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ACIP Evidence to Recommendations for Use of Lyophilized CVD 103-HgR Vaccine Among Children and Adolescents Aged 2─17 years						Print
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										**Question:**Should ACIP recommend lyophilized CVD 103-HgR vaccine for children and adolescents aged 2–17 years traveling to an area with active cholera transmission?
**Population**: Children and adolescents aged 2–17 years traveling to an area with active cholera transmission
**Intervention**: Lyophilized CVD 103-HgR (single-dose, oral, live-attenuated bacterial vaccine*)
**Comparison**: No cholera vaccine
**Outcomes**:
Cholera diarrhea, moderate or severe
Cholera diarrhea, any severity
Serious adverse events
Non-serious adverse events*4×108–2×109 colony forming units with buffer (50 ml if 2–5 years; 100 ml if 6–17 years)**Background:**  Cholera is an acute watery diarrheal illness, primarily caused by toxigenic *Vibrio cholerae* serogroup O1, that can cause severe dehydration and death within hours without treatment.1 Lyophilized CVD 103-HgR vaccine (CVD 103-HgR) (Vaxchora, Emergent BioSolutions, Gaithersburg, MD), a single-dose, live attenuated oral cholera vaccine derived from *V. cholerae*O1, is the only cholera vaccine licensed for use in the United States. In June 2016, the US Food and Drug Administration (FDA) approved lyophilized CVD 103-HgR for the prevention of cholera caused by *V. cholerae* O1 in adults aged 18 through 64 years traveling to cholera-affected area.2 ACIP currently recommends CVD 103-HgR for adults aged 18–64 years traveling to an area with active cholera transmission.3 In December 2020, FDA extended the approved usage of CVD 103-HgR to include children and adolescents aged 2 through 17 years.4
A Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) was completed for CVD 103-HgR to assess the certainty in evidence. Additional factors related to vaccination with CVD 103-HgR were assessed as part of the Evidence to Recommendations Framework (EtR), summarized below. Additional background information supporting the ACIP recommendations on the use of CVD 103-HgR can be found in the relevant publication of the recommendations referenced on the ACIP website.Public Health Problem
Public Health Problem
Criteria
Work Group Judgements
EvidenceIs cholera among children and adolescents aged 2–17 years traveling to an area with active cholera transmission a public health problem?
Probably yes
Cholera is endemic in more than 50 countries and can cause large epidemics.5 Cholera epidemics are associated with unsafe water and inadequate sanitation. Cholera is rare in the United States, though likely underreported. Most U.S. cases occur among travelers to countries where cholera is endemic or epidemic.6 During 2012–2018, 64 U.S. cases of cholera were reported to CDC’s Cholera and Other *Vibrio*Illness Surveillance (COVIS) system; 56 (88%) were travel-associated. Five cases (8%), all travel-associated, occurred in children and adolescents aged 2 through 17 years.
Infection with toxigenic *V. cholerae* O1 can cause a range of symptoms. Up to 10% of infections manifest as severe cholera, i.e., “cholera gravis,” profuse watery diarrhea that can cause severe dehydration and death within hours without treatment.1 Risk factors for cholera gravis include high dose exposure, increased gastric pH (e.g., from antacids, proton-pump inhibitory therapy, or partial gastrectomy), and blood type O.7,8 The case-fatality rate ranges from as high as 50% without treatment to <1% with appropriate fluid replacement therapy.9
Cholera infections among U.S. international travelers are rare because most do not travel to areas with active cholera transmission and are able to access safe water and food at their destination.10 Among travelers to cholera endemic areas, the risk of acquiring cholera varies by travel destination, travel activities, and access to safe food, water, and sanitation. A traveler’s risk of acquiring cholera and developing cholera gravis might not be clear at the pre-travel visit. Apart from the public health domain, cholera may pose a meaningful individual risk for travelers, particularly those with inadequate or delayed access to fluid replacement therapy.Benefits and Harms

Benefits and Harms
Criteria
Work Group Judgements
EvidenceHow substantial are the desirable anticipated effects?
Moderate
No studies directly assessed the efficacy or effectiveness of the current formulation of CVD 103-HgR in preventing cholera among children and adolescents aged 2 through 17 years. Assessment of benefits was based on immunobridging to adults, in whom efficacy has been demonstrated.11 The serum vibriocidal antibody response is commonly used as a correlate of protection, although it is most likely a surrogate marker.12Among children and adolescents aged 2–17 years in phase IV clinical trials, seroconversion (≥4-fold rise in serum vibriocidal antibody titer) on day 11 occurred among 393/399 (98.5%) CVD 103-HgR recipients and 1/67 (1.5%) placebo recipients (pooled relative risk [RR]: 65.99, 95% CI: 9.43–461.69; pooled absolute risk [AR]: 97,000 more per 100,000; 95% CI: 12,582 more to 100,000 more).13–15How substantial are the undesirable anticipated effects?
Small
Among children and adolescents aged 2–17 years in phase IV clinical trials, serious adverse events occurred among 1/468 (0.2%) vaccine recipients and 1/75 (1.3%) placebo recipients (pooled RR: 0.16, 95% CI: 0.01–2.53; pooled AR: 1,120 fewer per 100,000 (95% CI: 1,320 fewer to 2,040 more).13–15 No serious adverse events were assessed as related to vaccination.13–15Among children and adolescents aged 2–17 years in phase IV clinical trials, any solicited adverse event within 7 days after vaccination was reported by 258/468 (55.1%) vaccine recipients and 38/75 (50.7%) placebo recipients (pooled RR: 1.09, 95% CI: 0.86–1.38; pooled AR: 4,560 more per 100,000, 95% CI: 7,093 fewer to 19,253 more).13–15 Solicited adverse events more commonly reported by vaccine than placebo recipients included tiredness (35.7% vs. 30.7%; mostly mild), headache (27.4% vs. 25.3%, mostly mild), abdominal pain (27.8% vs. 18.7%; mostly mild) and lack of appetite (21.4% vs. 14.7%; mostly mild).13–16Do the desirable effects outweigh the undesirable effects?
Favors intervention
The work group concluded that the desirable effects of CVD 103-HgR outweigh the undesirable effects among children and adolescents aged 2–17 years traveling to an area with active cholera transmission.What is the overall certainty of this evidence for the critical outcomes?
Low
The level of certainty in the evidence assessing benefits of CVD 103-HgR among children and adolescents aged 2–17 years was type 2 (moderate) for the prevention of cholera diarrhea (moderate to severe and any severity). The level of certainty in evidence assessing potential harms after vaccination was type 3 (low) for both serious and non-serious adverse events. The overall certainty in evidence assessing critical outcomes was type 3 (low).Values

Values
Criteria
Work Group Judgements
EvidenceDoes the target population feel the desirable effects are large relative to the undesirable effects?
Is there important uncertainty about, or variability in, how patients value the outcomes?
Don’t know
No research evidence was identified. Cholera vaccines are optional. Individual travelers to areas with active cholera transmission can decide whether to get it based on their values.Acceptability
Acceptability
Criteria
Work Group Judgements
EvidenceIs the intervention acceptable to key stakeholders?
Yes
No research evidence was identified. Travel medicine providers and medical associations are likely to find it acceptable to administer CVD 103-HgR to children and adolescents aged 2–17 years traveling to an area with active cholera transmission.Resource Use

Resource Use
Criteria
Work Group Judgements
EvidenceIs the intervention a reasonable and efficient allocation of resources?
Don’t know
No research evidence was identified. A cost-effectiveness analysis was not conducted given the optional nature of CVD 103-HgR among travelers to an area with active cholera transmission.Equity
Equity
Criteria
Work Group Judgements
EvidenceWhat would be the impact of the intervention on health equity?
Varies
No research evidence was identified. Concern for possible inequity was discussed, given that underserved populations may have difficulty accessing and paying for the vaccine. Travelers visiting friends and relatives in cholera endemic areas are likely at highest risk for illness but may be uninsured. Travelers visiting friends and relatives are often less likely than other travelers to go to travel clinics and receive pre-travel vaccines.Feasibility
Feasibility
Criteria
Work Group Judgements
EvidenceIs the intervention feasible to implement?
Probably yes
No research evidence was identified. CVD 103-HgR is likely feasible to administer to children and adolescents aged 2–17 years. Administration might ideally occur in a travel clinic given that the dose preparation is more complicated than with the routine childhood vaccines and the vaccine may be optimally ingested with specific sweeteners (i.e., sucrose or stevia). The recommendation to vaccinate travelers aged 2–17 years to an area with active cholera transmission may impact health equity.Balance of Consequences
Desirable consequences probably outweigh undesirable consequences in most settings.
Is there sufficient information to move forward with a recommendation? Yes.
Policy option for ACIP consideration
ACIP recommends the intervention.
Draft recommendation: ACIP and CDC recommendations
CVD 103-HgR is recommended for children and adolescents aged 2–17 years traveling to an area with active cholera transmission.
Final deliberation and decision by the ACIP
Final ACIP recommendation
ACIP recommends the intervention.
CVD 103-HgR is recommended for children and adolescents aged 2–17 years traveling to an area with active cholera transmission.References
CDC. Cholera – *Vibrio cholerae*infection. Atlanta, GA: US Department of Health and Human Services, CDC; 2020. Accessed June 14, 2022. www.cdc.gov/cholera/illness.html
U.S. Food and Drug Administration. FDA News Release: FDA approves vaccine to prevent cholera for travelers. Silver Spring, MD. US Department of Health and Human Services, FDA, 2016. Accessed June 14, 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-vaccine-prevent-cholera-travelers
Wong KK, Burdette E, Mahon BE, Mintz ED, Ryan ET, Reingold AL. Recommendations of the Advisory Committee on Immunization Practices for Use of Cholera Vaccine. MMWR Morb Mortal Wkly Rep. 2017;66(18):2015–8.
U.S. Food and Drug Administration. Supplement Approval. Silver Spring, MD. US Department of Health and Human Services, FDA, 2020. Accessed June 14, 2022. https://www.fda.gov/media/144754/download
Ali M, Nelson AR, Lopez AL, Sack DA. Updated Global Burden of Cholera in Endemic Countries. PLoS Negl Trop Dis. 2015. 9(6): e0003832.
Loharikar A, Newton AE, Stroika S, et al. Cholera in the United States, 2001─2011: A reflection of patterns of global epidemiology and travel. Epidemiol Infect. 2015;143(4):695–703.
Glass RI, Holmgren J, Haley CE, et al. Predisposition for cholera of individuals with O blood group. Possible evolutionary significance. Am J Epidemiol 1985;121:791–6.
Bavishi C, DuPont HL. Systematic review: The use of proton pump inhibitors and increased susceptibility to enteric infection. Aliment Pharmacol Ther. 2011;34(11–12):1269–81.
Global Task Force on Cholera Control. Cholera Outbreak Response Field Manual. October 2019. Accessed June 14, 2022. https://www.gtfcc.org/wp-content/uploads/2020/05/gtfcc-cholera-outbreak-response-field-manual.pdf
CDC. Travelers’ Health. Cholera. Atlanta GA: US Department of Health and Human Services, CDC; 2022. Accessed June 14, 2022. https://wwwnc.cdc.gov/travel/diseases/cholera
Chen WH, Cohen MB, Kirkpatrick BD, et al. Single-dose live oral cholera vaccine CVD 103-HgR protects against human experimental infection with *Vibrio cholerae* O1 El Tor. Clin Infect Dis. 2016;62(11):1329–35.
Saha D, LaRocque RC, Khan AI, et al. Incomplete correlation of serum vibriocidal antibody titer with protection from *Vibrio cholerae* infection in urban Bangladesh. J Infect Dis. 2004;189(12):2318–22.
McCarty JM, Gierman EC, Bedell L, Lock MD, Bennett S. Safety and immunogenicity of live oral cholera vaccine CVD 103-HgR in children and adolescents aged 6─17 years. Am J Trop Med Hyg. 2020;102(1):48–57.
McCarty JM, Cassie D, Bedell L, Lock MD, Bennett S. Safety and Immunogenicity of Live Oral Cholera Vaccine CVD 103-HgR in Children Aged 2–5 Years in the United States. Am J Trop Med Hyg. 2020;104(3):861–5.
McCarty J (ed). Vaxchora in Children and Adolescents. Advisory Committee on Immunization Practices February 24–25, 2021 Meeting. Atlanta, GA: U.S. Department of Health and Human Services, CDC; 2021. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-02/24-25/03-Cholera-McCarty.pdf
U.S. Food and Drug Administration. Package Insert – VAXCHORA. Silver Spring, MD. U.S. Department of Health and Human Services, FDA, 2020. Accessed June 14, 2022. https://www.fda.gov/media/128415/downloadTop of Page
							
					
							Last Reviewed:  August 25, 2022						Source: 	National Center for Immunization and Respiratory Diseases
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