Maximizing protection from use of oral cholera vaccines in developing country settings

Abstract

When oral vaccines are administered to children in lower- and middle-income countries, they do not induce the same immune responses as they do in developed countries. Although not completely understood, reasons for this finding include maternal antibody interference, mucosal pathology secondary to infection, malnutrition, enteropathy, and previous exposure to the organism (or related organisms). Young children experience a high burden of cholera infection, which can lead to severe acute dehydrating diarrhea and substantial mortality and morbidity. Oral cholera vaccines show variations in their duration of protection and efficacy between children and adults. Evaluating innate and memory immune response is necessary to understand V. cholerae immunity and to improve current cholera vaccine candidates, especially in young children. Further research on the benefits of supplementary interventions and delivery schedules may also improve immunization strategies.

Keywords: :

• cholera
• oral vaccines
• children
• developing countries
• immunogenicity
• efficacy

Introduction

Vibrio cholerae is a highly transmissible organism that is found in aquatic reservoirs.¹ Cholera is a rapidly spreading, severely dehydrating diarrheal disease that represents a global challenge, with over 50 countries considered to be endemic for the disease.² Cholera outbreaks have become more frequent and prolonged in recent years in endemic areas with recurrent seasonal patterns, as well as non-endemic areas that are initiated by exogenous introduction of V. cholerae following complex emergencies, such as refugee crises or natural disasters (Figure 1).³ Recent crises in Pakistan, sub-Saharan Africa and Haiti provide contextual experience to support this idea, in which a sudden disruption results in the collapse of already tenuous water and sanitary facilities.^4-6 Estimations project that 1.4 billion people are at risk for cholera worldwide, with half of the resulting deaths being found in children under five years of age.⁷ Oral cholera vaccines (OCV) offer protection to those vaccinated through direct immunity and indirect protection to unvaccinated individuals via herd immunity.^8,9 Other intervention strategies are also required alongside vaccination in order to increase protection against cholera even further. Such measures include timely access to rehydration, antibiotics, hand washing, and improved water/sanitation initiatives. Most developing country populations live in conditions that perpetuate disease transmission and improvements in standards of living can take a long time to achieve. V. cholerae has the potential to cause large, rapidly spreading severe outbreaks that often cripple those public health systems that have limited clinical and financial resources.

Figure 1. Cholera world map, a disease of poverty.³

Lower reported efficacy of oral vaccines in children from resource poor countries have led to concerns regarding the public health impact of OCVs.¹⁰ While not completely understood, the most likely explanations for this reduced efficacy in poorer countries are linked to malnutrition, maternal antibody interference, parasitic infection, enteropathy, and the presence of pre-exisiting antibodies, all of which have the potential to compromise the mucosal immune response pathway. The following review aims to discuss key findings and measures that are important in optimizing both immunogenicity and efficacy of oral cholera vaccines in high-risk areas.

Pathogenesis and Immunological Basis of Cholera Vaccination

Infection requires small-intestine colonization by V. cholerae, with its pathogenicity mediated by a two-subunit cholera toxin. The pentameric B subunit binds the bacteria to the epithelial surface and is not associated with any toxicity, while the A subunit is responsible for stimulating a cascade causing severe secretory diarrhea.¹¹ Since vibrio pathogens have a mucosal port of entry, vaccination eliciting locally produced intestinal antibodies and stimulating immunological memory makes oral vaccines an attractive option for immunizing populations in resource-limited settings.¹²

Many currently available cholera vaccines work through inducing serum and mucosal antibodies to interfere with microbial invasion of the bloodstream. Humans can mount a systemic and local mucosal immune response in cholera.¹³ Antibody mediated protection is primarily directed toward the lipopolysaccharide (LPS) O antigen of cholera organisms and to a lesser degree to cholera toxin. While both O1 and O139 serogroups can elicit serum antitoxin responses, cross protection has not been shown to occur.¹⁴ Since the pathogen is thought to be non-invasive, it is widely believed that secretory IgA (sIgA) released from the intestinal lumen may play a substantial role in conferring protection. Serum vibriocidal antibody titers increase with age and studies have shown these to be inversely related to the risk of acquiring a cholera infection.¹⁵ Many surrogates of protection following vaccination are relative, meaning that protection is difficult to objectively quantify. In cholera, seroconversion is defined by a 4-fold increase in serum vibriocidal antibody titers against baseline and has served as an indicator that immune responses has been elicited in vaccinnees. While antibody levels in sufficient quantities are thought to prevent infection and severe disease, it should be noted that an adequate memory B cell and cell-mediated immune response are valuable for the control of established infection.¹⁶ Other parameters showing association with protection against cholera disease include LPS IgA and CTB IgA antibodies,¹⁷ and LPS IgG memory B-cell response.¹⁸

Certain intrinsic and genetic host factors are well recognized in influencing the outcome of V. cholerae exposure.¹⁹ Cholera infected subjects, who are blood group O suffer more severe symptoms and fatal outcomes,²⁰ but have also responded with higher antibody responses following the administration of a live OCV (CVD 103-HgR).²¹ Other significant factors in determining outcome of disease include repeated infections and poor nutritional status, which are both linked to low socioeconomic status and poor environmental conditions.²²

Immune Response to Oral Vaccination in Developing Countries

Immunization is a powerful and cost effective health intervention, preventing approximately three million deaths and protecting over 100 million lives from illness and disability every year.²³ Over two thirds of the world’s population live in developing countries, where infectious diseases cause most of the mortality among children under five years of age.²⁴ In general, oral mucosal/enteric vaccines, whether live, killed, viral, or bacterial, have been less immunogenic and efficacious when given to those living in LDCs, especially in young children.^25,26 Under performance has been observed in vaccines for both diarrheal and non-diarrheal diseases alike (Table 1). With specific regards to the new modified bivalent oral cholera vaccine, efficacy was much lower in children under 5 y (42%). Nevertheless, more cases seemed to be prevented by vaccination (10.5/1000) for children aged 1–5 y, compared with older age groups (5.5/1000 in 5–15 y and 3.1/1000 in ≥ 15 y). Though the reasons for this are not completely understood, issues relating to the intestinal environment appear to be important in vaccine hypo-responsiveness. Key factors associated with poor vaccine performance in developing countries include protein energy and micronutrient malnutrition, interference by maternal placental and breast milk antibodies, parasitic infections, and intestinal mucosal damage following environmental enteropathy. Another reason could be exposure to related organisms that elicit antibodies that cross react with either non-living or live attenuated vaccines, thus diminishing potency in LDCs. Infants and toddlers have limited exposure to antigens and therefore, mount inadequate anamnestic immune responses.²⁵ This is likely seen in all age groups from non-endemic areas due to a lack of any initial exposure.²⁷ For three years following El Tor V. cholerae disease, both young children and older individuals mount similar vibriocidal and Ab specific responses after natural infection.²⁸ Despite these similarities between the two age groups, currently available oral vaccines are less efficacious and offer a shorter duration of protection in young children than that found in older individuals. Memory B cells (MBC) are thought to play a crucial role in mediating long-term protective immunity by facilitating a rapid anamnestic response upon re-exposure to the antigen.²⁹ A recent investigation from an endemic region has demonstrated a significantly larger and longer lasting MBC response in adults who had natural cholera infection compared with those receiving vaccination with a killed oral cholera vaccine.³⁰ Meanwhile, helper T cells play an important role in the development of B-cell immunity, warranting further research of both MBC and cell-mediated immunity responses in children.^31,32

Table 1. Under-performing oral vaccines in the developing world

Diarrheal vaccines	Clinical phase	Target age	Protection (years of follow up)	Evaluation sites	Reference
ETEC
rCTB (K)	III	6–18 mo	PE 20%	Rural Egypt	92
Shigella
SC602 (L)	II	8–10 y 18–39 y	Seroconversion 2.7% 0%	Bangladesh	93
Rotavirus
Rotateq (L)	III	Infants	PE 39%	Ghana, Kenya, Mali	94
Rotarix (L)	III	Infants	PE 49–77%	Malawi, S. Africa	95
Cholera
Dukoral (K)	III	2–5 y > 5yrs	PE 47% (2 y) PE 61% (2yrs)	Bangladesh	52
Shanchol (K)	III	1–5 y	PE = 43% (5 y)	India	96
CVD-103HgR (L)	III	2–41 y	PE = 14% (4 y)^$	Indonesia	66
Non-diarrheal vaccines	Clinical phase	Target age	Protection	Evaluation sites	Reference
Typhoid
Ty21a (L)	III	5–19 y	33–74%* (3 y)	Chile	97
Polio
Sabin (L)	IV	infants,toddlers, school age	70–73% (immunogenicity vs type 1, 3 poliovirus)^#	India, sub-saharan Africa	98

PE, protective efficacy; $ no protection afforded by CVD 103 HgR in years 1–3 as well. * liquid formulation of Ty21a lyophilized powder had much higher efficacy compared with enteric coated capsules. # compared with 100% immunogenicity in children from industrialized countries

Although this phenomenon of diminished immunogenicity has been observed in all age groups, there are certain, specific confounding factors attributed to young infants. A level of immunity is transferred to the neonate in the form of maternal serum IgG via the placenta and sIgA and nonspecific protective immune cells through breast milk.³³ Specifically, breast milk from mothers in cholera endemic countries contain important antibodies and human milk glycans vital for the immune response.³⁴ While these serve as a valuable protective mechanism against disease, they can also modulate vaccine response. However, frequent intake of breast milk may inhibit the natural protection offered by antibodies and glycans found in maternal breast milk by preventing the vaccine strains from binding to the gut lumen.³⁵ Researchers in Bangladesh demonstrated higher vibriocidal immune responses in children for whom breastfeeding was withheld for 3 h before administration of a killed OCV compared with that of children who were breastfed 1 h before vaccination.³⁶ Though breastfeeding has been documented to reduce the risk of severe cholera in infants,^37,38 numerous examples of severe disease in neonates and young children have been increasingly reported.^39,40

Immune response relies on overall nutrition, and in the case of infants, maternal macro and micro nutrition. Malnutrition in resource-limited settings is commonly related to socio-economic status, which is linked to poor living conditions and a higher exposure to microbes. These concomitant factors commonly lead to repeated infection. Low anthropometric Z scores (weight for age) have been associated with a 9.5 odds ratio (OR) increase for overall mortality from diarrhea, in addition to increased and prolonged diarrhea in patients hospitalized with V. cholerae diarrhea.^41,42 Micronutrients, such as Vitamin A⁴³ and vitamin D⁴⁴ have been shown to improve vaccine immune response in infants and young children. Zinc supplementation has been shown to significantly lower diarrheal and respiratory disease, as well as improve morbidity from infections in infants and children.^45,46 Conversely, zinc deficiency can play a role in decreased response to respiratory vaccines.^27,47,48 Although the above studies provide encouraging results with the addition of zinc supplementation, challenges remain in implementing feasible schedules to ensure adequate levels of zinc are attained in the highest risk infants. Other micronutrients, such as vitamins B6, B12, C, E, folate, selenium, copper, magnesium, and iron need to be researched further, but have already been shown to offer great potential in improving immune function.⁴⁹

In contrast to those living in developed countries with relatively higher levels of sanitation, the mucosal gut lining of individuals living in impoverished settings of developing countries often reflect their continual exposure to fecal-contaminated environments. This leads to the intestinal microflora exhibiting a different composition, which is characterized by villous atrophy and crypt hyperplasia leading to inflammation of and malabsorption by the gut. This altered pathology of the gut’s function is known as environmental or tropical enteropathy. Frequent exposure to bacteria, viruses and parasites may serve as a valuable defense mechanism since such pathogens would have to face this primed, hostile immune environment. Instead of activating the innate immune system and enhancing the adaptive response, oral vaccines may be ultimately attenuated by a highly-activated immune system.⁵⁰ Furthermore, increased exposure to related organisms sharing common epitopes of the cholera vaccine may likely induce antibodies that can reduce OCV potency. While deworming has demonstrated significant effects on vibriocidal antibody responses to the live OCV, CVD 103-HgR in Ecuadorian children,⁵¹ there was no beneficial effect observed in the immune response of Bangladeshi children treated with antihelminthics, who received Dukoral^®.²⁷ Maintenance of normal gut microflora and architecture could be critical for normal intestinal function and mucosal immune response.

Overview of Immune Response to Potential OCV Vaccination

Currently, six oral cholera vaccines are in active use or in active clinical evaluation. This includes 2 killed and 4 live OCVs (Table 2).

Table 2. Oral cholera vaccines

Generic name:	WC-rBS	Modified WC-only	PXVX-0200*	Peru-15	Cuban 638	VA 1.4
Trade Name:	Dukoral^®	Shanchol^®	To be determined	CholeraGarde^®	vax-COLER^®	To be determined
Live/Killed:	Killed	Killed	Live	Live	Live	Live
Target	O1 Classical and El Tor	O1 (Classical and El-Tor) and O139	O1 Classical Inaba	O1 El Tor Inaba	O1 El Tor Ogawa	Non-toxigenic O1 El Tor Inaba
Regimen	2 doses given 7–42 d apart (3 doses for children 2–5 y)	2 doses given at least 14 d apart	1 dose	1 dose	1 dose	1 dose
Clinical Trial Results	Phase III complete - 2 y for adults - 6 mo for children 2–5 y of age	Phase III complete 5 y protection (appears to afford less protection in children < 5 y)	Phase II (safe and immunogenic) Phase III results expected in mid 2014	Phase 2 data demonstrates safety and immunogenicity in infants > 9mo	Phase 2 data demonstrates safety and immunogenicity in healthy adults	Phase 2 data demonstrates safety and immunogenicity in healthy adults
Age Range for Vaccination	≥ 2 y	> 1 y	≥ 2 y	Infants (9 mo) and above	Phase 3 planned to include pediatric group	Phase 3 planned to include pediatric group
Requirement for Oral Buffer	Yes	No	Yes	Yes	Yes	Yes
Storage Temperature	2–8 °C	2–8 °C	2–8 °C	-20 °C	-20 °C (2–8 °C for 3–4 mo)	-20 °C (40 °C lyophilized version)
Comments	WHO- prequalified	- WHO- prequalified - no buffer required - 5 y duration of protection^&	- single dose - tested in children, adults, and HIV infected	- single dose - tested in infants, adults, and HIV infected - Potential to be used in EPI schedule	- single dose - phase 3 testing to be conducted	- single dose -phase 2 tested with lyophilized version at 40 °C -phase 3 planned
Price to the Public Sector, per Dose	$5.25	$1.85 (Shanchol)      $0.80 (mORC-Vax)	Expected to be in the “low dollar” range	Not available	Not available	Not available

Notes: *Formerly licensed as Orachol/Mutachol (CVD-103HgR) but suspended by previous manufacturer after negative phase 3 results. This vaccine has since been recommercialized by PaxVax.^&66% protection of the bivalent killed OCV has been maintained at 66% over 5 y (Sur et al., submitted for publication, personal communication).

Killed oral cholera vaccines- capitalizing on dosing schedule flexibility

Dukoral^® is the first internationally licensed oral cholera vaccine. Though pre-qualified by the World Health Organization (WHO), it has mainly been used as a travelers’ vaccine, primarily due to its high price and formulation process. The vaccine is co-administered with a buffer (mixed with clean water) to protect the B subunit from being altered by gastric acid. A large randomized placebo-controlled trial in Bangladesh of predecessors to Dukoral^® (with and without the recombinant cholera toxin B subunit) in approximately 90 000 adults and children of 2 y and older revealed an 85% efficacy after six months and maintained 50% protection at 3 y of follow up for older children and adults.⁵²

Considering the need to provide a less expensive cholera vaccine for resource-poor countries with endemic cholera, a transfer of the Dukoral^® good manufacturing process (GMP) occurred, culminating in the development of a whole-cell, killed oral cholera vaccine in Vietnam. The Vietnamese vaccine differs from Dukoral^® in several important aspects. Since it does not contain cholera toxin B subunit, it does not elicit antitoxic immunity, nor does it require co-administration with buffer. It is also less expensive to manufacture. Over 20 million doses of this vaccine have been administered in public health programs in Vietnam. This vaccine has since been reformulated to an oral WC-only vaccine called mORCVAX^®.

In order to comply with WHO standards, transfer of manufacturing technologies for this Vietnamese vaccine has resulted in the development and licensure of Shanchol^®, a low cost alternative OCV produced in India. Several double-blind, randomized controlled trials (RCT) have evaluated a 2-dose regimen of this modified whole-cell vaccine. Shanchol^® consists of five strains of V. cholerae killed whole cells, including O1 classical and El Tor biotypes, plus O139 at 10E11 cfu. The vaccine is safe and highly immunogenic against V. cholerae O1, with 91% seroconversion rates of vibriocidal antibodies among Vietnamese adults.⁵³ A similar trial conducted in Kolkata, India, revealed high background immunity, yielding 53% seroconversion in adults and 80% in children.⁵⁴ Another highly endemic area in Bangladesh demonstrated an overall 73% immune response in infants (1–2 y), toddlers (2–5 y), and adults (18 y+) with no increase in any adverse events in vaccinees when compared with the placebo group.⁵⁵ While previous studies measured immune response 14 d after the second dose, the Bangladesh study found similarly high responses 7 d after the second dose. When comparing responses between one and two vaccine doses, investigators from Kolkata found that a single dose of Shanchol^® elicited a 4-fold increase in serum vibriocidal antibodies at a higher percentage when compared with two doses in both adults (65% → 46%) and children (87% →82%).⁵⁶ No increase in seroconversion following a second dose has been observed as a mechanism of the immune response generated.^57,58 It may also suggest that the intestinal mucosal response elicited by the first dose could be blunting the vibriocidal response of the second dose. Higher levels of pre-existing cross reactive OCV antibodies and presumably higher immunity in endemic areas also correlate with lower vaccine response.⁵² Still, vibriocidal antibody response does not truly reflect protection and at best is an indirect correlate of protection.

Shanchol^® has conferred 67% protection for 5 y in a double-blind, randomized, controlled trial among more than 67 000 children and adults in Kolkata, India.⁵⁹ Children aged 1–5 y, who are at greatest risk for severe disease, were significantly less protected with a collective protective efficacy of 42% over 5 y. A large OCV trial in Bangladesh has enrolled 267 000 individuals aged one year and above to measure the vaccine’s feasibility and effectiveness.⁶⁰ This was a three-armed study aimed to compare the vaccine against the vaccine plus interventions to promote standard washing and point-of-use water treatment in the community, and a control arm that promotes standard sanitary practices only. This study aims to evaluate the feasibility and impact of a vaccine together with important community interventions in a high-risk cholera endemic area. Several characteristics make the vaccine advantageous for use in the developing world. Shanchol^® does not contain the B subunit toxin and therefore does not require a buffer, making it simpler to administer and cheaper to manufacture. It is licensed for individuals from one year of age and above, and is administered in two doses. In September 2011, WHO included Shanchol^® on its list of prequalified vaccines, which has enabled purchase by United Nations (UN) agencies and widened its potential for implementation in affected areas. Recommendations by WHO for use of OCV as part of a total control package for endemic and epidemic area was first published in 2010.⁶¹

Investigations evaluating innovative delivery packages and schedules targeting high-risk populations (children under 5 y, HIV-positive individuals, pregnant women) are needed to improve current efficacy levels and optimize immunization program effectiveness. Data regarding the safety and immunogenicity of the modified, killed, whole-cell vaccine among infants need to be gathered in order to pave the way for the possible integration of this vaccine into cholera-endemic areas, where infants and children are most at risk.⁶² Furthermore, since no data exist regarding the concomitant use of this vaccine with other routine infant vaccines, it is important to determine if any interference exists between Shanchol^® and other antigens included in the Expanded Program on Immunization (EPI). Providing the killed, whole-cell vaccine as part of the EPI could make the introduction of cholera vaccines in endemic areas easier. A clinical trial evaluating safety and immunogenicity in the infant population (< 1 y) is also being planned. Considering the increased immune response following the first dose in a 14-d schedule, a recently completed study measuring responses after a prolonged dosing interval of 28 d suggests no difference in seroconversion rates between the 2 and 4 wk schedule.⁶³ With no rise in seroconversion rates after a second dose, efforts to evaluate a single dose regimen in a clinical field trial is being planned in order to evaluate its potential use in an epidemic setting. Also, similar vibriocidal responses reported for the 14 and 28-d schedule may endorse the inclusion of OCV into national immunization schemes, such as the EPI schedule for infants, which could assist in producing higher vaccination rates in endemic areas. Furthermore, flexibility with the administration of 2 doses over a month could ease logistical requirements in an epidemic setting following a natural disaster, allowing for stabilization of community infrastructure, as well as aiding in the delivery of OCV.

Live oral cholera vaccines- potential for extended protection with a single dose

There are currently four live attenuated oral cholera vaccines in active clinical programs. As well as improving administration schedules by presenting the possibility of a single dose regimen, these vaccine candidates potentially offer greater efficacy, rapid onset of protection, and longer duration, which would be valuable in conferring the highest level of containment in outbreak settings.⁶⁴ All four vaccines are administered as a single dose, require buffer co-administration, and are in the planning stages for phase 3 protective efficacy studies.

The vaccine candidate with the longest clinical history is CVD 103-HgR (University of Maryland, USA), which has been shown to be safe and immunogenic in North American volunteers and generated antibodies within one week of dosing.⁶⁵ Despite a large phase 3 efficacy trial in Indonesian children and adults failing to show protection during any of the four years of follow up,⁶⁶ the vaccine was associated with a 79% risk reduction of cholera when given via mass vaccination following an epidemic in Micronesia.⁶⁷ Due to these conflicting results, commercial production was suspended in 2004. However, its favorable safety and immunogenicity profiles in adults, children and HIV positive individuals has led to efforts to re-commercialize this vaccine (PXVX0200, PAXVAX, USA).^68-71 Phase 3 trials are expected to be completed in mid-2014. The lyophylized formulation is the only live vaccine candidate that does not need to be stored frozen (-20 C), but still requires cold chain and co-administration with a buffer. Plans for subsequent generation formulations aim to be more suited to being used in endemic setting use by negating the need for cold chain or a buffer.

Other live vaccines actively being tested and in advanced stages of clinical trials include Peru-15 (CholeraGarde^®, Harvard Medical School, USA), V. cholerae 638 (Finlay Institute, Cuba), and VA 1.4 (Government of India). Peru-15 has gone through successful safety/immunogenicity trials in US volunteers, as well as in Bangladeshi children aged 9 mo to 5 y of age, where infants were noted to have the lowest antibody titer response.⁷² Early results from Bangladesh indicate no interference between Peru-15 and the measles vaccine in infants less than one year of age.⁷³ A recently completed trial with this vaccine in Thailand also demonstrated safety and immunogenicity in HIV positive adults.⁷⁴ Investigators in Cuba have developed a new oral vaccine containing the 638 live, attenuated cholera strain. Phase 1 and 2 trials in adult populations from Cuba and Mozambique have demonstrated favorable safety and immunogenicity.^75,76 The Indian Department of Biotechnology is moving forward with a new live OCV (VA1.3) that has been shown to be safe and has produced an excellent immune response when tested in adult males from Kolkata, India. This vaccine, derived from a non-toxigenic strain of Vibrio cholerae El Tor, Inaba did not result in any increased adverse events compared with placebo and elicited a 57% seroconversion rate in adult males from the endemic setting of Kolkata.⁷⁷ It has been reformulated and since renamed as VA 1.4.

Considerations in OCV Implementation and Delivery

Contrary to conventional belief, cholera vaccine protective efficacy does not need to be very high in order to be effective as a public health intervention. Vaccine herd protection is the ability to reduce person-person transmission through mass vaccination programs, which adds to a vaccine’s protective efficacy thereby increasing the public health impact of OCVs. For highly transmissible diseases, protective efficacy does not necessarily serve as an absolute measure of vaccine protection, as is the case in outbreak settings with poor access to clean water (urban slums or refugee camps), where incidence can rise to as high as 50 cases/1000. Even with a lower efficacy, a vaccine demonstrating herd protective effects that is used in high incidence areas, could prevent a large number of severe cholera cases. Currently available whole-cell, killed OCVs have been shown to provide significant herd protection in both vaccinated and non-vaccinated populations, including children too young to be vaccinated, even in areas of modest vaccine coverage. This provides convincing evidence to public health decision makers when deciding on including a vaccine into their EPI programs or not. Simulation models suggest that when vaccine coverage rates over 50% are achieved with the modified, killed, whole-cell vaccine, outbreaks in endemic regions could be reduced by 93%.^8,9 Furthermore, it has been deemed very cost effective in high incidence areas such as India, Bangladesh, and Mozambique.^78,79 A recent investment case estimating vaccine cost effectiveness for over 30 countries projected to be early OCV adopters found the vaccine to be very cost effective, especially for programs targeting children.^80,81 When considering vaccine delivery, isolating specific age groups may prove to add extra operational and ethical challenges. The price per dose of Shanchol^® currently stands at US$1.85, though this may gradually decline as more producers enter the market. Proven effectiveness with herd protection in all age groups, a highly tolerated safety profile, simple administration, and low cost are vital characteristics that make a vaccine useful in endemic and post-disaster settings.

The updated WHO position recommends the use of OCVs as a tool to help control endemic cholera and should be considered in epidemic situations.⁸² Important areas that still require research to be performed include updating disease burden rates and trends, as well as an improvement in rapid, reliable, and inexpensive surveillance methods. As with any vaccine, improvements in the logistical use of OCVs (heat stability, multi-dose vials, single-dose regimen) would greatly aid in facilitating its introduction into high risk field settings in resource-scarce countries. Short-term modeling analysis of the Haitian epidemic suggests that expedient use of a limited supply of OCVs could have had substantial impact if targeted to high-risk populations, especially when complementing improvements in water and sanitation.⁸³ Discussions for the possible use of a cholera vaccine stockpile following the disasters in Pakistan and Haiti offer an attractive mechanism for OCV introduction, with the hopes of yielding both public health and humanitarian benefits.⁸⁴ A comprehensive cholera response, that links prevention with care will require a concerted international effort to reach those who are most affected and in greatest need.

Public immunization campaigns with the modified, killed, whole-cell OCV have successfully been performed in high risk areas, including India, Bangladesh, Haiti, and Guinea.^60,85-87 Though most trials have been conducted in Asia, the vaccine is not expected to act any differently in non-Asian populations. Even so, clinical investigations have recently been completed in Zanzibar (Dukoral^®), while a trial in Ethiopia (Shanchol^®), demonstrated similar safety and immunogenicity in healthy African adults and children to those found in Asian trials.^88,89 These trials can help pave the way for the possible use of this vaccine in any endemic and outbreak setting throughout resource-scarce areas. A double blind, phase 3, randomized, controlled trial is underway to generate evidence for the potential use of a single dose OCV regimen. The critical issue is the question of efficacy and the duration of protection of a single dose, which would be an important step toward beginning the dossier for single-dose vaccination in outbreak settings. Another ongoing study evaluating the effect of booster doses suggests that a single booster dose of killed OCV can elicit vibriocidal titers similar to those levels produced by a primary series in adults and children residing in endemic areas, which could help to ease logistical challenges faced in maintaining protection in cholera endemic areas.⁹⁰ Investigations on memory B cell and cell-mediated immune responses are lacking in children, and such studies would be interesting to offer important insights into differences in protection offered by natural infection vs. current vaccine options.

Conclusion

Both killed and live oral cholera vaccines will face several key challenges, which will be crucial in improving the protective impact of vaccines in areas and communities at high risk for endemic and epidemic cholera. Complementary behavioral modification efforts to improve water sanitation and hygiene in high risk communities will also provide great benefit in preventing other high disease burden enteric water-borne diseases, such as enterotoxigenic E. coli, Shigella, and Rotavirus.

Even though reduced immunogenicity in the LDC vaccinee presents numerous challenges in achieving effective protection against cholera, many innovative approaches are being investigated. Safe water supplies combined with adequate sanitation and improved hygiene are essential to reduce cholera and other enteric diseases in the future.⁹¹ Unfortunately, such progress can take decades to achieve and will provide little relief to unstable and mobile populations. In this context, a safe and affordable vaccine to protect against cholera would be a welcome public health tool. Continued efforts to evaluate and optimize immunization strategies will be vital in achieving maximum benefit to those most at risk.

Abbreviations:
EPI	=	Expanded Programme on Immunization
HIV	=	human immunodeficiency virus
LDC	=	least developing countries
OCV	=	oral cholera vaccine
RCT	=	randomized controlled trial
UN	=	United Nations
WHO	=	World Health Organization

Acknowledgments

We are grateful to Dr Daniel T. Leung (icddr,b and Massachusetts General Hospital, Harvard Medical School) for his helpful review of this manuscript.

Potential conflicts of interest: SND and AC are staff of the International Vaccine Institute, which has supported the reformulation and use of the bivalent inactivated oral cholera vaccine, Shanchol^® globally.

10.4161/hv.29199