Obtaining and Evaluating Evidence with Grading of Recommendations, Assessment, Development and Evaluation 

(GRADE) for Lyophilized CVD 103-HgR Vaccine

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available unpublished data from the vaccine manufacturer.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

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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). 

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 

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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-thanexpected 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 

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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). 

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 

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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. 

Summary of quality of evidence across outcomes

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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. 

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
Table 1: 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 PXVX0200 OR PaxVax 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

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
Table 2: 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

* Diarrhea volume over course of illness

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
Table 3: 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

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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%

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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%

* 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. 

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
Table 4: CVD 103-HgR vibriocidal antibody seroconversion (20 RCTs, 3 observational; VE range 68% to approaching 100%)

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 postbooster9/31 (29) Not assessed

Ogawa - booster 7/31 (22.6) Not assessed

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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

SuArehawaratana

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

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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%

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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%

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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)

14 days 48/54 (88.9) 0/11 (0) Large Large

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

* Relative risk and VE reported as “Large” for studies in which zero individuals in the comparison (non-vaccinated) group developed the outcome of 

interest.

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
† 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. 

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
Table 5: Serious and systemic adverse events reported for studies of CVD 103-HgR (21 RCTs, 4 Observational)

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)

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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) —

SuArehawaratana

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)

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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)

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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)

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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) 1⁄4 (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)

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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)

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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)

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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)

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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)

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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)

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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)

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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

* 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. 

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
Table 6: 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 lifethreatening 

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

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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 

3 RCTs 1 No 

serious

No serious Serious (-1) No serious No serious None 2 2

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
co-administered 

vaccines and 

medications

1 Obs 3 No 

serious

No serious Serious (-1) No serious No serious None 4

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

https://wwwdev.cdc.gov/vaccines/acip/recs/grade/cholera-CVD-103-HgR.pdf 2/2019
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