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.

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.

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.

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.

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.

Joint reviews and inspections: strategic forms of collaboration for strengthening the regulatory oversight of vaccine clinical trials in Africa.

Vaccine developers are required to submit a clinical trial application to the authorities in each country where a clinical trial will be conducted. The application has to be made both to the relevant Ethics Committees and to the National Regulatory Authorities, and only after appropriate clearance by both can a clinical trial commence. This paper describes two specific strategies, joint reviews of vaccine clinical trial applications and joint inspections of clinical trial sites by groups of countries, as part of a WHO initiative to strengthen capacity for the regulatory oversight of clinical trials in Africa. Significantly, the joint reviews and inspections contributed to reinforcing the capacities of the regulatory authorities as well as defining an efficient process to maximize the quality of the reviews and minimize undue delays. Finally we will suggest complementary mechanisms to overcome the potential limitations of joint reviews and inspections.

Regulatory oversight of clinical trials in Africa: progress over the past 5 years.

Randomized controlled clinical trials represent the best way to establish the therapeutic or preventive value of medicines. This decade has seen a strong shift in the location of clinical trials from industrialized countries to developing countries, including many in Africa. However, without independent strong regulatory and ethical oversight of clinical trials the safety of research subjects, and scientific integrity of clinical data cannot be verified. This article draws up a portrait of clinical trials regulation in Africa in support of development of priority medicines, highlights challenges and presents the progress made by countries under WHO guidance over the past 5 years.

Cohort study of the association of antibody levels to AMA1, MSP119, MSP3 and GLURP with protection from clinical malaria in Ghanaian children.

BACKGROUND: Antigen-specific antibody-mediated immune responses play an important role in natural protection against clinical malaria, but conflicting estimates of this association have emerged from immuno-epidemiological studies in different geographical settings. This study was aimed at assessing in a standardized manner the relationship between the antibody responses to four malaria vaccine candidate antigens and protection from clinical malaria, in a cohort of Ghanaian children. METHODS: Standardized ELISA protocols were used to measure isotype and IgG subclass levels to Apical Membrane Antigen 1 (AMA1), Merozoite Surface Protein 1-19 (MSP119), Merozoite Surface Protein 3 (MSP3) and Glutamate Rich Protein (GLURP) antigens in plasma samples from 352 Ghanaian children, aged three to 10 years with subsequent malaria surveillance for nine months. This is one of a series of studies in different epidemiological settings using the same standardized ELISA protocols to permit comparisons of results from different laboratories. RESULTS: The incidence rate of malaria was 0.35 episodes per child per year. Isotype and IgG subclasses for all antigens investigated increased with age, while the risk of malaria decreased with age. After adjusting for age, higher levels of IgG to GLURP, MSP119, MSP3 and IgM to MSP119, MSP3 and AMA1 were associated with decreased malaria incidence. Of the IgG subclasses, only IgG1 to MSP119 was associated with reduced incidence of clinical malaria. A previous study in the same location failed to find an association of antibodies to MSP119 with clinical malaria. The disagreement may be due to differences in reagents, ELISA and analytical procedures used in the two studies. When IgG, IgM and IgG subclass levels for all four antigens were included in a combined model, only IgG1 [(0.80 (0.67-0.97), p = 0.018)] and IgM [(0.48 (0.32-0.72), p < 0.001)] to MSP119 were independently associated with protection from malaria. CONCLUSION: Using standardized procedures, the study has confirmed the importance of antibodies to MSP119 in reducing the risk of clinical malaria in Ghanaian children, thus substantiating its potential as a malaria vaccine candidate.

CyProQuant-PCR: a real time RT-PCR technique for profiling human cytokines, based on external RNA standards, readily automatable for clinical use.

BACKGROUND: Real-time PCR is becoming a common tool for detecting and quantifying expression profiling of selected genes. Cytokines mRNA quantification is widely used in immunological research to dissect the early steps of immune responses or pathophysiological pathways. It is also growing to be of clinical relevancy to immuno-monitoring and evaluation of the disease status of patients. The techniques currently used for "absolute quantification" of cytokine mRNA are based on a DNA standard curve and do not take into account the critical impact of RT efficiency. RESULTS: To overcome this pitfall, we designed a strategy using external RNA as standard in the RT-PCR. Use of synthetic RNA standards, by comparison with the corresponding DNA standard, showed significant variations in the yield of retro-transcription depending the target amplified and the experiment. We then developed primers to be used under one single experimental condition for the specific amplification of human IL-1beta, IL-4, IL-10, IL-12p40, IL-13, IL-15, IL-18, IFN-gamma, MIF, TGF-beta1 and TNF-alpha mRNA. We showed that the beta-2 microglobulin (beta2-MG) gene was suitable for data normalisation since the level of beta2-MG transcripts in naive PBMC varied less than 5 times between individuals and was not affected by LPS or PHA stimulation. The technique, we named CyProQuant-PCR (Cytokine Profiling Quantitative PCR) was validated using a kinetic measurement of cytokine transcripts under in vitro stimulation of human PBMC by lipopolysaccharide (LPS) or Staphylococcus aureus strain Cowan (SAC). Results obtained show that CyProQuant-PCR is powerful enough to precociously detect slight cytokine induction. Finally, having demonstrated the reproducibility of the method, it was applied to malaria patients and asymptomatic controls for the quantification of TGF-beta1 transcripts and showed an increased capacity of cells from malaria patients to accumulate TGF-beta1 mRNA in response to LPS. CONCLUSION: The real-time RT-PCR technique based on a RNA standard curve, CyProQuant-PCR, outlined here, allows for a genuine absolute quantification and a simultaneous analysis of a large panel of human cytokine mRNA. It represents a potent and attractive tool for immunomonitoring, lending itself readily to automation and with a high throughput. This opens the possibility of an easy and reliable cytokine profiling for clinical applications.