Exploring the feasibility of integration of surveillance for intussusception into the routine monitoring of adverse events following immunization by countries of the WHO African Region for Africa.

Surveillance for intussusception (IS) post-rotavirus vaccine introduction in World Health Organization Africa Region (WHO/AFRO) has been restricted mainly to the large referral teaching hospitals. The choice of these facilities for surveillance was made to utilize the abundant expertise of specialists in paediatrics and surgery in these hospitals who can diagnose and manage such patients with IS. The surveillance has been well coordinated by the African Intussusception Surveillance Network established in 2012. This network has supported surveillance across the African region and has accumulated a huge database of IS cases in children < 1 year with findings that have demonstrated safety of the monovalent rotavirus vaccine, Rotarix (GlaxoSmithKline). However, safety data on the pentavalent and RotaTeq (Merck Vaccine) is not yet available from the African region. Although, this network has provided much needed data, there is an inherent bias in monitoring and reporting of IS cases in only large tertiary hospitals. This time limited special project does not capture suspected intussusception cases with no access to hospital facilities used for monitoring IS. Additionally, the design requires extensive resources to support collection of high-quality data for monitoring IS, which is unsustainable. For these reasons suitable linkages between IS monitoring and routine Adverse Event Following Immunization (AEFI) should be established for continuity of monitoring of this condition. We propose alignment of the two systems that offers opportunity for high profile recognition and to enhance a sustainable system for diagnosis, treatment and continuous assessment of intussusception occurring in infancy.

Global selective sweep of a highly inbred genome of the cattle parasite Neospora caninum.

Neospora caninum, a cyst-forming apicomplexan parasite, is a leading cause of neuromuscular diseases in dogs as well as fetal abortion in cattle worldwide. The importance of the domestic and sylvatic life cycles of Neospora, and the role of vertical transmission in the expansion and transmission of infection in cattle, is not sufficiently understood. To elucidate the population genomics of Neospora, we genotyped 50 isolates collected worldwide from a wide range of hosts using 19 linked and unlinked genetic markers. Phylogenetic analysis and genetic distance indices resolved a single genotype of N. caninum Whole-genome sequencing of 7 isolates from 2 different continents identified high linkage disequilibrium, significant structural variation, but only limited polymorphism genome-wide, with only 5,766 biallelic single nucleotide polymorphisms (SNPs) total. Greater than half of these SNPs (∼3,000) clustered into 6 distinct haploblocks and each block possessed limited allelic diversity (with only 4 to 6 haplotypes resolved at each cluster). Importantly, the alleles at each haploblock had independently segregated across the strains sequenced, supporting a unisexual expansion model that is mosaic at 6 genomic blocks. Integrating seroprevalence data from African cattle, our data support a global selective sweep of a highly inbred livestock pathogen that originated within European dairy stock and expanded transcontinentally via unisexual mating and vertical transmission very recently, likely the result of human activities, including recurrent migration, domestication, and breed development of bovid and canid hosts within similar proximities.

Elimination of Epidemic Meningitis in the African Region: Progress and Challenges: 2010-2016.

BACKGROUND: Epidemics of meningococcal disease constitute a major public health challenge in Africa, affecting mostly the 24 countries of the meningitis belt. These epidemics led to a call for a call for a safe, effective and affordable conjugate vaccine against the major serogroup responsible for recent epidemics by leaders of the region. OBJECTIVE: This paper documents experiences with efforts at eliminating epidemic meningitis in the African Region. METHOD: The meningoccocal serogroup A conjugate vaccine was developed, licensed and offered to more than 235 million people through mass vaccination campaigns in 16 countries since 2010. Future plans include providing the vaccine to the remaining countries in the African Meningitis Belt and, to implement the vaccine into routine national infant immunization programme and to organise catch-up immunization campaigns every 5 years for unvaccinated <5 year-olds who had missed their routine vaccinations. RESULTS: The success of the project is evidenced by the large declines in cases of group A meningococcal disease since 2010, with no cases reported in vaccinated persons across the 16 countries, reflecting the highly effective nature of the vaccine. The successful control of serogroup A meningococcal disease has highlighted the need to tackle other meningococcal serogroups through development of polyvalent conjugate vaccines with the aim of eliminating epidemics of meningococcal meningitis in the African region.

Introduction of Inactivated Poliovirus Vaccine and Trivalent Oral Polio Vaccine/Bivalent Oral Polio Vaccine Switch in the African Region.

The Polio Eradication and Endgame Strategic plan outlines the phased removal of oral polio vaccines (OPVs), starting with type 2 poliovirus-containing vaccine and introduction of inactivated polio vaccine in routine immunization to mitigate against risk of vaccine-associated paralytic polio and circulating vaccine-derived poliovirus. The objective includes strengthening routine immunization as the primary pillar to sustaining high population immunity. After 2 years without reporting any wild poliovirus (July 2014-2016), the region undertook the synchronized switch from trivalent OPV (tOPV) to bivalent OPV (bOPV) as recommended by the Strategic Advisory Group of Experts on Immunization. Consequently the 47 countries of the World Health Organization (WHO) African Region switched from the use of tOPV to bOPV within the stipulated period of April 2016. Planning started early, routine immunization was strengthened, and technical and financial support was provided for vaccine registration, procurement, destruction, logistics, and management across countries by WHO in collaboration with the United Nations Children's Fund (UNICEF) and partners. National commitment and ownership, as well as strong coordination and collaboration between UNICEF and WHO and with partners, ensured success of this major, historic public health undertaking.

Effect of IPTp on Plasmodium falciparum antibody levels among pregnant women and their babies in a sub-urban coastal area in Ghana.

BACKGROUND: Women exposed to Plasmodium infection develop antibodies and become semi-immune. This immunity is suppressed during pregnancy making both the pregnant woman and the foetus vulnerable to the adverse effects of malaria, particularly by Plasmodium falciparum. Intermittent preventive treatment of malaria in pregnancy (IPTp) with Sulfadoxine-pyrimethamine (SP) tablets is one of the current interventions to mitigate the effects of malaria on both the pregnant woman and the unborn child. The extent to which IPTp may interfere with the acquisition of protective immunity against pregnancy-associated malaria (PAM) is undefined in Ghana. METHODS: Three-hundred-and-twenty pregnant women were randomly enrolled at the antenatal clinic (ANC) in Madina, Accra. Venous blood samples were obtained at first ANC registration and at 4-week intervals (post-IPTp administration). Placental and cord blood samples were obtained at delivery and the infants were followed monthly for 6 months after birth. Anti-IgG and IgM antibodies against a crude antigen preparation and the glutamate-rich protein (GLURP) of P. falciparum were quantified by the enzyme-linked immunosorbent assay (ELISA). RESULTS: There was a general decline in the trend of mean concentrations of all the antibodies from enrolment to delivery. The levels of antibodies in cord blood and placenta were well correlated. Children did not show clinical signs of malaria at 6 months after birth. CONCLUSIONS: IgG against both crude antigen and GLURP were present in placenta and cord blood and it is therefore concluded that there is a trend of declining antibody from enrolment to delivery and IPTp-SP may have reduced malaria exposure, however, this does not impact on the transfer of antibodies to the foetus in utero. The levels of maternal and cord blood antibodies at delivery showed no adverse implications on malaria among the children at 6 months. However, the quantum and quality of the antibody transferred needs further investigation to ensure that the infants are protected from severe episodes of malaria.

Polio eradication in the African Region on course despite public health emergencies.

The World Health Organization, African Region is heading toward eradication of the three types of wild polio virus, from the Region. Cases of wild poliovirus (WPV) types 2 and 3 (WPV2 and WPV3) were last reported in 1998 and 2012, respectively, and WPV1 reported in Nigeria since July 2014 has been the last in the entire Region. This scenario in Nigeria, the only endemic country, marks a remarkable progress. This significant progress is as a result of commitment of key partners in providing the much needed resources, better implementation of strategies, accountability, and innovative approaches. This is taking place in the face of public emergencies and challenges, which overburden health systems of countries and threaten sustainability of health programmes. Outbreak of Ebola and other diseases, insecurity, civil strife and political instability led to displacement of populations and severely affected health service delivery. The goal of eradication is now within reach more than ever before and countries of the region should not relent in their efforts on polio eradication. WHO and partners will redouble their efforts and introduce better approaches to sustain the current momentum and to complete the job. The carefully planned withdrawal of oral polio vaccine type II (OPV2) with an earlier introduction of one dose of inactivated poliovirus vaccine (IPV), in routine immunization, will boost immunity of populations and stop cVDPVs. Environmental surveillance for polio viruses will supplement surveillance for AFP and improve sensitivity of detection of polio viruses.

Contribution of polio eradication initiative to strengthening routine immunization: Lessons learnt in the WHO African region.

BACKGROUND: Important investments were made in countries for the polio eradication initiative. On 25 September 2015, a major milestone was achieved when Nigeria was removed from the list of polio-endemic countries. Routine Immunization, being a key pillar of polio eradication initiative needs to be strengthened to sustain the gains made in countries. For this, there is a huge potential on building on the use of polio infrastructure to contribute to RI strengthening. METHODS: We reviewed estimates of immunization coverage as reported by the countries to WHO and UNICEF for three vaccines: BCG, DTP3 (third dose of diphtheria-tetanus toxoid- pertussis), and the first dose of measles-containing vaccine (MCV1).We conducted a systematic review of best practices documents from eight countries which had significant polio eradication activities. RESULTS: Immunization programmes have improved significantly in the African Region. Regional coverage for DTP3 vaccine increased from 51% in 1996 to 77% in 2014. DTP3 coverage increased >3 folds in DRC (18-80%) and Nigeria from 21% to 66%; and >2 folds in Angola (41-87%), Chad (24-46%), and Togo (42-87%). Coverage for BCG and MCV1 increased in all countries. Of the 47 countries in the region, 18 (38%) achieved a national coverage for DTP3 ⩾90% for 2years meeting the Global Vaccine Action (GVAP) target. A decrease was noted in the Ebola-affected countries i.e., Guinea, Liberia and Sierra Leone. CONCLUSIONS: PEI has been associated with increased spending on immunization and the related improvements, especially in the areas of micro planning, service delivery, program management and capacity building. Continued efforts are needed to mobilize international and domestic support to strengthen and sustain high-quality immunization services in African countries. Strengthening RI will in turn sustain the gains made to eradicate poliovirus in the region.

A STAT6 Intronic Single-Nucleotide Polymorphism is Associated with Clinical Malaria in Ghanaian Children.

Malaria pathogenesis may be influenced by IgE responses and cytokine cross-regulation. Several mutations in the IL-4/STAT6 signaling pathway can alter cytokine cross-regulation and IgE responses during a Plasmodium falciparum malarial infection. This study investigated the relationship between a STAT6 intronic single-nucleotide polymorphism (rs3024974), total IgE, cytokines, and malaria severity in 238 Ghanaian children aged between 0.5 and 13 years. Total IgE and cytokine levels were measured by ELISA, while genotyping was done by polymerase chain reaction-restriction fragment length polymorphism (RFLP). Compared with healthy controls, heterozygosity protected against clinical malaria: uncomplicated malaria (odds ratios [OR] = 0.13, P < 0.001), severe malarial anemia (OR = 0.18, P < 0.001), and cerebral malaria (OR = 0.39, P = 0.022). Levels of total IgE significantly differed among malaria phenotypes (P = 0.044) and rs3024974 genotypes (P = 0.037). Neither cytokine levels nor IL-6/IL-10 ratios were associated with malaria phenotypes or rs3024974 genotypes. This study suggests a role for rs3024974 in malaria pathogenesis and offers further insights into an IL-4/STAT6 pathway mutation in malaria pathogenesis.

Regulatory Pathways That Facilitated Timely Registration of a New Group A Meningococcal Conjugate Vaccine for Africa's Meningitis Belt Countries.

BACKGROUND: Through its normative and public health leadership roles, the World Health Organization (WHO) plays a key role in the availability of vaccine products in low-and middle-income countries. The recent introduction of a new group A meningococcal conjugate vaccine, PsA-TT (MenAfriVac), in Africa exemplifies this process. WHO requires that any new vaccine to be introduced in countries for public health reasons and supplied through United Nations centralized mechanisms be licensed by the national regulatory agency (NRA) in the producing country, then prequalified and given a marketing authorization in the user countries. METHODS: PsA-TT was manufactured by the Serum Institute of India, Ltd (SIIL), which submitted a license application in April 2009 to the Drug Controller General of India (DCGI), the Indian NRA responsible for licensing vaccines. WHO encouraged the DCGI to establish a collaboration with Health Canada's Centre for Vaccine Evaluation for the review. Through this collaborative effort, registration was facilitated and in December 2009 an export license was granted to SIIL, which subsequently submitted an application for WHO prequalification. RESULTS: Given the importance of the vaccine, WHO "fast tracked" the prequalification review, and after a detailed review and site visit, WHO prequalification was granted to PsA-TT in June 2010. Country use of the new vaccine could not occur until the vaccine was a registered product in each country seeking its use. WHO facilitated country reviews by conducting regulatory training exercises (in French and English) for country NRA staff, which used the PsA-TT registration as a case study. CONCLUSIONS: PsA-TT was gradually registered in African countries as vaccine introduction proceeded. The regulatory pathway for this new group A meningococcal conjugate vaccine proved to be a useful training opportunity both in India and Africa, because the availability of the vaccine was a high African public health priority, as well as for WHO as a case study to facilitate registration of vaccines based on reliance on other regulatory bodies.

Lessons Learned From Enhancing Vaccine Pharmacovigilance Activities During PsA-TT Introduction in African Countries, 2010-2013.

BACKGROUND: The rollout of the group A meningococcal vaccine, PsA-TT, in Africa's meningitis belt countries represented the first introduction of a vaccine specifically designed for this part of the world. During the first year alone, the number of people who received the vaccine through mass vaccination campaigns was several hundredfold higher than that of subjects who participated in the closely monitored clinical trials. Implementation of a system to identify rare but potentially serious vaccine reactions was therefore a high priority in the design and implementation of those campaigns. METHODS: National authorities and their technical partners set up effective vaccine pharmacovigilance systems, including conducting active surveillance projects. RESULTS: Implementation of national expert advisory groups to review serious adverse events following immunization in all countries and active monitoring of conditions of interest in 3 early-adopter countries did not identify particular concerns with the safety profile of PsA-TT, which had already provided tremendous public health benefits. CONCLUSIONS: Lessons learned from this experience will help to improve preparations for future vaccine introductions in resource-poor settings and capitalize on such efforts to advance vaccine safety systems in the future.

High Levels of IL-10 and CD4+CD25hi+ Treg Cells in Endemic Burkitt's Lymphoma Patients.

BACKGROUND: The interplay between Epstein-Barr virus infection, malaria, and endemic Burkitt's Lymphoma is not well understood. Reports show diminished EBV-specific Th1 responses in children living in malaria endemic areas and deficiency of EBNA1-specific IFN-γ T cell responses in children with endemic Burkitt's Lymphoma (eBL). This study, therefore, examined some factors involved in the loss of EBNA-1-specific T cell responses in eBL. METHODS: T-cell subset frequencies, activation, and IFN-γ- or IL-4-specific responses were analyzed by flow-cytometry. Plasma cytokine levels were measured by ELISA. RESULTS: CD4+ and CD8+ cells in age- and sex-matched healthy controls (n = 3) expressed more IFN-γ in response to all immunostimulants than in pediatric endemic BL (eBL) patients (n = 4). In healthy controls, IFN-γ expression was higher than IL-4 expression, whereas in eBL patients the expression of IL-4 by CD4+ cells to EBNA-1 was slightly higher than IFN-γ. Moreover, the blood levels of TNF-α was significantly lower (p = 0.004) while IL-10 was significantly higher (p = 0.038), in eBL patients (n = 21) compared to controls (n = 16). Additionally, the frequency of CD4+CD25hi+ T cells was higher in both age-matched acute uncomplicated malaria (n = 26) and eBL (n = 14) patients compared to healthy controls (n = 19; p = 0.000 and p = 0.027, respectively). CONCLUSION: The data suggest that reduced Th1 response in eBL might be due to increased levels of IL-10 and T reg cells.

Update on Elimination of Epidemic Meningitis in the African Region

At the demand of the African ministries of health; a new conjugate vaccine was developed by Serum Institute of India Limited (SIIL) against meningococcal A meningitis; the germ responsible for more than 95 of the meningitis epidemics in Africa; through a partnership between WHO and PATH and; with the financial support from the Bill et Melinda Gates Foundation. The vaccine is being introduced in all the 26 countries of the meningitis belt between 2010 and 2016. So far; 153 million people have been vaccinated in 12 countries. The vaccine is efficacious; no case of meningococcal meningitis A has been identified among vaccinated individuals and in post-campaign carriage studies. The overall number of meningitis cases dropped sharply during epidemic seasons in the countries of the belt. The vaccine will be introduced via routine immunization by the end of 2015

Vaccine Safety and Pharmacovigilance in the African Region

In recent years the WHO African Region has seen a growth in clinical development of new vaccines as well as their introduction into the national immunization programmes of many countries. Recognizing the critical need for vaccine safety and pharmacovigilance; WHO has been supporting individual and institutional capacity building in the Region to strengthen the monitoring and response to adverse events following immunization through implementation of the Global Vaccine Safety Blueprint. This framework is discussed along with general points about the importance of ensuring vaccine safety and the system needed to enable this. The article ends with a brief overview of the status of vaccine safety and pharmacovigilance and the key priorities for countries in the Region for the immediate future

Age-related pattern and monocyte-acquired haemozoin associated production of erythropoietin in children with severe malarial anaemia in Ghana.

BACKGROUND: Malaria continues to be a global health challenge, affecting more than half the world's population and causing approximately 660,000 deaths annually. The majority of malaria cases are caused by Plasmodium falciparum and occur in sub-Saharan Africa. One of the major complications asscociated with malaria is severe anaemia, caused by a cycle of haemoglobin digestion by the parasite. Anaemia due to falciparum malaria in children has multifactorial pathogenesis, which includes suppression of bone marrow activity. Recent studies have shown that haemozoin, which is a by-product of parasite haemoglobin digestion, may play an important role in suppression of haemoglobin production, leading to anaemia. In this study we correlated the levels of erythropoietin (EPO), as an indicator of stimulation of haemoglobin production, to the levels of monocyte acquired haemozoin in children with both severe and uncomplicated malaria. There was a significantly negative correlation between levels of haemozoin-containing monocytes and EPO, which may suggest that haemozoin suppresses erythropoiesis in severe malaria. A multiple linear regression analysis and simple bar was used to investigate associations between various haematological parameters. METHODS: To examine the levels of erythropoietin in the age categories, the levels of erythropoietin was measured using a commercial Enyme-Linked Immunosorbent Assay (ELISA). Giemsa-stained blood smears were used to determine percentage pigment containing monocytes. The haemozoin containing monocytes was expressed as a percentage of the total number of monocytes. To obtain the number of haemozoin containing monocytes/µL the percentage of haemozoin containing monocytes was multiplied by the absolute number of monocytes/µL from the automated haematology analyzer. RESULTS: The levels of erythropoietin in younger children (<3 years) was significantly higher than in older children with a similar degree of malaria anaemia (Hb levels) (p < 0.005). Haemozoin-containing monocytes were relatively higher in severe malaria anaemia patients compared to those with uncomplicated malaria (p < 0.001). CONCLUSIONS: Age purportedly has a direct effect on background levels of erythropoietin. With corresponding decreased levels of erythropoietin in older children with the same degree of severe malarial anaemia, conceivably, the bone marrows of younger children with acute malaria may be less sensitive to erythropoietin.

Prevalence of peripheral blood parasitaemia, anaemia and low birthweight among pregnant women in a suburban area in coastal Ghana.

INTRODUCTION: Malaria and anaemia have adverse effects in pregnant women and on the birth weight of infants in malaria endemic areas. P. falciparum malaria, the most virulent species continues to be a major health problem in sub-Saharan Africa. This study was carried out to establish the prevalence of pregnancy-associated malaria and its associated consequences including maternal anaemia and low birthweight (LBW) deliveries and placental malaria among pregnant women in a sub-urban area in coastal Ghana. METHODS: A facility-based investigation was carried out among 320 pregnant women seeking antenatal care in a hospital in suburban coastal Ghana. Information on the use of Insecticide Treated Nets (ITNs) and Intermittent Preventive Treatment in pregnancy (IPTp) were collected using a structured questionnaire at enrollment. Venous blood was collected for microscopy and screening for Glucose 6-phosphate dehydrogenase (G6PD) deficiency. Haemoglobin concentration was obtained from an automatic blood analyzer. Placental smears and birth weight measurements were taken at delivery. RESULTS: The prevalence of Plasmodium falciparum parasitaemia was 5%. The mean haemoglobin (Hb) level at registration was 11.44 g/dL (95% CI 11.29 - 11.80). Placental blood parasitaemia and low birthweight were 2.5% and 3% respectively. ITN possession was 31.6% with 5.4% usage. The IPTp coverage was 55%. CONCLUSION: The prevalence of malaria and anaemia among the pregnant women were low at enrollment. Placental blood parasitaemia and LBW at delivery were also low. These are clear indications of the high coverage of the IPTp. Increase in ITN use will further improve birthweight outcomes and reduce placental malaria.

Effective vaccine safety systems in all countries: a challenge for more equitable access to immunization.

Serious vaccine-associated adverse events are rare. To further minimize their occurrence and to provide adequate care to those affected, careful monitoring of immunization programs and case management is required. Unfounded vaccine safety concerns have the potential of seriously derailing effective immunization activities. To address these issues, vaccine pharmacovigilance systems have been developed in many industrialized countries. As new vaccine products become available to prevent new diseases in various parts of the world, the demand for effective pharmacovigilance systems in low- and middle-income countries (LMIC) is increasing. To help establish such systems in all countries, WHO developed the Global Vaccine Safety Blueprint in 2011. This strategic plan is based on an in-depth analysis of the vaccine safety landscape that involved many stakeholders. This analysis reviewed existing systems and international vaccine safety activities and assessed the financial resources required to operate them. The Blueprint sets three main strategic goals to optimize the safety of vaccines through effective use of pharmacovigilance principles and methods: to ensure minimal vaccine safety capacity in all countries; to provide enhanced capacity for specific circumstances; and to establish a global support network to assist national authorities with capacity building and crisis management. In early 2012, the Global Vaccine Safety Initiative (GVSI) was launched to bring together and explore synergies among on-going vaccine safety activities. The Global Vaccine Action Plan has identified the Blueprint as its vaccine safety strategy. There is an enormous opportunity to raise awareness for vaccine safety in LMIC and to garner support from a large number of stakeholders for the GVSI between now and 2020. Synergies and resource mobilization opportunities presented by the Decade of Vaccines can enhance monitoring and response to vaccine safety issues, thereby leading to more equitable delivery of vaccines worldwide.