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. 1The 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 1,345 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.345 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;345 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).34 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).346

Two studies reported data on serious adverse events through day 181 after vaccination (Table 3b).34 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).346 No serious adverse events were determined to be related to vaccination (Table 3b, Table 4).346

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.346 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).346 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).348

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).

Tables and appendices

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)

References in this table:3456

_{^aIn an oral challenge study of adults 18–45 years old, the correlation coefficient between cumulative diarrhea (L) and fold-increase in SVA was -0.75 at 10 days and -0.69 at 3 months.7
^b≥4-fold rise in serum vibriocidal antibody level
^cPrimary outcome used for GRADE}

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

References in this table:34

_{^aThrough day 181. The clinical trials defined serious adverse events as an adverse event meeting one of the following criteria: resulted in death, was life-threatening, required hospitalization or the prolongation of an existing hospitalization, resulted in a persistent or significant disability or incapacity, resulted in a congenital anomaly or birth defect, required medical or surgical intervention to prevent impairment or damage, other serious important medical event.}

_{^bAdditional unpublished data obtained from the manufacturer's February 2021 presentation to ACIP. Overall, among children and adolescents aged 2–17 years, 1/468 (0.2%) vaccine recipients and 1/75 (1.3%) placebo recipients reported SAEs within 6 months post-vaccination.⁶}

_{^cRight leg fracture deemed unrelated to the vaccine by the sponsor.}

_{^dPneumonia and asthma requiring hospitalization.}

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

References in this table:34

_{^aIncludes tiredness, headache, abdominal pain, lack of appetite, nausea, vomiting, fever, and diarrhea. Frequencies of individual symptoms did not differ between vaccine and placebo groups, except among 2─5-year-olds: vomiting was significantly more frequent in the placebo group.}

_{^bIncludes one case of potentially life-threatening fever T>40oC}

Table 4: GRADE Summary of Findings

_{CI: confidence interval; RR: risk ratio}

_{^aLoss to follow-up for SVA at day 11: 2–5-year cohort (CVD 103 HgR: 47/150 (32%); Placebo: 6/26 (24%)), 6–11-year cohort (CVD 103-HgR 25/321 (8%); Placebo: 6/53 (11%)).}

_{^bSerious concern for indirectness because efficacy is inferred from immunobridging. SVA seroconversion is an indirect correlate of protection with biologic plausibility. Dichotomous definition of seroconversion (≥4-fold rise in titer) is different than fold-increases in SVA. In an adult challenge study (Chen, 2016), the correlation coefficient between cumulative diarrhea (L) and fold-increase in serum vibriocidal antibodies was -0.75 at day 10 and -0.69 at 3 months.}

_{^cThe RCTs enrolled healthy children and adolescents aged 2─17 years and my not represent all children and adolescents in this age group, such as those with immunocompromising conditions.}

_{^dIn the double-blind, placebo-controlled phase IV study, seroconversion (≥4-fold rise in serum vibriocidal antibody titer) on day 11 occurred among 292/296 (98.6% [98.3% CI: 95.9─99.6%]) CVD 103-HgR recipients aged 6─17 years and among 101/103 (98.1% [98.3% CI: 91.5─99.6%]) CVD 103-HgR recipients aged 2─5 years. Seroconversion in each of these age groups met prespecified non-inferiority criteria (lower limit of the 96.7% CIs on the difference between the groups exceeding -10) compared with adults 18─45 years from a phase III lot consistency study.}

_{^eLoss to follow-up for SAEs (CVD 103-HgR 3/471 (0.6%), placebo 4/79 (5%)).}

_{^fNo SAEs were attributed to the vaccine in either study.}

_{^gVery serious concern for imprecision based on the small sample size to assess rare serious adverse events, the small number of events, and the wide 95% confidence interval that crosses the line of no effect.}

_{^hLoss to follow-up for solicited adverse events CVD 103-HgR: 3/471 (0.6%), placebo: 4/79 (5%).}

_{ⁱSolicited adverse events were reported by a lower percentage of study participants aged 2–5 years (CVD 103-HgR: 40.4%, placebo: 34.6%) than aged 6–17 years (CVD 103-HgR: 61.8%, placebo: 59.2%). This may relate to limited language skills in the younger age group and was deemed not serious.}

_{^jSerious concern for imprecision because the wide 95% confidence intervals cross the line of no effect.}

Table 5: Summary of evidence for outcomes of interest

Appendix 1: Studies Included in the Review of Evidence

References in this appendix:345

Appendix 2. Search Strategies