National Center for Emerging and Zoonotic Infectious Diseases

Background on cholera and CVD 103-HgR 

Jennifer P. Collins, MD, MSc 

CDC Lead, Cholera Vaccine Work Group 

Advisory Committee on Immunization Practices 

February 25, 2021 
Background on cholera 

▪

▪

▪

▪

▪

Toxin-mediated, acute watery diarrheal illness 

Caused by toxigenic Vibrio cholerae O1 or O139 

– Curved, motile, Gram-negative rods 

Can be severe and rapidly fatal without proper 

treatment 

Endemic in >50 countries 

Can cause large epidemics 

Photo: CDC Public Health Image Library 

2 
Microbiology and pathogenesis 

3 
Vibrio cholerae is a diverse species with 

pathogenic and non-pathogenic variants 

V. cholerae 

(>200 serogroups) 

4 
Vibrio cholerae is a diverse species with 

pathogenic and non-pathogenic variants 

V. cholerae 

(>200 serogroups) 

O1 

biotypes: El Tor, classical 

serotypes: Inaba, Ogawa 

5 
Vibrio cholerae is a diverse species with 

pathogenic and non-pathogenic variants 

V. cholerae 

(>200 serogroups) 

Toxigenic O1 

Toxigenic O139 

cholera 

epidemics

6 
Vibrio cholerae is a diverse species with 

pathogenic and non-pathogenic variants 

V. cholerae 

(>200 serogroups) 

Toxigenic O1 

Toxigenic O139 

other pathogenic 

serogroups (± toxigenic) 

gastroenteritis 

Non-toxigenic 

O1, O139 

cholera 

epidemics 

7 
 

Cholera epidemics are associated with unsafe 

water and inadequate sanitation 

▪ V. cholerae has an aquatic reservoir 

▪ Human infection 

–

–

–

–

ingestion of contaminated water or food 

direct fecal-oral transmission 

secondary cases rare if sanitation adequate 

incubation period: hours to 5 days 

8 Photo: Public Health Image Library, ID: 19647 
 

 

Cholera 

is a 

toxinmediated 

disease 

9 

Image credits: 

“Stomach” icon by Hermine Blanquart from the nounproject.com 

“Intestines” icon by Tom Fricker from the nounproject.com
Cholera 

is a 

toxinmediated 

disease 

Unusual ability to survive 

and replicate in the 

small intestine 

lumen 

epithelium 

10 
Non-invasive (do not 

enter the intestinal 

epithelium) Cholera 

is a 

toxinmediated 

disease 

lumen 

epithelium 

11 
Produce cholera toxin 

Cholera 

is a 

toxinmediated 

disease 

lumen 

epithelium

12 
Cholera toxin subunit A 

enters the cytoplasm 

and causes secretory 

Cholera diarrhea 

is a 

toxinmediated 

disease 

lumen 

epithelium 

13 
Epidemiology 

14 
Cholera can cause explosive epidemics 

▪

▪

▪

–

–

first non-O1 cause of epidemic cholera 

Seven pandemics have been reported since 1817 

The current global pandemic (El Tor O1) began in 1961 

Serogroup O139 first emerged in 1992, in Asia 

now causes a small portion of cases 

15 
 

 

Asia and sub-Saharan Africa have the highest 

burden of cholera deaths 

Countries reporting cholera deaths and imported cases to the 

World Health Organization (WHO), 2019 

Source: WHO Weekly Epidemiological Record. 11 Sept 2020. 16 
 

Cholera cases reported to WHO increased during 2017–2019 

Source: WHO Weekly Epidemiological Record. 11 Sept 2020. 

Annual 

cholera 

cases and 

mortality 

reported by 

year –WHO, 

1989–2019 

17 
 

Cholera in the United States and other highincome countries is primarily travel-associated 

▪ Most international travelers 

from the United States do not 

get cholera 

–

–

Do not visit areas with 

active cholera 

transmission 

Have good access to safe 

food and water 

▪ CDC monitors areas with 

active cholera transmission 

https://wwwnc.cdc.gov/travel/diseases/cholera#areas 18 
Like most infections, cholera is underreported in 

the United States 

Pathogen identified 

Specimen tested for cholera 

(not routine) 

Specimen submitted 

Person seeks care 

Person becomes ill 

19 
 

 

Cholera in the United States, 2001−2011

▪

▪

–

–

▪

▪

111 cholera cases over 11-year period 

Age 

1–85 years (median 44 years) 

15 (14%) 2–19 years old 

108 diagnosed by stool culture; 107 were V. cholerae O1 

No deaths 

20 Loharikar A et al. Cholera in the United States, 2001-2011: a reflection of patterns of global epidemiology and travel. Epidemiol Infect. 2015 Mar;143(4):695-703. 
 

Case count 

Oct 2010: onset of epidemic cholera in Haiti 

Year 

90 (81%) cases associated with international travel,

2001–2011 

21 Loharikar A et al. Cholera in the United States, 2001-2011: a reflection of patterns of global epidemiology and travel. Epidemiol Infect. 2015 Mar;143(4):695-703. 
Cholera in the United States, 2012–2018 

▪ 64 patients with cholera reported 

▪ Age 

– 11 months–87 years (median 51 years) 

– 5 (8%) 2–17 years old 

▪ All V. cholerae O1 

▪ 2 deaths (adults) 

22 
 

Cholera in the United States, 2012–2018 

Age group 

(years) 

Travelassociated* Not travelassociated Total 

<2 2 0 2 

2–5 2 0 2 

6–17 3 0 3 

≥18 49 8 57 

Total 56 8 64 

23 *International travel in the 7 days before illness began 
 

56 (88%) cases were travel-associated 

Age group 

(years) 

Travelassociated* Not travelassociated Total 

<2 2 0 2 

2–5 2 0 2 

6–17 3 0 3 

≥18 49 8 57 

Total 56 8 64 

24 *International travel in the 7 days before illness began 
 

5 (8%) cases in children and adolescents 

2–17 years old 

Age group 

(years) 

Travelassociated* Not travelassociated Total 

<2 2 0 2 

2–5 2 0 2 

6–17 3 0 3 

≥18 49 8 57 

Total 56 8 64 

25 *International travel in the 7 days before illness began 
 

5 (8%) cases in children and adolescents 

2–17 years old 

Age group 

(years) 

Travelassociated* Not travelassociated Total 

<2 2 0 2 

2–5 2 0 2 

6–17 3 0 3 

≥18 49 8 57 

Total 56 8 64 

26 *International travel in the 7 days before illness began 
Domestic/Unknown

Other travel

Hispaniola travel

No travel

16 

14 

12 

10 

Case count 8 

6 

4 

2 

0 

2012 2013 2014 2015 2016 2017 2018 

Year 

No travel 

Travel - other 

Travel - Hispaniola 

Annual case counts 15 or fewer during 2012–2018 

27 
Clinical manifestations and diagnosis 

28 
-

-

-

Clinical manifestations of cholera infection vary 

Asymptomatic 

~75% 

Cholera 

gravis 

~10% 

Risk factors: 

High dose 

exposure 

Low gastric 

acidity 

Blood group O 

29 
Cholera gravis is rapidly fatal if untreated 

▪ Profuse watery diarrhea 

▪ “Rice-water stools” flecked with mucus and epithelial cells

▪ Vomiting 

▪ Leg cramps 

▪ Severe dehydration 

–

–

–

–

loss of skin turgor 

hypotension 

weak pulse 

altered mental status 

30 
A definitive diagnosis of cholera is based on culture 

of stool or rectal swab 

▪ Transport media and selective culture media needed 

▪ Other stool tests 

– Rapid antigen 

– Darkfield microscopy 

– Molecular assays 

▪ Acute/convalescent serology sometimes used 

Image: iStock by Getty images, ID: 638143058 31 
 

Fluid management is the primary focus of cholera 

treatment 

▪ Patients with cholera gravis 

may require up to 350 mL/kg 

of fluids within the first 24 

hours of illness 

▪ Moderately to severely ill 

patients should receive 

antibiotic therapy 

Photo: iStock by Getty images, ID: 817180340 32 
Immune response and vaccines 

33 
 

Immune response to cholera is serogroup-specific 

(O1 or O139) 

▪ El Tor O1 and O139 

– genomes are very similar 

– identical cholera toxin genes 

▪ Immune responses targeting cholera toxin common after cholera; do not 

mediate long-term protection 

▪ Vibriocidal antibodies are best marker for protection against V. cholerae 

infection 

– Every two-fold increase associated with ~40% reduction in risk of cholera* 

▪ Lipopolysaccharide-specific memory B cells may play role in mediating longterm protection** 

*Mosley et al. Bull World Health Organ 1969; 40: 187–97. 

34 **Patel et al. Clin Vaccine Immunol 10: 842–848; 2012 
CVD 103-HgR was derived from wild-type V. cholerae O1 

▪ Single-dose, live, attenuated oral vaccine 

–

–

–

–

–

Inaba serotype, classic biotype 

Cross-protective against other O1 serotypes and biotypes 

94% of gene encoding enterotoxin subunit A deleted 

Expression of non-toxic B subunit left intact 

Contains a marker to differentiate from wild-type Vibrio 

▪ Lyophilized (freeze-dried powder) 

▪ Reconstituted with a buffer solution to neutralize stomach acid 

35 
Commercial formulations of CVD 103-HgR 

▪ Orochol, Mutacol (Berna) 

– 5x108 colony-forming unit (CFU) dose 

– Licensed in non-US countries in the 1990s 

– Production discontinued in 2004 

36 
 

Commercial formulations of CVD 103-HgR 

▪ Vaxchora (Emergent BioSolutions) 

–

–

–

Dose range: 4x108–2x109 CFU 

Volume with buffer 

• 100 ml if ≥6 years 

• 50 ml if 2–5 years 

Licensed by FDA 

• Adults 18 – 64 years (June 2016) 

• Children 2–17 years (December 2020) 

37 
Current ACIP recommendations for lyophilized 

CVD 103-HgR 

38 
Work group findings — efficacy & immunogenicity 

▪ Efficacy against severe diarrhea (fecal output >3L/24 hours) after oral toxigenic V. 

cholerae O1 challenge* 

–

–

Current formulation: estimated to be 90% at 10 days, 80% at 3 months 

Similar efficacy in studies of the previous formulation 

▪ Vibriocidal antibody response 

– Both formulations of the vaccine effectively induce these 

39 *GRADE evidence type 1 
 

Work group findings — adverse events 

▪

–

–

–

Adverse events** 

No vaccine-related serious adverse events for either formulation 

Current formulation: slightly higher prevalence of diarrhea (mostly mild) among 

vaccine vs. placebo recipients (3.8% vs. 1.6%) 

No other differences between vaccinated and unvaccinated groups 

40 **GRADE evidence type 3 
ACIP currently recommends CVD 103-HgR for 

adult travelers (18–64 years old) from the United 

States to an area of active cholera transmission. 

41 
ACIP currently recommends CVD 103-HgR for 

adult travelers (18–64 years old) from the United 

States to an area of active cholera transmission. 

Policy topic under consideration: 

Should ACIP cholera vaccine recommendations be expanded 

to include children and adolescents 2–17 years old? 

42 
Recently published pediatric studies 

43 
44 

Studies of prior formulation of CVD 103-HgR 

among children 
 

Studies of prior formulation of CVD 103-HgR 

among children 

▪ 5x108 CFU dose was much less immunogenic among children in Indonesia than 

among adults in industrialized countries* 

▪ 5x109 CFU dose 

–

–

–

–

–

51–81% vibriocidal seroconversion 

Shedding of vaccine strain was infrequent 

Vaccine generally well tolerated; fever more common among vaccine 

recipients in one study (18 vs. 9%)** 

Single-dose did not confer long-term protection*** 

Dose was higher than Vaxchora (4x108–2x109 CFU) 

*Suharyono et al. Lancet. 1992;340:689-94 

**Simanjuntak et al. JID. 1993;168:1169-76 

45 ***Richie et al. Vaccine. 2000; 18; 2399-2410 
 

Summary 

▪

–

–

–

–

▪

–

–

Cholera 

Toxin-mediated, acute watery diarrheal illness that can be severe and 

rapidly fatal without proper treatment 

Endemic in >50 countries and can cause explosive epidemics 

Most US cases occur among travelers to cholera-endemic areas 

Immune response is serogroup-specific (O1 or O139) 

CVD 103-HgR 

Single-dose, live, attenuated serogroup O1 oral vaccine 

ACIP currently recommends for adult travelers (18–64 years old) from 

the United States to an area of active cholera transmission 

46 
 

 

 

Thank you! 

For more information, contact CDC 

1-800-CDC-INFO (232-4636) 

TTY: 1-888-232-6348 www.cdc.gov 

The findings and conclusions in this report are those of the authors and do not necessarily represent the 

official position of the Centers for Disease Control and Prevention.