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No more cholera inoculation

Chan JS

Family Practitioner, 1973;1(1):19.

Matched MeSH terms: Cholera Vaccines
Effect of heat on cholera vibrio: its implication for vaccine manufacture

Ghosh HK

Med J Malaya, 1969 Mar;23(3):179-80.
PMID: 4240070
Matched MeSH terms: Cholera Vaccines*
Fulltext Global economic evaluation of oral cholera vaccine: A systematic review

Teoh SL, Kotirum S, Hutubessy RCW, Chaiyakunapruk N

Hum Vaccin Immunother, 2018 02 01;14(2):420-429.
PMID: 29099647 DOI: 10.1080/21645515.2017.1392422

World Health Organization recommends oral cholera vaccine (OCV) to prevent and control cholera, but requires cost-effectiveness evidence. This review aimed to provide a critical appraisal and summary of global economic evaluation (EE) studies involving OCV to guide future EE study. Full EE studies, published from inception to December 2015, evaluating OCV against cholera disease were included. The included studies were appraised using WHO guide for standardization of EE of immunization programs. Out of 14 included studies, almost all (13/14) were in low- and middle-income countries. Most studies (11/14) evaluated mass vaccination program. Most of the studies (9/14) incorporated herd protective effect. The most common influential parameters were cholera incidence, OCV coverage, herd protection and OCV price. OCV vaccination is likely to be cost-effective when targeted at the population with high-risk of cholera and poor access to health care facilities when herd protection effect is incorporated and OCV price is low.

Matched MeSH terms: Cholera Vaccines/administration & dosage; Cholera Vaccines/economics*; Cholera Vaccines/immunology*
Fulltext Construction and evaluation of V. cholerae O139 mutant, VCUSM21P, as a safe live attenuated cholera vaccine

Murugaiah C, Nik Mohd Noor NZ, Mustafa S, Manickam R, Pattabhiraman L

PLoS One, 2014;9(2):e81817.
PMID: 24505241 DOI: 10.1371/journal.pone.0081817

Cholera is a major infectious disease, affecting millions of lives annually. In endemic areas, implementation of vaccination strategy against cholera is vital. As the use of safer live vaccine that can induce protective immunity against Vibrio cholerae O139 infection is a promising approach for immunization, we have designed VCUSM21P, an oral cholera vaccine candidate, which has ctxA that encodes A subunit of ctx and mutated rtxA/C, ace and zot mutations. VCUSM21P was found not to disassemble the actin of HEp2 cells. It colonized the mice intestine approximately 1 log lower than that of the Wild Type (WT) strain obtained from Hospital Universiti Sains Malaysia. In the ileal loop assay, unlike WT challenge, 1×10⁶ and 1×10⁸ colony forming unit (CFU) of VCUSM21P was not reactogenic in non-immunized rabbits. Whereas, the reactogenicity caused by the WT in rabbits immunized with 1×10¹⁰ CFU of VCUSM21P was found to be reduced as evidenced by absence of fluid in loops administered with 1×10²-1×10⁷ CFU of WT. Oral immunization using 1×10¹⁰ CFU of VCUSM21P induced both IgA and IgG against Cholera Toxin (CT) and O139 lipopolysaccharides (LPS). The serum vibriocidal antibody titer had a peak rise of 2560 fold on week 4. Following Removable Intestinal Tie Adult Rabbit Diarrhoea (RITARD) experiment, the non-immunized rabbits were found not to be protected against lethal challenge with 1×10⁹ CFU WT, but 100% of immunized rabbits survived the challenge. In the past eleven years, V. cholerae O139 induced cholera has not been observed. However, attenuated VCUSM21P vaccine could be used for vaccination program against potentially fatal endemic or emerging cholera caused by V. cholerae O139.

Matched MeSH terms: Cholera Vaccines/genetics; Cholera Vaccines/immunology*; Cholera Vaccines/pharmacology
Repeated dose toxicity evaluation of a cold chain-free, live, attenuated oral cholera vaccine in Sprague Dawley rats

Xian TH, Parasuraman S, Sinniah K, Ravichandran M, Prabhakaran G

Vaccine, 2019 01 29;37(5):711-720.
PMID: 30630696 DOI: 10.1016/j.vaccine.2018.12.027

The repeated dose toxicity of a prototype cold chain-free, live, attenuated oral cholera vaccine containing 5 × 106 CFU/mL of the VCUSM14P strain was evaluated in Sprague Dawley (SD) rats (single dose administered daily for 30 days) to ascertain its safety for clinical use. Repeated dose toxicity studies for cholera vaccines in the literature have administered 2 or 3 fixed doses at 7, 14, 21 or 69 day intervals. The present study reports an evaluation of 30 repeated doses of cholera vaccine administered at three different concentrations (Group II (1.25 × 106 CFU), Group III (2.5 × 106 CFU) and Group IV (5 × 106 CFU)) in SD rats. The liquid vaccine was administered orally to the rats with the respective dose every day, and normal saline was administered to the control group (Group I). No significant difference (P > 0.05) was observed in the body weights and biochemical parameters of the rats after 15 and 30 repeated doses compared to those of the control group. However, compared to those of Group I, a significant increase (P 

Matched MeSH terms: Cholera Vaccines/administration & dosage*; Cholera Vaccines/toxicity*
Fulltext Immunogenicity and protective efficacy of a live, oral cholera vaccine formulation stored outside-the-cold-chain for 140 days

Xian TH, Sinniah K, Yean CY, Krishnamoorthy V, Bahari MB, Ravichandran M, et al.

BMC Immunol, 2020 05 25;21(1):29.
PMID: 32450807 DOI: 10.1186/s12865-020-00360-1

BACKGROUND: Cholera, an acute watery diarrhoeal disease caused by Vibrio cholerae serogroup O1 and O139 across the continents. Replacing the existing WHO licensed killed multiple-dose oral cholera vaccines that demand 'cold chain supply' at 2-8 °C with a live, single-dose and cold chain-free vaccine would relieve the significant bottlenecks and cost determinants in cholera vaccination campaigns. In this direction, a prototype cold chain-free live attenuated cholera vaccine formulation (LACV) was developed against the toxigenic wild-type (WT) V. cholerae O139 serogroup. LACV was found stable and retained its viability (5 × 106 CFU/mL), purity and potency at room temperature (25 °C ± 2 °C, and 60% ± 5% relative humidity) for 140 days in contrast to all the existing WHO licensed cold-chain supply (2-8 °C) dependent killed oral cholera vaccines.
RESULTS: The LACV was evaluated for its colonization potential, reactogenicity, immunogenicity and protective efficacy in animal models after its storage at room temperature for 140 days. In suckling mice colonization assay, the LACV recorded the highest recovery of (7.2 × 107 CFU/mL) compared to those of unformulated VCUSM14P (5.6 × 107 CFU/mL) and the WT O139 strain (3.5 × 107 CFU/mL). The LACV showed no reactogenicity even at an inoculation dose of 104-106 CFU/mL in a rabbit ileal loop model. The rabbits vaccinated with the LACV or unformulated VCUSM14P survived a challenge with WT O139 and showed no signs of diarrhoea or death in the reversible intestinal tie adult rabbit diarrhoea (RITARD) model. Vaccinated rabbits recorded a 275-fold increase in anti-CT IgG and a 15-fold increase in anti-CT IgA antibodies compared to those of rabbits vaccinated with unformulated VCUSM14P. Vibriocidal antibodies were increased by 31-fold with the LACV and 14-fold with unformulated VCUSM14P.
CONCLUSION: The vaccine formulation mimics a natural infection, is non-reactogenic and highly immunogenic in vivo and protects animals from lethal wild-type V. cholerae O139 challenge. The single dose LACV formulation was found to be stable at room temperature (25 ± 2 °C) for 140 days and it would result in significant cost savings during mass cholera vaccination campaigns.

Matched MeSH terms: Cholera Vaccines/immunology*
Immunohistochemical, histological and ultrastructural evaluation of protection provided by cholera vaccine against V. cholerae O139

Murugaiah C, Nik Mohd Noor NZ, Al-Talib H, Mustafa S, Manickam R, Pattabhiraman L

Microb Pathog, 2020 Mar;140:103964.
PMID: 31904450 DOI: 10.1016/j.micpath.2020.103964

In our previous study, complete protection was observed in rabbit immunized with 1 × 1010 CFU of live attenuated VCUSM21P vaccine against challenge with 1 × 109 CFU Vibrio cholerae O139. In the present study, we investigated whether the vaccines can effectively protect immunized animals from any pathologic changes using histological, immunohistochemical and ultrastructural techniques. Severe pathology is evident in wild type injected ileum in non-immunized, showing extensive villous destruction, edema, necrosis and inflammation with infiltration of large numbers of inflammatory cells, extensive damage to the villi and microvilli with pore formation. Histology of ileum injected with wild type in immunized rabbit shows no significant pathological changes except for a few inflammatory cells in lamina propria with mild edema in mucosa and submucosa. immunohistochemical staining revealed O139 antigens of wild type are seen in the lamina propria of edematous villi, muscularis mucosa and submucosa with weak presence in the muscle coat in non-immunized rabbit after challenged with wild type in non-immunized rabbits, but in immunized rabbit localisation of the O139 LPS antigen is seen at the tips of the intact villi, within lamina propria and muscularis mucosa only. These observations suggest that the vaccine can effectively protect animals from any pathologic changes and eliminate V. cholerae O139 from the immunized animals.

Matched MeSH terms: Cholera Vaccines/administration & dosage*; Cholera Vaccines/immunology
Construction and evaluation of a O139 Vibrio cholerae vaccine candidate based on a hemA gene mutation

Ravichandran M, Ali SA, Rashid NH, Kurunathan S, Yean CY, Ting LC, et al.

Vaccine, 2006 May 1;24(18):3750-61.
PMID: 16102875

In this paper, we describe the development of VCUSM2, a live metabolic auxotroph of Vibrio cholerae O139. Auxotrophy was achieved by mutating a house keeping gene, hemA, that encodes for glutamyl-tRNA reductase, an important enzyme in the C5 pathway for delta-aminolevulenic acid (ALA) biosynthesis, which renders this strain dependent on exogenous ALA for survival. Experiments using the infant mouse and adult rabbit models show that VCUSM2 is a good colonizer of the small intestine and elicits greater than a four-fold rise in vibriocidal antibodies in vaccinated rabbits. Rabbits vaccinated with VCUSM2 were fully protected against subsequent challenge with 1 x 10(11) CFU of the virulent wild type (WT) strain. Experiments using ligated ileal loops of rabbits show that VCUSM2 is 2.5-fold less toxic at the dose of 1 x 10(6) CFU compared to the WT strain. Shedding of VCUSM2 in rabbits were found to occur for no longer than 4 days and its maximum survival rate in environmental waters is 8 days compared to the greater than 20 days for the WT strain. VCUSM2 is thus a potential vaccine candidate against infection by V. cholerae O139.

Matched MeSH terms: Cholera Vaccines/administration & dosage; Cholera Vaccines/genetics; Cholera Vaccines/immunology*
Oral vaccination with Lactococcus lactis expressing the Vibrio cholerae Wzm protein to enhance mucosal and systemic immunity

Zamri HF, Shamsudin MN, Rahim RA, Neela V

Vaccine, 2012 May 2;30(21):3231-8.
PMID: 22426330 DOI: 10.1016/j.vaccine.2012.02.012

A gene associated with lipopolysaccharide (LPS) transport was cloned from a local clinical Vibrio cholerae O1 strain of the Ogawa serotype by using the Lactococcus lactis nisin-controlled expression (NICE) system. The V. cholerae wzm gene, which codes for an integral membrane transporter protein, was expressed and targeted to the cytoplasmic membrane, and was crudely isolated through simple centrifugation and SDS solubilization. To examine seroreactivity of this construct, rabbits were orally fed with 10(9) cfu/ml of live, recombinant L. lactis carrying the wzm gene, induced with nisin prior to administration. Recombinant plasmids were retrieved from L. lactis cultured directly from stool samples of inoculated rabbits. Reverse-transcriptase PCR of wzm using the retrieved plasmids confirmed transcription of this gene, indicating viability and stability of the recombinants in vivo. The L. lactis-Wzm construct elicited substantial levels of IgG and sIgA, and challenge with virulent V. cholerae O1 evoked severe diarrhoea in the naive, non-immunised control group, but not in those fed with either recombinant or non-recombinant L. lactis. Oral administration with recombinant L. lactis expressing the V. cholerae wzm gene increases both systemic and mucosal immunity, whereas L. lactis itself appears capable of protecting against the diarrhoeal symptoms caused by V. cholerae. Wzm is a conserved membrane protein associated with the LPS endotoxin, and together with the food-grade L. lactis, represent an attractive target for the development of a safer, live anti-infective therapy against V. cholerae.

Matched MeSH terms: Cholera Vaccines/administration & dosage; Cholera Vaccines/immunology*
Construction and characterization of an auxotrophic ctxA mutant of O139 Vibrio cholerae

Chan M, Cheong TG, Kurunathan S, Chandrika M, Ledon T, Fando R, et al.

Microb Pathog, 2010 Nov;49(5):211-6.
PMID: 20558271 DOI: 10.1016/j.micpath.2010.06.001

Cholera caused by the O139 serogroup still remains a public health concern in certain regions of the world and the existing O1 vaccines do not cross-protect cholera caused by this serogroup. An aminolevulinic acid (ALA) auxotroph vaccine candidate against the O139 serogroup, designated as VCUSM2, was recently developed. It was found to be immunogenic in animal model studies but showed mild reactogenic effects due to the presence of two intact copies of Vibrio cholerae toxin (CTX) genetic element. In the present study we have modified the ctx operon by systematic allelic replacement methodology to produce a mutant strain, designated as VCUSM14. This strain has two copies of chromosomally integrated and mutated ctxA gene, encoding immunogenic but not toxic cholera toxin A subunit (CT-A). The amino acids arginine and glutamic acid at position 7th and 112th, respectively, in CT-A of VCUSM14 were substituted with lysine (R7K) and glutamine (E112Q), respectively. Two copies of the ace and zot genes present in the ctx operon were also deleted. Cholera toxin-ELISA using GM1 ganglioside showed that the both wild type CT and mutated CT were recognized by anti-CT polyclonal antibodies. VCUSM14 produced comparatively less amount of antigenic cholera toxin when compared to the VCUSM2 and Bengal wild type strain. VCUSM14 did not elicit fluid accumulation when inoculated into rabbit ileal loops at doses of 10(6) and 10(8) CFU. The colonization efficiency of VCUSM14 was one log lower than the parent strain, VCUSM2, which can be attributed to the ALA auxotrophy and less invasive properties of VCUSM14. VCUSM14, thus a non-reactogenic auxotrophic vaccine candidate against infection by O139 V. cholerae.

Matched MeSH terms: Cholera Vaccines/genetics*; Cholera Vaccines/immunology*
Construction and characterization of rtxA and rtxC mutants of auxotrophic O139 Vibrio cholerae

Cheong TG, Chan M, Kurunathan S, Ali SA, ZiNing T, Zainuddin ZF, et al.

Microb Pathog, 2010 Feb;48(2):85-90.
PMID: 19900531 DOI: 10.1016/j.micpath.2009.11.001

Vibrio cholerae is a Gram-negative bacterium that causes diarrheal disease. V. cholerae O1 and O139 serogroups are toxigenic and are known to cause epidemic cholera. These serogroups produce cholera toxin and other accessory toxins such as accessory cholera enterotoxin, zonula occludens toxin, and multifunctional, autoprocessing repeat in toxin (MARTX). In the present study, we incorporated mutated rtxA and rtxC genes that encode MARTX toxin into the existing aminolevulinic acid (ALA) auxotrophic vaccine candidate VCUSM2 of V. cholerae O139 serogroup. The rtxC mutant was named VCUSM9 and the rtxC/rtxA mutant was named VCUSM10. VCUSM9 and VCUSM10 were able to colonize intestinal cells well, compared with the parent vaccine strain, and produced no fluid accumulation in a rabbit ileal loop model. Cell rounding and western blotting assays indicated that mutation of the rtxC gene alone (VCUSM9 strain) did not abolish MARTX toxicity. However mutation of both the rtxA and rtxC genes (VCUSM10) completely abolished MARTX toxicity. Thus we have produced a new, less reactogenic, auxotrophic rtxC/rtxA mutated vaccine candidate against O139 V. cholerae.

Matched MeSH terms: Cholera Vaccines*
Cholera in the Kedah River area

Chen PC

Med J Malaya, 1970 Jun;24(4):247-56.
PMID: 4248344
Matched MeSH terms: Cholera Vaccines