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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 (VaxchoraTM), 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 The work group also pursued available unpublished data from the vaccine manufacturer.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

Evidence retrieval strategy
Database Search terms
Medline
(OVID)
1946-
Cholera Vaccines/ OR PXVX0200 OR PaxVax OR CVD 103-HgR OR Mutacol OR Vaxchora OR ((Vaccines, Attenuated/OR ((live OR attenuated OR oral) ADJ2 vaccin*).ti,ab.) AND (exp Vibrio cholerae/ OR Cholera Toxin/ OR Cholera/ OR cholera*.ti,ab.))
NOT
(Exp animals/ not exp humans/)
Embase
(OVID)
1947-
Cholera Vaccine/ OR PXVX0200 OR PaxVax OR CVD 103-HgR OR Mutacol OR Vaxchora OR ((live vaccine/OR ((live OR attenuated OR oral) ADJ2 vaccin*).ti,ab.) AND (exp Vibrio cholerae/ OR Cholera Toxin/ OR Cholera/ OR cholera*.ti,ab.))
NOT
(Exp animals/ not exp humans/)
Cochrane Library [mh “Cholera Vaccines”] OR Tables OR “CVD 103-HgR” OR Mutacol OR Vaxchora OR (([mh “Vaccines, Attenuated”]OR ((live OR attenuated OR oral) NEAR/2 vaccin*):ti,ab) AND ([mh “Vibrio cholera”] OR [mh “Cholera Toxin”] OR [mh Cholera] OR cholera*:ti,ab))
Clinical Trials.gov PXVX0200 OR PaxVax OR CVD 103-HgR OR Mutacol OR Vaxchora OR cholera vaccine

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

CVD 103-HgR vaccination outcomes, importance, and data availability
Outcome Importance Data available
Benefits
Prevent cholera death Critical Yes, limited
Prevent life-threatening (>5L*) cholera diarrhea Critical Yes, limited
Prevent severe (>3L*) cholera diarrhea Critical Yes
Prevent cholera diarrhea of any severity Important Yes
Induce vibriocidal antibody response Important Yes
Harms
Serious adverse events Critical Yes
Systemic adverse events Critical Yes
Decrease effectiveness of co-administered vaccines or medications Critical Yes, limited

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

CVD 103-HgR prevention of cholera diarrhea: challenge and field studies
Study Setting Type Population Time between vaccination and challenge/outcome Vaccinated persons,
n/N (%)
Comparison persons, n/N (%) RR (95% CI)† VE†
Cholera death (0 studies)
No studies assessed this outcome
Life-threatening cholera diarrhea (>5L) (1 RCT, VE 86–93%)
Chen, Cohen 2014 (2) U.S. RCT Adults (18-45y) 10 days 1/35 (2.9) 28/66 (42.4) 0.1 (0.01–0.5) 93%
3 months 2/33 (6.1) 0.1 (0.04–0.6) 86%
Severe cholera diarrhea (>3L) (3 RCTs, VE 79–91%)
Tacket 1999 (7) U.S. RCT Adults (18-40y) 3 months 1/28 (3.6) 9/23 (39.1) 0.1 (0.01–0.7) 91%
Adults (18-40y) Blood Group O 3 months 1/15 (6.7) 4/8 (50) 0.1 (0.02–1) 87%
Richie 2000 (1) Indonesia RCT Adults and children, 2-41y Up to 54 months 11/33696 (<1) 7/33812 (<1) 1.6 (0.6–4.1) N/A
Chen, Cohen 2014 (2) U.S. RCT Adults (18-45y) 10 days 2/35 (5.7) 39/66 (59.1) 0.1 (0.02–0.4) 90%
3 months 4/33 (12.1) 0.2 (0.1–0.5) 79%
Any severity cholera diarrhea (4 RCTs, 3 Observational, VE range 14% to approaching 100%)
Levine 1988 (4) U.S. RCT Adult college students 1 month 2/6 (33.3) 7/8 (87.5) 0.4 (0.1–1.2) 62%
Tacket 1992 (5) U.S. Obs Adults (18-39y) 8 days 0/11 (0) 8/11 (72.7) Small Large
4 to 6 months 0/14 (0) 10/15 (66.7) Small Large
Losonsky 1993 (6) U.S. Obs Adults 8 days 0/36 (0) 8/11 (72.7) Small Large
30 days 0/36 (0) 7/13 (53.8) Small Large
6 months 0/36 (0) 10/15 (66.7) Small Large
Tacket 1999 (7) U.S. RCT Adults (18-40y) 3 months 5/28 (17.9) 21/23 (91.3) 0.2 (0.1–0.4) 80%
Adults (18-40y) Blood group O 3 months 4/15 (26.7) 7/8 (87.5) 0.3 (0.1–0.7) 70%
Richie 2000 (1) Indonesia RCT Adults and children, 2–41y Up to 54 months 43/33696 (0.1) 50/33812 (0.1) 0.9 (0.6–1.3) 14%
Calain 2004 (8) Micronesia Obs Adults and children, ≥2y Up to 4 months 50/14587 (0.3) 258/15664 (1.6) 0.2 (0.2–0.3) 79%
Chen, Cohen 2014 (2) U.S. RCT Adults (18-45y) 10 days 5/35 (14.3) 61/66 (92.4) 0.2 (0.1–0.3) 85%
3 months 15/33 (45.5) 61/66 (92.4) 0.5 (0.3–0.7) 51%

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%)

CVD 103-HgR vibriocidal antibody seroconversion
Study Setting Type Population Serotype or Subgroup Time between vaccination and measurement Vaccinated persons,
n/N (%)
Comparison persons,
n/N (%)
RR (95% CI)* VE*, †
Levine 1988 (4) U.S. RCT Adult college students Inaba 1 month 24/25 (96) Not assessed
Migasena 1989 (19) Thailand RCT Adults (20-30y) Inaba 10, 21, & 28 days (peak given) 11/12 (91.7) 0/12 (0) Large Large
Ogawa 10, 21 & 28 days (peak given) 9/12 (75) 0/12 (0) Large Large
Cryz 1990 (20) Switzerland RCT Adults (21-45y) Inaba 10 days 19/25 (76) 0/25 (0) Large Large
21 days 22/25 (88) Large Large
Ogawa 10 days 14/25 (56) Large Large
21 days 17/25 (68) Large Large
Cryz 1992 (21) Switzerland Obs Adults Inaba – booster 21 days post-booster 9/31 (29) Not assessed
Ogawa – booster 7/31 (22.6) Not assessed
Kotloff 1992 (22) U.S. RCT Adult college students (18-40y) Inaba 8, 15, 21, or 28 days (at least one) 91/94 (96.8) Not assessed
Su-Arehawaratana 1992 (23) Thailand RCT Adult soldiers, 108 dose Inaba 9 or 28 days 13/33 (39.4) Not assessed
Adult civilians, 108 dose Inaba 9 or 28 days 19/30 (63.3) Not assessed
Adult soldiers, 108 dose Inaba 7, 14, 21, or 28 days 13/39 (33.3) 1/39 (2.6) 13 (1.8–94.6) 92%
Adult soldiers, 109 dose Inaba 7, 14, 21, or 28 days 17/40 (42.5) 1/39 (2.6) 16.6 (2.3–118.6) 94%
Tacket 1992 (5) U.S. Obs Adults (18-39y) Inaba, dose 3–5 x 108 10 days, 28 days, 4 to 6 months 20/21 (95.2) Not assessed
Inaba, dose 3–5 x 109 10 days, 28 days, 4 to 6 months 7/7 (100) Not assessed
Gotuzzo 1993 (24) Peru RCT Adults (18-38y), low SES Inaba, 5 x 108 dose 7 days or 28 days 19/39 (48.7) 6/38 (15.8) 3.1 (1.4–6.9) 68%
Inaba, 5 x 109 dose 28/39 (71.8) 6/38 (15.8) 4.5 (2.1–9.7) 78%
Adults (18-38y), high SES Inaba, 5 x 108 dose 31/40 (77.5) 8/41 (19.5) 4 (2.1–7.6) 75%
Inaba, 5 x 109 dose 31/40 (77.5) 8/41 (19.5) 4 (2.1–7.6) 75%
Lagos 1993 (25) Chile RCT Healthy adults (18-35y) Inaba 8 or 28 days 34/40 (85) 2/41 (4.9) 17.4 (4.5–67.8) 94%
Wasserman 1993 (26) U.S. RCT Adult college students (18-40y) Inaba 20 days or 28 days  §
Cryz 1995 (14) Austria RCT Adults (16-56y) Inaba 24/29 (82.8) 2/29 (6.9) 12 (3.1–46.2) 92%
Kollaritsch 1996 (15) Austria RCT Adults Inaba 14 days 244/260 (93.8) 6/65 (9.2) 10.2 (4.7–21.8) 90%
Ogawa 208/260 (80) 0/65 (0) Large Large
Kollaritsch 1997 (16) Austria RCT Adults (>18) Inaba 14 days 41/45 (91.1) Not assessed
Taylor 1997 (27) U.S. RCT Adults (18-40y) Inaba 7 or 10 days 14/14 (100) 0/4 (0) Large Large
Ogawa 13/14 (92.9)
Peru Inaba 7 or 10 days 122/165 (73.9) 0/55 (0) Large Large
Ogawa 95/165 (57.6)
Perry 1998 (28) Mali RCT Adults, HIV+ (18-46y) Inaba 12 or 24 days 21/36 (58.3) Not assessed
Adults, HIV- (18-47y) 22/31 (71) Not assessed
Tacket 1999 (7) U.S. RCT Adults (18-40y) Inaba 10 days 39/43 (90.7) 1/42 (2.4) 38.1 (5.5–264.8) 97%
Taylor 1999 (29) Panama RCT Adults (18-40y) Inaba 10-14 days 21/32 (65.6) 0/35 (0) Large Large
Ogawa 10-14 days 17/32 (53.1) 0/35 (0) Large Large
Kollaritsch 2000 (17) Austria Obs Adults, mean age 23.6-28.6y Primary immunization 42/52 (80.8) Not assessed
Reimmunization at 2.5y 29/51 (56.9) Not assessed
Reimmunization at 3.5y 17/26 (65.4) Not assessed
Richie 2000 (1) Indonesia RCT Children and adults (≥10y) Inaba 10 days 85/142 (59.9) 4/107 (3.7) 16 (6.1–42.3) 94%
Chen, Cohen 2014 (2) U.S. RCT Adults (18-45y) Inaba 7 days 75/94 (79.8) 2/102 (2) 40.7 (10.3–161.1) 98%
10 days 84/94 (89.4) 45.6 (11.5–180.1) 98%
28 days 85/94 (90.4) 46.1 (11.7–182.2) 98%
90 days 85/94 (90.4) 46.1 (11.7–182.2) 98%
180 days 85/94 (90.4) 46.1 (11.7–182.2) 98%
Chen, Greenberg 2014 (9) U.S. RCT Adults (21-48y) Inaba 10 days 45/54 (83.3) 0/11 (0) Large Large
14 days 48/54 (88.9)
28 days 44/54 (81.5)
PaxVax study  PXVX-VC-200-004 (11) U.S. RCT Adults (18–46y) Inaba 11 days 2513/2687 (93.5) 14/334 (4) 22.3 (13.4–37.3) 96%
PaxVax study PXVX-VC-200-005 (10) U.S. RCT Adults (46–64y) Inaba 11 days 263/291 (90.4) 0/99 (0) Large Large

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)

Serious and systemic adverse events reported for studies of CVD 103-HgR
Study Setting Type Population Outcome Vaccine, n/N (%) Comparison, n/N (%) RR (95% CI)
Levine 1988 (4) U.S. RCT Adult college students diarrhea 1/25 (4) Not assessed
Migasena 1989 (19) Thailand RCT Adults (20-30y) adults 0/12 (0) 0/12 (0)
Cryz 1990 (20) Switzerland RCT Adults (21-45y) abdominal pain 0/25 (0) 1/25 (4)
diarrhea 2/25 (8) 2/25 (8) 1 (0.2–6.6)
Cryz 1992 (21) Switzerland Obs Adults diarrhea 1/31 (3.2) Not assessed
Kotloff 1992 (22) U.S. RCT Adult college students (18-40y) abdominal pain 9/94 (9.6) 11/94 (11.7) 0.8 (0.4–1.9)
anorexia 3/94 (3.2) 1/94 (1.1) 3 (0.3–28.3)
borborygmi 49/94 (52.1) 51/94 (54.3) 1 (0.7–1.3)
diarrhea 8/94 (8.5) 3/94 (3.2) 2.7 (0.7–9.7)
fever 2/94 (2.1) 2/94 (2.1) 1 (0.1–7)
headache 8/94 (8.5) 10/94 (10.6) 0.8 (0.3–1.9)
malaise 1/94 (1.1) 3/94 (3.2) 0.3 (0–3.1)
vomiting 2/94 (2.1) 0/94 (0)
Su-Arehawaratana 1992 (23) Thailand RCT Adults, soldiers, and civilians (18-26y) study 1 diarrhea 11/102 (10.8) 13/104 (12.5) 0.9 (0.4–1.8)
study 4 diarrhea 3/119 (2.5) 2/79 (2.5) 1 (0.2–5.8)
Tacket 1992 (5) U.S. RCT Adult college students (18-40y) study group 1 0/14 (0) 0/15 (0)
study group 2 0/11 (0) 0/11 (0)
Gotuzzo 1993 (24) Peru RCT Adults (18-38y), high SES, 5 x 108 dose diarrhea 0/41 (0) 2/44 (4.5)
vomiting 0/41 (0) 0/44 (0)
abdominal pain 3/41 (7.3) 3/44 (6.8) 1.1 (0.2–5)
fever 1/41 (2.4) 2/44 (4.5) 0.5 (0.1–5.7)
Adults (18-38y), low SES, 5 x 108 dose diarrhea 2/41 (4.9) 3/40 (7.5) 0.7 (0.1–3.7)
vomiting 3/41 (7.3) 1/40 (2.5) 2.9 (0.3–27)
abdominal pain 17/41 (41.5) 16/40 (40) 1 (0.6–1.8)
fever 3/41 (7.3) 4/40 (10) 0.7 (0.2–3.1)
Adults (18-38y), high SES, 5 x 109 dose diarrhea 1/40 (2.5) 2/44 (4.5) 0.6 (0.1–5.8)
vomiting 0/40 (0) 0/44 (0)
abdominal pain 1/40 (2.5) 3/44 (6.8) 0.4 (0–3.4)
fever 0/40 (0) 2/44 (4.5)
Adults (18-38y), low SES, 5 x 109 dose diarrhea 4/41 (9.8) 3/40 (7.5) 1.3 (0.3–5.4)
vomiting 0/41 (0) 1/40 (2.5)
abdominal pain 15/41 (36.6) 16/40 (40) 0.9 (0.5–1.6)
fever 1/41 (2.4) 4/40 (10) 0.2 (0–2.1)
Lagos 1993 (25) Chile RCT Adults (18-35y) *
Losonsky 1993 (6) U.S. Obs Adults diarrhea 0/36 (0) Not assessed
Cryz 1995 (14) Austria RCT Adults (16-56y) abdominal pain 11/102 (10.8) 4/90 (4.4) 2.4 (0.8–7.4)
diarrhea 11/102 (10.8) 18/90 (20) 0.5 (0.3–1.1)
fever 0/102 (0) 2/90 (2.2)
nausea 3/102 (2.9) 5/90 (5.6) 0.5 (0.1–2.2)
other 1/102 (1) 1/90 (1.1) 0.9 (0.1–13.9)
rash 1/102 (1) 0/90 (0)
vomiting 0/102 (0) 0/90 (0)
Kollaritsch 1996 (15) Austria RCT Adults nausea 38/256 (14.8) 6/65 (9.2) 1.6 (0.7–3.6)
vomiting 6/256 (2.3) 1/65 (1.5) 1.5 (0.2–12.4)
diarrhea 77/256 (30.1) 19/65 (29.2) 1 (0.7–1.6)
abdominal pain 40/256 (15.6) 6/65 (9.2) 1.7 (0.8–3.8)
fever 7/256 (2.7) 1/65 (1.5) 1.8 (0.2–14.2)
headache 96/256 (37.5) 28/65 (43.1) 0.9 (0.6–1.2)
fatigue 127/256 (49.6) 37/65 (56.9) 0.9 (0.7–1.1)
rash 8/256 (3.1) 3/65 (4.6) 0.7 (0.2–2.5)
Kollaritsch 1997 (16) Austria RCT Adults (>18) diarrhea 10/45 (22.2) Not assessed
nausea 9/45 (20)
vomiting 0/45 (0)
abdominal pain 10/45 (22.2)
headache 23/45 (51.1)
malaise 20/45 (44.4)
cutaneous 3/45 (6.7)
Taylor 1997 (27) Peru, U.S. RCT Adults (18-40y), Peru abdominal pain 23/165 (13.9) 9/55 (16.4) 0.9 (0.4–1.7)
diarrhea 4/165 (2.4) 1/55 (1.8) 1.3 (0.2–11.7)
fever 1/165 (0.6) 0/55 (0)
vomiting 2/165 (1.2) 0/55 (0)
Adults (18-40y), U.S. diarrhea 2/14 (14.3) ¼ (25) 0.6 (0.1–4.8)
Perry 1998 (28) Mali RCT Adults (18-50y), HIV+ Diarrhea 2/27 (7.4) 1/27 (3.7) 2 (0.2–20.8)
Vomiting 1/34 (2.9) 1/34 (2.9) 1 (0.1–15.3)
fever 6/36 (16.7) 6/36 (16.7) 1 (0.4–2.8)
Adults (18-50y), HIV- Diarrhea 1/27 (3.7) 2/27 (7.4) 0.5 (0–5.2)
Vomiting 1/34 (2.9) 1/34 (2.9) 1 (0.1–15.3)
fever 5/34 (14.7) 6/34 (17.6) 0.8 (0.3–2.5)
Wiedermann 1998 (30) Austria Obs Adults and children <1-81y abdominal pain 137/1963 (7) Not assessed
diarrhea 308/1963 (15.7)
vomiting 23/1963 (1.2)
nausea 167/1963 (8.5)
rash 56/1963 (2.9)
fever 38/1963 (1.9)
Tacket 1999 (7) U.S. RCT Adults (18-40y) diarrhea 2/43 (4.7) 1/42 (2.4) 2 (0.2–20.7)
fever 0/42 (0) 0/42 (0)
headache 15/43 (34.9) 13/42 (31) 1.1 (0.6–2.1)
malaise 10/43 (23.3) 14/42 (33.3) 0.7 (0.3–1.4)
nausea 10/43 (23.3) 9/42 (21.4) 1.1 (0.5–2.4)
vomiting 5/43 (11.6) 1/42 (2.4) 4.9 (0.6–40.1)
Taylor 1999 (29) Panama RCT U.S. military in Panama abdominal pain 4/32 (12.5) 0/35 (0)
diarrhea 0/32 (0) 0/35 (0)
fever 0/32 (0) 1/35 (2.9)
nausea 0/32 (0) 2/35 (5.7)
vomiting 0/32 (0) 3/35 (8.6)
Kollaritsch 2000 (17) Austria Obs Adults, mean age 23.6y, primary immunization Diarrhea 15/52 (28.8) Not assessed
Nausea 8/52 (15.4)
Vomiting 1/52 (1.9)
Abd pain 4/52 (7.7)
Headache 20/52 (38.5)
Fatigue 21/52 (40.4)
Rash 5/52 (9.6)
Other 11/52 (21.2)
Any 38/52 (73.1)
Adults, mean age 28.6y, reimmunization @ 2.5y Diarrhea 13/51 (25.5)
Nausea 5/51 (9.8)
Vomiting 0/51 (0)
Abd pain 7/51 (13.7)
Headache 16/51 (31.4)
Fatigue 11/51 (21.6)
Rash 0/51 (0)
Other 8/51 (15.7)
Any 31/51 (60.8)
Adults, mean age 23.7y, reimmunization @ 3.5y Diarrhea 6/26 (23.1)
Nausea 7/26 (26.9)
Vomiting 0/26 (0)
Abd pain 2/26 (7.7)
Headache 12/26 (46.2)
Fatigue 12/26 (46.2)
Rash 1/26 (3.8)
Other 3/26 (11.5)
Any 19/26 (73.1)
Richie 2000 (1) Indonesia RCT Adults and children 2–41y abdominal pain 19/538 (3.5) 19/539 (3.5) 1 (0.5–1.9)
diarrhea 30/538 (5.6) 27/539 (5) 1.1 (0.7–1.8)
fever 26/538 (4.8) 37/539 (6.9) 0.7 (0.4–1.1)
headache 46/538 (8.6) 39/539 (7.2) 1.2 (0.8–1.8)
itching 8/538 (1.5) 4/539 (0.7) 2 (0.6–6.6)
nausea 18/538 (3.3) 16/539 (3) 1.1 (0.6–2.2)
rash 2/538 (0.4) 2/539 (0.4) 1 (0.1–7.1)
seizure 0/538 (0) 0/539 (0)
vomiting 11/538 (2) 8/539 (1.5) 1.4 (0.6–3.4)
Leyten 2005 (31) Netherlands RCT Adult traveling internationally abdominal pain 7/65 (10.8) 12/69 (17.4) 0.6 (0.3–1.5)
Chen, Cohen 2014 (2) U.S. RCT Adults (18-45y) abdominal pain 20/95 (21.1) 20/102 (19.6) 1.1 (0.6–1.9)
anorexia 17/95 (17.9) 23/102 (22.5) 0.8 (0.5–1.4)
asthenia 32/95 (33.7) 33/102 (32.4) 1 (0.7–1.6)
diarrhea 1/95 (1.1) 3/102 (2.9) 0.4 (0–3.4)
fever 2/95 (2.1) 1/102 (1) 2.1 (0.2–23.3)
headache 23/95 (24.2) 31/102 (30.4) 0.8 (0.5–1.3)
nausea/vomiting 14/95 (14.7) 21/102 (20.6) 0.7 (0.4–1.3)
Chen, Greenberg 2014 (9) U.S. RCT Adults (21-48y) abdominal pain 10/55 (18.2) 3/11 (27.3) 0.7 (0.2–2)
anorexia 3/55 (5.5) 1/11 (9.1) 0.6 (0.1–5.2)
asthenia 6/55 (10.9) 0/11 (0)
diarrhea 1/55 (1.8) 0/11 (0)
fever 1/55 (1.8) 1/11 (9.1) 0.2 (0–3)
headache 8/55 (14.5) 2/11 (18.2) 0.8 (0.2–3.3)
nausea/vomiting 4/55 (7.3) 1/11 (9.1) 0.8 (0.1–6.5)
PaxVax study  PXVX-VC-200-004 (11) U.S. RCT Adults (18–46y) tiredness 856/2734 (31.3) 94/343 (27.4) 1.1 (1-1.4)
headache 791/2734 (28.9) 81/343 (23.6) 1.2 (1-1.5)
abdominal pain 510/2734 (18.7) 58/343 (16.9) 1.1 (0.9-1.4)
nausea/vomiting 501/2734 (18.3) 52/343 (15.2) 1.2 (0.9-1.6)
lack of appetite 451/2734 (16.5) 57/343 (16.6) 1 (0.8-1.3)
diarrhea 106/2734 (3.9) 4/343 (1.2) 3.3 (1.2-9)
fever 17/2734 (0.6) 4/343 (1.2) 0.5 (0.2-1.6)
headache 60/295 (20.3) 30/99 (30.3) 0.7 (0.5-1)
PaxVax study PXVX-VC-200-005 (10) U.S. RCT Adults (46–64y) tiredness 59/295 (20) 36/99 (36.4) 0.6 (0.4-0.8)
abdominal pain 42/295 (14.2) 13/99 (13.1) 1.1 (0.6-1.9)
nausea/vomiting 35/295 (11.9) 12/99 (12.1) 1 (0.5-1.8)
lack of appetite 24/295 (8.1) 12/99 (12.1) 0.7 (0.3-1.3)
diarrhea 7/295 (2.4) 2/99 (2) 1.2 (0.2-5.6)
fever 2/295 (0.7) 0/99 (0) Large

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

Evidence type for outcomes for CVD 103-HgR vaccine in adult travelers
Outcome Studies Initial evidence Risk of bias Inconsistency Indirectness Imprecision Publication Bias Other Final evidence type Overall evidence type
Prevent cholera death 0 N/A N/A N/A N/A N/A N/A N/A N/A Insufficient evidence to evaluate outcome
Prevent life-threatening cholera diarrhea 1 RCT 1 No serious No serious No serious No serious No serious Strength of assoc. (+2) 1 1
Prevent severe cholera diarrhea 3 RCTs 1 No serious Serious
(-1)
No serious No serious No serious Strength of assoc. (+2) 1 1
Prevent cholera diarrhea of any severity 4 RCTs 1 No serious Serious
(-1)
No serious No serious No serious Strength of assoc. (+2) 1 1
3 Obs 3 Serious (-1) No serious Serious
(-1)
No serious No serious Strength of assoc. (+2) 3
Induce vibriocidal antibody response 20 RCTs 1 No serious No serious No serious No serious No serious Strength of assoc. (+2) 1 1
3 Obs 3 No serious No serious Serious
(-1)
No serious No serious Strength of assoc. (+2) 2
Serious/systemic adverse events 21 RCTs 1 No serious No serious Serious (-1) Serious (-1) No serious None 3 3
4 Obs 3 No serious No serious Serious (-1) No serious No serious None 4
Decrease effectiveness of co-administered vaccines and medications 3 RCTs 1 No serious No serious Serious (-1) No serious No serious None 2 2
1 Obs 3 No serious No serious Serious (-1) No serious No serious None 4

Table 6 Footnotes

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

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