Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) for Lyophilized CVD 103-HgR Vaccine

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Introduction

In 2016, lyophilized CVD 103-HgR (Vaxchora^TM), a single-dose, live attenuated oral cholera vaccine, was approved for the prevention of cholera caused by V. cholerae O1 in adults traveling to cholera-affected areas. Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was adopted by CDC in 2011 as the framework for evaluating the scientific evidence that informs recommendations for vaccine use. The GRADE approach considers benefits and harms, evidence type, values and preferences, and health economic analysis. The main policy question for the GRADE evaluation of CVD 103-HgR use was, “Should live attenuated oral cholera vaccine CVD 103-HgR be recommended for use in adults 18–64 years old at risk of travel-related exposure to toxigenic Vibrio cholerae O1?” Factors influencing the strength of the recommendation included the balance between benefits and harms, the importance of key outcomes based on the knowledge and perspective of workgroup members, and the evidence type for each of the outcomes. Economic analyses were not formally considered in the body of evidence, as travel vaccines are usually paid for by the travelers and are often not covered by publically funded health care plans.

Methods

The work group performed a systematic review of Medline, Embase, Cochrane Library, and ClinicalTrials.gov, for papers in any language. Search terms are described in Table 1. Articles were included if they presented data on CVD 103-HgR and 1) involved human subjects; 2) reported primary data; 3) included data relevant to the outcome measures being assessed; and 4) included data for the dose being approved. Studies without adult participants 18 years of age or older were excluded. These studies were further limited to those published between 1988, when CVD 103-HgR was first developed, and January 2016. The work group also pursued available unpublished data from the vaccine manufacturer. After review of the titles and abstracts, 78 studies were identified for further review. Of these, 41 studies, including 1 cost-benefit analysis, did not include CVD 103-HgR data or any primary data, and 8 studies did not include adult participants. This left 29 studies for inclusion in the GRADE evaluation. The work group reviewed articles of the currently available formulation of lyophilized CVD 103-HgR vaccine as well as literature pertaining to an older formulation of the vaccine (previously marketed as Orochol^® or Mutacol^®). Bibliographies were reviewed for additional relevant references.

Beneficial and harmful outcomes of vaccination to consider, as well as the importance of these outcomes, were proposed by the work group and presented to ACIP. The work group evaluated disease epidemiology and burden, severity of the disease, vaccine efficacy and effectiveness, vaccine safety, and economic and implementation considerations to propose the recommendation category. The accompanying policy note that summarizes the ACIP findings and conclusions was drafted based on the recommendation and revised based on feedback from ACIP voting members. The CDC Director approved these recommendations prior to publication. Opinions of individual members of ACIP may differ to some extent from the recommendation in this document, as this recommendation is the position of CDC based on the ACIP recommendation to the CDC Director.

Postmarketing surveillance studies and additional data pertaining to use of the vaccine will be reviewed by ACIP as they become available, and recommendations will be updated as needed.

Results

Critically important beneficial outcomes included prevention of cholera death, prevention of life-threatening cholera diarrhea (>5L volume over the illness course), and prevention of severe cholera diarrhea (>3L volume over the illness course). Critically important harmful outcomes included serious adverse events, systemic adverse events, and a decrease in the effectiveness of co-administered vaccines or medications. Prevention of cholera diarrhea of any severity and induction of a vibriocidal antibody response were considered important beneficial outcomes (Table 2).

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Efficacy of CVD 103-HgR in prevention of cholera diarrhea: challenge and field studies

The efficacy of CVD 103-HgR vaccine has been evaluated with cholera challenge studies, in which vaccinated individuals ingest toxigenic V. cholerae O1, and by immunogenicity studies. Vibriocidal antibodies are a marker for protection against V. cholerae infection. Efficacy was evaluated using evidence from the older and newer formulations of CVD 103-HgR vaccine, where available. The body of evidence indicates that the vaccine is effective. Evidence for specific outcomes is described below.

Prevention of death from cholera

The available evidence was insufficient to determine whether CVD 103-HgR prevented death from cholera (Table 3). Challenge studies were not designed to examine this outcome. A large Indonesian field randomized controlled trial (RCT) with the older vaccine formulation did not assess deaths from cholera, but it found no difference between vaccinated and unvaccinated populations in deaths from diarrhea of any etiology over four years, using verbal autopsy method (1). Of note, this study was not cluster-randomized, and incidence of cholera in the study setting was much lower than anticipated in both vaccinated and unvaccinated groups.

Prevention of life-threatening cholera diarrhea (>5L)

One RCT found that CVD 103-HgR significantly reduced the proportion of volunteers who developed cholera diarrhea of >5L after challenge with toxigenic V. cholerae O1 in the vaccinated group compared with the placebo group (2) (Table 3). The vaccine efficacy (VE) was 93% for those challenged 10 days post-vaccination and 86% for those challenged 3 months post-vaccination.

Prevention of severe cholera diarrhea (>3L)

Two challenge studies (RCTs) found that CVD 103-HgR significantly reduced the proportion of volunteers who developed cholera diarrhea of >3L after challenge with toxigenic V. cholerae O1 in the vaccinated group compared with the placebo group. In one study, challenge occurred 3 months after vaccination (VE 91%), and in the other, challenge occurred 10 days (VE 90%) or 3 months (VE 79%) after vaccination (2) (Table 3). The large field RCT in Indonesia, was not cluster-randomized and had lower-than-expected incidence of cholera overall, raising the possibility that herd immunity may have led to a decrease in incidence in unvaccinated as well as vaccinated participants (3). This study found no difference in severe cholera diarrhea, as assessed by sentinel surveillance over four years, in vaccinated versus unvaccinated individuals (1).

Prevention of cholera diarrhea of any severity

Evidence for prevention of cholera diarrhea was evaluated with four RCTs and three observational studies (Table 3). There were five challenge studies in adults (2, 4-7), which include one RCT conducted with the new formulation of the vaccine (2). The challenge studies showed consistent results indicating effectiveness of CVD 103-HgR in reducing the proportion who developed cholera diarrhea of any severity in the vaccinated group compared with the placebo group. The lowest VE in these studies was 51% at 3 months post-vaccination (2); in two observational challenge studies, no vaccinated individuals developed cholera diarrhea, and the VE approached 100% (5, 6). The Indonesia field RCT, which was not cluster-randomized and had lower-than-expected incidence of cholera overall, showed no difference between the vaccinated and unvaccinated population in cholera diarrhea detected by sentinel hospital surveillance over four years (1). When CVD 103-HgR was used for a mass vaccination campaign during a cholera outbreak in Micronesia, the incidence of cholera diarrhea was lower in the vaccinated population than the unvaccinated population (0.3% versus 1.6%) (8).

Immunogenicity

Twenty RCTs and three observational studies were used to assess the evidence for immunogenicity of CVD 103-HgR, including four studies using the newer formulation of the vaccine (Table 4). The 19 studies using the older formulation of the vaccine show a consistent effect of induction of vibriocidal antibodies; VE in most studies was >90%, and the time frame for most serologic studies was within 1 week to 1 month of vaccination. The four RCTs with the newer formulation of the vaccine show that seroconversion (defined as a ≥4-fold rise in vibriocidal antibodies from baseline) occurred in 89–93% of vaccinated adults, with a VE of ≥96% (2, 9-11).

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Safety

Serious adverse events

There were 21 RCTs and 4 observational studies that examined the occurrence of serious adverse events (Table 5). In a large Indonesian field study that was not cluster-randomized, there was no difference in overall mortality between the vaccinated and unvaccinated populations over four years (1). The remaining 23 studies reported no serious adverse events linked to the vaccine among 6,589 individuals who received CVD 103-HgR.

Systemic adverse events

There were 21 RCTs and 4 observational studies that examined the occurrence of systemic adverse events. None of these individual studies detected differences between the vaccinated and unvaccinated groups in the occurrence of any systemic adverse events (Table 5). When studies of the new formulation were pooled (2, 10, 11), there was a slight increase in diarrhea (≥4 loose stools per 24 hours), which was mostly mild, in vaccine versus placebo recipients (3.8 versus 1.6%; p=0.008).

Post-marketing data

CVD 103-HgR was previously marketed as Orochol^® or Mutachol^® in several countries before manufacture ceased for business reasons. Of more than 500,000 Orochol^® doses sold, the following adverse events after vaccination were spontaneously reported: hospitalization with fever, gastroenteritis, vomiting, and hemorrhagic cerebrospinal fluid in one 11-month-old infant; Guillain Barré syndrome in a person who received CVD 103-HgR, yellow fever vaccine, Ty21a vaccine, and diphtheria and polio vaccines; angioedema (one report); and loss of hair (one report) (12, 13). Of more than 250,000 Orochol^® E (a higher dose formulation) doses sold, there were no spontaneously reported adverse reactions.

Co-administration

Three randomized controlled trials and one observational cohort study reported co-administration of an older formulation of CVD 103-HgR with Ty21a vaccine and measured anti-Salmonella serotype Typhi LPS antibodies among study participants receiving both vaccines (14-17). Anti-Typhi LPS antibodies were detected in 62–83% of participants (470 adults) after primary immunization; in comparison, one RCT reported that 66% of participants who received Ty21a alone developed anti-Typhi LPS antibodies. One study examined the immunogenicity of yellow fever (YF) 17D vaccine in combination with an older formulation of CVD 103-HgR or CVD 103-HgR and Ty21a; all 58 individuals who received both YF 17D and CVD 103-HgR developed anti-YF antibodies (18).

One study evaluated an older formulation of CVD 103-HgR in combination with different medications and vaccines including Ty21a, YF 17D, oral polio vaccine, mefloquine, chloroquine, and proguanil (16). Significantly lower rates of vibriocidal seroconversion were noted when CVD 103-HgR was co-administered with chloroquine (67%) versus alone (91%). No decrease in immunogenicity was noted for CVD 103-HgR when co-administered with mefloquine, proguanil, YF 17D, or oral polio vaccine.

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Summary of quality of evidence across outcomes

The evidence type was downgraded for indirectness for studies using the older formulation of CVD 103-HgR vaccine, which is slightly different from the currently available formulation of CVD 103-HgR. Studies that evaluated the immunogenicity of CVD 103-HgR rather than effectiveness against oral cholera challenge were downgraded for indirectness. The overall body of evidence, which included studies with the newer lyophilized CVD 103-HgR formulation, studies with oral cholera challenge, as well as other studies, consistently indicated strong efficacy. The overall evidence type for efficacy of CVD 103-HgR was graded as 1 (RCTs or overwhelming evidence from observational studies), indicating the strongest level of evidence (Table 6).

While many studies evaluated the safety of the older formulation of CVD 103-HgR vaccine, there were relatively few recipients of the newer lyophilized vaccine formulation. Few studies evaluated the effectiveness of CVD 103-HgR when co-administered with other vaccines or medications, and all of these were with the older formulation of the vaccine. The evidence type for safety outcomes was downgraded for indirectness and imprecision for an overall evidence type of 3 (observational studies, or RCTs with notable limitations).

Summary

After reviewing available evidence and the GRADE evaluation for use of CVD 103-HgR, ACIP voted in June 2016 to recommend use of lyophilized CVD 103-HgR vaccine in adults 18–64 years old traveling to areas of active toxigenic V. cholerae O1 transmission (recommendation Category A). See Recommendations of the Advisory Committee on Immunization Practices (ACIP) for use of cholera vaccine.

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Tables

Table 1. Evidence retrieval strategy

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Table 2. CVD 103-HgR vaccination outcomes, importance, and data availability

Table 2 Footnotes

* Diarrhea volume over course of illness

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Table 3. CVD 103-HgR prevention of cholera diarrhea: challenge and field studies

Table 3 Footnotes

* VE calculated from studies as 100*(1-relative risk).
† Relative risk reported as “Small” and VE as “Large” for studies in which zero individuals in the intervention group developed the outcome of interest.
Abbreviations: RCT, randomized controlled trial; Obs, observational study; VE, vaccine efficacy; RR, relative risk; CI, confidence interval.

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Table 4. CVD 103-HgR vibriocidal antibody seroconversion (20 RCTs, 3 observational; VE range 68% to approaching 100%)

Table 4 Footnotes

* Relative risk and VE reported as “Large” for studies in which zero individuals in the comparison (non-vaccinated) group developed the outcome of interest.
† VE calculated as 100*(1-inverse of relative risk).
§ Mean GMTs reported for vaccinated and comparison groups. Proportions of participants developing vibriocidal antibodies were not reported.
Abbreviations: RCT, randomized controlled trial; Obs, observational study; VE, vaccine efficacy; RR, relative risk; CI, confidence interval.

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Table 5. Serious and systemic adverse events reported for studies of CVD 103-HgR (21 RCTs, 4 Observational)

Table 5 Footnotes

* No significant differences in systemic adverse events, including fever, vomiting, anorexia, abdominal pain, headache, borborygmi, liquid stools, diarrhea.
Abbreviations: RCT, randomized controlled trial; Obs, observational study; RR, relative risk; CI, confidence interval.

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Table 6. Evidence type for outcomes for CVD 103-HgR vaccine in adult travelers

Table 6 Footnotes

Abbreviations: RCT, randomized controlled trial; Obs, observational study

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