The Gram negative bacterium, Vibrio cholerae (Vc) causes cholera, an enteric disease that has killed untold
numbers of humans. In the 19th century, whole-cell (W-C) cholera vaccines were tested in humans. Field trials (1960s-
70s) of injected, killed W-C (kW-C) Vc showed cholera-specific immune responses (antibodies, Abs) could be induced
with a single dose in certain cohorts, but more durable immunity was sought with oral cholera vaccines. Newer, killed
(two doses) and later modified live (one dose) W-C cholera vaccines for oral delivery were developed and extensively
tested. After over 200 years, no consensus exists as to what are protective Vc antigens or how to identify them. An enduring
cholera vaccine for children <5 years of age and Vc-antigen naïve individuals is still needed. The cholera outbreak in
Haiti underscores some unresolved issues associated with the current cholera vaccines. Annually, is there enough cholera
vaccine for those who need it? Who needs to be vaccinated and when? Given the displacement of populations during
flooding like in Pakistan or in Haiti due to an earthquake, can a single dose of the kW-C cholera vaccine function to prevent
or to contain an outbreak? What does ‘working’ entail: solely preventing deaths, or that plus long term immunity?
Can a single formulation of Vc antigens be used for endemic or epidemic cholera which may require reactive vaccination
for epidemics, but prophylactic vaccination for endemic cholera? The immunologic realities given the logistic issues for
the different needs of a cholera vaccine are discussed.