Live Oral Cholera Vaccine CVD Research Articles

Pre-existing Helicobacter pylori serum IgG enhances the vibriocidal antibody response to CVD 103-HgR live oral cholera vaccine in Malian adults

Accumulating evidence indicates that persistent Helicobacter pylori gastric infection influences immune responses to oral enteric vaccines. We studied the association between pre-existing H. pylori serum IgG and serum pepsinogens levels (PGs) as markers of gastric inflammation and the immune response to single-dose live oral cholera vaccine CVD 103-HgR in Malian adults. Baseline sera obtained during a phase 2 safety/immunogenicity clinical trial of cholera vaccine CVD 103-HgR among 93 healthy Malian adults were tested for H. pylori IgG antibodies and PGI and PGII levels using enzyme linked immunosorbent assays. Overall 74/93 (80%) vaccine recipients were H. pylori IgG seropositive at baseline. Vibriocidal antibody seroconversion (≥ fourfold increase 14 days following administration of CVD 103-HgR compared to baseline) among vaccine recipients was 56%. However, vibriocidal antibody seroconversion was markedly higher among H. pylori seropositives than seronegatives 64% vs. 26% (p = 0.004); adjusted relative risk: 2.20 (95% confidence intervals 1.00–4.80; p = 0.049). Among H. pylori seropositive vaccine recipients, there were no significant associations between PGI, PGII and PGI:PGII levels and vibriocidal seroconversion. The enhanced seroconversion to oral cholera vaccine CVD 103-HgR among H. pylori seropositive African adults provides further evidence of the immunomodulating impact of H. pylori on oral vaccine immunogenicity.

Safety and Immunogenicity of Live Oral Cholera Vaccine CVD 103-HgR in Children and Adolescents Aged 6-17 Years.

.The attenuated recombinant Vibrio cholerae O1 vaccine strain CVD 103-HgR, redeveloped as PXVX0200, elicits a rapid serum vibriocidal antibody (SVA) response and protects against cholera-induced diarrhea in adult volunteer challenge trials but has not been studied in children in developed countries. We performed a phase 4, placebo-controlled, double-blind, multicenter study to assess the safety, immunogenicity, and tolerability of a single, oral dose of PXVX0200 in children and adolescents aged 6–17 years in the United States and bridged immunogenicity to adults aged 18–45 years from a separate lot consistency study. Volunteers were randomized to receive a single dose of 1 × 109 colony forming units (CFU) of PXVX0200 or placebo. Immunogenicity endpoints included SVA levels on days 1, 11, and 29 in volunteers aged 6–17 years and also on days 91 and 181 in volunteers aged 12–17 years. Safety was assessed by comparing solicited signs and symptoms on days 1–8, unsolicited adverse events (AEs) through day 29, and serious AEs through day 181. A total of 374 participants were enrolled, comprising 321 vaccine and 53 placebo recipients. The SVA seroconversion rates 10 days after immunization were 98.6% and 2.1% in vaccine and placebo recipients, respectively, and the vaccine seroconversion rate was non-inferior to the 93.5% rate seen in adults aged 18–45 years. Most reactogenicity was mild to moderate, and there were no vaccine-related serious AEs. The complete dose was consumed in 95.3% and 98.1% of vaccine and placebo recipients, respectively. PXVX0200 appears safe, immunogenic, and well tolerated in children and adolescents aged 6–17 years.

Age-related immunogenicity and reactogenicity of live oral cholera vaccine CVD 103-HgR in a randomized, controlled clinical trial

Aging is accompanied by a decline in immune function which can lead to decreased responses to vaccines. Attenuated recombinant Vibrio cholerae O1 vaccine strain CVD 103-HgR elicits a rapid serum vibriocidal antibody (SVA) response and protects against cholera diarrhea in volunteer challenge studies but has not been studied in older adults. We evaluated CVD 103-HgR (PXVX0200) in adults age 46–64, compared them to previously studied adults age 18–45, and studied age-related immunogenicity across adults 18–64 years of age. Volunteers were randomized to receive a single dose of 1 × 109 CFU of PXVX0200 or placebo. Immunogenicity endpoints included SVA and anti-cholera toxin (CT) antibody levels on days 1, 11, 29, 91 and 181 and lipopolysaccharide (LPS) and CT-specific IgA and IgG memory B cells on days 1, 91 and 181. Safety was assessed by comparing solicited signs and symptoms on days 1–8 and other adverse events through day 181. 2979 volunteers received vaccine, including 291 age 45–64. Day 11 seroconversion occurred in 90.4% of older adults vs 93.5%% of younger adults and met the endpoint of demonstrating non-inferiority between the two groups. Significant increases in LPS-specific IgG and IgA and CT-specific memory IgG memory B cells were seen at days 91 and 181. There appeared to be a continuous age-related decline in SVA seroconversion and geometric mean titers, but not memory B cell responses, across the 18–64 year age range. Most reactogenicity was mild and was more common in the placebo group. PXVX0200 appears safe and immunogenic in older adults.Clinical Trials Registration: clinicaltrials.gov NCT02100631.

Efficacy trial of single-dose live oral cholera vaccine CVD 103-HgR in North Jakarta, Indonesia, a cholera-endemic area

A randomized, double-blind, placebo-controlled efficacy trial of one dose of CVD 103-HgR live oral cholera vaccine was performed in Indonesia from 1993 to 1997. 67,508 persons aged 2–41 years ingested vaccine or placebo and were followed for four years, detecting cholera cases using hospital-based surveillance. A nested reactogenicity study (538 vaccinees, 535 controls) revealed no vaccine-attributable side effects. A nested immunogenicity study ( N=657) showed vibriocidal seroresponses in 64–70% of vaccinees vs 1–2% of controls. Cholera incidence was lower than expected. 103 cases of Vibrio cholerae O1 El Tor diarrhea were detected, 93 evaluable for vaccine efficacy (43 vaccine, 50 placebo; efficacy=14%). A suggestion of protection was observed among persons with blood group O [ P=0.12]. Only seven cases occurred within six months of vaccination, precluding assessment of short-term efficacy. In Jakarta, single-dose CVD 103-HgR did not confer long-term protection. Short-term protection from a single-dose and long-term protection from two doses have yet to be studied.

Effect of small bowel bacterial overgrowth on the immunogenicity of single-dose live oral cholera vaccine CVD 103-HgR.

Several live oral vaccines (polio, bovine rotavirus, CVD 103-HgR cholera) are less immunogenic in developing than in industrialized countries. It was hypothesized that proximal small bowel bacterial overgrowth (common in children in less developed countries but rare in industrialized settings) diminishes the vibriocidal antibody response to CVD 103-HgR. In total, 202 fasting Santiago schoolchildren aged 5-9 years had lactulose breath H2 tests to detect proximal small bowel bacteria 1 day before ingesting CVD 103-HgR. Florid small bowel overgrowth was observed in 10 (5.6%) of 178 analyzable children. In children with florid overgrowth, vibriocidal seroconversion differed little from other children (60% vs. 67%), but the geometric mean titer was lower (160 vs. 368; P=.25). By logistic regression, increased peak breath H2 at small bowel time points was associated with diminished seroconversion (P=.04), as was the interaction of H2 value and weight (children >25 kg had lower seroconversion rates among subjects with heaviest overgrowth).

Attenuated live cholera vaccine strain CVD 103-HgR elicits significantly higher serum vibriocidal antibody titers in persons of blood group O

Persons of blood group O are at increased risk of developing cholera gravis. In a randomized, placebo-controlled, double-blind safety-immunogenicity trial of live oral cholera vaccine CVD 103-HgR in 5- to 9-year-old Chilean children, vibriocidal antibody seroconversion (74% overall) did not differ by blood group. However, the reciprocal geometric mean titer (GMT) in blood group O vaccines (GMT = 486) was higher than that in non-O vaccines (GMT = 179) (P < 0.02).

Immunologic Response to Oral Cholera Vaccination in a Crossover Study: A Novel Placebo Effect

The authors conducted a two-period crossover study of the reactogenicity and immunogenicity of live oral cholera vaccine CVD 103-HgR among US university students. Subjects ingested 5 x 10(8) colony forming units of either killed Escherichia coli K12 placebo or vaccine, followed by the opposite treatment one week later. Surprisingly, the dynamics of the immunologic response were influenced by prior ingestion of placebo. Subjects who received placebo first showed stronger vibriocidal antibody responses 2 weeks after vaccination compared with subjects who received vaccine first; this same pattern was seen for antitoxin titers. The authors suggest that ingestion of E. coli K12 one week prior to immunization boosts the immunologic response to vaccine by an unknown mechanism. Future crossover studies that examine immunologic outcomes might be designed to explore the ubiquity of such an effect.

Safety and immunogenicity of single-dose live oral cholera vaccine CVD 103-HgR in 5-9-year-old Indonesian children

Oral vaccines offer great promise as public-health measures to prevent disease in less-developed countries. CVD 103-HgR, a genetically engineered, attenuated, Vibrio cholerae 01 strain has proved effective in industrialised countries. We have assessed the safety, immunogenicity, and excretion of this live cholera vaccine in children in north Jakarta, Indonesia. 412 children aged 5-9 years received single doses of 5 × 10 6, 5 × 10 7, 5 × 10 8, 5 × 10 9, or 1 × 10 10 colony forming units (CFU) of CVD 103-HgR or placebo (5 × 10 8 inactivated Escherichia coli K-12) with buffer. All doses were well tolerated. The 5 × 10 8 CFU dose, which is highly immunogenic in subjects in industrialised countries (> 90% seroconversion), elicited seroconversions of vibriocidal antibody in only 16% of Indonesian children. By contrast, a single 5 × 10 9 CFU dose of vaccine resulted in high rates (75% and 87%) of seroconversion with two different batches of vaccine. A batch prepared with a centrifugation step gave significantly higher geometric mean titres (16-fold increase over baseline) than did a batch in which there was a filtration step between fermentation and lyophilisation (10-fold increase over baseline). At a 5 × 10 9 CFU dose, CVD 103-HgR is well tolerated and highly immunogenic in Indonesian children and should therefore be further investigated for use as a one-dose live oral cholera vaccine in developing countries.