Status: withdrawn from the market

Organizations involved:

Wyeth – Manuf.; R&D; Tech.; World mark.; Former

Description: Cholera Vaccine is an aqueous suspension of equal amounts of inactivated (killed) Vibrio cholerae (or V. comma) subtypes (serotypes) Ogawa (NIH 41) and Inaba (NIH 35A3) bacteria. The primary immunogenic components are cholera toxin protein and bacterial surface lipo-polysaccharides, which induce V. cholerae-neutralizing antibodies.

Cholera vaccine was supplied in 1.5 and 20 mL vials, and stored at 2-8˚C (refrigerated). The vaccine contained 8 units of each of the two serotype antigens per mL.

Nomenclature: Cholera Vaccine/Wyeth [BIO]; Cholera Vaccine [FDA USAN]; Cholera Vaccine USP [USP]; NDC 0008-0342-01; NDC 0008-0342-02 [NDC]

History: An inactivated cholera vaccine was first approved in 1917. The method of manufacture and the characteristics of this simple, yet generally effective, inactivated bacterial vaccine have remained largely unchanged since this vaccine was first developed about a century ago.

Companies.: Cholera Vaccine was manufactured until recently by Wyeth, CBER/FDA est. no. 0003. Wyeth has closed its Marietta facilities, discontinuing manufacture of this and also other older vaccines. The vaccine was marketed in the U.S. by Wyeth, and internationally by affiliated companies.

Manufacture: The bacteria are cultured on trypticase soy agar medium, harvested from the medium by injection of buffered sodium chloride solution, and inactivated by addition of 0.5% phenol. Phenol at a concentration of 0.5% is also present as a preservative in the finished product.

FDA class: Biologic PLA

CBER class: Bacterial Antigens and Vaccines

Approvals: Date = 19520716; first approval, PLA

Indications: [full text of “Indication and Usage” section from product insert/labeling]:

Active immunization against cholera is indicated only for individuals traveling to or residing in countries where cholera is endemic or epidemic.

Status: FDA approval was voluntarily withdrawn by Wyeth in 2003. No cholera vaccine is currently approved or available in the U.S. The Centers for Disease Control and Prevention (CDC) currently does not recommend use of any cholera vaccine. The vaccine had not been recommended by CDC and other authorities for travelers, because of the brief and incomplete immunity it offers. No cholera vaccination requirements currently exist for entry or exit in any country. CDC notes that two other vaccines (see Competition section below) are available outside the U.S., but does not recommend their use. Both vaccines provide somewhat better immunity with fewer side-effects than Wyeth’s cholera vaccine.

Medical: Field studies carried out in endemic cholera areas have shown cholera vaccines to be have about 50% effectiveness for prevention of cholera disease. The vaccine has side effects and is not generally recommended except for those traveling or residing in areas with high levels of endemic cholera.

The primary immunization course consists of two doses administered 7-30 days apart. The vaccine may be administered subcutaneously, intramuscularly, or intradermally. For persons over 10 yrs, individual doses (for both primary series and boosters) are 0.2 mL, 0.5 mL, and 0.5 mL for the intradermal, subcutaneous and intramuscular routes, respectively. The intradermal route is satisfactory for persons 5 years of age or older. Booster doses may be given every 6 months if needed for travel or for residence in highly endemic, unsanitary areas (with likely exposure to V. cholerae bacteria in feces, e.g., sewage, or contaminated food or water).

Local reactions including erythema, induration, pain, and tenderness at the site of injection occur in most recipients, and may persist for several days. Recipients may develop malaise, headache, and mild to moderate temperature elevations, which may persist for one or two days.

Market: Average Wholesale Price (AWP) not available (product not in 2005 or 2004 Red Book).

Competition: There currently is no cholera vaccine approved in the U.S. Other cholera vaccines in international markets include Dukoral (see related entry below) and Mutacol. Dukoral is the only vaccine that can provide travelers with protection against both cholera and entero-toxigenic E. coli. Dukoral received approval in Canada in Feb. 2003.

Mutacol (Orochol; CVD-103HgR) is a live oral vaccine manufactured and marketed in only few countries, including Australia, Canada and Switzerland, by Berna Biotech Ltd., now merged into Crucell N.V. The vaccine has not been approved by the European Union, and its is not recommended by the World Health Organization (WHO), while Dukoral does come with a WHO recommendation. Sales have been projected by one source to be CHF 2 million [$1.56 million, on 4/20/06] in 2006.

R&D: AVANT Immunotherapeutics, Inc., now Celldex Therapeutics, Inc., in collaboration with the Walter Reed Army Institute of Research (WRAIR), in Dec. 2002 started a Phase II trial of CholeraGarde (Peru-15) single-dose live oral cholera vaccine in adult and pediatric subjects in Bangladesh. In Jan. 2004, positive preliminary results were reported from the adult portion of this trial which showed that vaccine was well tolerated with over 70% of the vaccinated adults responding with a favorable immune response. This two year study is expected to be completed in the second half of 2004. A Phase IIb challenge study using live virulent V. cholerae had previously demonstrated the ability of CholeraGarde to provide complete protection against moderate and severe diarrhea, the study’s primary endpoint. Freeze-dried (lyophilized) CholeraGarde is currently stored at -20˚C. This is a major problem for preserving this vaccine in critical settings where it is most needed. In July 2005, Harvard Medical School received nearly $500,000 from the National Institutes of Health (NIH) to develop a VitriLife formulation of lyophilized CholeraGarde, with AVANT as a subcontractor and receiving $374,000 of this funding over a twelve-month period. VitriLife is a proprietary technology that confers thermostability to live bacterial vaccines. The VitriLife vacuum-drying process turns vaccines and other biologics into a stable, glass foam product without the need for freezing. As of mid-2005, over 400 people had received CholeraGarde in the U.S. and Bangladesh. AVANT initiated a double-blind, placebo-controlled, Phase III in Bangladesh in 2006. In Aug. 2006, the International Vaccine Institute (IVI) granted AVANT $21 million from the Bill & Melinda Gates Foundation for a Cholera Vaccine Initiative (CHOVI), including further clinical trials of CholeraGarde. IVI will conduct Phase II and Phase III trials in Bangladesh and India beginning in 2007, using clinical materials produced by AVANT.

In March 2001, Acambis plc and Swiss Serum & Vaccine Inst. (now Berna Biotech Ltd., merged into Crucell N.V.) formed a collaboration for development of an oral typhoid/cholera combination vaccine.

Other cholera vaccines in development include a killed O1 and O139 whole cell oral vaccine in Vietnam; a live attenuated oral vaccine from the Finlay Institute, Cuba, in Phase II in 2006; a live attenuated O139 strains vaccine from the University of Maryland in Phase I in 2006; a conjugate vaccine from Pasteur Institute in preclinical studies in 2006, and a DNA vaccine from Putra University, Malaysia in preclinical studies in 2006.