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

James M McCarty, Emma C Gierman, Lisa Bedell, Michael D Lock, Sean Bennett, James M McCarty, Emma C Gierman, Lisa Bedell, Michael D Lock, Sean Bennett

Abstract

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.

Trial registration: ClinicalTrials.gov NCT03220737.

Conflict of interest statement

Disclosure: All authors attest that they meet the AJTMH criteria for authorship.

Figures

Figure 1.
Figure 1.
Participant disposition. Consolidated Standards of Reporting Tools (CONSORT) diagram for pediatric trial: Reasons for withdrawal were as follows: 10 participants withdrew consent, 10 were lost to follow-up, two were noncompliant with the protocol, and one ineligible participant was accidentally randomized and withdrawn.
Figure 2.
Figure 2.
Geometric mean titer evels by age cohort and treatment group. Cohort 2 (aged 6–11 years) titers followed to day 29 only. This figure appears in color at www.ajtmh.org.

References

    1. Weil AA, Ryan ET, 2018. Cholera: recent updates. Curr Opin Infect Dis 31: 1–7.
    1. Camacho A, et al. 2018. Cholera epidemic in Yemen, 2016–18: an analysis of surveillance data. Lancet Glob Health 6: e680–e690.
    1. Organization Pan American Health , 1991. Cholera situation in the Americas: an update. Epidemiol Bull 12: 1–14.
    1. Newton A, et al. 2011. Cholera in the United States associated with epidemic in Hispaniola. Emerg Infect Dis 17: 2166–2168.
    1. Ali M, Nelson AR, Lopez AL, Sack DA, 2015. Updated global burden of cholera in endemic countries. PLoS Negl Trop Dis 9: e0003832.
    1. Eberhart-Phillips J, et al. 1996. An outbreak of cholera from food served on an international aircraft. Epidemiol Infect 116: 9–13.
    1. Enzensberger R, Besier S, Baumgartner N, Brade V, 2005. Mixed diarrhoeal infection caused by Vibrio cholerae and several other enteric pathogens in a 4-year-old child returning to Germany from Pakistan. Scand J Infect Dis 37: 73–75.
    1. Reyes-Corcho A, Pinsker RW, Sarkar S, Bagheri F, Patel MC, Lam P, González A, 2012. Cholera gravis associated with acute renal failure in a traveler from Haiti to the United States. Travel Med Infect Dis 10: 236–239.
    1. World Health Organization , 2017. Cholera vaccines: WHO position paper-August 2017. Wkly Epidemiol Rec 92: 477–500.
    1. Mosley WH, Ahmad S, Benenson AS, Ahmed A, 1968. The relationship of vibriocidal antibody titre to susceptibility to cholera in family contacts of cholera patients. Bull World Health Organ 38: 777–785.
    1. Mosley WH, McCormack WM, Ahmed A, Chowdhury AK, Barui RK, 1969. Report of the 1966–67 cholera vaccine field trial in rural East Pakistan. 2. Results of the serological surveys in the study population–the relationship of case rate to antibody titre and an estimate of the inapparent infection rate with Vibrio cholerae. Bull World Health Organ 40: 187–197.
    1. Levine MM, Black RE, Clements ML, Cisneros L, Nalin DR, Young CR, 1981. Duration of infection-derived immunity to cholera. J Infect Dis 143: 818–820.
    1. Levine MM, Chen WH, Kaper JB, Lock M, Danzig L, Gurwith M, 2017. PaxVax CVD 103-HgR single-dose live oral cholera vaccine. Expert Rev Vaccines 16: 197–213.
    1. Suharyono, et al. 1992. Safety and immunogenicity of single-dose live oral cholera vaccine CVD 103-HgR in 5–9 year-old Indonesian children. Lancet 340: 689–694.
    1. Simanjuntak CH, et al. 1993. Safety, immunogenicity, and transmissibility of single-dose live oral cholera vaccine strain CVD 103-HgR in 24- to 59-month-old Indonesian children. J Infect Dis 168: 1160–1176.
    1. Lagos R, Avendano A, Prado V, Horwitz I, Wasserman S, Losonsky G, 1995. Attenuated live cholera vaccine strain CVD 103-HgR elicits significantly higher serum vibriocidal antibody titers in persons of blood group O. Infect Immun 62: 707–709.
    1. Lagos R, Losonsky G, Abrego P, San Martin O, Prado V, Wasserman S, Levine MM, 1996. Tolerance, immunogenicity, excretion and transmission of the live-attenuated cholera vaccine CVD 103-HgR. Double blind paired study in Chilean 24-to 59-month old children. Bol Med Hosp Infant Mex 53: 214–220.
    1. Wiedermann G, Kollaritsch H, Jeschko E, Kundi M, Herzog C, Wegmuller B, 1998. Adverse events after oral vaccination against cholera with CVD 103-HgR. Wien Klin Wochenschr 110: 376–378.
    1. Lagos R, Fasano A, Wasserman SS, Prado V, San Martin O, Abrego P, Losonsky GA, Alegria S, Levine MM, 1999. Effect of small bowel bacterial overgrowth on the immunogenicity of single-dose live oral cholera vaccine CVD 103-HgR. J Infect Dis 180: 1709–1712.
    1. Lagos R, Martin OS, Wasserman SS, Prado V, Losonsky GA, Bustamante C, Levine MM, 1999. Palatability, reactogenicity and immunogenicity of engineered live oral cholera vaccine CVD 103-HgR in Chilean infants and toddlers. Pediatr Infect Dis J 18: 624–630.
    1. Richie E, Punjabi NH, Sidharta Y, Peetosutan K, Sukandar M, Wasserman SS, 2000. Efficay trial of single-dose live oral cholera vaccine CVD 103-HgR in North Jakarta, Indonesia, a cholera endemic area. Vaccine 18: 2399–2410.
    1. Cooper PJ, Chico ME, Losonsky G, Sandoval C, Espinel I, Sridhara R, 2000. Albendazole treatment of children with ascariasis enhances the vibriocidal antibody response to the live attenuated oral cholera vaccine CVD 103-HgR. J Infect Dis 182: 1199–1206.
    1. Faucher JF, Binder R, Missinou MA, Matsiegui PB, Grus H, Neubauer R, 2002. Efficacy of atovaquone/proguanil for malaria prophylaxis in children and its effect on the immunogenicity of live oral typhoid and cholera vaccines. Clin Infect Dis 35: 1147–1154.
    1. Swiss Serum and Vaccine Institute Berne Orochol [package insert]; 2000.
    1. Chen WH, Greenberg RN, Pasetti MF, Livio S, Lock M, Gurwith M, Levine MM, 2014. Safety and immunogenicity of single-dose live oral cholera vaccine strain CVD 103-HgR, prepared from new master and working cell banks. Clin Vaccine Immunol 21: 66–73.
    1. Chen WH, et al. 2016. Single-dose live oral cholera vaccine CVD 103-HgR protects against human experimental infection with Vibrio cholerae O1 El Tor. Clin Infect Dis 62: 1329–1335.
    1. Haney DJ, Lock MD, Simon JK, Harris J, Gurwith M, 2017. Antibody-based correlates of protection against cholera analysis of a challenge study in a cholera-naïve population. Clin Vaccine Immunol 24: 1–11.
    1. McCarty JM, Lock MD, Hunt KM, Simon JK, Gurwith M, 2018. Safety and immunogenicity of single-dose live oral cholera vaccine strain CVD 103-HgR in healthy adults age 18–45. Vaccine 36: 833–840.
    1. McCarty JM, Lock MD, Bennett S, Hunt KM, Simon JK, Gurwith M, 2019. Age related immunogenicity and reactogenicity of live oral cholera vaccine CVD 103-HgR in a randomized, controlled clinical trial. Vaccine 37: 1389–1397.
    1. Sack DA, Qadri F, Svennerholm AM, 2008. Determinants of responses to oral vaccines in developing countries. Ann Nestle [Engl] 66: 71–79.
    1. Levine MM, 2010. Immunogenicity and efficacy of oral vaccines in developing countries: lessons from a live cholera vaccine. BMC Biol 8: 129.
    1. Czerkinsky C, Holmgren J, 2015. Vaccines against enteric infections for the developing world. Philos Trans R Soc Lond B Biol Sci 370: 20150142.
    1. Lim J, 2011. Hedonic scaling: a review of methods and theory. Food Qual Prefer 22: 733–747.
    1. Beneson AS, Saad A, Mosley WH, 1968. Serological studies in cholera. 2. The vibriocidal antibody response of cholera patients determined by a microtechnique. Bull World Health Organ 38: 277–285.
    1. Agresti A, Coull BA, 1998. Approximate is better than “exact” for interval estimation of binomial proportions. Am Stat 52: 119–126.
    1. Mascarello M, Deiana M, Maurel C, Lucarelli C, Luzzi I, Luzzait R, 2013. Cholera with severe renal failure in an Italian tourist returning from Cuba, July 2013. Euro Surveill 18: 20572.
    1. Slesak G, Fleck R, Jacob D, Grunow R, Schafer J, 2016. Imported cholera with acute renal failure after a short business-trip to the Philippines, Germany, October 2015. Euro Surveillance 21: 1–3.
    1. Fritzell B, 1998. Bridging studies. Dev Biol Stand 95: 181–188.
    1. Mosley WH, Beneson AS, Barui R, 1968. A serological survey for cholera antibodies in rural East Pakistan. 2. A comparison of antibody titres in the immunized and control population of a cholera-vaccine field-trial area and the relation of antibody titre to cholera case rate. Bull World Health Organ 38: 335–346.
    1. Glass RI, Svennerholm A, Khan MR, Huda S, Huq MI, Holmgren J, 1985. Seroepidemiologic studies of El Tor cholera in Bangladesh: association of serum antibody levels with protection. J Infect Dis 151: 236–242.
    1. Levine MM, Kaper JB, 1995. Live oral cholera vaccine: from principle to product. Bull Inst Pasteur 93: 243–253.
    1. Tacket CO, Losonsky G, Nataro JP, Cryz SJ, Edelman R, Kaper JB, Levine MM, 1992. Onset and duration of protective immunity in challenged volunteers after vaccination with live oral cholera vaccine CVD 103-HgR. J Infect Dis 166: 837–841.
    1. Tacket CO, 1999. Randomized, double-blind, placebo-controlled, multicentered trial of the efficacy of a single dose of live oral cholera vaccine CVD 103-hgr in preventing cholera following challenge with Vibrio cholerae O1 El Tor Inaba three months after vaccination. Infect Immun 67: 6341–6345.
    1. Levine MM, Kaper JB, Herrington D, Ketley J, Losonsky G, Tacket C, 1988. Safety, immunogenicity and efficacy of recombinant live oral cholera vaccines CVD 103 and CVD 103-HgR. Lancet 2: 467–470.
    1. Cryz S, Levine MM, Kaper JB, Furer E, Althaus B, 1990. Randomized, double-blind, placebo-controlled trial to evaluate the efficacy and immunogenicity of the live oral cholera vaccine CVD 103-HgR in Swiss adults. Vaccine 8: 577–580.
    1. Kotloff W, Wasserman SS, O’Donnell S, Losonsky GA, Cryz SJ, Levine MM, 1992. Safety and immunogenicity in North America of a single dose of live oral cholera vaccine CVD 103-HgR: results of a randomized, placebo-controlled, double-blind cross-over trial. Infect Immun 60: 4430–4432.
    1. Migasena S, Pitisuttitham P, Prayurahong P, Suntharasami P, Supanaranond W, Desakorn V, 1989. Preliminary assessment of the safety and immunogenicity of live oral cholera vaccine strain CVD 103-HgR in health Thai adults. Infect Immun 57: 3261–3264.
    1. Ternik R, Liu F, Bartlett JA, Khong YM, Tan DCT, Dixit T, Wang S, Galella EA, Goa Z, Klein S, 2018. Assessment of swallowability and palatability of oral dosage forms in children: report from an M-CERSI pediatric formulation workshop. Int J Pharm 536: 570–581.
    1. Mistry P, Batchelor H; SPaeDD-UK project , 2017. Methodology used to assess acceptability of oral pediatric medicines: a systematic literature search and narrative review. Pediatr Drugs 19: 223–233.
    1. Saha A, Rosewell A, Hayen A, MacIntyre CR, Qadri F, 2017. Improving immunization approaches to cholera. Expert Rev Vaccines 16: 235–248.

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