ACIP Evidence to Recommendations for Use of Lyophilized CVD 103-HgR Vaccine Among Children and Adolescents Aged 2─17 years

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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 Evidence
Is 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 Evidence
How 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.12
Among 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).13–15
How 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.13–15
Among 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).13–16
Do 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 Evidence
Does 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 Evidence
Is 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 Evidence
Is 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 Evidence
What 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 Evidence
Is 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

  1. 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
  2. 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
  3. 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.
  4. 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
  5. Ali M, Nelson AR, Lopez AL, Sack DA. Updated Global Burden of Cholera in Endemic Countries. PLoS Negl Trop Dis. 2015. 9(6): e0003832.
  6. 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.
  7. 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.
  8. 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.
  9. 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
  10. 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
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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
  16. 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/download
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