering their programmatic implementation. Such a postlicensure evaluation of vaccine effectiveness was undertaken in Chile. METHODS: After its licensure in Chile polyribosylribitol phosphate-tetanus toxoid protein conjugate vaccine (PRP-T), combined with diphtheria-tetanus-pertussis vaccine, was introduced into the Expanded Program on Immunization schedules in 36 health centers throughout metropolitan Santiago for 12 months, whereas 35 similar health centers administered only diphtheria-tetanus toxoid-pertussis vaccine. Bacteriologic surveillance data for invasive Hib cases collected over the ensuing 30 months were analyzed. RESULTS: In an intent-to-vaccinate (effectiveness) analysis, PRP-T provided 90.2% protection (95% confidence interval, 74.5 to 100%) against invasive Hib disease (40 vs. 4 cases, P < 0.001). Vaccine effectiveness was 91.3% against meningitis (22 vs. 2 cases) and 80% against pneumonia and empyema (10 vs. 2 cases, P = 0.039). Vaccine efficacy among infants who received all three doses of PRP-T was 91.7% (95% confidence interval, 64.8 to 100%). CONCLUSIONS: Programmatic use of Hib conjugate vaccine administered in combination with diphtheria-tetanus-pertussis vaccine constitutes a highly effective and practical intervention in Chile, a newly industrializing country.
Bacterial Capsules↗
Factors influencing secondary vibriocidal immune responses: relevance for understanding immunity to cholera.
Although serum vibriocidal activity is used extensively as a marker of immunity to O1 Vibrio cholerae, there are limitations in this assay to detect instances of reexposure. We define the conditions operative in producing secondary vibriocidal responses in North American volunteers primed with either wild-type V. cholerae 1, 4, or 6 months later. Secondary serum vibriocidal responses occurred under two distinct secondary challenge conditions. The first occurred when secondary challenge produced a breakthrough in clinical protection. Following secondary exposure, 14 of 22 (64%) and 1 of 29 (3%) subjects with and without vibrio stool excretion, respectively, had secondary responses (P < 0.001); 5 of 6 (83%) and 10 of 45 (22%) subjects with or without diarrhea, respectively, mounted a secondary response (P = 0.006). The second condition occurred in the presence of full clinical protection but was dependent on the time interval between exposure. No subject (0 to 17) vaccinated with CVD 103-HgR and given homologous wild-type challenge within 4 months mounted a secondary vibriocidal response (P = 0.0009). The majority of the serum vibriocidal activity was of the immunoglobulin M (IgM) isotype, seen in 96 and 73% of subjects following primary and secondary exposure, respectively. Vibriocidal activity in the IgG fraction following primary and secondary exposures occurred with < or = 50% of volunteers; lipopolysaccharide (LPS)-specific IgG1 and IgG3 subclass responses supported the vibriocidal isotype data. However, following primary exposure, IgG4 LPS responses predominated, occurring in 81% of responding volunteers. These data suggest that, under certain conditions of secondary exposure to V. cholerae O1 antigens, when there is sufficient active local immunity present, there is a block of vibrio antigen resampling at the M cell level. We discuss the implications of and possible explanations for these findings.
Adolescent↗
Further characterization of delta aroA delta virG Shigella flexneri 2a strain CVD 1203 as a mucosal Shigella vaccine and as a live-vector vaccine for delivering antigens of enterotoxigenic Escherichia coli.
The use of attenuated delta aroA delta virG Shigella flexneri 2a strain CVD 1203 as a live vector for enterotoxigenic Escherichia coli (ETEC) antigens is reported. CVD 1203 alone or expressing colonization factor antigen fimbriae and CS3 fibrillae of ETEC was given to guinea pigs and mice, orogastrically (o.g.) or intranasally (i.n.). CVD 1203 given i.n. elicited high titers of antilipopolysaccharide (anti-LPS) immunoglobulin A (IgA) and was protective in guinea pigs against a homologous conjunctival challenge. Whereas a strong IgA response against colonization factor antigen CS3, and Shigella LPS was detected in tears and serum of guinea pigs after o.g. or i.n. immunization, the i.n. route elicited significantly higher antibody titers. A strong serum IgG response was also observed against the ETEC antigens, although no serum anti-LPS IgG response was detected. The immune response in mice followed a pattern similar to that in guinea pigs, and the difference between the responses after o.g. and i.n. administration was even more remarkable.
3-Phosphoshikimate 1-Carboxyvinyltransferase↗
Protective immunity to Shiga-like toxin I following oral immunization with Shiga-like toxin I B-subunit-producing Vibrio cholerae CVD 103-HgR.
This study addresses a mechanism for inducing systemic immunity to Shiga-like toxins by oral administration of a Shiga-like toxin I B-subunit-expressing Vibrio cholerae vaccine strain [CVD 103-HgR(pDA60)]. Two sets of three rabbits were given either CVD 103-HgR or CVD 103-HgR(pDA60) orally. All rabbits immunized with CVD 103-HgR(pDA60) developed neutralizing serum antibodies to Shiga-like toxin I. None of the controls developed such antibodies.
Administration, Oral↗
Expression and immunogenicity of pertussis toxin S1 subunit-tetanus toxin fragment C fusions in Salmonella typhi vaccine strain CVD 908.
Salmonella typhi vaccine strain CVD 908 can deliver heterologous antigens to the host immune system following mucosal immunization. Stable expression of foreign proteins in Salmonella cells often requires antigen-specific engineering strategies. Fusion of antigens to stabilizing proteins has proven to be a successful strategy for rescuing otherwise unstable proteins. We designed plasmids to allow the fusion of antigens to the amino terminus or carboxyl terminus of fragment C of tetanus toxin, separated by a 4-amino-acid hinge region. Towards the ultimate goal of developing a live oral diphtheria-pertussis-tetanus vaccine, we used these plasmids to stably express the S1 subunit of pertussis toxin in CVD 908. Driven by the anaerobically inducible nirB promoter, the S1 subunit alone was expressed poorly in Salmonella cytoplasm. In contrast, hybrid proteins with S1 fused to either the amino or carboxyl terminus of fragment C were expressed at a high level in CVD 908 and were recognized in Western blot (immunoblot) analysis by monoclonal antibodies directed to S1 and to fragment C. Mice were immunized by the oral or intranasal routes with CVD 908 derivatives harboring these recombinant plasmids. All fusion proteins elicited serum antibody responses to fragment C following intranasal immunization, whereas oral inoculation did not. The configuration of antigens constituting the fusion was critical; S1 fused to the amino terminus of fragment C was less effective than S1 fused to the carboxyl terminus in generating anti-fragment C antibodies. CVD 908 expressing truncated S1 fused to the carboxyl terminus of fragment C elicited neutralizing serum pertussis antitoxin following intranasal immunization of mice.
Animals↗