Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Lyophilized CVD 103-HgR Vaccine Among Children and Adolescents Aged 2–17 Years

Overview

A Grading of Recommendations, Assessment, Development and Evaluation (GRADE) review of the evidence for benefits and harms for use of lyophilized CVD 103-HgR vaccine (CVD 103-HgR) among children and adolescents aged 2–17 years was presented to the Advisory Committee for Immunization Practices (ACIP) on January 12, 2022. GRADE evidence type indicates the certainty of estimates from the available body of evidence, ranging from type 1 (high certainty) to type 4 (very low certainty).¹ The policy question was “Should ACIP recommend lyophilized CVD 103-HgR vaccine for children and adolescents aged 2–17 years traveling to an area with active cholera transmission?” (Table 1).

The potential benefits pre-specified by the ACIP Cholera Vaccine Work Group were moderate to severe cholera diarrhea (critical) and cholera diarrhea of any severity (critical). The two pre-specified harms were serious adverse events (SAEs) (critical) and non-serious adverse events (important) (Tables 1 and 2). The work group conducted a systematic review of evidence on the benefits and harms of CVD 103-HgR among children and adolescents aged 2–17 years old. Studies identified were assessed using a modified GRADE approach.¹

Regarding benefits, no studies of CVD 103-HgR in children and adolescents aged 2–17 years directly assessed vaccine efficacy or effectiveness against cholera diarrhea. The available data from randomized control trials (RCTs) demonstrated that, compared with placebo, vaccination was associated with a higher risk of serum vibriocidal antibody (SVA) seroconversion (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). The evidence certainty was downgraded for serious imprecision, and the final level of certainty was type 2 (moderate) for both benefits.

Regarding harms, the available data from RCTs demonstrated the vaccine and placebo arms had a similar risk of serious adverse events (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); no serious adverse events were judged to be related to the vaccine among 468 recipients aged 2–17 years within 6 months of vaccination. The risk of non-serious adverse events was similar between the vaccine and placebo groups (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). For both harms, the evidence certainty was downgraded for very serious imprecision, and the final certainty was type 3 (low).

Introduction

In December 2020, the U.S. Food and Drug Administration (FDA) extended the approved usage of Vaxchora to include children and adolescents aged 2 through 17 years.² As part of the process used by the Advisory Committee for Immunization Practices (ACIP), a systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) assessment of the evidence for CVD 103-HgR among children and adolescents aged 2–17 years was conducted and presented to ACIP on January 12, 2022.¹

Methods

We conducted systematic reviews of evidence on the benefits and harms of CVD 103HgR in children and adolescents aged 2–17 years using a modified GRADE approach.¹ The policy question was “should CVD 103-HgR be recommended for children and adolescents aged 2–17 years traveling to an area with active cholera transmission?” (Table 1).

During Work Group calls, members were asked to pre-specify and rate the importance of relevant patient-important outcomes (including benefits and harms) before the GRADE assessment. No conflicts of interest were reported by CDC and ACIP Cholera Vaccine Work Group members involved in the GRADE analysis. The pre-specified benefits (importance) were moderate to severe cholera diarrhea (critical) and cholera diarrhea of any severity (critical). The two pre-specified harms were serious adverse events (SAEs) (critical) and non-serious adverse events (important) (Table 2). Indirect effects of vaccination were not considered as part of GRADE.

We identified studies written in English through PubMed, Embase, and Cochrane Library. Records of relevant Phase I, II, III, or IV clinical trials were included if they 1) provided data on the current formulation and dose of CVD 103-HgR, 2) involved human subjects aged 2–17 years, 3) reported primary data relevant to the efficacy and safety outcomes, and 4) were conducted in cholera non-endemic settings. In addition, unpublished and other relevant data were obtained by hand-searching reference lists and by consulting with vaccine manufacturers and subject matter experts. Characteristics of all included studies are shown in Appendix 1,^3–5 and evidence retrieval methods are shown in Appendix 2.

The evidence certainty assessment addressed risk of bias, inconsistency, indirectness, imprecision, and other characteristics. The GRADE assessment across the body of evidence for each outcome was presented in an evidence profile; the evidence certainty of Type 1, 2, 3, or 4 corresponds to high, moderate, low, or very low certainty, respectively.

Results

The results of the GRADE assessments were presented to ACIP on January 12, 2022. Overall, 571 records were identified and screened; 557 records were excluded based on the title because they were published before the current formulation was available (n=404), they did not report a cholera vaccine trial (n=105), or they reported on a different cholera vaccine or non-endemic setting (n=48). Of the 14 articles deemed eligible for full-text review, 11 were excluded (10 for being conducted in adults, and 1 for being a different formulation). The remaining 3 articles were included in the evidence synthesis and GRADE assessment (Appendix 1). These three records summarized a phase IV, randomized, double-blind placebo-controlled trial among children and adolescents aged 2–17 years.^3–5 When data relevant to the PICO outcomes were not available in these records, additional data were obtained from the study sponsor.⁶

No studies of CVD 103-HgR in children and adolescents aged 2–17 years directly assessed vaccine efficacy or effectiveness. Assessment of both benefits (moderate to severe cholera diarrhea and cholera diarrhea of any severity) was based on immunobridging to adults, in whom efficacy has been demonstrated.⁷ Three studies in children and adolescents aged 2–17 years reported data on immunogenicity;^3–5 two of these reported on serum vibriocidal antibody (SVA) seroconversion (defined as ≥4-fold rise in serum vibriocidal antibody titer) on day 11, the primary immunologic parameter used to assess both benefits (Table 3a).^3,4 Seroconversion on day 11 was more likely among CVD 103-HgR recipients (98.5%) than placebo recipients (1.5%) (pooled RR: 65.99, 95% CI: 9.43–461.69; pooled AR: 97,000 more per 100,000, 95% CI: 12,582 more to 100,000 more) (Table 3a, Table 4).^3,4,6

Two studies reported data on serious adverse events through day 181 after vaccination (Table 3b).^3,4 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).^3,4,6 No serious adverse events were determined to be related to vaccination (Table 3b, Table 4).^3,4,6

The frequency of any solicited adverse event within 7 days was used to assess the outcome non-serious adverse events, with data available from two studies.^3,4,6 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 to 1.38; pooled AR: 4,560 more per 100,000, 95% CI: 7,093 fewer to 19,253 more) (Table 3c, Table 4).^3,4,6 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).^3,4,8

GRADE Summary

For all outcomes, the initial evidence level was type 1 (high) because all available data were from randomized control trials. For moderate to severe cholera diarrhea and cholera diarrhea of any severity, CVD 103-HgR effectively induces SVA seroconversion, an imperfect correlate of protection against cholera. The evidence certainty was downgraded for serious indirectness because efficacy was inferred from immunobridging, and the final evidence certainty was type 2 (moderate). For serious adverse events, none were judged to be related to the vaccine; the evidence certainty was downgraded for very serious imprecision, and the final evidence certainty was type 3 (low). The frequency of non-serious adverse events was not meaningfully different among CVD 103-HgR versus placebo recipients; the evidence certainty was downgraded for very serious imprecision, and the final evidence certainty was type 3 (low) (Table 5).

References

1. Ahmed F. U.S. Advisory Committee on Immunization Practices (ACIP) Handbook for Developing Evidence-based Recommendations, Version 1.2. Atlanta GA: U.S. Department of Health and Human Services, CDC; 2013. Accessed June 14, 2022. www.cdc.gov/vaccines/acip/recs/grade/downloads/handbook.pdf
2. U.S. Food and Drug Administration. Supplement Approval. Silver Spring, MD. U.S. Department of Health and Human Services, FDA, 2020. Accessed June 14, 2022. https://www.fda.gov/media/144754/download
3. 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.
4. 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.
5. McCarty JM, Cassie D, Bedell L, Lock MD, Bennett S. Long-term immunogenicity of live oral cholera vaccine CVD 103-HgR in adolescents aged 12─17 years in the United States. Am J Trop Med Hyg. 2021;104(5):1758–60.
6. 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
7. 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.
8. 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

Table 1: Policy Question and PICO

*4×10⁸–2×10⁹ colony forming units with buffer (50 ml if 2–5 years; 100 ml if 6–17 years)

Table 2: Outcomes and Rankings

*Three options: 1. Critical; 2. Important but not critical; 3. Not important for decision making

Table 3a: Summary of studies relevant to prevention of moderate to severe cholera diarrhea and cholera diarrhea of any severity (indirect evidence assessed using immunobridging^a)

Table 3b: Summary of studies reporting serious adverse events^a

Table 3c: Summary of studies reporting non-serious adverse events

Table 4: GRADE Summary of Findings

Table 5: Summary of evidence for outcomes of interest

Appendix 1: Studies Included in the Review of Evidence

Appendix 2. Search Strategies