Development of Vaccines against Cholera and Diarrhoea Due to Enterotoxigenic Escherichia Coli: Memorandum from a WHO Meeting

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Development of vaccines against choleraand diarrhoea due to entertoxigenic Escherichia coli: Memorandum from a WHO meeting (*1)

Introduction

Althogh parental cholera vaccines have existed for a century, they have not played a significant role in the control of cholera since induce only a low level of immunity over a short period. Research is under way to develop effective oral vaccines based on nonliving organisms and atgens, or on live, attenuated strains of Vibrio cholerae O1. the meeting discussed the results that have recently emerged from such studies, including a field of two formulations of an inactivated oral cholera vaccine in Bangladesh> research on protective antigens of V. cholerae O1 that might lead to improved inactivated vaccines> and studies of the safety, immunogenicity, and eficacy of live cholera vaccines in volunteers. Recommendation for furher research in these areas were also made.

Diarrhoea due to enterotoxigenic Escherichia coli (ETEC) is an important problem in most developing countries, but progress towards the development of vaccines for this disease has been slow. However, important recent results on the virulence antigens of ETEC have led to the development of possible candidate vaccines, and the first of these has reached the stage of initial evaluation in humans.

cholera vaccines

Epidemiological aspects

Currently, cholera is reported to WHO by about 35 countries. Left untreated, it is still one of the most dangerous infectious diseases, with case-fatality rates of up to 40%. An estimated 5.5 million cases of cholera occur in the world each year, causing about 20 000 deaths in Africa and 100 000in Asia. About one-third of the deaths involve children under 5 years of age> one-quarter, children aged 5-14years> and the remainder, adults. (*a)

Epidemics of cholera that occur in previously uninfected areas with seronegative populations affect all age groups equally and are often associated with a single mode of spread. Such epidemics are characterized by a relatively low rate of asymptomatic infection and there is usually no enviromental reservoir of infection. In contrast, with endemic cholera, disease incidence is highest for 2-15-year-olds and declines with increasing age, except for women of child-bearing age, for whom the incidence is higher. Yearly seasonal outbreaks are prominent and transmission is associated with the following: an enviromental, aquatic resevior> multiple modes of spread (contaminated water or food, occasionally person-to-person contact)> and frequent asymptomatic infections, leading to a high prevalence of antibody among 20-years-olds.

In endemic areas, risk factors for severe cholera include: absence of low titres of vibriocidal antibodies> close contact with the family of a cholera patient> low gastric acidity (whether naturally acquired, surgically induced, or resulting from the use of antacids)> absence of breast-feeding(among children under 3 years of age)> and O blood group. the existence of natural immunity to V. cholerae O1 in endemic setting is suggested by the declining attack rate with increasing age, the lower attack rates in persons with elevated levels of vibriocidal antibody, and epidemiological evidence that one episode of cholera evokes substantial protection against a second. In Bangladesh, the prevalence of vibriocidal antibody is 40% among 5-year-olds and 80% among 20-years-olds. It is estimated that every person in Bangladesh is exposed to V. cholerae O1 at least once every 13 years, and that some people may be exposed annually> immunity appears to be boosted with each infection, including asymptomic infections.

Groups that may benefit from effective cholera immunization include children and adults in endemic areas, refugees in camps where the sanitary conditions are poor, and populations in non-endemic areas that are threatened by nearby epidemics. International travellers experience a very low risk of cholera, which would probably not be changed measurably by vaccination.

Even today, many people in Africa and Asia live in areas that experience a high incidence of cholera and where effective treatment is unavailable. In such areas, mortality due to cholera remains high and epidemics cause panic and severe social and economic problems. Hence, there is continuing need for an effective vaccine against the disease. Based on the concept that natural protection against cholera is conferred by intestinal antibacterial and antitoxic antibodies, research in the 1980s focused on the development of oral vaccines that would induce protective immunity by stimulating an intestinal immune response against one or more relevant antigens of V. cholerae O1.

Important antigens of Vibrio cholerae O1

Studies in animals and humans have shown that V. cholerae cell-wall lipopolysaccharide (LPS) and cholera toxin (CT) both evoke protective immune responses. Atnibodies to these substances protect synergistically in the gut. Antibacterial immunity is mainly afforded by antibodies to LPS, but antibodies to other cell-associated protein antigens may also be important in this respect. Antitoxic immunity is primarily directed against the B subunit (BS) of cholera toxin.

Colonization of the human intestine by V. cholerae O1, which is aprerequisite for developing diarrhoel disease, is complex and requires the coordinated expressions of chemotatic and motility functions, proteolytic enxymes, haemagglutinins, colonization pili, and finally, production of CT. The prevention of bacterial adherence would block the pathogenesis of cholera at its earlieststate. Recent studies of infant mice and volunteers have indicated that a pilus elaborated by both classical and the El Tor biotype of V. cholerae O1 is probably designated TCP E1 Tor biotype of V. Cholerae O1 is probably required for colonization. This pilus has been designated TCP (toxin coregulated pilus) because the growth conditions that modulate its level of expression also modulate toxin production. In addition , the major pilus structural gene (tcpA) and the toxin genes are part of a virulence regulon (toxR). Because of their critical roles in the pathogenesis of cholera, toxR-regulated surface and secreted proteins (in particular TCP and cholera txin B subunit (CT-BS)) are potential immunogens for use in combination vaccines, in addition to LPS.

Rabbit polyclonal antiserum directed against TCP has been found to be protective in passive immuniation experiments in infant mice challenged with either Ogawa or Inaba strains of V. Cholerae O1. The protective activity of anti-TCP serum is lost after it has been absorbed with wild-type V. cholerae O1, but is retained after absorption with a pilus-negative mutant. This suggest that protection is associated with the anti-TCP antibodies. The sequences of the tcpA genes from the two classical strains of V. cholerae O1 (Ogawa 395 and Inaba 569B) are identical. The sequence of the tcpA gene from an E1 Tor strain of Ogaa serotype (E7946) …