Alejandro Costa

Stockpiling oral cholera vaccine

Cholera is re-emerging as a threat on the global public health stage. The number of reported cases worldwide is back at the peak level observed two decades ago,1 new Vibrio cholerae strains have appeared and antimicrobial resistance has increased. Weak surveillance systems and the possibility of travel and trade sanctions contribute to widespread underreporting of cholera cases, which results in great uncertainty surrounding global disease burden estimates. Such estimates suggest that about 1.4 billion people are at risk of cholera and that the risk is highest among children under five years of age. Annually 2.8 million cases and 91 000 deaths from cholera occur in endemic countries; non-endemic countries contribute another 87 000 cases and 2500 deaths.2 Although effective preventive and therapeutic regimens are well established, clearly cholera remains poorly controlled in both outbreak and endemic contexts. Cholera-related morbidity and mortality are particularly high during humanitarian crises. Large cholera epidemics in Zimbabwe (2008–2009), Haiti (2011) and now Sierra Leone (2012) have made the international community aware of the need to not merely control endemic disease, but also to strengthen epidemic preparedness and response capacity. In 2011, the Sixty-fourth World Health Assembly issued a resolution calling for a reinvigorated focus on cholera and defined a range of actions required of the World Health Organization (WHO) and its Member States towards creating an integrated, comprehensive strategy for cholera prevention and control.3 As part of this strategy, WHO is facilitating a multi-partner initiative aimed at establishing a stockpile of oral cholera vaccine (OCV) for use in outbreak response as an adjunct to established prevention and control measures. This approach was endorsed in September 2011 by global cholera experts, who affirmed that such a stockpile is both necessary and feasible.4 There are currently two stockpile candidate oral cholera vaccines, both prequalified by WHO. A WHO technical working group convened in April 2012 and defined the required characteristics of a stockpiled vaccine, the epidemiological and operational considerations for deployment, and the mechanisms for stockpile governance, replenishment and appraisal.5 This working group agreed on an initial OCV stockpile of 2 million annual doses to be available for epidemic response in low-income countries. The International Coordinating Group (ICG) has a decade of experience as a decision-making partnership that oversees the meningococcal and yellow fever vaccine stockpiles and their deployment. The ICG is composed of experts from four organizations: Medecins sans Frontieres, the International Federation of the Red Cross and Red Crescent Societies, the United Nations Children’s Fund and WHO, which is both a decision-making partner and the ICG’s secretariat. All members of the ICG, including WHO, will oversee the proposed OCV stockpile. The WHO technical working group emphasized that deployment of the stockpiled vaccine must be guided by epidemiological, technical and operational evidence, some of which remains incomplete and must be consolidated as experience is gained. While acknowledging the difficulties in predicting outbreaks and the need for more detailed empirical data, the working group created an advisory framework for assessing outbreak severity based on three criteria: the biological susceptibility of the population, the social vulnerability of the population and the risk of spatial extension. For each of these criteria, the working group defined epidemiological and demographic indicators, thresholds for deciding when to deploy the vaccine and indicators for determining the anticipated impact of a vaccination campaign. The framework proposed by the working group is intended only to inform decision-making; actual deployment of the OCV from the stockpile would follow not only an analysis of these indicators, but also an assessment of programmatic factors, such as local capacity to organize a mass vaccination campaign and prevailing security conditions. Progress is being made on the working group’s action plans for 2012. The work streams are focused on advocacy for funding, negotiations with vaccine producers and preparedness planning for countries and regions. A stockpile evaluation group has been established to define and implement the detailed monitoring required. As experience and data accrue, the results of this evaluation should enable continuous improvement in the structure and functioning of the stockpile. Successful assessment of a stockpile vaccination campaign will require reinforcement of surveillance systems in most locations where an epidemic is likely to arise. Public health interventions, such as case management, enhanced environmental control, improved hygiene and sanitation and social mobilization, should form the backbone of all cholera control programmes. In turn, these interventions depend on effective surveillance and strong health-care systems. This initial, necessarily small, OCV stockpile will not constitute sufficient preparedness for a large or sustained epidemic, its use should complement existing measures as part of a reinvigorated and comprehensive approach to meeting the new challenges involved in global cholera control and prevention.

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

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.

A second affordable oral cholera vaccine: implications for the global vaccine stockpile

On Dec 23, 2015, WHO prequalifi ed a second aff ordable oral cholera vaccine (OCV), Euvichol (Eubiologics, South Korea), which is expected to double current global OCV production and has the potential to further increase production capacity. The increased production will have implications for vaccine availability and reduced costs per dose, and will ultimately represent an added value for global cholera prevention and control. Vaccine prequalifi cation is a WHO-led activity intended to ensure that vaccines purchased by UN procurement agencies will be acceptable under conditions of use in national immunisation programmes in low-income and middle-income countries (LMICs). Prequalifi cation also indicates that a vaccine meets WHO recommendations for quality, safety, and effi cacy—enabling wider implementation of the vaccine in resourcelimited contexts. Cholera is endemic in more than 50 countries, with an estimated at-risk population of 1·5 billion, plus an annual estimated morbidity of more than 2 million cases and nearly 100 000 deaths. However, public attention is only garnered when outbreaks strike disaster-ravaged areas. Successful cholera control depends on a long-term commitment to improve water quality and sanitation systems, but an eff ective vaccine serves as an important component in a comprehensive prevention package. In 2001, WHO prequalifi ed the OCV Dukoral (SBLVaccin, Sweden) for purchase by UN agencies. Through a successful technology transfer agreement, a modifi ed bivalent formulation, Shanchol (Shantha Biotechnics, India), was developed and manufactured and was prequalifi ed in 2011. Both Shanchol and the newly prequalifi ed Korean vaccine (Euvichol) are reformulated versions of Dukoral. Because these newer versions do not contain the cholera toxin, they do not require co-administration with an oral buff er, making these versions both easier to deliver in challenging fi eld conditions and substantially less costly for the standard two-dose regimen (US

Reaching international GMP standards for vaccine production: challenges for developing countries

3·7 for Shanchol and Euvichol vs >

Achievements and challenges for the use of killed oral cholera vaccines in the global stockpile era

10·5 for Dukoral). In July, 2013, a global OCV stockpile was created. A stockpile is a mechanism to encourage change in vaccine use for underserved populations: a change from low demand, low production, high unit costs, and inequitable distribution, to an increased demand and production, lower unit costs, and greater equity of distribution. The Gavi Alliance approved funding of US

Preparedness for Infectious Threats

115 million from 2014–18 for a global stockpile delivery strategy for use in epidemic and endemic settings. Since inception, 21 shipments of OCV have been approved to be used in large preventive or reactive vaccination campaigns (about 4 million doses) in 11 countries. Because of limited supply, OCV is released from this stockpile after review and recommendation of country applications by the International Coordinating Group, composed of UNICEF, Médecins Sans Frontières, The International Federation of Red Cross, and WHO. The vaccine has been used successfully in various contexts—humanitarian crises (eg, South Sudan and Ethiopia), disease outbreaks (eg, Guinea, Malawi, Tanzania, and Iraq), and endemic hotspots (eg, Bangladesh, Democratic Republic of Congo, and Haiti). A major development during 2015 was that OCV demand exceeded supply (fi gure). The main reasons for this increase in demand are the observed feasibility of mass OCV campaigns and their ability to confer

Determining Measles‐Containing Vaccine Demand and Supply: An Imperative to Support Measles Mortality Reduction Efforts

Standards for vaccine production have been increasing at a rapid rate. Current standards of good manufacturing practice (GMP) had been thought to be out of the reach of developing country vaccine producers, many of whom are in the public sector, overseen by unvalidated national regulatory authorities (NRAs). With the advent of the GMP regulations in 1963 and their application to vaccine production, even many industrialized country manufacturers with stringent NRA oversight had difficulties. This article assesses the ability of developing country manufacturers to meet GMP by the only currently available global indicator: WHO prequalification. As recently as 1996, no developing country NRA was considered able to enforce GMP compliance. That number increased to four in 2002 and six in 2006, with a concomitant increase in the number of manufacturers considered to be operating to GMP standards. Examples of the difficulties faced by manufacturers in achieving this are given, as well as implications for the future vaccine market.

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

ABSTRACT Cholera remains an important but neglected public health threat, affecting the health of the poorest populations and imposing substantial costs on public health systems. Cholera can be eliminated where access to clean water, sanitation, and satisfactory hygiene practices are sustained, but major improvements in infrastructure continue to be a distant goal. New developments and trends of cholera disease burden, the creation of affordable oral cholera vaccines (OCVs) for use in developing countries, as well as recent evidence of vaccination impact has created an increased demand for cholera vaccines. The global OCV stockpile was established in 2013 and with support from Gavi, has assisted in achieving rapid access to vaccine in emergencies. Recent WHO prequalification of a second affordable OCV supports the stockpile goals of increased availability and distribution to affected populations. It serves as an essential step toward an integrated cholera control and prevention strategy in emergency and endemic settings.

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

With the emergence of epidemic Neisseria meningitidis W135 meningitis in Burkina Faso during early 2002, the public health community was faced with the challenge of providing access to an appropriate and affordable vaccine in time for the upcoming 2003 epidemic season.Recognizing the implications of the emergent threat, the World Health Organization developed a strategy, established a public–private partnership to provide the needed vaccine, and then ensured that a stockpile was available for future use.The trivalent N meningitidis ACW135 polysaccharide vaccine that resulted is now one of the primary tools for epidemic response in African meningitis belt countries. It will remain so for the foreseeable future and until appropriate and affordable conjugate vaccines become part of national immunization programs in the region.

A global pandemic influenza vaccine action plan

Measles remains a major cause of mortality with an estimated 745,000 deaths in 2001. The timely, sustained, and uninterrupted supply of affordable vaccines is critical for global efforts to reduce measles mortality. The measles vaccine supply needs to be considered in the context of vaccine security. In 2000, the World Health Organization (WHO) and United Nations Childrens Fund (UNICEF) issued a number of new recommendations for measles control that resulted in a two-fold increase in the number of measles-containing vaccine (MCV) doses administered between 2000 and 2002. Any additional increments in mass campaigns must be duly planned and have time lines so that vaccine production capacities are increased to optimal levels. The cornerstone of vaccine security efforts remains at the country level. WHO and UNICEF, with major partners, will review progress on measles mortality reduction and assess the feasibility of global measles eradication. Strong collaboration by all key stakeholders will be invaluable.