CHOLERA VACCINES

Whole cell, killed parenteral vaccines stimulate the development of short-term immunity to V cholerae O1. Approximately 50-60% of people living in endemic regions were reported for 3-6 months. However these vaccines are least effective in young children who are at high risk from cholera and it's adverse consequences. Protective efficacy in naive people from non-endemic regions is likely to be less. Parenteral vaccines are associated with local reactions in approximately 50% of vaccines and 10-20% develop more generalized systemic reactions such as fever and malaise. A parenteral vaccine consisting of phenol-inactivated whole cell V cholerae strains Ogawa (usually classic biotype) is licensed, but is not yet produced. The vaccine's limited efficacy, lack of utility in control of cholera outbreaks, and frequent adverse reactions make this vaccine no longer useful.

ORAL VACCINES

The oral vaccines have been licensed for commercial use: the killed whole cell V cholerae plus recombinant B subunit of cholera toxin vaccine (rCTB-WC; Dukoral; SBL Vaccine AB, Stockholm, Sweden), and the live attenuated V cholerae O1 strain CVD 103 -HgR vaccine (Orochol; Berna Biotech Ltd., Berne, Switzerland; known as Mutachol in Canada). Dukarol does not contain the A subunit of cholera toxin and therefore no pathogenic toxin is present.

PHAGE IN THE TIME OF CHOLERA

Bacteriophage (bacterial viruses) were heralded as revolutionary therapeutic agents soon after the discovery by Felix d'Herelle in 1917 of an invisible microbe capable of lysing bacteria. Bacterophage appeared to be efficient killers of their bacterial hosts. We now know that their life history is far more complex than first assumed, so the idea of the phage's potential, as curative or prophylaxis spread quickly to research institutes in Europe, North America, and Asia. d'Herelle himself spearheaded many of these efforts, the most famous of which was the initiation of an extensive campaign to use phage in the treatment and prevention of cholera in colonial India. The authors of one such study conclude by noting that 'the results establish sufficient probability in favor of a significant effect of the administration of bacteriophage to form a basis of practical policy in the treatment and prevention of cholera in villages'. The early hopes never fulfilled the expectations, for both clinical and political reasons, and the eventual development of broad spectrum antibiotics provided a more reliable, effective means of control of bacterial infections. The rise of antibacterial resistance has, in turn, revived interests in bacteriophage therapy, despite concerns and uncertainties as to its effectiveness. We consider rather an alternative approach to modern bacteriophage therapy by revisiting the idea of inoculating bacteriophage directly into the environment.

Most tests, theories, and proposals to implement bacteriophage therapy regard the human body as the potential site for intervention. But for many bacterial diseases affecting human health, the pool of infecting bacteria comes from water, soils, foods, and other host organisms; some of these potential sources of infection do not posses a complex immune system capable of selectively eliminating foreign agents. By contrast with agricultural settings, where environmental application of phage as bio-control is already being considered, we believe there exists as an yet overlooked opportunity to reduce the severity, extent, and persistence of some bacterial epidemics by developing ecologically based cures for human disease.

A suitable target disease is cholera. Recent studies have demonstrated a substantial correlation between the increase in density of cholera-specific phage and the decrease in density of V cholera in both water sources and fecal matter from infected patients. The reasons are apparently simple; the presence of V cholera provides an opportunity for the spread, and increase of phage, which leads to decreasing host density, which in turn leads to the washout/death of phage. A comprehensive description of cholera disease dynamics involve many factors including environmental seasonality, long distance dispersal mediated by alternative hosts, as well as life history modalities that enable V cholera to respond to stressful conditions. Without diminishing the importance of these and other factors, in the case of cholera it is apparent that phage and bacteria go through alternating boom-and-bust cycles. What are the practical steps of intervention so as to minimize the likelihood of devastating epidemic booms of V cholera?

Briefly, the peak of phage lags behind the peak of bacteria. Growing O1 and /O139 serogroup-specific phage in the laboratory and then adding phage to at-risk water sources may augment the ability of phage to keep pace with the dynamics of its host and suppress the spread of an epidemic. In a sense we are suggesting altering the (natural course) of host-phage population dynamics with artificial injection of phage. The utility and affectivity of any such ecological inoculation depend on careful balancing of environmental connectivity of infected areas, risks to human populations, as well as the life history and parameterization of biocontrol agent themselves. Ultimately, limiting and/or eliminating an undesirable bacterial population constitutes a problem in co-evolutionary biological control. Likely sources of intervention include source of drinking water, wells, and sewage systems so as to minimize the flow of bacterial agents into water used for drinking and bathing. Assessments of lifetime of phage in local habitats would be necessary because conditions (e.g. temperature, salinity, PH) change over the course of intervention. In addition, the ecohydrology of the affected region may be important, since intervention strategies will depend on whether disease outbreaks are localized to isolated sites, linked to seasonal flooding, or occur in riverine corridors. These concerns notwithstanding, cholera-specific phage are already found in natural environments and strong evidence exists that their presence leads to the decline of cholera epidemics .The risks associated with ecological bacteriophage therapy should be mitigated by the use of virulent, rather than temperate, strains of phage. If the origins of the seasonal cholera epidemics are harbored within environmental pools, then efforts should be made to seek out the most effective means of adding bacteriophage to eliminate the incubation and growth of V cholerae populations when they are at their most vulnerable. Thus far, the spread of cholera has been mitigated by improvements in water quality, low cost preventive measures in-at-risk regions (e.g. filtering water through sari clothes), and by improvement of post infection treatment (e.g. single-dose antibiotic therapy), although the global chloramphenicol has not abated. Bacteriophage could become an additional tool in the public-health struggle against cholera.