Systemic, Mucosal, and Memory Immune Responses following Cholera

Vibrio cholerae O1, the major causative agent of cholera, remains a significant public health threat. Although there are available vaccines for cholera, the protection provided by killed whole-cell cholera vaccines in young children is poor. An obstacle to the development of improved cholera vaccines is the need for a better understanding of the primary mechanisms of cholera immunity and identification of improved correlates of protection. Considerable progress has been made over the last decade in understanding the adaptive and innate immune responses to cholera disease as well as V. cholerae infection. This review will assess what is currently known about the systemic, mucosal, memory, and innate immune responses to clinical cholera, as well as recent advances in our understanding of the mechanisms and correlates of protection against V. cholerae O1 infection.

Modern History of Cholera Vaccines and the Pivotal Role of icddr,b

The rapid spread of the 7 th cholera pandemic over Asia in the 1960s led to several large field studies that revealed that the traditional injectable cholera vaccines had poor efficacy, usually less than 50% for only 3-6 months, which led WHO in the 1970s to stop recommending cholera vaccination. At the same time, it stimulated research that has led to the development of the effective orally administered cholera vaccines (OCVs) that today are a cornerstone in WHO´s strategy for “Ending Cholera – A Global Roadmap to 2030”. The first effective OCV, Dukoral™, containing a mixture of inactivated Vibrio cholerae bacteria and cholera toxin B subunit, was licenced in 1993 and is together with two similar inactivated whole-cell OCVs, Shanchol™ and Euvichol™/Euvichol-Plus™, the OCVs currently prequalified and recommended by WHO. This brief review is a personalized account of the “modern history” of the development of these now universally recognized effective tools for the control and ultimate elimination of cholera, and of the pivotal role of icddr,b and Bangladesh for this development.

An Update on Cholera Immunity and Current and Future Cholera Vaccines

Individual resistance to cholera infection and disease depends on both innate host factors and adaptive immunity acquired by a previous infection or vaccination. Locally produced, intestinal-mucosal secretory IgA (SIgA) antibodies against bacterial surface lipopolysaccharide (LPS) O antigens and/or secreted cholera toxins are responsible for the protective adaptive immunity, in conjunction with an effective mucosal immunologic memory that can elicit a rapid anamnestic SIgA antibody response upon re-exposure to the antigen/pathogen even many years later. Oral cholera vaccines (OCVs), based on inactivated Vibrio cholerae whole-cell components, either together with the cholera toxin B subunit (Dukoral™) or administered alone (Shanchol™/Euvichol-Plus™) were shown to be consistently safe and effective in large field trials in all settings. These OCVs are recommended by the World Health Organisation (WHO) for the control of both endemic cholera and epidemic cholera outbreaks. OCVs are now a cornerstone in WHO’s global strategy found in “Ending Cholera: A Global Roadmap to 2030.” However, the forecasted global demands for OCV, estimated by the Global Alliance for Vaccines and Immunization (GAVI) to 1.5 billion doses for the period 2020–2029, markedly exceed the existing manufacturing capacity. This calls for an increased production capacity of existing OCVs, as well as the rapid introduction of additional and improved vaccines under development.

Cholera, the Current Status of Cholera Vaccines and Recommendations for Travellers

Cholera is endemic in approximately 50 countries, primarily in Africa and South and Southeast Asia, and in these areas, it remains a disease associated with poverty. In developed nations, cholera is rare, and cases are typically imported from endemic areas by returning travellers. Cholera is readily preventable with the tools available to modern medicine. In developing nations, cholera transmission can be prevented through improved water, sanitation, and hygiene services and the use of oral cholera vaccines (OCVs). For travellers, risk can be mitigated by practicing regular hand hygiene and consuming food and water from safe sources. OCVs should be considered for high-risk travellers likely to be exposed to cholera patients or contaminated water and food. There are currently three World Health Organization pre-qualified OCVs, which are based on killed whole-cell strains of Vibrio cholerae. These established vaccines offer significant protection in adults and children for up to 2 years. A novel live attenuated vaccine that provides rapid-onset protection in adults and children is licensed in the USA and Europe only. Live attenuated OCVs may mimic the natural infection of V. cholerae more closely, generating rapid immune responses without the need for repeat dosing. These potential benefits have prompted the ongoing development of several additional live attenuated vaccines. The objective of this article is to provide a general review of the current landscape of OCVs, including a discussion of their appropriate use in international travellers.

Transient Intestinal Colonization by a Live-Attenuated Oral Cholera Vaccine Induces Protective Immune Responses in Streptomycin-Treated Mice

ABSTRACT Current mouse models for evaluating the efficacy of live oral cholera vaccines (OCVs) have important limitations. Conventionally raised adult mice are resistant to intestinal colonization by Vibrio cholerae, but germfree mice can be colonized and have been used to study OCV immunogenicity. However, germfree animals have impaired immune systems and intestinal physiology; also, live OCVs colonize germfree mice for many months, which does not mimic the clearance kinetics of live OCVs in humans. In this study, we leveraged antibiotic-treated, conventionally raised adult mice to study the effects of transient intestinal colonization by a live OCV V. cholerae strain. In a single-dose vaccination regimen, we found that HaitiV, a live-attenuated OCV candidate, was cleared by streptomycin-treated adult mice within 2 weeks after oral inoculation. This transient colonization elicited far stronger adaptive immune correlates of protection against cholera than did inactivated whole-cell HaitiV. Infant mice from HaitiV-vaccinated dams were also significantly more protected from choleric disease than pups from inactivated-HaitiV-vaccinated dams. Our findings establish the benefits of antibiotic-treated mice for live-OCV studies as well as their limitations and underscore the immunogenicity of HaitiV. IMPORTANCE Oral cholera vaccines (OCVs) are being deployed to combat cholera, but current killed OCVs require multiple doses and show little efficacy in young children. Live OCVs have the potential to overcome these limitations, but small-animal models for testing OCVs have shortcomings. We used an antibiotic treatment protocol for conventional adult mice to study the effects of short-term colonization by a single dose of HaitiV, a live-OCV candidate. Vaccinated mice developed vibriocidal antibodies against V. cholerae and delivered pups that were resistant to cholera, whereas mice vaccinated with inactivated HaitiV did not. These findings demonstrate HaitiV’s immunogenicity and suggest that this antibiotic treatment protocol will be useful for evaluating the efficacy of live OCVs.

Transient intestinal colonization by a live-attenuated oral cholera vaccine induces protective immune responses in streptomycin-treated mice

Current mouse models for evaluating the efficacy of live oral cholera vaccines (OCVs) have important limitations. Conventionally raised adult mice are resistant to intestinal colonization by Vibrio cholerae, but germ-free mice can be colonized and have been used to study OCV immunogenicity. However, germ free animals have impaired immune systems and intestinal physiology; also, live OCVs colonize germ free mice for many months, which does not mimic the clearance kinetics of live OCVs in humans. Here, we leverage antibiotic-treated, conventionally raised adult mice to study the effects of transient intestinal colonization by a live OCV V. cholerae strain. In a single dose vaccination regimen, we found that HaitiV, a live-attenuated OCV candidate, was cleared by streptomycin treated adult mice within a week after oral inoculation. This transient colonization elicited far stronger adaptive immune correlates of protection against cholera than did inactivated whole-cell HaitiV. Infant mice from HaitiV vaccinated dams were also significantly protected from choleric disease than pups from inactivated-HaitiV dams. Our findings establish the benefits of antibiotic treated mice for live OCV studies as well as its limitations and underscore the immunogenicity of HaitiV.ImportanceOral cholera vaccines (OCVs) are being deployed to combat cholera but current killed OCVs require multiple doses and show little efficacy in young children. Live OCVs have the potential to overcome these limitations but small animal models for testing OCVs have shortcomings. We used an antibiotic treatment protocol for conventional adult mice to study the effects of short-term colonization by a single dose of HaitiV, a live OCV candidate. Vaccinated mice developed vibriocidal antibodies against V. cholerae and delivered pups that were resistant to cholera, whereas mice vaccinated with inactivated HaitiV did not. These findings demonstrate HaitiV’s immunogenicity and suggest that this antibiotic treatment protocol will be useful for evaluating the efficacy of live OCVs.