William Perea

Effectively introducing a new meningococcal A conjugate vaccine in Africa: The Burkina Faso experience

A new Group A meningococcal (Men A) conjugate vaccine, MenAfriVac™, was prequalified by the World Health Organization (WHO) in June 2010. Because Burkina Faso has repeatedly suffered meningitis epidemics due to Group A Neisseria meningitidis special efforts were made to conduct a country-wide campaign with the new vaccine in late 2010 and before the onset of the next epidemic meningococcal disease season beginning in January 2011. In the ensuing five months (July-November 2010) the following challenges were successfully managed: (1) doing a large safety study and registering the new vaccine in Burkina Faso; (2) developing a comprehensive communication plan; (3) strengthening the surveillance system with particular attention to improving the capacity for real-time polymerase chain reaction (PCR) testing of spinal fluid specimens; (4) improving cold chain capacity and waste disposal; (5) developing and funding a sound campaign strategy; and (6) ensuring effective collaboration across all partners. Each of these issues required specific strategies that were managed through a WHO-led consortium that included all major partners (Ministry of Health/Burkina Faso, Serum Institute of India Ltd., UNICEF, Global Alliance for Vaccines and Immunization, Meningitis Vaccine Project, CDC/Atlanta, and the Norwegian Institute of Public Health/Oslo). Biweekly teleconferences that were led by WHO ensured that problems were identified in a timely fashion. The new meningococcal A conjugate vaccine was introduced on December 6, 2010, in a national ceremony led by His Excellency Blaise Compaore, the President of Burkina Faso. The ensuing 10-day national campaign was hugely successful, and over 11.4 million Burkinabes between the ages of 1 and 29 years (100% of target population) were vaccinated. African national immunization programs are capable of achieving very high coverage for a vaccine desired by the public, introduced in a well-organized campaign, and supported at the highest political level. The Burkina Faso success augurs well for further rollout of the Men A conjugate vaccine in meningitis belt countries.

Defining the syndrome associated with congenital Zika virus infection.

Zika virus infection in humans is usually mild or asymptomatic. However, some babies born to women infected with Zika virus have severe neurological sequelae. An unusual cluster of cases of congenital microcephaly and other neurological disorders in the WHO Region of the Americas, led to the declaration of a public health emergency of international concern by the World Health Organization (WHO) on 1 February 2016. By 5 May 2016, reports of newborns or fetuses with microcephaly or other malformations – presumably associated with Zika virus infection – have been described in the following countries and territories: Brazil (1271 cases); Cabo Verde (3 cases); Colombia (7 cases); French Polynesia (8 cases); Martinique (2 cases) and Panama (4 cases). Additional cases were also reported in Slovenia and the United States of America, in which the mothers had histories of travel to Brazil during their pregnancies.1 Zika virus is an intensely neurotropic virus that particularly targets neural progenitor cells but also – to a lesser extent – neuronal cells in all stages of maturity. Viral cerebritis can disrupt cerebral embryogenesis and result in microcephaly and other neurological abnormalities.2 Zika virus has been isolated from the brains and cerebrospinal fluid of neonates born with congenital microcephaly and identified in the placental tissue of mothers who had had clinical symptoms consistent with Zika virus infection during their pregnancies.3–5 The spatiotemporal association of cases of microcephaly with the Zika virus outbreak and the evidence emerging from case reports and epidemiologic studies, has led to a strong scientific consensus that Zika virus is implicated in congenital abnormalities.6,7 Existing evidence and unpublished data shared with WHO highlight the wider range of congenital abnormalities probably associated with the acquisition of Zika virus infection in utero. In addition to microcephaly, other manifestations include craniofacial disproportion, spasticity, seizures, irritability and brainstem dysfunction including feeding difficulties, ocular abnormalities and findings on neuroimaging such as calcifications, cortical disorders and ventriculomegaly.3–6,8–10 Similar to other infections acquired in utero, cases range in severity; some babies have been reported to have neurological abnormalities with a normal head circumference. Preliminary data from Colombia and Panama also suggest that the genitourinary, cardiac and digestive systems can be affected (Pilar Ramon-Pardo, unpublished data). The range of abnormalities seen and the likely causal relationship with Zika virus infection suggest the presence of a new congenital syndrome. WHO has set in place a process for defining the spectrum of this syndrome. The process focuses on mapping and analysing the clinical manifestations encompassing the neurological, hearing, visual and other abnormalities, and neuroimaging findings. WHO will need good antenatal and postnatal histories and follow-up data, sound laboratory results, exclusion of other etiologies and analysis of imaging findings to properly delineate this syndrome. The scope of the syndrome will expand as further information and longer follow-up of affected children become available. The surveillance system that was established as part of the epidemic response to the outbreak initially called only for the reporting of microcephaly cases. This surveillance guidance has been expanded to include a spectrum of congenital malformations that could be associated with intrauterine Zika virus infection.11 Effective sharing of data is needed to define this syndrome. A few reports have described a wide range of abnormalities,3–6,8–10 but most data related to congenital manifestations of Zika infection remain unpublished. Global health organizations and research funders have committed to sharing data and results relevant to the Zika epidemic as openly as possible.12 Further analysis of data from cohorts of pregnant women with Zika virus infection are needed to understand all outcomes of Zika virus infection in pregnancy. Thirty-seven countries and territories in the Region of the Americas now report mosquito-borne transmission of Zika virus and risk of sexual transmission. With such spread, it is possible that many thousands of infants will incur moderate to severe neurological disabilities. Therefore, routine surveillance systems and research protocols need to include a larger population than simply children with microcephaly. The health system response, including psychosocial services for women, babies and affected families will need to be fully resourced. The Zika virus public health emergency is distinct because of its long-term health consequences and social impact. A coordinated approach to data sharing, surveillance and research is needed. WHO has thus started coordinating efforts to define the congenital Zika virus syndrome and issues an open invitation to all partners to join in this effort.

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.

An outbreak of yellow fever with concurrent chikungunya virus transmission in South Kordofan, Sudan, 2005

From September through December 2005, an outbreak of hemorrhagic fever occurred in South Kordofan, Sudan. Initial laboratory test results identified IgM antibodies against yellow fever (YF) virus in patient samples, and a YF outbreak was declared on 14 November. To control the outbreak, a YF mass vaccination campaign was conducted and vector control implemented in parts of South Kordofan. Surveillance data were obtained from the Sudan Federal Ministry of Health. Clinical information and serum samples were obtained from a subset of patients with illness during the outbreak. Nomads, health personnel and village chiefs were interviewed about the outbreak. Mosquitoes were collected in 11 villages and towns in North and South Kordofan. From 10 September to 9 December 2005 a total of 605 cases of outbreak-related illness were reported, of which 45% were in nomads. Twenty-nine percent of 177 patients seen at clinics in Julud and Abu Jubaiyah had illness consistent with YF. Five of 18 unvaccinated persons with recent illness and 4 of 16 unvaccinated asymptomatic persons had IgM antibodies to YF virus. IgM antibodies to chikungunya virus were detected in five (27%) ill persons and three (19%) asymptomatic persons. These results indicate that both chikungunya and YF occurred during the outbreak.

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.

Artesunate and sulfadoxine-pyrimethamine combinations for the treatment of uncomplicated Plasmodium falciparum malaria in Uganda: a randomized, double-blind, placebo-controlled trial

Drug-resistant malaria is spreading in Africa. The few available drugs might be safeguarded if combined with an artemisinin derivative. We investigated the efficacy, safety, and tolerability of 2 combinations of artesunate with sulfadoxine-pyrimethamine (SP) in a mesoendemic region in Uganda with SP resistance, from September 1999 to June 2000. In a randomized, double-blind, placebo-controlled trial, 420 children aged 6-59 months with uncomplicated Plasmodium falciparum malaria were assigned SP alone (25 mg/kg sulfadoxine, 1.25 mg/kg pyrimethamine) or combined with artesunate (AS; 4 mg/kg/d) for either 1 d (SPAS1) or 3 d (SPAS3). Children were followed-up for 28 d. Day 14 cure rates were 84.6% (99/117) with SPAS3 and 61.9% (73/118) with SPAS1 compared with 55.8% (86/154) with SP. Corresponding day 28 results were 74.4% (87/117) and 45.2% (52/115) compared with 40.5% (62/153). A significant improvement was obtained with the addition of 3 d, but not 1 d, of artesunate (risk ratio [RR] = 1.5, 95% CI 1.3-1.8 at 14 d and RR = 1.8, 95% CI 1.5-2.3 at 28 d). Both AS regimens achieved significantly faster parasite clearance and lower gametocyte carriage. All drug regimens were well tolerated, but SP alone was ineffective. Treatment efficacy improved with SPAS3 but the cure rate at day 28 was modest. The combinations were well tolerated and safe. In areas where SP resistance is prevalent other combinations should be considered.

The First Use of the Global Oral Cholera Vaccine Emergency Stockpile: Lessons from South Sudan

Andrew Azman and colleagues describe their experience of deploying >250,000 doses of oral cholera vaccine in South Sudan in 2014

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

Immunogenicity and safety of yellow fever vaccine among 115 HIV-infected patients after a preventive immunisation campaign in Mali.

3·7 for Shanchol and Euvichol vs >

Exposure Patterns Driving Ebola Transmission in West Africa: A Retrospective Observational Study.

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