Field Trial of Oral Cholera Vaccines in Bangladesh: Results of One Year of Follow-Up

Clemens, John D.; Harris, Jeffrey R.; Sack, David A.; Chakraborty, J.; Ahmed, Faruque; Stanton, Bonita; Khan, Shafiqul Islam; B, Kay; Huda, Nurul; Khan, M. R.; Yunus, Mohammad; Rao, Malla R.; Svennerholm, Ann‐Mari; Holmgren, Jan

doi:10.1093/infdis/158.1.60

Cited by 151 publications

(86 citation statements)

References 22 publications

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“…A highly plausible explanation for the drastic reduction in cholera cases in the Jakarta trial accompanied by a low-point estimate of vaccine efficacy came subsequently when Ali et al (37) reported a reanalysis of the first-year results of the large-scale randomized controlled field trial in Bangladesh that assessed the efficacy of three oral doses of the B subunit (BS)/inactivated wholecell cholera vaccine (the precursor of Dukoral) or whole-cell vaccine alone, versus placebo (38). This innovative reanalysis examined vaccine efficacy in relation to the proportion of the target population in a geographically separated baris (patrilineally related clusters of households) that was vaccinated.…”

Section: Discussionmentioning

confidence: 99%

Safety and Immunogenicity of Single-Dose Live Oral Cholera Vaccine Strain CVD 103-HgR, Prepared from New Master and Working Cell Banks

Chen¹,

Greenberg²,

Pasetti³

et al. 2013

Clin. Vaccine Immunol.

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c Currently, no cholera vaccine is available for persons traveling from the United States to areas of high cholera transmission and who for reasons of occupation or host factors are at increased risk for development of the disease. A single-dose oral cholera vaccine with a rapid onset of protection would be particularly useful for such travelers and might also be an adjunct control measure for cholera outbreaks. The attenuated Vibrio cholerae O1 vaccine strain CVD 103-HgR harbors a 94% deletion of the cholera toxin A subunit gene (ctxA) and has a mercury resistance gene inserted in the gene encoding hemolysin A. We undertook a phase I randomized placebo-controlled two-site trial to assess the safety and immunogenicity of a preliminary formulation of CVD 103-HgR prepared from new master and working cell banks. Healthy young adults were randomized (5:1 vaccinees to placebo recipients) to receive a single oral dose of ϳ4.4 ؋ 10 8 CFU of vaccine or a placebo. Blood serum vibriocidal and cholera toxin-specific IgG antibodies were measured before and 10, 14, and 28 days following vaccination or placebo. Excretion of the vaccine strain in the stool was assessed during the first week postvaccination. A total of 66 subjects were enrolled, comprising 55 vaccinees and 11 placebo recipients. The vaccine was well tolerated. The overall vibriocidal and anti-cholera toxin seroconversion rates were 89% and 57%, respectively. CVD 103-HgR is undergoing renewed manufacture for licensure in the United States under the auspices of PaxVax. Our data mimic those from previous commercial formulations that elicited vibriocidal antibody seroconversion (a correlate of protection) in ϳ90% of vaccinees. (This study has been registered at ClinicalTrials.gov under registration no. NCT01585181.)

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Section: Discussionmentioning

confidence: 99%

Safety and Immunogenicity of Single-Dose Live Oral Cholera Vaccine Strain CVD 103-HgR, Prepared from New Master and Working Cell Banks

Chen¹,

Greenberg²,

Pasetti³

et al. 2013

Clin. Vaccine Immunol.

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“…However, the fusions retained some toxicity (A.-M. Svennerholm, personal communication). The CT-B component of the currently licensed cholera vaccine contributes to its protection against LT-ETEC diarrhea (6)(7)(8). A CT-B-ST vaccine could accordingly give protection against both ETEC enterotoxins.…”

Section: St Vaccinologymentioning

confidence: 99%

Heat-Stable Enterotoxin of EnterotoxigenicEscherichia colias a Vaccine Target

et al. 2010

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5Enterotoxigenic Escherichia coli (ETEC) is responsible for 280 million to 400 million episodes of diarrhea and about 380,000 deaths annually. Epidemiological data suggest that ETEC strains which secrete heat-stable toxin (ST), alone or in combination with heat-labile toxin (LT), induce the most severe disease among children in developing countries. This makes ST an attractive target for inclusion in an ETEC vaccine. ST is released upon colonization of the small intestine and activates the guanylate cyclase C receptor, causing profuse diarrhea. To generate a successful toxoid, ST must be made immunogenic and nontoxic. Due to its small size, ST is nonimmunogenic in its natural form but becomes immunogenic when coupled to an appropriate large-molecular-weight carrier. This has been successfully achieved with several carriers, using either chemical conjugation or recombinant fusion techniques. Coupling of ST to a carrier may reduce toxicity, but further reduction by mutagenesis is desired to obtain a safe vaccine. More than 30 ST mutants with effects on toxicity have been reported. Some of these mutants, however, have lost the ability to elicit neutralizing immune responses to the native toxin. Due to the small size of ST, separating toxicity from antigenicity is a particular challenge that must be met. Another obstacle to vaccine development is possible cross-reactivity between anti-ST antibodies and the endogenous ligands guanylin and uroguanylin, caused by structural similarity to ST. Here we review the molecular and biological properties of ST and discuss strategies for developing an ETEC vaccine that incorporates immunogenic and nontoxic derivatives of the ST toxin.

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“…Strains of the classical biotype, which had probably been responsible for most of the epidemic disease in the 19th century and much of the 20th century, were largely replaced as the predominant cause of epidemic cholera by strains of the El Tor biotype in most of the regions where cholera is endemic, beginning in 1961. However, the classical biotype strains reemerged as a predominant epidemic strain in parts of Bangladesh in 1982 (8,25) and coexisted with the El Tor strains, causing disease until 1993. A second new epidemic strain, carrying the O139 rather than the O1 antigen, emerged in southern Asia in 1992 (7,24).…”

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confidence: 99%

New Variants of Vibrio cholerae O1 Biotype El Tor with Attributes of the Classical Biotype from Hospitalized Patients with Acute Diarrhea in Bangladesh

et al. 2002

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The sixth pandemic of cholera and, presumably, the earlier pandemics were caused by the classical biotype of Vibrio cholerae O1, which was progressively replaced by the El Tor biotype representing the seventh cholera pandemic. Although the classical biotype of V. cholerae O1 is extinct, even in southern Bangladesh, the last of the niches where this biotype prevailed, we have identified new varieties of V. cholerae O1, of the El Tor biotype with attributes of the classical biotype, from hospitalized patients with acute diarrhea in Bangladesh. Twentyfour strains of V. cholerae O1 isolated between 1991 and 1994 from hospitalized patients with acute diarrhea in Matlab, a rural area of Bangladesh, were examined for the phenotypic and genotypic traits that distinguish the two biotypes of V. cholerae O1. Standard reference strains of V. cholerae O1 belonging to the classical and El Tor biotypes were used as controls in all of the tests. The phenotypic traits commonly used to distinguish between the El Tor and classical biotypes, including polymyxin B sensitivity, chicken cell agglutination, type of tcpA and rstR genes, and restriction patterns of conserved rRNA genes (ribotypes), differentiated the 24 strains of toxigenic V. cholerae O1 into three types designated the Matlab types. Although all of the strains belonged to ribotypes that have been previously found among El Tor vibrios, type I strains had more traits of the classical biotype while type II and III strains appeared to be more like the El Tor biotype but had some classical biotype properties. These results suggest that, although the classical and El Tor biotypes have different lineages, there are possible naturally occurring genetic hybrids between the classical and El Tor biotypes that can cause cholera and thus provide new insight into the epidemiology of cholera in Bangladesh. Furthermore, the existence of such novel strains may have implications for the development of a cholera vaccine.New epidemic strains of toxigenic Vibrio cholerae have appeared at least twice in recent human history (10). Strains of the classical biotype, which had probably been responsible for most of the epidemic disease in the 19th century and much of the 20th century, were largely replaced as the predominant cause of epidemic cholera by strains of the El Tor biotype in most of the regions where cholera is endemic, beginning in 1961. However, the classical biotype strains reemerged as a predominant epidemic strain in parts of Bangladesh in 1982 (8, 25) and coexisted with the El Tor strains, causing disease until 1993. A second new epidemic strain, carrying the O139 rather than the O1 antigen, emerged in southern Asia in 1992 (7, 24). The O139 and El Tor O1 strains continue to cause epidemics of cholera, and there are indications that the incidence of cholera due to the O139 serogroup is on the rise in parts of India and Bangladesh.The classical and El Tor biotypes of V. cholerae are closely related in their O-antigen biosynthetic genes (21, 31), although these two biotypes diffe...

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Field Trial of Oral Cholera Vaccines in Bangladesh: Results of One Year of Follow-Up

Cited by 151 publications

References 22 publications

Safety and Immunogenicity of Single-Dose Live Oral Cholera Vaccine Strain CVD 103-HgR, Prepared from New Master and Working Cell Banks

Safety and Immunogenicity of Single-Dose Live Oral Cholera Vaccine Strain CVD 103-HgR, Prepared from New Master and Working Cell Banks

Heat-Stable Enterotoxin of EnterotoxigenicEscherichia colias a Vaccine Target

New Variants of Vibrio cholerae O1 Biotype El Tor with Attributes of the Classical Biotype from Hospitalized Patients with Acute Diarrhea in Bangladesh

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