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. 2014 Sep 29;92(12):881–893. doi: 10.2471/BLT.14.139949

Post-licensure deployment of oral cholera vaccines: a systematic review

Déploiement après homologation des vaccins oraux contre le choléra: une revue systématique

Utilización de vacunas orales contra el cólera posterior a la aprobación de su uso: una revisión sistemática

نشر لقاحات الكوليرا الفموية بعد ترخيص استخدامها: استعراض منهجي

口服霍乱疫苗许可部署：系统回顾

Постлицензионный опыт применения пероральной противохолерной вакцины: систематический обзор

Stephen Martin a, Anna Lena Lopez b, Anna Bellos a, Jacqueline Deen c,✉, Mohammad Ali c, Kathryn Alberti d, Dang Duc Anh e, Alejandro Costa a, Rebecca F Grais f, Dominique Legros a, Francisco J Luquero f, Megan B Ghai a, William Perea a, David A Sack c
PMCID: PMC4264394  PMID: 25552772

Abstract

Objective

To describe and analyse the characteristics of oral cholera vaccination campaigns; including location, target population, logistics, vaccine coverage and delivery costs.

Methods

We searched PubMed, the World Health Organization (WHO) website and the Cochrane database with no date or language restrictions. We contacted public health personnel, experts in the field and in ministries of health and did targeted web searches.

Findings

A total of 33 documents were included in the analysis. One country, Viet Nam, incorporates oral cholera vaccination into its public health programme and has administered approximately 10.9 million vaccine doses between 1997 and 2012. In addition, over 3 million doses of the two WHO pre-qualified oral cholera vaccines have been administered in more than 16 campaigns around the world between 1997 and 2014. These campaigns have either been pre-emptive or reactive and have taken place under diverse conditions, such as in refugee camps or natural disasters. Estimated two-dose coverage ranged from 46 to 88% of the target population. Approximate delivery cost per fully immunized person ranged from 0.11–3.99 United States dollars.

Conclusion

Experience with oral cholera vaccination campaigns continues to increase. Public health officials may draw on this experience and conduct oral cholera vaccination campaigns more frequently.

Introduction

Vibrio cholerae O1 and O139 causes severe diarrhoea and the main strategies to prevent the disease are to promote hygiene and to ensure safe water and sanitation. These basic needs are often not met in endemic areas with seasonal cholera outbreaks or during man-made or natural disasters in impoverished areas. An additional tool for cholera prevention and control is the oral cholera vaccine. In October 2009, the World Health Organization (WHO) Strategic Advisory Group of Experts on immunization recommended that oral cholera vaccination should be considered as a reactive strategy during outbreaks, in addition to the already recommended preventive use of oral cholera vaccine in endemic areas.1 A vaccine stockpile was created in 2012, with an initial two million doses to be available mainly for epidemic response in low-income countries.2 In November 2013, the global alliance for vaccines and immunizations (Gavi Alliance) approved a financial contribution towards the stockpile to expand its use. With the availability of the oral cholera vaccine stockpile, more governments might consider cholera vaccination where needed.

A monovalent inactivated vaccine containing killed whole-cells of V. cholerae serogroup O1 and the B-subunit of cholera toxin was the first oral cholera vaccine to obtain international licensure in 1991 and WHO prequalification in 2001. The vaccine is marketed as Dukoral® (Crucell, Netherlands). Randomized, placebo-controlled trials of earlier versions of Dukoral® in Bangladesh and the current recombinant B-subunit whole cell vaccine in Peru showed that the vaccine is safe and confers an initial protection of approximately 85% in the first months.3,4 Follow-up studies in Bangladesh estimated a 62% protection during the first year, 57% during the second year and negligible thereafter.3

During the mid-1980s, the National Institute of Hygiene and Epidemiology in Viet Nam developed an oral cholera vaccine for the country’s public health programme. A two-dose regimen of a first-generation of monovalent (anti-O1) cholera vaccine had an estimated efficacy of 66% against the El Tor strain of V. cholerae.5 In 1997, the vaccine was augmented with killed V. cholerae serogroup O139 whole cells to create a bivalent vaccine,6 which was locally licensed as ORC-Vax™ (Vabiotech, Viet Nam). After changing production procedures in 2009, the vaccine was reformulated and licensed as mORC-Vax™ (Vabiotech, Viet Nam) and is currently used in Viet Nam’s public health programme.7 However, the vaccine is not pre-qualified by WHO.

To make the mORC-Vax™ internationally available, manufacture of the reformulated vaccine was transferred to Shantha Biotechnics Ltd in India, where the national regulatory authority is approved by WHO.8 This led to the development of Shanchol™, which is the third currently-available oral cholera vaccine. A randomized, placebo-controlled trial in India showed that Shanchol™ is safe and confers 67% protective efficacy against cholera within two years of vaccination,8 66% at three years9 and 65% at five years10 of follow-up. Shanchol™ was licensed in India in 2009 and received WHO pre-qualification in 2011.

A comparison of the three oral cholera vaccines is shown in Table 1.11,12 The safety, relative effectiveness and duration of protection of the different types of oral cholera vaccine has previously been reviewed.13 Here we conduct a systematic review of post-licensure oral cholera vaccines. The objective of the review is to generate information – by describing and analysing the campaigns – that can be used to inform planning for the future use of these vaccines.

Table 1. Oral cholera vaccines, 2014.

Vaccine Dukoral®11 ORC-Vax™ and mORC-Vax™11,12 Shanchol™11
Manufacturer Crucell (the Netherlands) Vabiotech (Viet Nam) Shantha Biotechnics Ltd (India)
Description Monovalent inactivated vaccine Bivalent inactivated vaccine Bivalent inactivated vaccine
Components Killed whole-cells of V. cholerae O1 (Classical and El Tor biotypes) and recombinant B-subunit of cholera toxin Killed whole cells of V. cholerae O1 (Classical and El Tor biotypes) and V. cholerae O139 Killed whole cells of V. cholerae O1 (Classical and El Tor biotypes) and V. cholerae O139
Recommended age 2 years and older 1 year and older 1 year and older
Delivery Oral Oral Oral
Doses Two doses ≥ 1 week apart Two doses ≥ 2 weeks apart Two doses ≥ 2 weeks apart
Buffer Yes. Buffer dissolved in 75 mL (2–6 years old) or 150 mL (> 6 years old) water Not required Not required
Licensure International (1991) Viet Nam (1997/2009) India (2009)
WHO pre-qualification Yes (2001) No Yes (2011)
Storage temperature 2–8 °C 2–8 °C 2–8 °C
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Methods

Search

We searched the Cochrane database of systematic reviews and its database of abstracts and reviews of effects from 1990 to the present and found no reviews of oral cholera vaccination campaigns.

We conducted a systematic review of published documents on post-licensure vaccination campaigns using one of three oral cholera vaccines following the search and analysis process recommended in the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. We searched PubMed and the WHO website using “cholera vaccination”, “cholera outbreak response” and “cholera vaccination campaign” as search terms with no date or language restrictions. The bibliographies of the retrieved articles were also screened for relevant papers. Reports, presentations and international organization or company documents were obtained through targeted web searches. We also contacted public health personnel, experts in the field and in ministries of health for further information.

All identified documents in English that described campaigns using oral cholera vaccine were assessed for appropriateness using the following selection criteria. We included all documents describing campaigns using Dukoral® after 1991, ORC-Vax™ after 1997, mORC-Vax™ after 2009 and Shanchol™ after 2009. Campaigns organized either as part of a public health response to endemic or epidemic cholera, pilot campaigns, demonstration projects, assessments of feasibility and acceptability, as well as studies of vaccine effectiveness were included. Each campaign may have more than one reference, describing different aspects of the vaccination (e.g. feasibility, coverage, cost, etc.). We excluded documents describing pre-licensure trials, reports on knowledge and perception of cholera and oral cholera vaccines, as well as planning or policy briefs that did not describe actual oral cholera vaccine deployment.

By adhering to the pre-defined inclusion and exclusion criteria, we could make a valid comparison across articles. To assess the broad picture of the vaccine campaigns, we did not exclude any document based on quality or deficiency of reporting. Information from the published and unpublished documents was extracted and entered into a spreadsheet independently by two of the authors and then corroborated and summarized by a third author.

Definitions

Oral cholera vaccine campaigns can either be pre-emptive or reactive. Pre-emptive or preventive vaccination refers to campaign implementation before a cholera outbreak begins, ideally in conjunction with improved water, hygiene and sanitation. Pre-emptive vaccination may be conducted before the next seasonal outbreak in sites where cholera regularly occurs, in communities adjacent to an area with cholera or during humanitarian emergencies to prevent cholera. Reactive campaigns are those implemented after a cholera outbreak has started and while cholera cases are still being detected in the target population.14 In areas where cholera tends to occur all year-round, the distinction between pre-emptive and reactive vaccination may be difficult.

The target population was defined as the number of individuals living in a circumscribed area to whom oral cholera vaccine is offered. The target population may be an estimate based on administrative population figures or a more precise figure based on a study census. Coverage was defined as the percentage of the target population who received one dose and two doses (fully immunized) of the vaccine, except when otherwise indicated (i.e. community surveys were used to calculate vaccine coverage in some campaigns particularly when a precise target population number was not known). The approximate total number of oral cholera vaccine doses deployed was defined as the sum of the first and second dose recipients; when data on the first dose recipients were not available, we multiplied the number of fully vaccinated individuals by two. We plotted the number of approximate doses deployed in oral cholera vaccine campaigns by country. Countries were colour-coded by the number of cholera cases reported in 2005,15 using ArcMap 10.0 (ESRI, Redlands, USA). Adverse events following immunization were defined as medical incidents that take place after an immunization and cause concern. Adverse events following immunization may be coincidental or causally associated. A serious adverse event following immunization is one that requires hospitalization and/or causes birth defects, permanent damage, or death.

To allow comparison of the expenses for vaccination across various campaigns, the expenses were grouped into the following categories: vaccine and/or international shipment costs, computers and other capital expenses, international consultants, local storage and transport, meetings, social mobilization, training, local salaries, supplies and waste management and the detection and management of adverse events following immunization. The delivery cost per fully immunized person was calculated using the total local expenses (excluding vaccine, international shipment and consultant costs) as the numerator and the number of fully immunized persons as the denominator.

Results

We identified 173 unique documents of potential relevance and 33 of these met the inclusion criteria (Fig. 1).16–48 In addition, we obtained information about recent campaigns through personal communications with two co-authors (DL and KA). We mapped the approximate number of doses administered in post-licensure oral cholera vaccination campaigns from 1997 to 2014 (Fig. 2) and plotted them by year (Fig. 3). As of August 2014, 280 000 oral cholera vaccine doses from the stockpile were shipped to Ethiopia, 280 000 to Guinea, 400 000 to Haiti and 300 000 to South Sudan. For campaigns with detailed data available, the characteristics and main findings are shown in Table 2 and the vaccination logistics by target population size is shown in Table 3.

Fig. 1.

Fig. 1

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Flowchart for the selection of documents on oral cholera vaccination campaigns

Fig. 2.

Fig. 2

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Post-licensure oral cholera vaccination campaigns, 1997–2014

Fig. 3.

Administration of Dukoral® or Shanchol™ in post-licensure oral cholera vaccination campaigns globally, 1997–2014

a Number of vaccinations in 2014 counted from January to August.

Fig. 3

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Table 2. Characteristics and main findings of post-licensure oral cholera vaccination campaign studies, 1997–2014.

Vaccine and year of the campaign Site Setting Type and purpose of the vaccination campaign Eligibility criteria Target population Coverage
 Main findings
Received 1st dose, no. (%) Received 2nd dose, no. (%)
Dukoral®
1997 Adjumani district, Uganda Refugee camp, rural Pre-emptive vaccination to assess feasibility in a stable refugee camp setting16,17 ≥ 1 year old 44 000 35 613 (81) 27 607 (62) Oral cholera vaccination of a large refugee population is feasible.16 During a cholera epidemic in the area the following year, cholera attack rates were 0.59% in the non-refugee Ugandan villages, 0.04% in the 30 non-vaccinated refugee camps and 0.00% in the six vaccinated refugee camps17
2000 Mayotte Island, Comoros Urban and rural Pre-emptive vaccination campaign to prevent a cholera epidemic18 NA 145 000 NA 93 000 (64) NA
2003–2004 Beira, Mozambique Urban Pre-emptive vaccination in an endemic area with seasonal outbreaks. Effectiveness study in an HIV-endemic sub-Saharan African site20,21 Non-pregnant women, ≥ 2 years old children 19 550 14 164 (72) 11 070 (57) Mass vaccination was feasible but required considerable logistic support and planning.20 One or more doses conferred 78% protection (95% CI: 39–92) against cholera during the year post vaccination21
2004 South Darfur, Sudan Refugee camp, rural Pre-emptive vaccination to assess feasibility during the acute phase of an emergency (i.e. refugee camp of internally displaced persons)22,23 ≥ 2 years old 45 825 42 502 (93) 40 330 (88) Although planning and implementation requirements were significant, the campaign was successful because of the strong support and commitment of the refugee community and collaborators22,23
2005 Aceh, Indonesia Site of internally displaced persons Pre-emptive vaccination to assess feasibility during the acute phase of an emergency (i.e. post-tsunami)23,24 ≥ 2 years old 78 870 62 505 (79) 54 627 (69) Challenges in the coordination, heavy logistics and frequent aftershocks complicated and delayed implementation. Difficulties in maintaining a cold chain resulted in 11.7% vaccine losses23,24
2009 Zanzibar, the United Republic of Tanzania Urban and rural Pre-emptive vaccination in an endemic area with seasonal outbreaks. Effectiveness study to measure direct and indirect protection26–28 Non-pregnant women, ≥ 2 years old children 48 178 27 678 (57) 23 921 (50) Confirmed direct vaccine effectiveness of 79% (95% CI: 47–92). First study to show vaccine herd protection in an African setting: 75% (95% CI: 11–93%) indirect protection in the higher coverage group compared with the lower coverage group.26 No evidence of a harmful effect of gestational exposure to the vaccine.27 First use of personal digital assistants for direct data entry during a survey enumeration and mass vaccination28
ORC-Vax™ and mORC-Vax™
1998–2012 Viet Nam Endemic urban and rural areas Pre-emptive and reactive vaccinations of children integrated into the country’s public health programme33 Non-pregnant women, ≥ 1 year old children ≈10.9 million doses NA NA Viet Nam is the only country in the world to regularly use oral cholera vaccinations. Since 1997, the number of cholera cases in Viet Nam has declined, in association with increased vaccination use as well as improvements in socioeconomic and water and sanitation conditions33
1998 and 2000 Hue, Viet Nam Urban and rural Pre-emptive vaccination campaign in a cholera-endemic area. Study to assess long term effectiveness30,31 Non-pregnant women, ≥ 1 year old children 149 557 (1998) and 137 082 (2000) In 1998: 125 135 (84) and in 2000:104 706 (76) In 1998:118 703 (79) and in 2000:103 226 (75) Mass immunization is feasibly administered through the public health system.30 Direct vaccine effectiveness 3 to 5 years after vaccination was 50% (95% CI: 9–63)31
2008 Hanoi, Viet Nam Urban Reactive vaccination campaign during an on-going outbreak32 Non-pregnant women, ≥ 1 year old children ≈370 000 > 10 years old NA ≈80% vaccinated Protective effectiveness of 76% (95% CI: 5–94). First study to document reactive use of oral cholera vaccination during an outbreak32
Shanchol™
2011 Odisha, India Rural Pre-emptive vaccination campaign and feasibility study34 Non-pregnant woman, ≥ 1 year old 51 488 31 552 (61) 23 751 (46) Feasible to vaccinate using governmental set-up34
2011 Dhaka, Bangladesh Endemic urban areas Pre-emptive vaccination. Cluster randomized study with three arms: vaccine, vaccine plus safe water and hand washing practice and no intervention35 Non-pregnant women, ≥ 1 year old children 172 754 141 839 (82) 123 666 (72) Feasible to use the national immunization set-up.35 On-going study of vaccine effectiveness
2012 Port-au-Prince, Haiti Urban Reactive vaccination campaign. Pilot study36 ≥ 1 year old children 70 000 52 357 (75) 47 540 (68) Effort, community mobilization and organizational capacity needed for a successful campaign where there were logistical and security challenges36
2012 Bocozel and Grand Saline, Haiti Rural Reactive vaccination campaign. Pilot study37–40 ≥ 1 year old children ≈50 000 45 417 41 238 (Estimated 77–79% in Bocozel and 63% in Grand Saline) The campaign integrated with the other components of cholera control was found to be feasible and acceptable37–40
2012 Choiseul and Shortland, Solomon Islands Rural Pre-emptive vaccination campaign near an area with a cholera outbreak41 Children 1–14 years old in high-risk areas NA 11 888 11 318 NA
2012 Tak Province, Thailand Refugee camps, rural Pre-emptive vaccination campaign with a knowledge, attitudes and practices survey42 Non-pregnant women, ≥ 1 year old children 43 968 36 325 (83) 26 753 (61) First use of Shanchol™ in a stable refugee camp setting42
2012 Boffa and Forecariah regions, Guinea Rural Reactive vaccination campaign during an on-going outbreak and feasibility study43–45 ≥ 1 year old children ≈209 000 (≈163 000 in Boffa and ≈46 000 Forecariah) 172 544 143 706 (Based on administrative population figures, 68% in Boffa and 51% in Forecariah. Household survey immediately after campaign 76%)43 First use of Shanchol™ in sub-Saharan Africa. The campaign was successful despite short preparation time, remote rural setting and highly mobile population.43,44 Protective effectiveness of 87% (95% CI: 56–96)45
2013 Maban county, South Sudan Refugee camps, rural Pre-emptive vaccination campaign in an area with escalating Hep E outbreak46,47 ≥ 1 year old children 146 317 NA 132 000 (> 85% by survey) The campaign was successful despite logistical challenges46,47
2013 Petite Anse and Cerca Carvajal, Haiti Urban and rural Pre-emptive vaccination campaign in a cholera-endemic areaa ≥ 1 year old children > 110 000 113 045 102 250 NA
2014 South Sudan Internally displaced persons camps Pre-emptive vaccination campaign48 Non pregnant women, ≥ 1 year old children 152 000 125 311 (72) 76 088 (awaiting coverage surveys) Humanitarian crisis. First use of global OCV stockpile. Fixed and mobile teams. Second round in one site was co-administered with meningitis vaccine48
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CI: confidence interval; Hep E: Hepatitis E; NA: information not available; OCV: oral cholera vaccination.

a Information obtained through personal communications with Kathryn Alberti, UNICEF, New York, USA.

Table 3. Logistics of oral cholera vaccination campaigns, 1997–2013.

Target population size Site, year Vaccine Max. days per round Total duration Delivery method Approximate doses delivered/day Staff
< 50 000 Adjumani district, Uganda, 199716 Dukoral® 4 Just over 1 month 15 vaccination sites 250–1735 114 persons: 19 nurses/midwives, 21 nursing aides, 44 community health workers and 30 persons without qualifications
Esturro, Beira, Mozambique, 2003–200420 Dukoral® 9 1 month Outposts in churches and schools 08:00–15:00 6 days/week Average 609 One supervisor and 15–23 members per outpost
Zanzibar, the United Republic of Tanzania, 200926 Dukoral® 15 Just over 1 month Eight vaccination posts on each of the two islands. 8 hours daily NA Local health care workers and villagers
Aceh, Indonesia, 200523,24 Dukoral® NA 5 months Three-phase approach, three different geographical areas with approximately one month between each phase. Fixed vaccination sites with some door-to-door mop-up 100–250 4 members per team
50 000 to 100 000 Odisha, India, 201134 Shanchol™ 3 1 month Vaccination booths within 10–15 minute walking distance from villagers open 07:00–17:00 daily NA At each booth: 1 midwife and 5–6 community health workers/volunteers
City of God, Port-au-Prince and Bocozel and Grand Saline, Artibonite Department, Haiti, 201236,38 Shanchol™ Urban: NA Rural: 10 3 months per site Urban: door-to-door pre-registration and vaccination at 9 fixed sites.
Rural: fixed posts, mobile posts and door-to-door		 NA Urban campaign: 500 staff, 75 teams of 4 workers, plus 15 supervisors
Rural: 40 teams of 4 workers each led by 20 supervisors
Viet Nam 1998 and 200030,31 ORC-Vax™ 9 1 month Specifically designated sites, also used by EPI. 90 sites 139 (max) 90 teams
> 100 000 Viet Nam 200832 ORC-Vax™ 3 13 days Commune health centres NA NA
Mirpur, Dhaka, Bangladesh 201135 Shanchol™ 3-day cycles One and half months Fixed outreach vaccination sites. Sixty vaccine clusters were grouped into five cycles. In each 3-day vaccination cycle, 12 clusters were covered. The teams then moved on to the next cycle and thus all clusters were covered two times in two rounds 900–1000 76 vaccinators, 220 volunteers and 12 first line supervisors
Boffa and Forecariah regions, Guinea 201243,44 Shanchol™ 6 3 months Decentralized semi-mobile strategy. Most sites in place for only 1 day. In rural areas, teams could cover three sites in one day 774 (avg) 43 teams of 9 to 20 people
Maban county, South Sudan 201346,47 Shanchol™ 7 Just over 1 month Semi-mobile strategy, fixed points for first days of round, then mix of fixed sites and mop-up for last days of round. Also, in each MSF clinic 1150 Teams of 10 people at each site, plus 14 people per camp for mobilization
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EPI: Expanded Programme on Immunization; MSF: Médecins Sans FrontièresNA. OCV: oral cholera vaccine.

Dukoral®

About 526 017 doses of Dukoral® were administered in six vaccination campaigns from 1997 to 2009, all of which were pre-emptive (Table 2).16–29 These included two feasibility studies in refugee camps16,17,22,23 and one campaign following a natural disaster.23,24 The percentage of fully immunized persons ranged from 50–88%. There were two effectiveness studies in sub-Saharan Africa, which confirmed direct vaccine protection of 78–79%, 12 to 15 months following vaccination,21,26 as well as herd protection.26 We found one document stating that 137 000 Dukoral® doses were delivered to Myanmar in 200818 but we were unable to find more information.

The duration of the vaccination campaigns ranged from one to five months and consisted of two rounds at a 10- to 14-day interval (Table 3). Each round took 4 to 15 days.16,20,23,24,26 A cold chain for vaccine delivery was reportedly maintained at 2–8 °C from storage to administration in Aceh, Indonesia,24 Beira, Mozambique20 and Zanzibar, United Republic of Tanzania.26 In Uganda, the vaccine was maintained at room temperature.16 Vaccination teams were able to vaccinate 100 to 1735 persons per day.16,20,23,24,26 Reported adverse events following immunization in Mozambique20 and Uganda16 were minor and non-specific. Delivery cost per fully immunized person ranged from 0.53 United States dollars (US$) to US$ 3.66 (Table 4).

Table 4. Cost of post-licensure oral cholera vaccinations, 1997–2013.

Characteristic Uganda, 199716 Mozambique,a 2003–200420 Indonesia, 200523,24 United Republic of Tanzania, 200929 India,a 201134 Bangladesh, 201135 Guinea, 201244 South Sudan, 201346
Oral cholera vaccine Dukoral® Dukoral® Dukoral® Dukoral® Shanchol™ Shanchol™ Shanchol™ Shanchol™
Price per vaccine dose, US$ Free Free 4.70 5.00 2.22 1.00 1.85b 2.40b
Number fully immunized persons 27 607 44 156 54 627 23 921 23 751 123 666 143 706 71 912
Vaccine and/or international shipment costs, US$ 4 421 6 608 665 247 555 000 122 629 284 529 632 782b 661 690b
Computers and other capital expenses, US$ 1 600 900 4 738 NA NA NA NA NA
International consultants, US$ NA NA 124 230 110 000 NA NA NA 133 917b
Local storage and transport, US$ 3 239 33 510 5 159 NA 2 081 43 701 175 930b 115 428b
Meetings, community mobilization, training, local salaries, supplies and waste management, US$ 5 395 54 269 159 275 87 500 20 625c 157 932 106 630b 171 766b
Adverse event following immunization monitoring and management, US$ NA NA NA NA 4 237 NA NA NA
Total cost for the vaccination campaign, US$ 14 655 (0.53) 95 287 (2.16) 958 649 (17.55) 752 500 (31.46) 149 572 (6.30) 486 162 (3.93) 915 342 (6.37)b 1 082 801 (15.06)b
Total local delivery cost (per person), US$d 14 655 (0.53) 88 679 (2.01) 169 172 (3.10) 87 500 (3.66) 26 943 (1.13) 201 633 (1.63) 282 560 (1.97)b 287 197 (3.99)b
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NA: not available; US$: United States dollar.

a Including vaccinations outside the study target population.

b Costs originally reported in Euro. US$ was calculated using the conversion rate as of 1 February 2013: 1 Euro to US$ 1.37.

c Itemized as follows: Social mobilization US$ 5603 and vaccine administration US$ 15 022.

d Excluding vaccine, international shipment and consultant costs.

ORC-Vax™ and mORC-Vax™

In Viet Nam, an estimated 10.9 million doses of ORC-Vax™ and mORC-VAX™ have been deployed from 1997 to 2013 through targeted mass vaccination or – to children – through the Expanded Programme of Immunization in cholera-endemic regions.30–33 Documented coverage during the vaccination of half of the communes in Hue was 79% (118 703/149 557) in 1998 and 75% (103 226/137 082) in the other half in 2000; long term vaccine effectiveness (three to five years after the campaign) was 50%.30,31 (Table 2).Vaccine coverage was not precisely quantified in the 2008 Hanoi campaign; vaccine effectiveness was 76%.32 The duration of the vaccination campaigns ranged from two to four weeks with each round taking 3 to 9 days (Table 3).30–32 Mass campaigns are held yearly in Hue and are part of the routine public health provision, requiring minimal additional costs. The delivery cost in Hue during a 2013 campaign was US$ 0.11 per fully immunized person.33

Shanchol™

Since WHO pre-qualification, Shanchol™ has been increasingly used in campaigns.34–48 About 2 649 189 doses have been administered in more than 10 campaigns (Table 2; data from the most recent campaigns in Ethiopia, Guinea and Haiti are not yet available), three of which were described as reactive. The percentage of fully immunized persons ranged from approximately 46–85% (Table 2). A study in Odisha, India 2011, found that oral cholera vaccination through the Indian public health system is feasible.34 The campaign in Dhaka, Bangladesh 2011, includes an assessment of vaccine effectiveness with and without other interventions.35 The two vaccination campaigns in Haiti in 2012 were pilot projects that paved the way for the launching of a national cholera vaccination programme integrated in a long-term plan to address water safety and sanitation.36–40 There was a third campaign in Haiti in 2013 that was part of this plan. Shanchol™ was deployed for pre-emptive vaccination in the Solomon Islands in 2012, following reports of cholera in a nearby area.41 The vaccination campaign in Thailand, 2012, was conducted to prevent seasonal outbreaks in a stable camp setting.42 The vaccination campaign in Guinea, 2012, was the first reactive oral cholera vaccine campaign in sub-Saharan Africa and the first time that Shanchol™ was used in an African setting.43–45 The campaigns in Guinea and in Maban county, South Sudan 2013 confirmed that large-scale vaccinations under logistically difficult conditions are feasible.46,47 The campaign in internally displaced persons camps in South Sudan in 2014, was the first to use the oral cholera vaccine stockpile.48

The Shanchol™ campaigns were conducted in 1–3 months.34–48 The 2012 Haiti campaign was carried out in two phases due to an overlapping national oral polio vaccination campaign.36–40 The number of persons vaccinated per day ranged from 774–1150.35,43–48 No serious adverse events following immunization were reported. In campaigns in Odisha, Dhaka and in Haiti in 2012, acold chain for vaccine was maintained at 2–8 °C from storage to delivery on site.34–40 In the campaigns in Guinea and in 2013 in South Sudan cold chain was maintained until the day of vaccination, during which vaccines were transported to vaccination sites and used at ambient temperature43–47 (Table 3).

The delivery costs of Shanchol™ through the existing government health system in Bangladesh35 and India34 were US$ 1.63 and US$ 1.13, respectively, per fully immunized person. The local expenses of reactive deployment in Guinea were US$ 1.97,45 while costs in Maban, South Sudan were US$ 3.99 per fully immunized person (Table 4).47

Discussion

We estimate that about 3 175 206 doses of Dukoral® and Shanchol™ have been deployed in vaccination campaigns in areas affected by cholera around the world from 1997 to 2014. Only one country, Viet Nam, incorporates oral cholera vaccination into its public health programme and has used more than 10 million doses since 1997. Recently larger numbers of doses have been deployed in different areas globally but the vaccine is still under-used compared to the 1.4 billion people at risk of cholera in endemic areas.15 There is a shortage of licensed, WHO-prequalified cholera vaccines to meet global endemic and epidemic needs and insufficient supply is often cited as an obstacle to wider vaccine use.49 Availability of an oral cholera vaccine stockpile may lead to a larger vaccine supply through more consistent and predictable demands and may help increase vaccine use. Insufficient vaccine supply can be addressed by encouraging manufacturers to increase production capacity.

The deployments of oral cholera vaccine have previously been pre-emptive but recent experiences in Guinea43–45 and Haiti36–40 have shown that reactive mass vaccinations are feasible., The number of cases and deaths that can be prevented by reactive vaccination depends on the characteristics of the outbreak, with greatest impact during large and long-lasting outbreaks usually seen in populations with no recent exposure to the disease.14 With the development of an oral cholera vaccine stockpile and possibility of rapid deployment, increased reactive use of oral cholera vaccine is anticipated.

To be able to compare the campaigns, we calculated the total delivery cost per fully immunized person by excluding the expenditures for vaccine, shipment and technical experts, but the estimates still varied considerably. Deployment costs were lowest in Hue, Viet Nam, where the vaccine is administered routinely through the public health system30,33 but a similar delivery strategy may not be possible in other cholera-endemic areas or during the acute phase of emergencies. The requirement for co-administration of a buffer with the Dukoral® vaccine complicates the delivery of such vaccine and likely increases its delivery costs. Both mORC-Vax™ and Shanchol™ do not require a buffer, which should streamline the delivery and reduce logistical requirements.

This analysis has several limitations. First, there was a wide variation in the methods used to calculate coverage and costs in the vaccination campaigns. Some coverage estimations were precise, while others were approximations. Although we attempted to make the costing comparable, the calculated figures should be interpreted with caution. There are large variations in the costing of some items that cannot merely be explained by differences in site conditions and access. There are also local variables such as distance from central storage to the vaccine administration sites, campaign duration and vaccine storage conditions that affect the costs. Variations in campaign logistics also influence the estimates. Differences may also arise from the methods used to calculate expenses. For future campaigns, estimating cost using a standardized method would be very useful. Second, reporting was not consistent, as some information about the campaign, such as coverage, delivery, adverse events following immunization monitoring and other details, were not always measured or reported. We obtained the least information on the oral cholera vaccine campaigns in the Comoros and the Solomon Islands. Third, information from the more recent post-licensure vaccination campaigns is not yet available. Updated reporting will be required. Fourth, 24% (8/33) of documents included in the analysis were not published in peer-reviewed journals but were the only available sources of data for some of the vaccination campaigns. Fifth, many of the campaigns were done in collaboration between ministries of health and external health agencies (e.g. Médecins Sans Frontières, WHO, Partners for Health, United States’ Centers for Disease Control and Prevention). It will be important to continue to monitor and evaluate future campaigns using vaccine from the stockpile and implemented mainly by ministries of health.

Despite these limitations, our findings provide important lessons. The number of oral cholera vaccination campaigns is increasing and experience has been documented in a variety of settings. The increasing use of oral cholera vaccine is reassuring but more needs to be done to encourage its use where needed. Since the creation of the stockpile, a higher number of doses have been used and this increase will likely continue with the availability of an oral cholera vaccine stockpile and as more experience is gained with campaigns. Data from the deployments confirm the effectiveness, safety and feasibility of mass oral cholera vaccination. While the two-dose vaccination schedule may be perceived as an impediment to delivery and coverage, the experience with both Dukoral® and Shanchol™ disproves this perception. In addition, community education on cholera control and distribution of other preventive measures such as soap and chlorine solution were feasibly integrated into recent vaccination campaigns.35,37–39,43–45 We also found that there were substantial differences in how the campaigns were reported making comparisons difficult. A more systematic approach to decision-making – such as a rapid assessment tool – and a standardized method for data collection, monitoring and evaluation should be pursued, supported and published. This will ensure appropriate documentation of future campaigns.

Funding:

This research was supported by the World Health Organization and by the Delivering Oral Vaccine Effectively (DOVE) project. DOVE is supported by the Bill & Melinda Gates Foundation and administered through the Johns Hopkins Bloomberg School of Public Health.

Competing interests:

None declared.

References

  • 1.Meeting of the Strategic Advisory Group of Experts on immunization, October 2009 - conclusions and recommendations. Wkly Epidemiol Rec. 2009;84(50):517–32. [PubMed] [Google Scholar]
  • 2.Martin S, Costa A, Perea W. Stockpiling oral cholera vaccine. Bull World Health Organ. 2012;90(10):714. 10.2471/BLT.12.112433 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Clemens JD, Sack DA, Harris JR, Van Loon F, Chakraborty J, Ahmed F, et al. Field trial of oral cholera vaccines in Bangladesh: results from three-year follow-up. Lancet. 1990;335(8684):270–3. 10.1016/0140-6736(90)90080-O [DOI] [PubMed] [Google Scholar]
  • 4.Sanchez JL, Vasquez B, Begue RE, Meza R, Castellares G, Cabezas C, et al. Protective efficacy of oral whole-cell/recombinant-B-subunit cholera vaccine in Peruvian military recruits. Lancet. 1994;344(8932):1273–6. 10.1016/S0140-6736(94)90755-2 [DOI] [PubMed] [Google Scholar]
  • 5.Trach DD, Clemens JD, Ke NT, Thuy HT, Son ND, Canh DG, et al. Field trial of a locally produced, killed, oral cholera vaccine in Vietnam. Lancet. 1997;349(9047):231–5. 10.1016/S0140-6736(96)06107-7 [DOI] [PubMed] [Google Scholar]
  • 6.Trach DD, Cam PD, Ke NT, Rao MR, Dinh D, Hang PV, et al. Investigations into the safety and immunogenicity of a killed oral cholera vaccine developed in Viet Nam. Bull World Health Organ. 2002;80(1):2–8. [PMC free article] [PubMed] [Google Scholar]
  • 7.National EPI Review Report: Vietnam – 30 March to 10 April 2009. Ha Noi: United Nations Children’s Fund; 2009. Available from: http://www.unicef.org/vietnam/EPI_NATIONAL_Review_Report_Vietnam_2009_Final.pdf [cited 2013 Aug 6].
  • 8.Sur D, Lopez AL, Kanungo S, Paisley A, Manna B, Ali M, et al. Efficacy and safety of a modified killed-whole-cell oral cholera vaccine in India: an interim analysis of a cluster-randomised, double-blind, placebo-controlled trial. Lancet. 2009;374(9702):1694–702. 10.1016/S0140-6736(09)61297-6 [DOI] [PubMed] [Google Scholar]
  • 9.Sur D, Kanungo S, Sah B, Manna B, Ali M, Paisley AM, et al. Efficacy of a low-cost, inactivated whole-cell oral cholera vaccine: results from 3 years of follow-up of a randomized, controlled trial. PLoS Negl Trop Dis. 2011;5(10):e1289. 10.1371/journal.pntd.0001289 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Bhattacharya SK, Sur D, Ali M, Kanungo S, You YA, Manna B, et al. 5 year efficacy of a bivalent killed whole-cell oral cholera vaccine in Kolkata, India: a cluster-randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2013;13(12):1050–6. 10.1016/S1473-3099(13)70273-1 [DOI] [PubMed] [Google Scholar]
  • 11.Clemens J, Shin S, Sur D, Nair GB, Holmgren J. New-generation vaccines against cholera. Nat Rev Gastroenterol Hepatol. 2011;8(12):701–10. 10.1038/nrgastro.2011.174 [DOI] [PubMed] [Google Scholar]
  • 12.Pena D. Vietnam develops world’s best cholera vaccine. People’s World. 2009 Jun 5. New York: Long View Publishing Co; 2009. Available from: http://www.peoplesworld.org/vietnam-develops-world-s-best-cholera-vaccine/ [cited 2013 Aug 6].
  • 13.Sinclair D, Abba K, Zaman K, Qadri F, Graves PM. Oral vaccines for preventing cholera. Cochrane Database Syst Rev. 2011;3(3):CD008603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Reyburn R, Deen JL, Grais RF, Bhattacharya SK, Sur D, Lopez AL, et al. The case for reactive mass oral cholera vaccinations. PLoS Negl Trop Dis. 2011;5(1):e952. 10.1371/journal.pntd.0000952 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Ali M, Lopez AL, You YA, Kim YE, Sah B, Maskery B, et al. The global burden of cholera. Bull World Health Organ. 2012;90(3):209–218A. 10.2471/BLT.11.093427 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Legros D, Paquet C, Perea W, Marty I, Mugisha NK, Royer H, et al. Mass vaccination with a two-dose oral cholera vaccine in a refugee camp. Bull World Health Organ. 1999;77(10):837–42. [PMC free article] [PubMed] [Google Scholar]
  • 17.Dorlencourt F, Legros D, Paquet C, Neira M, Ivanoff B, Le Saout E. Effectiveness of mass vaccination with WC/rBS cholera vaccine during an epidemic in Adjumani district, Uganda. Bull World Health Organ. 1999;77(11):949–50. [PMC free article] [PubMed] [Google Scholar]
  • 18.Crucell vaccine wards off cholera threat in Myanmar and Zanzibar [Internet]. Leiden: Crucell; 2009. Available from: http://www.crucell.com/feature_cholera_vaccination_campaign. [cited 2014 Sep 26].
  • 19.Olsson L, Parment P-A. Present and future cholera vaccines. Expert Rev Vaccines. 2006;5(6):751–2. 10.1586/14760584.5.6.751 [DOI] [PubMed] [Google Scholar]
  • 20.Cavailler P, Lucas M, Perroud V, McChesney M, Ampuero S, Guérin PJ, et al. Feasibility of a mass vaccination campaign using a two-dose oral cholera vaccine in an urban cholera-endemic setting in Mozambique. Vaccine. 2006;24(22):4890–5. 10.1016/j.vaccine.2005.10.006 [DOI] [PubMed] [Google Scholar]
  • 21.Lucas ME, Deen JL, von Seidlein L, Wang XY, Ampuero J, Puri M, et al. Effectiveness of mass oral cholera vaccination in Beira, Mozambique. N Engl J Med. 2005;352(8):757–67. 10.1056/NEJMoa043323 [DOI] [PubMed] [Google Scholar]
  • 22.Darfur disease outbreak control bulletin. 2004 Aug 15. Geneva: World Health Organization; 2004. Available from: www.who.int/disasters/repo/14372.pdf [cited 2013 Aug 6].
  • 23.Chaignat CL, Monti V, Soepardi J, Petersen G, Sorensen E, Narain J, et al. Cholera in disasters: do vaccines prompt new hopes? Expert Rev Vaccines. 2008;7(4):431–5. 10.1586/14760584.7.4.431 [DOI] [PubMed] [Google Scholar]
  • 24.Use of the two-dose oral cholera vaccine in the context of a major natural disaster: Report of a vaccination campaign in Aceh Province, Indonesia. Geneva: World Health Organization; 2005. [Google Scholar]
  • 25.Oo KN, Aung WW, Thu HM, Htun MM, Aye KS, Kyaw MP, et al. Coverage and side-effects of oral cholera (Dukoral) vaccine in Department of Medical Research (Lower Myanmar). Myanmar Health Sci Res J. 2011;23:63–4. [Google Scholar]
  • 26.Khatib AM, Ali M, von Seidlein L, Kim DR, Hashim R, Reyburn R, et al. Effectiveness of an oral cholera vaccine in Zanzibar: findings from a mass vaccination campaign and observational cohort study. Lancet Infect Dis. 2012;12:837–44. 10.1016/S1473-3099(12)70196-2 [DOI] [PubMed] [Google Scholar]
  • 27.Hashim R, Khatib AM, Enwere G, Park JK, Reyburn R, Ali M, et al. Safety of the recombinant cholera toxin B subunit, killed whole-cell (rBS-WC) oral cholera vaccine in pregnancy. PLoS Negl Trop Dis. 2012;6(7):e1743. 10.1371/journal.pntd.0001743 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Ali M, Deen JL, Khatib A, Enwere G, von Seidlein L, Reyburn R, et al. Paperless registration during survey enumerations and large oral cholera mass vaccination in Zanzibar, the United Republic of Tanzania. Bull World Health Organ. 2010;88(7):556–9. 10.2471/BLT.09.070334 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Schaetti C, Weiss MG, Ali SM, Chaignat CL, Khatib AM, Reyburn R, et al. Costs of illness due to cholera, costs of immunization and cost-effectiveness of an oral cholera mass vaccination campaign in Zanzibar. PLoS Negl Trop Dis. 2012;6(10):e1844. 10.1371/journal.pntd.0001844 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Vu DT, Hossain MM, Nguyen DS, Nguyen TH, Rao MR, Do GC, et al. Coverage and costs of mass immunization of an oral cholera vaccine in Vietnam. J Health Popul Nutr. 2003;21(4):304–8. [PubMed] [Google Scholar]
  • 31.Thiem VD, Deen JL, von Seidlein L, Canh G, Anh DD, Park JK, et al. Long-term effectiveness against cholera of oral killed whole-cell vaccine produced in Vietnam. Vaccine. 2006;24(20):4297–303. 10.1016/j.vaccine.2006.03.008 [DOI] [PubMed] [Google Scholar]
  • 32.Anh DD, Lopez AL, Thiem VD, Grahek SL, Duong TN, Park JK, et al. Use of oral cholera vaccines in an outbreak in Vietnam: a case control study. PLoS Negl Trop Dis. 2011;5(1):e1006. 10.1371/journal.pntd.0001006 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Anh DD, Lopez AL, Tran HTM, Cuong NV, Thiem VD, Ali M, et al. Oral cholera vaccine development and use in Vietnam. PLoS Med. 2014;11(9):e1001712. 10.1371/journal.pmed.1001712 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Kar SK, Sah B, Patnaik B, Kim YH, Kerketta AS, Shin S, et al. Mass vaccination with a new, less expensive oral cholera vaccine using public health infrastructure in India: the Odisha model. PLoS Negl Trop Dis. 2014;8(2):e2629. 10.1371/journal.pntd.0002629 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Khan IA, Saha A, Chowdhury F, Khan AI, Uddin MJ, Begum YA, et al. Coverage and cost of a large oral cholera vaccination program in a high-risk cholera endemic urban population in Dhaka, Bangladesh. Vaccine. 2013;31(51):6058–64. 10.1016/j.vaccine.2013.10.021 [DOI] [PubMed] [Google Scholar]
  • 36.Rouzier V, Severe K, Juste MAJ, Peck M, Perodin C, Severe P, et al. Cholera vaccination in urban Haiti. Am J Trop Med Hyg. 2013;89(4):671–81. 10.4269/ajtmh.13-0171 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Ivers LC, Farmer PE, Pape WJ. Oral cholera vaccine and integrated cholera control in Haiti. Lancet. 2012;379(9831):2026–8. 10.1016/S0140-6736(12)60832-0 [DOI] [PubMed] [Google Scholar]
  • 38.Ivers LC, Teng JE, Lascher J, Raymond M, Weigel J, Victor N, et al. Use of oral cholera vaccine in Haiti: a rural demonstration project. Am J Trop Med Hyg. 2013;89(4):617–24. 10.4269/ajtmh.13-0183 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Aibana O, Franke MF, Teng JE, Hilaire J, Raymond M, Ivers LC. Cholera vaccination campaign contributes to improved knowledge regarding cholera and improved practice relevant to waterborne disease in rural Haiti. PLoS Negl Trop Dis. 2013;7(11):e2576. 10.1371/journal.pntd.0002576 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Teng JE, Thomson DR, Lascher JS, Raymond M, Ivers LC. Using Mobile Health (mHealth) and geospatial mapping technology in a mass campaign for reactive oral cholera vaccination in rural Haiti. PLoS Negl Trop Dis. 2014;8(7):e3050. 10.1371/journal.pntd.0003050 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Report of external review of Expanded Programme on Immunization. Solomon Islands; Ministry of Health and Medical Services: 2012.
  • 42.Date K, Phares C. OCV project in Thailand. In: Vaccines For Enteric Diseases; 2013 Nov 6–8; Bangkok, Thailand. [Google Scholar]
  • 43.Luquero FJ, Grout L, Ciglenecki I, Sakoba K, Traore B, Heile M, et al. First outbreak response using an oral cholera vaccine in Africa: vaccine coverage, acceptability and surveillance of adverse events, Guinea, 2012. PLoS Negl Trop Dis. 2013;7(10):e2465. 10.1371/journal.pntd.0002465 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Ciglenecki I, Sakoba K, Luquero FJ, Heile M, Itama C, Mengel M, et al. Feasibility of mass vaccination campaign with oral cholera vaccines in response to an outbreak in Guinea. PLoS Med. 2013;10(9):e1001512. 10.1371/journal.pmed.1001512 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Luquero FJ, Grout L, Ciglenecki I, Sakoba K, Traore B, Heile M, et al. Use of Vibrio cholerae vaccine in an outbreak in Guinea. N Engl J Med. 2014;370(22):2111–20. 10.1056/NEJMoa1312680 [DOI] [PubMed] [Google Scholar]
  • 46.Mass oral cholera vaccination campaign (OCV) in Maban County in the refugee camps and host population in the direct surroundings of the camps. Implementation, feasibility, coverage and acceptability. Amsterdam: Médecins Sans Frontières; 2013. [Google Scholar]
  • 47.Conan N, Lenglet A. Vaccination coverage with Oral Cholera Vaccine (OCV), Maban County, South Sudan. December 2012–February 2013: Survey report. Amsterdam: Médecins Sans Frontières; 2013. [Google Scholar]
  • 48.Oral cholera vaccine campaign among internally displaced persons in South Sudan. Wkly Epidemiol Rec. 2014;89(20):214–20. [PubMed] [Google Scholar]
  • 49.Oral Cholera Vaccine stockpile for cholera emergency response. Geneva: World Health Organization; 2013. Available from: http://www.who.int/cholera/vaccines/Briefing_OCV_stockpile.pdf [cited 2014 Sep 26].

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