Background
Cholera is an important public health problem worldwide, causing outbreaks in the developing world in areas where lapses in sanitation occur. In 2005, 131,943 cholera cases and 2,272 deaths were reported to the World Health Organization (WHO), with more countries reporting cholera outbreaks than in previous years. The true figures are likely to be much higher, due to under-reporting, and as much as 120,000 deaths are estimated to occur each year from cholera. Recent outbreaks in West Africa have resulted in case fatality rates of as high as 40%.

The provision of safe water and food, the establishment of adequate sanitation systems, and the implementation of personal and community hygiene constitute the main public health interventions against cholera. However, these measures cannot be fully implemented in the near future in most places where cholera occurs. Consequently, since 1999, WHO has advocated the use of new-generation cholera vaccines as important tools in the prevention and control of cholera.

A child drinks oral cholera vaccine during a mass oral cholera vaccination campaign, which was carried out in Beira, Mozambique, from December 2003 to January 2004.

In the past two decades, considerable progress has been made in the development of both live and killed oral cholera vaccines. A vaccine produced by the Swedish company SBL (Dukoral™) consists of killed whole-cell Vibrio cholerae O1 with a purified recombinant B-subunit of cholera toxin (rBS-WC). Dukoral™ requires the administration of two doses given one to six weeks apart and is licensed for persons two years and older. The vaccine has been found to be safe and protective (85-90% at six months; 62% at one year and around 50% at three years in Bangladesh and in two other randomized, placebo-controlled Phase III trials in cholera-endemic settings in Peru. Another killed oral vaccine partly modeled on the Swedish vaccine has been developed in Vietnam and is currently produced and used in that country. This vaccine, which contains killed cholera whole cells of V. cholerae O1 and O139 without the B-subunit cholera toxin (WC), is effective in persons aged one and above and also requires two doses. It confers levels of protection similar to those of the SBL vaccine, but has the advantage of being inexpensive to produce, thus making it appropriate for use in public health programs in developing countries. A third new-generation cholera vaccine, the live, attenuated oral vaccine, CVD 103HgR or Orochol™, produced by Berna Biotech (Switzerland) has been licensed in the US and Europe for use by travelers to cholera-endemic settings, but did not demonstrate protection in a cholera-endemic setting (Jakarta, Indonesia). Several other live cholera vaccines are also in various stages of development. The DOMI Cholera Program has therefore focused on the accelerated introduction of killed, whole-cell-based oral cholera vaccines.

The DOMI Cholera Program is a multi-faceted program of research and technical assistance aimed at accelerating the use of new-generation cholera vaccines in cholera-endemic countries. The program has activities in five countries: Bangladesh, India, Indonesia, Mozambique and Vietnam.

Goals

The goals of the program are to:

• Provide the data and analyses necessary for the rational targeting and implementation of vaccines against cholera in endemic areas;
• Facilitate the introduction, in a rational fashion, of killed oral cholera vaccine into the public health programs in cholera-endemic countries in Asia and Africa;
• Provide pre-licensure clinical evidence of the safety and immunogenicity of at least one experimental cholera vaccine in a cholera-endemic setting in Asia;
• Enhance the global production capacity of killed oral cholera vaccine by working with international producers, facilitating technology transfer for local production of the vaccine to qualified producers in Asia, and providing training to improve local production and regulation of the vaccine.

• Prospective surveillance of cholera in three endemic settings (Jakarta, Indonesia; Kolkata, India and Beira, Mozambique). These studies, based on stool culture confirmation and passive surveillance, revealed high annual incidence of cholera (0.5 - 4.8/1,000), especially in children under five years of age. Children 2-5 years old had an annual incidence rate of 13/1,000 in Beira and 8/1,000 in Kolkata (BMC Infectious Diseases, Archives of Disease in Childhood).The highest rate in Kolkata was among children under two years old (9.3/1,000), highlighting the need for cholera vaccines that can be used in very young children, especially in highly-endemic areas. A study of cholera outbreaks near Karachi, Pakistan in 2002/03 found both V. cholerae O1 and O139 strains to be causes of the outbreaks and that the main risk factors were contaminated water sources and household contacts (Trans R Soc Trop Med Hyg).
  
  
• Cholera vaccine studies:
  
  

  	In Beira, Mozambique, DOMI conducted a mass demonstration project using the rBS-WC vaccine (Dukoral™) in 2003/04, which showed mass cholera vaccination to be programmatically feasible and in high demand amongst the population (Vaccine). A case-control study conducted during the first year following vaccination, reported in The New England Journal of Medicine, revealed that the vaccine conferred approximately 80% overall protection against cholera and 90% protection against cholera of life-threatening severity. These findings are the first evaluation of the effectiveness of a modern cholera vaccine in sub-Saharan Africa and the first to show a cholera vaccine to be effective in a population with a high seroprevalence of HIV.
  	Prior to technology transfer to a developing country vaccine manufacturer in India, Phase II studies among adults in Vietnam (Vaccine. 2007 Jan 22;25(6):1149-55. Epub 2006 Sep 29) and in both adults and children in Kolkata, India were performed. Following the successful completion of these studies, DOMI is conducting the first large-scale double-blinded, randomized Phase III clinical trial of the reformulated Vietnamese WC vaccine in Kolkata, India. Nearly 70,000 persons one year and older were given either the cholera vaccine or a placebo in mid-late 2006 in three slum areas of the city. Three years of disease surveillance following vaccination will take place to provide vaccine efficacy rates of this low-cost vaccine, which is being "internationalized" for use in endemic countries. This surveillance is being continued under CHOVI.
  	DOMI has also conducted important analyses of herd protection for killed oral cholera vaccines, using incidence data following large-scale Phase III clinical trials conducted in Bangladesh in the mid-1980s. The cluster-randomized design of the trials allowed for comparison of cholera incidence among both those vaccinated against cholera and those who received a placebo in various clusters. The results show that in clusters with vaccine coverage of >51%, placebo recipients had cholera incidence rates nearly as low as those vaccinated in the same clusters, while placebo recipients in clusters with vaccine coverage below 28% had incidence rates of more than 2.5 times that of vaccines. This study, published in The Lancet in 2005, suggests that even moderate levels of coverage with whole-cell killed cholera vaccine can have a major impact on the entire community and that herd effects need to be included in analyses of the impact and cost-effectiveness of cholera vaccination.

  
  
• Economic and socio-behavioral studies of cholera and cholera vaccination. Studies conducted in several of the cholera program field sites have revealed strong familiarity with and knowledge of cholera amongst the populations in these settings, as well as high population demand for free or low-cost cholera vaccines. Cost-of-illness studies have also been conducted in four research sites.
  
  

Collaborators on the DOMI Cholera Vaccine Program:

• AVANT Immunotherapeutics, Needham, MA, USA
• BioFarma, Indonesia
• CHAEM and Ministry of Health, Mozambique
• EpiCentre, Paris, France
• Gothenburg University, Sweden
• ICDDR,B, Dhaka, Bangladesh
• National Institute of Cholera and Enteric Diseases (NICED), Kolkata, India
• National Institute of Health Research and Development (NIHRD), Jakarta, Indonesia
• National Institute of Hygiene and Epidemiology (NIHE), Hanoi, Vietnam
• Shantha Biotechnics, Hyderabad, India
• Swedish Bacteriological Laboratories (SBL), Sweden
• VaBiotech, Hanoi, Vietnam

Last Updated : May 2007