Recommendations for the prevention of severe cholera in travelers
Individual protection measures
All travelers to cholera-affected areas should consume safe food and water, wash hands often with soap and safe water, and follow recommended sanitation practices (https:/ /www.cdc.gov/cholera/preventionsteps.html). Travelers who develop severe diarrhea should seek prompt medical attention, especially fluid replacement.
Population recommended for vaccination against CVD 103-HgR
ACIP recommends CVD 103-HgR for travelers 2-64 years of age to an area with active cholera transmission. An area of active cholera transmission is defined as a province, state or other administrative subdivision of a country where cholera is endemic or epidemic caused by V.cholerae O1 and includes areas where cholera has been active in the past year and which are prone to recurrent cholera outbreaks (2). An area of active cholera transmission does not include areas where only rare imported or sporadic cases have been reported. The CDC’s Travel Health Branch monitors areas with active cholera transmission and updates the list of affected countries monthly (https://wwwnc.cdc.gov/travel/news-announcements/cholera-vaccine-for- travelers).
CVD 103-HgR is not recommended for travelers who are not visiting areas with active cholera transmission. Most travelers from the United States do not visit areas with active cholera transmission (https://wwwnc.cdc.gov/travel/diseases/cholera#areas). No country requires cholera vaccination as a condition of entry.
CVD 103-HgR booster doses
There are no data on the safety or effectiveness of cholera prevention with booster doses of the currently licensed CVD 103-HgR. The duration of protection conferred by the primary vaccination beyond the period of 3 months evaluated in adults aged 18 to 45 is not known. The ACIP does not have a recommendation regarding the use of booster doses.
In an open-label study of the previous formulation, 31 Swiss adults aged 23 to 48 received a single booster dose 15 or 24 months after the initial dose (37). One patient reported an adverse reaction (i.e. mild diarrhea). Efficacy has not been directly assessed and a minority (i.e. approximately 25%) of participants experienced serum vibriocidal antibody seroconversion (a four-fold increase or more in titer) after the booster dose . The relationship between serum vibriocidal antibody levels and efficacy has not been established beyond 3 months after vaccination.
Administration of CVD 103-HgR
Healthcare providers should consult the package insert for detailed administration instructions (35). CVD 103-HgR should be administered ≥ 10 days prior to travel to an area of active cholera transmission. Recipients should avoid consuming food or drink for 60 minutes before or after vaccine administration.
Administration instructions differ for recipients aged 2 to 5 years compared to recipients aged 6 to 64 years. For all recipients, preparation of the dose begins with reconstitution of the packet of buffer in 100 ml of bottled or purified, non-carbonated, unflavoured, cold or room temperature water. Tap water should not be used as it contains chlorine which may affect the viability of orally ingested live attenuated bacterial vaccines. For recipients 6-64 years of age, mix the active component (i.e. lyophilized V.cholerae CVD 103-HgR) with the full volume of reconstituted buffer solution (100 mL). For children 2-5 years old, discard half of the reconstituted buffer solution (50 mL) before adding the active ingredient; this step reduces the volume of the vaccine (i.e. to facilitate consumption) while maintaining the specified potency (38).
To improve palatability, approximately all (93%) children and adolescents aged 2-17 years participating in the clinical trial added Pure Via brand stevia (1 g), a plant-derived sweetener, to CVD 103-HgR reconstituted (39). At the January 12, 2022 ACIP meeting, the manufacturer presented unpublished data demonstrating that CVD 103-HgR should not be mixed with food and beverages (e.g. rice cereal, applesauce, apple juice, or milk), due to excessive foaming, or with flavorings of medicines that contain propylene glycol, which is bactericidal (38). Data support that the vaccine can be mixed with sucrose (table sugar, 1-4g or ¼-1 tsp) or stevia sweetener (1g or 1 packet; brands tested: Pure Via, Sweet Additions, Truvia, Splenda Naturals and Sweetleaf) without the vaccine potency falling below the minimum specification (38). Healthcare providers may consider administering CVD 103-HgR with sucrose or a stevia-based sweetener to facilitate consumption of the full dose, although guidelines regarding the use of sweeteners are not included in notice at the time of this publication.
Co-administration of other drugs or vaccines with CVD 103-HgR
Antibiotics. Since the immune response to CVD 103-HgR relies on the replication of live attenuated vaccine organisms in the small intestine, antibiotics given before or after the vaccine could decrease the efficacy of the vaccine. The result will depend on factors such as the timing, half-life and spectrum of the antibiotic. The optimal interval between CVD 103-HgR and the reception of antibiotics is unknown.
The package insert states that CVD 103-HgR should not be given to patients who have received oral or parenteral antibiotics within the previous 14 days (35). A time of less than 14 days between discontinuation of antibiotics and administration of CVD 103-HgR may be acceptable in certain circumstances, for example if travel cannot be avoided until 14 days have elapsed after discontinuation antibiotics.
The package insert does not specify a minimum optimal duration between the end of CVD 103-HgR and the start of antibiotics (35). Under certain circumstances, antibiotics may be clinically necessary after the vaccine (ie to treat an unrelated infection). Approximately all (>93%) vaccinees aged 2–45 years demonstrated vibriocidal antibody seroconversion ≤ 10 days post-vaccination (27,29,31).
Antimalarials. Chloroquine may decrease the immune response to CVD 103-HgR (35). The manufacturer recommends that CVD 103-HgR be given ≥ 10 days before starting chloroquine. Doxycycline, a tetracycline antibiotic, is often used for malaria prophylaxis. The optimal time between the end of 103-HgR CVD and the start of doxycycline is unknown.
Other vaccines. No data are available on the co-administration of currently licensed CVD 103-HgR with other vaccines, including live attenuated enteric-coated oral typhoid vaccine (Ty21a, marketed as Vivotif [Emergent BioSolutions, Gaithersburg, MD]). The expert opinion of the ACIP working group postulated that buffer CVD 103-HgR could interfere with the enteric-coated formulation of Ty21a and concluded that taking the first dose of Ty21a ≥ 8 hours after ingestion of CVD 103-HgR could decrease the potential interference of the vaccine buffer with the Ty21a vaccine.
Contraindications, precautions and other considerations for the use of CVD 103-HgR
Allergy. CVD 103-HgR should not be given to people with a history of severe allergic reaction (eg, anaphylaxis) to any component of this vaccine or any cholera vaccine.
Age. There are no data on the safety and effectiveness of the CVD 103-HgR vaccine currently available in children under 2 years of age or in adults ≥ 65 years of age.
Pregnancy and lactation. No data exist on the use of currently licensed CVD 103-HgR during pregnancy or lactation. Potential travelers who are pregnant and their clinicians should consider the risks associated with travel to areas of active cholera transmission. The V.cholerae The O1 vaccine strain is not absorbed systemically; thus, maternal exposure to the vaccine should not lead to exposure of the fetus or nursing infant to the vaccine. However, the vaccine strain could be excreted in the feces for ≥ 7 days after vaccination and, theoretically, the vaccine strain could be transmitted to an infant during vaginal delivery. A breastfed infant could theoretically benefit from maternally derived vaccine antibodies present in breast milk.
People with impaired immunocompetence. There are no data on the use of the currently licensed CVD 103-HgR formulation in immunocompromised populations. Individuals with impaired immunocompetence and their clinicians should consider the risks associated with travel to areas of active cholera transmission. Consultation with an immunology or infectious disease specialist should be considered if travel to an area with active cholera transmission is necessary. ACIP generally advises against giving live vaccines to people with most forms of impaired immunocompetence (https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html).
A study of the previous formulation of CVD 103-HgR in 38 HIV-positive adults without clinical AIDS in Mali found that vibriocidal seroconversion was slightly lower in HIV-positive participants than in HIV-negative participants (58% versus 71%) (40). No significant difference in the occurrence of systemic adverse events was observed between the vaccinated and comparison populations.
Load shedding and transmission. CVD 103-HgR is an oral live attenuated vaccine that can be excreted in the feces for ≥ 7 days after vaccination and potentially transmitted to close contacts. In phase I studies of the current vaccine, the vaccine strain was cultured from stool in 11% of vaccinees on any day up to 7 days post-vaccination (18). In the same study, the vaccine strain was not isolated from stool collected from 24 household contacts of vaccinees on day 7 post-vaccination (18). However, a subsequent transmission could have been missed.
Although washing hands after using the restroom and before preparing or handling food is part of the CDC’s routine handwashing guidelines (41), the package insert specifies that vaccinated individuals should wash their hands thoroughly in these circumstances for ≥ 14 days after vaccination (35). Caregivers of vaccinees who wear a diaper or need help going to the bathroom (eg, young children) should also follow this recommendation.
Vaccine Adverse Event Reporting and Additional Information
Adverse events that occur in a patient following 103-HgR CVD vaccination should be reported to the Vaccine Adverse Event Reporting System (VAERS), whether or not the vaccine caused the event. Instructions for reporting to VAERS are available at https://vaers.hhs.gov/reportevent.html or by calling 1 800 822 7967. Additional information about cholera and CVD 103-HgR is available at https://www.cdc.gov/cholera/index.html.