Cholera vaccines for the developing world.

Cholera remains as a global public health threat affecting most of the developing world. In endemic areas, young children are most affected. Outbreaks are reported increasingly from more countries. Improvements in water and sanitation may be the mainstays of cholera prevention but in the short term, vaccines provide an alternative in cholera control. Since 1999, the World Health Organization has advocated the use of oral cholera vaccines as an adjunct in the control of cholera. Although internationally available, oral cholera vaccines are not extensively used in public health settings in developing countries where they are most needed. We review oral cholera vaccines that are currently available and in the pipeline including the need for policies that will ensure more extensive usage of these vaccines.

Biosafety aspects of the recombinant live oral Vibrio cholerae vaccine strain CVD 103-HgR.

The development of live attenuated vaccines, allowing for the safe and effective immunisation at mucosal surfaces, is a strategy of great interest for vaccinologists. The main advantage of this approach over conventional parenteral vaccines is the induction of strong mucosal immune responses, allowing targeting of the pathogen at the initial point of contact with the host. Further advantages include the ease of administration, high acceptance by vaccines, and relatively low production costs. Finally, well-characterised, safe and immunogenic vaccine strains are well suited as vectors for the mucosal delivery of foreign vaccine antigens and of DNA vaccines. However, such vaccines, when based on or containing genetically modified organisms (GMOs), are facing new and specific regulatory hurdles, particularly regarding the potential risks for humans and the environment. In this contribution we address selected aspects of the risk assessment of live attenuated bacterial vaccines covered in the course of the registration of vaccine strain CVD 103-HgR as a recombinant live oral vaccine against cholera.

[Anticholera vaccines and vaccination]. / Vaccins et vaccination anticholériques.

Cholera is still an important diarrhoeal disease in developing countries. The impact of cholera out-break is tremendous for a country at human and economic level. WHO estimates that diarrhoeal diseases cause about 2.8 million deaths per year in developing countries. Officially, cholera is causing around 120,000 deaths per year. The poorest population (from slums and refugee camps) are the most vulnerable target for cholera infection. Development of simple cheap and effective vaccine is highly recommended. This article aims at giving an update on the currently available and future vaccines for the prevention of diarrhoea due to Vibrio cholerae O1 and O139.

Cholera.

Despite more than a century of study, cholera still presents challenges and surprises to us. Throughout most of the 20th century, cholera was caused by Vibrio cholerae of the O1 serogroup and the disease was largely confined to Asia and Africa. However, the last decade of the 20th century has witnessed two major developments in the history of this disease. In 1991, a massive outbreak of cholera started in South America, the one continent previously untouched by cholera in this century. In 1992, an apparently new pandemic caused by a previously unknown serogroup of V. cholerae (O139) began in India and Bangladesh. The O139 epidemic has been occurring in populations assumed to be largely immune to V. cholerae O1 and has rapidly spread to many countries including the United States. In this review, we discuss all aspects of cholera, including the clinical microbiology, epidemiology, pathogenesis, and clinical features of the disease. Special attention will be paid to the extraordinary advances that have been made in recent years in unravelling the molecular pathogenesis of this infection and in the development of new generations of vaccines to prevent it.

Vacunas contra el cólera / Vaccines against cholera

El cólera es una enfermedad aguda e infecciosa que fue descrita antes de la época de Hipócrates en el siglo V AC. Se describieron varias epidemias de esta enfermedad en Asia entre los siglos XV y XVIII. A mediados del siglo XIX John Snow en Inglaterra fue el primero en describir las medidas de prevención de la enfermedad a raíz de una epidemia ocurrida en Londres. En 1883, Robert Koch realizó el descubrimiento del agente causal, Vibrio cholerae, un bacilo curvo de gran movilidad. Durante los siglos XIX y XX han ocurrido siete pandemias de cólera; en la actualidad ocurre la transmisión de la séptima. El cólera es una de las causas más importantes de morbilidad y mortalidad de algunos países de Asia y Africa y desde 1991 también en Latinoamérica. Desde principios del siglo se ha empleado una vacuna parenteral elaborada con una cepa de V. cholerae 01, inactivada con calor, la cual únicamente induce 50 por ciento de protección en jóvenes y adultos, durante un período de aproximadamente 6 meses. El empleo de adyuvantes no ha tenido influencia en su eficiencia, sino por el contrario incrementa las reacciones colaterales. Las perspectivas para el desarrollo de una vacuna eficaz contra el cólera se basan en el hecho de que más del 90 por ciento de los sujetos infectados en forma natural quedan protegidos para una segunda reinfección. El avance del desarrollo de las vacunas del cólera se ha podido efectuar gracias a un mejor conocimiento de los mecanismos de patogenicidad y antigenicidad del agente etiológico, aunque persisten incógnitas importantes. La vacuna ideal contra el cólera debería ser tan eficaz como la infección natural, sin riesgo de causar enfermedad infecciosa, de fácil administración, de bajo costo, de una sola dosis, inocua, que proteja contra la infección y obviamente contra la enfermedad grave, con protección de larga duración y probablemente de administración oral

Field trial of oral cholera vaccines in Bangladesh: results from three-year follow-up.

The protective efficacy (PE) of B subunit killed whole-cell (BS-WC) and killed whole-cell-only (WC) oral cholera vaccines was assessed in a randomised double-blind field trial among children aged 2-15 years and women over 15 years in rural Bangladesh. Among the 62 285 subjects who received three doses of BS-WC, WC, or Escherichia coli K12 strain placebo, cumulative PE at 3 years of follow-up was 50% for BS-WC and 52% for WC. PE was similar against severe and non-severe cholera, but was significantly lower in children who were vaccinated at 2-5 years (26% for BS-WC; 23% for WC) than in older persons (63% for BS-WC; 68% for WC). Among persons vaccinated at 2-5 years, protection at 4-6 months of follow-up was similar to that for older persons, but rapidly waned thereafter and was not evident during the third year of follow-up. In contrast, persons vaccinated at older ages were protected even in the third year of follow-up (PE 40% for BS-WC; 62% for WC). PE was substantially higher against classical cholera (58% for BS-WC; 60% for WC) than against El Tor cholera (39% and 40%).

Safety, immunogenicity, and efficacy of recombinant live oral cholera vaccines, CVD 103 and CVD 103-HgR.

The genes encoding the A (toxic) subunit of cholera toxin were deleted from pathogenic Vibrio cholerae O1 strain 569B by recombinant techniques, leaving intact production of immunogenic, non-toxic B subunit. The resultant strain, CVD 103, evaluated for safety, immunogenicity, and efficacy as a live oral vaccine, was highly attenuated and elicited strong antibacterial and antitoxic immune responses; a single dose significantly protected volunteers against challenge with pathogenic V cholerae O1 of either serotype or biotype. A further derivative, CVD 103-HgR, which has an Hg++-resistance gene to differentiate it from wild-type vibrios, was also well-tolerated, immunogenic, and protective; moreover, faecal excretion of this derivative was significantly lower than that of CVD 103, which should minimise environmental spread of the vaccine. CVD 103-HgR is a candidate for expanded clinical trials in endemic areas.