Experimental challenge studies in the development of vaccines for infectious diseases.
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Communicable Disease Control↗
Biomedical subjects
M M Levine
Publications and source records attributed to M M Levine.
Influence of disease burden, public perception, and other factors on new vaccine development, implementation, and continued use.
The development, implementation, and continued use of new vaccines depends on several factors. Although disease burden seems like an obvious quantitative measure for setting priorities for new vaccine development and use, resources are not always allocated proportionately. This is particularly evident for diseases that are unique (or largely limited) to people in developing countries. Public pressure based on perceptions of the risks associated with a disease or vaccine, the cost of new vaccines, and the ability to incorporate them into existing vaccination programmes also need to be considered in the decision to introduce new vaccines. Vaccine manufacturers play an important part in development of new vaccines, and therefore, the issues that are important to them, namely, production, intellectual property rights, and product liability, must be addressed. By advocating rational decisions, supported by accurate information, scientists and public-health professionals can have an important role in transforming the potential of new vaccines into the reality of new vaccine-preventable diseases.
Animals↗
Oral vaccines against cholera: lessons from Vietnam and elsewhere.
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Administration, Oral↗
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↗
Evaluation of a bivalent (CVD 103-HgR/CVD 111) live oral cholera vaccine in adult volunteers from the United States and Peru.
To provide optimum protection against classical and El Tor biotypes of Vibrio cholerae O1, a single-dose, oral cholera vaccine was developed by combining two live, attenuated vaccine strains, CVD 103-HgR (classical, Inaba) and CVD 111 (El Tor, Ogawa). The vaccines were formulated in a double-chamber sachet; one chamber contained lyophilized bacteria, and the other contained buffer. In the first study, 23 U.S. adult volunteers received CVD 103-HgR at 10(8) CFU plus CVD 111 at 10(8), 10(7), or 10(6) CFU, CVD 111 alone at 10(7) CFU, or placebo. In the second study, 275 Peruvian adults were randomized to receive CVD 103-HgR at 10(9) CFU plus CVD 111 at 10(9) or 10(8) CFU, CVD 111 alone at 10(9) CFU, CVD 103-HgR alone at 10(9) CFU, or placebo. Three of 15 U.S. volunteers who received CVD 111 at 10(7) or 10(8) CFU developed mild diarrhea, compared to none of 4 who received CVD 111 at 10(6) CFU and 1 of 4 who received placebo. Twelve (63%) of 19 vaccine recipients shed the El Tor vaccine strain. All but one volunteer developed significant Ogawa and Inaba vibriocidal antibody titers. Volunteers who received CVD 111 at 10(7) CFU had geometric mean Ogawa titers four to five times higher than those of volunteers who received the lower dose. In the second study, all dosage regimens were well tolerated in Peruvians. About 20% of volunteers who received CVD 111 at the high dose excreted the El Tor organism, compared to 7% in the low-dose group. CVD 111 was detected in the stools of two placebo recipients, neither of whom had symptoms or seroconverted. In all vaccine groups, 69 to 76% developed fourfold rises in Inaba vibriocidal antibodies. Among those who received the bivalent vaccine, 53 to 75% also developed significant rises in Ogawa vibriocidal antibodies. We conclude that it is feasible to produce a single-dose, oral bivalent vaccine that is safe and immunogenic against both biotypes (El Tor and classical) and both serotypes (Inaba and Ogawa) of cholera for populations in both developed and developing parts of the world.
Administration, Oral↗
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↗
Attenuated Salmonella typhi and Shigella as live oral vaccines and as live vectors.
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Administration, Oral↗
[Temporal variation of genotypes and serotypes of enterohemorrhagic E Coli isolated from Chilean children with intestinal infections or hemolytic uremic syndrome].
BACKGROUND: Infections by enterohemorrhagic E. Coli may be asymptomatic, may cause diarrhea, sometimes bloody or a hemolytic uremic syndrome in 2 to 7% of children. These diseases appear sporadically or as outbreaks. Host and agent factors influence the appearance of hemolytic uremic syndrome. AIM: To study the distributions and prevalence of virulence genes and enterohemorrhagic E. Coli serogroups isolated from Chilean children. MATERIALS AND METHODS: Thirty six strains isolated from children with hemolytic uremic syndrome (8 obtained in 1988-1989, 15 obtained in 1990-1993 and 13 obtained in 1995-1996), 33 strains from asymptomatic children, obtained in similar periods and 30 strains from children with bloody diarrhea, obtained in 1995-1996 were studied. Virulence factors were investigated with a colony hybridization technique using probes that identify virulence genes. Serotypes were identified with commercial antisera. RESULTS: Both SLTI and SLTII genes predominated in strains obtained from children with hemolytic uremic syndrome in 1988-1989 and 1995-1996 and SLTI gene predominated in strains obtained in 1990-1993. Similar temporal variations in virulence genes of strains obtained from asymptomatic children were observed. SLTI/SLTII pattern predominated in strains obtained from children with bloody diarrhea and the frequency of O157 serogroup was lower, compared to strains obtained from children with hemolytic uremic syndrome. CONCLUSIONS: There was a temporal variation in toxigenic genotypes of enterohemorrhagic E. Coli strains, but no association between these genotypes and the risk for hemolytic uremic syndrome was observed.
Chi-Square Distribution↗
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↗