Modelling the Cost-Effectiveness of Hepatitis A in South Africa.

The World Health Organization (WHO) recommends the consideration of introducing routine hepatitis A vaccination into national immunization schedules for children ≥ 1 years old in countries with intermediate HAV endemicity. Recent data suggest that South Africa is transitioning from high to intermediate HAV endemicity, thus it is important to consider the impact and cost of potential routine hepatitis A vaccination strategies in the country. An age-structured compartmental model of hepatitis A transmission was calibrated with available data from South Africa, incorporating direct costs of hepatitis A treatment and vaccination. We used the calibrated model to evaluate the impact and costs of several childhood hepatitis A vaccination scenarios from 2023 to 2030. We assessed how each scenario impacted the burden of hepatitis A (symptomatic hepatitis A cases and mortality) as well as calculated the incremental cost per DALY averted as compared to the South African cost-effectiveness threshold. All costs and outcomes were discounted at 5%. For the modelled scenarios, the median estimated cost of the different vaccination strategies ranged from USD 1.71 billion to USD 2.85 billion over the period of 2023 to 2030, with the cost increasing for each successive scenario and approximately 39-52% of costs being due to vaccination. Scenario 1, which represented the administration of one dose of the hepatitis A vaccine in children < 2 years old, requires approximately 5.3 million vaccine doses over 2023-2030 and is projected to avert a total of 136,042 symptomatic cases [IQR: 88,842-221,483] and 31,106 [IQR: 22,975-36,742] deaths due to hepatitis A over the period of 2023 to 2030. The model projects that Scenario 1 would avert 8741 DALYs over the period of 2023 to 2030; however, it is not cost-effective against the South African cost-effectiveness threshold with an ICER per DALY averted of USD 21,006. While Scenario 3 and 4 included the administration of more vaccine doses and averted more symptomatic cases of hepatitis A, these scenarios were absolutely dominated owing to the population being infected before vaccination through the mass campaigns at older ages. The model was highly sensitive to variation of access to liver transplant in South Africa. When increasing the access to liver transplant to 100% for the baseline and Scenario 1, the ICER for Scenario 1 becomes cost-effective against the CET (ICER = USD 2425). Given these findings, we recommend further research is conducted to understand the access to liver transplants in South Africa and better estimate the cost of liver transplant care for hepatitis A patients. The modelling presented in this paper has been used to develop a user-friendly application for vaccine policy makers to further interrogate the model outcomes and consider the costs and benefits of introducing routine hepatitis A vaccination in South Africa.

Expanding the reach of vaccinology training in Africa: leveraging the success of the Annual African Vaccinology Course.

Introduction: It is estimated that one in five African children lack access to recommended life-saving vaccines. This situation has been exacerbated by the COVID-19 pandemic which disrupted routine immunization services in several parts of the region. To better support recovery efforts and get immunization programmes back on track, policy makers, programme managers, immunization providers and academics need continuous upskilling. Unfortunately, the vaccinology training needed by these cadres remains limited and oftentimes inaccessible within our context. In addition, cadres should be continuously updated on advances in vaccinology so as to keep abreast with this rapidly evolving field. This calls for new and accessible approaches to training vaccinologists in Africa where the demand is high. Methods: The aim of this proof-of-concept study was to ascertain the training needs of alumni of the Annual African Vaccinology Course and assess the effectiveness of an online webinar series in meeting those needs. Results: We found that alumni from across Africa required refresher training to gain up-to-date information about new developments in vaccinology, leverage opportunities to reinforce and consolidate their knowledge, and exchange country-specific experiences with their counterparts. A prominent motivation for refresher training was the rapid developments and challenges brought on by the COVID-19 pandemic. Drawing on the expressed needs of our alumni, we developed a webinar training series. This series aimed to provide participants with training on current and emerging trends in vaccinology with a focus on the regional context. Online participation in the webinar series was found to be comparable to previous in-person training, reaching a diverse group of cadres, and allowing for participation of a richer global faculty due to fewer cost constraints. Further to this, a post-training survey indicated that generally, alumni training needs were successfully met. Discussion: The findings suggest that an online approach can be used to expand the reach of vaccinology training in Africa.

The COVID-19 experience in Africa and the Middle East.

AIMS: The experience of Africa and the Middle East with the COVID-19 pandemic has been unique, which can be attributed, in part, to disparities within these regions. METHODS: This review describes COVID-19 emergence, epidemiology, vaccination strategies and uptake, and lessons learned within Africa and the Middle East. RESULTS: For vaccines to be effective in curtailing COVID-19, a global approach to vaccination is required. However, vaccine inequities exist in Africa and the Middle East, with countries with better healthcare infrastructure having advantages in acquiring and delivering vaccines. Currently, the greatest challenges to the effective rollout of COVID-19 vaccination in Africa and the Middle East are funding, healthcare resources, infrastructure, and vaccine access and hesitancy. While mechanisms to support vaccine access in low- and middle-income countries are initiated, their success has been limited and vaccine inequity is arguably the biggest hurdle to a successful response. The collection of surveillance data at both regional and global levels is also critical in response to the pandemic and provides the necessary tools and data to drive vaccine development. CONCLUSION: These considerations of the learnings can help refine the pandemic response and inform countries to better prepare for similar public health emergencies.

Learnings from previous epidemics enabled African nations to respond rapidly and cohesively to the emergence of the COVID-19 pandemic; similarly, nations in the Middle East also drew on previous outbreaks of other viruses to respond robustly, although perhaps less cohesively than the African nations.The populations of Africa and the Middle East share many of the same comorbidities (with the exception of HIV in Africa) and risk factors as other regions of the world, and both have experienced multiple waves of COVID-19 infections as new genetic variants of SARS-CoV-2 have evolved.African and Middle Eastern nations have had a wide range of success in vaccine rollout and uptake due to several factors including national wealth/income, populations with varying levels of vaccine hesitancy, and a range of access to private and/or public healthcare.Current challenges, some of which are being addressed by governmental and international entities, include a lack of vaccine- and surveillance-related infrastructure, needed improvement in regulatory standards, and persistent financial strains on healthcare systems that hinder improvements in vaccine delivery.

A retrospective study assessing the clinical outcomes and costs of acute hepatitis A in Cape Town, South Africa.

BACKGROUND: While some evidence has been demonstrated the cost-effectiveness of routine hepatitis A vaccination in middle-income countries, the evidence is still limited in other settings including in South Africa. Given this, the evidence base around the cost of care for hepatitis A needs to be developed towards considerations of introducing hepatitis A vaccines in the national immunisation schedule and guidelines. OBJECTIVES: To describe the severity, clinical outcomes, and cost of hepatitis A cases presenting to two tertiary healthcare centers in Cape Town, South Africa. METHODS: We conducted a retrospective folder review of patients presenting with hepatitis A at two tertiary level hospitals providing care for urban communities of metropolitan Cape Town, South Africa. Patients included in this folder review tested positive for hepatitis A immunoglobulin M between 1 January 2008 and 1 March 2018. RESULTS: In total, 239 folders of hepatitis A paediatric patients < 15 years old and 212 folders of hepatitis A adult patients [Formula: see text] 15 years old were included in the study. Before presenting for tertiary level care, more than half of patients presented for an initial consultation at either a community clinic or general physician. The mean length of hospital stay was 7.45 days for adult patients and 3.11 days for paediatric patients. Three adult patients in the study population died as a result of hepatitis A infection and 29 developed complicated hepatitis A. One paediatric patient in the study population died as a result of hepatitis A infection and 27 developed complicated hepatitis A, including 4 paediatric patients diagnosed with acute liver failure. The total cost per hepatitis A hospitalisation was $1935.41 for adult patients and $563.06 for paediatric patients, with overhead costs dictated by the length of stay being the largest cost driver. CONCLUSION: More than 1 in every 10 hepatitis A cases (13.3%) included in this study developed complicated hepatitis A or resulted in death. Given the severity of clinical outcomes and high costs associated with hepatitis A hospitalisation, it is important to consider the introduction of hepatitis A immunisation in the public sector in South Africa to potentially avert future morbidity, mortality, and healthcare spending.

Developing vaccinology expertise for Africa: fifteen years and counting.

For 15 years, the Annual African Vaccinology Course (AAVC) hosted by the Vaccines for Africa Initiative, has been at the forefront of vaccinology training in Africa. The AAVC was developed in 2005 in response to the growing demand for vaccinology training in Africa. To date, 958 policy makers, immunization managers, public and private health practitioners, scientists, postgraduate and postdoctoral students have been trained. These participants are from 44 of the 54 African countries. The course content covers diverse topics such as considerations for new vaccine introduction, mathematical modelling, and emerging and re-emerging vaccine preventable diseases. As the landscape of vaccinology continues to evolve, the AAVC aims to expand the reach of vaccinology training using blended learning approaches which will incorporate online and face-to-face formats, while expanding access to this popular course. Ultimately, the AAVC endeavours to develop a big pool of vaccinology expertise in Africa and to strengthen regional ownership for immunization programmes.

Co-detection of Bordetella pertussis and other respiratory organisms in children hospitalised with lower respiratory tract infection.

Multiple potential pathogens are frequently co-detected among children with lower respiratory tract infection (LRTI). Evidence indicates that Bordetella pertussis has an important role in the aetiology of LRTI. We aimed to study the association between B. pertussis and other respiratory pathogens in children hospitalised with severe LRTI, and to assess clinical relevance of co-detection. Nasopharyngeal (NP) swabs and induced sputa (IS) were tested with a B. pertussis specific PCR; additionally, IS was tested for other pathogens using a multiplex PCR. We included 454 children, median age 8 months (IQR 4-18), 31 (7%) of whom tested positive for B. pertussis. Children with B. pertussis had more bacterial pathogens detected (3 versus 2; P < 0.001). While B. pertussis showed no association with most pathogens, it was independently associated with Chlamydia pneumoniae, Mycoplasma pneumoniae and parainfluenza viruses with adjusted risk ratios of 4.01 (1.03-15.64), 4.17 (1.42-12.27) and 2.13 (1.03-4.55), respectively. There was a consistent increased risk of severe disease with B. pertussis. Patterns indicated even higher risks when B. pertussis was co-detected with any of the three organisms although not statistically significant. Improving vaccine coverage against B. pertussis would impact not only the incidence of pertussis but also that of severe LRTI generally.

Risk factors for Bordetella pertussis disease in hospitalized children.

INTRODUCTION: Despite a resurgence of disease, risk factors for pertussis in children in low and middle-income countries are poorly understood. This study aimed to investigate risk factors for pertussis disease in African children hospitalized with severe LRTI. METHODS: A prospective study of children hospitalized with severe LRTI in Cape Town, South Africa was conducted over a one-year period. Nasopharyngeal and induced sputum samples from child and nasopharyngeal sample from caregiver were tested for Bordetella pertussis using PCR (IS481+/hIS1001). History and clinical details were documented. RESULTS: 460 children with a median age of 8 (IQR 4-18) months were enrolled. B. pertussis infection was confirmed in 32 (7.0%). The adjusted risk of confirmed pertussis was significantly increased if infants were younger than two months [aRR 2.37 (95% CI 1.03-5.42]), HIV exposed but uninfected (aRR 3.53 [95% CI 1.04-12.01]) or HIV infected (aRR 4.35 [95% CI 1.24-15.29]). Mild (aRR 2.27 [95% CI 1.01-5.09]) or moderate (aRR 2.70 [95% CI 1.13-6.45]) under-nutrition in the children were also associated with higher risk. The highest adjusted risk occurred in children whose caregivers had B. pertussis detected from nasopharyngeal swabs (aRR 13.82 [95% CI 7.76-24.62]). Completion of the primary vaccine schedule (three or more doses) was protective (aRR 0.28 [95% CI 0.10-0.75]). CONCLUSIONS: HIV exposure or infection, undernutrition as well as detection of maternal nasal B. pertussis were associated with increased risk of pertussis in African children, especially in young infants. Completed primary vaccination was protective. There is an urgent need to improve primary pertussis vaccine coverage in low and middle-income countries. Pertussis vaccination of pregnant women, especially those with HIV infection should be prioritized.

Characterisation of the environmental presence of hepatitis A virus in low-income and middle-income countries: a systematic review and meta-analysis.

OBJECTIVE: To characterise the environmental presence of hepatitis A virus (HAV) in low- and middle-income countries (LMICs). DESIGN: Systematic review and meta-analysis. DATA SOURCES: EBSCOhost, PubMed, Scopus, ScienceDirect, Clinical Key and Web of Science were searched. Grey literature was sourced by searching the following electronic databases: Open Grey, National Health Research Database and Mednar. ELIGIBILITY CRITERIA FOR INCLUDING STUDIES: Cross-sectional and ecological studies reporting HAV environmental presence and conducted in LMICs between January 2005 and May 2019, irrespective of language of publication. DATA EXTRACTION AND DATA SYNTHESIS: Relevant data were extracted from articles meeting the inclusion criteria, and two reviewers independently assessed the studies for risk of bias. High heterogeneity of the extracted data led to the results being reported narratively. RESULTS: A total of 2092 records were retrieved, of which 33 met the inclusion criteria. 21 studies were conducted in Tunisia, India and South Africa, and the rest were from Philippines, Pakistan, Morocco, Chad, Mozambique, Kenya and Uganda. In Tunisian raw sewage samples, the prevalence of HAV ranged from 12% to 68%, with an estimated average detection rate of 50% (95% CI 25 to 75), whereas HAV detection in treated sewage in Tunisia ranged from 23% to 65%, with an estimated average detection rate of 38% (95% CI 20 to 57). The prevalence of HAV detection in South African treated sewage and surface water samples ranged from 4% to 37% and from 16% to 76%, with an estimated average detection rates of 15% (95% CI 1 to 29) and 51% (95% CI 21 to 80), respectively. Over the review period, the estimated average detection rate of environmental HAV presence appeared to have declined by 10%. CONCLUSION: The quality of included studies was fair, but sampling issues and paucity of data limited the strength of the review findings. PROSPERO REGISTRATION NUMBER: CRD42019119592.

The burden of laboratory-confirmed pertussis in low- and middle-income countries since the inception of the Expanded Programme on Immunisation (EPI) in 1974: a systematic review and meta-analysis.

BACKGROUND: An effective vaccine against Bordetella pertussis was introduced into the Expanded Programme on Immunisation (EPI) by WHO in 1974, leading to a substantial global reduction in pertussis morbidity and mortality. In low- and middle-income countries (LMICs), however, the epidemiology of pertussis remains largely unknown. This impacts negatively on pertussis control strategies in these countries. This study aimed to systematically and comprehensively review published literature on the burden of laboratory-confirmed pertussis in LMICs over the 45 years of EPI. METHODS: Electronic databases were searched for relevant literature (1974 to December 2018) using common and MeSH terms for pertussis. Studies using PCR, culture or paired serology to confirm Bordetella pertussis and parapertussis in symptomatic individuals were included if they had clearly defined numerators and denominators to determine prevalence and mortality rates. RESULTS: Eighty-two studies (49,167 participants) made the inclusion criteria. All six WHO regions were represented with most of the studies published after 2010 and involving mainly upper middle-income countries (n = 63; 77%). PCR was the main diagnostic test after the year 2000. The overall median point prevalence of PCR-confirmed Bordetella pertussis was 11% (interquartile range (IQR), 5-27%), while culture-confirmed was 3% (IQR 1-9%) and paired serology a median of 17% (IQR 3-23%) over the period. On average, culture underestimated prevalence by 85% (RR = 0.15, 95% CI, 0.10-0.22) compared to PCR in the same studies. Risk of pertussis increased with HIV exposure [RR, 1.4 (95% CI, 1.0-2.0)] and infection [RR, 2.4 (95% CI, 1.1-5.1)]. HIV infection and exposure were also related to higher pertussis incidences, higher rates of hospitalisation and pertussis-related deaths. Pertussis mortality and case fatality rates were 0.8% (95% CI, 0.4-1.4%) and 6.5% (95% CI, 4.0-9.5%), respectively. Most deaths occurred in infants less than 6 months of age. CONCLUSIONS: Despite the widespread use of pertussis vaccines, the prevalence of pertussis remains high in LMIC over the last three decades. There is a need to increase access to PCR-based diagnostic confirmation in order to improve surveillance. Disease control measures in LMICs must take into account the persistent significant infant mortality and increased disease burden associated with HIV infection and exposure.

Systematic review of the global epidemiology of viral-induced acute liver failure.

OBJECTIVES: The aetiology and burden of viral-induced acute liver failure remains unclear globally. It is important to understand the epidemiology of viral-induced ALF to plan for clinical case management and case prevention. PARTICIPANTS: This systematic review was conducted to synthesize data on the relative contribution of different viruses to the aetiology of viral-induced acute liver failure in an attempt to compile evidence that is currently missing in the field. EBSCOhost, PubMed, ScienceDirect, Scopus and Web of Science were searched for relevant literature published from 2009 to 2019. The initial search was run on 9 April 2019 and updated via PubMed on 30 September 2019 with no new eligible studies to include. Twenty-five eligible studies were included in the results of this review. RESULTS: This systematic review estimated the burden of acute liver failure after infection with hepatitis B virus, hepatitis A virus, hepatitis C virus, hepatitis E virus, herpes simplex virus/human herpesvirus, cytomegalovirus, Epstein-Barr virus and parvovirus B19. Data were largely missing for acute liver failure after infection with varicella-zostervirus, human parainfluenza viruses, yellow fever virus, coxsackievirus and/or adenovirus. The prevalence of hepatitis A-induced acute liver failur was markedly lower in countries with routine hepatitis A immunisation versus no routine hepatitis A immunisation. Hepatitis E virus was the most common aetiological cause of viral-induced acute liver failure reported in this review. In addition, viral-induced acute liver failure had poor outcomes as indicated by high fatality rates, which appear to increase with poor economic status of the studied countries. CONCLUSIONS: Immunisation against hepatitis A and hepatitis B should be prioritised in low-income and middle-income countries to prevent high viral-induced acute liver failure mortality rates, especially in settings where resources for managing acute liver failure are lacking. The expanded use of hepatitis E immunisation should be explored as hepatitis E virus was the most common cause of acute liver failure. REGISTRATION: PROSPERO registration number: CRD42017079730.

Diagnostic limitations of clinical case definitions of pertussis in infants and children with severe lower respiratory tract infection.

INTRODUCTION: Diagnosis of pertussis is challenging especially in infants. Most low and middle-income countries (LMIC) lack resources for laboratory confirmation, relying largely on clinical diagnosis alone for both case management and surveillance. This necessitates robust clinical case definitions. OBJECTIVES: This study assesses the accuracy of clinical case definitions with and without lymphocytosis in diagnosing pertussis in children with severe lower respiratory tract infection (LRTI) in a LMIC setting. METHODS: Children hospitalized with severe LRTI in a South African hospital were prospectively enrolled and evaluated for pertussis using PCR on respiratory samples. Clinical signs and differential white cell counts were recorded. Sensitivity and specificity of pertussis clinical diagnosis using WHO and Global Pertussis Initiative (GPI) criteria; and with addition of lymphocytosis were assessed with PCR as the reference standard. RESULTS: 458 children <10 years were enrolled. Bordetella pertussis infection was confirmed in 32 (7.0%). For WHO criteria, sensitivity was 78.1% (95% CI 60.7-89.2%) and specificity 15.5% (95% CI 12.4-19.3%); for GPI sensitivity was 34.4% (95% CI 20.1-52.1) and specificity 64.8% (95% CI 60.1-69.2%). Area under the curve (AUC) on receiver operating character (ROC) analysis was 0.58 (95% CI 0.46-0.70 for WHO criteria, and 0.72 (95% CI 0.56-0.88) for GPI with highest likelihood ratios of 5.33 and 4.42 respectively. Diagnostic accuracy was highest between five and seven days of symptoms for both criteria. Lymphocytosis had sensitivity of 31.3% (95% CI 17.5-49.3%) and specificity of 70.7% (95% CI 66.1-74.8%) and showed a marginal impact on improving clinical criteria. CONCLUSION: Clinical criteria lack accuracy for diagnosis and surveillance of pertussis. Non-outbreak settings should consider shorter durations in clinical criteria. New recommendations still fall short of what is required for a viable clinical screening test which means the need to improve access to laboratory diagnostic support remains crucial.

Improving vaccination uptake among adolescents.

BACKGROUND: Adolescent vaccination has received increased attention since the Global Vaccine Action Plan's call to extend the benefits of immunisation more equitably beyond childhood. In recent years, many programmes have been launched to increase the uptake of different vaccines in adolescent populations; however, vaccination coverage among adolescents remains suboptimal. Therefore, understanding and evaluating the various interventions that can be used to improve adolescent vaccination is crucial. OBJECTIVES: To evaluate the effects of interventions to improve vaccine uptake among adolescents. SEARCH METHODS: In October 2018, we searched the following databases: CENTRAL, MEDLINE Ovid, Embase Ovid, and eight other databases. In addition, we searched two clinical trials platforms, electronic databases of grey literature, and reference lists of relevant articles. For related systematic reviews, we searched four databases. Furthermore, in May 2019, we performed a citation search of five other websites. SELECTION CRITERIA: Randomised trials, non-randomised trials, controlled before-after studies, and interrupted time series studies of adolescents (girls or boys aged 10 to 19 years) eligible for World Health Organization-recommended vaccines and their parents or healthcare providers. DATA COLLECTION AND ANALYSIS: Two review authors independently screened records, reviewed full-text articles to identify potentially eligible studies, extracted data, and assessed risk of bias, resolving discrepancies by consensus. For each included study, we calculated risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CI) where appropriate. We pooled study results using random-effects meta-analyses and assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included 16 studies (eight individually randomised trials, four cluster randomised trials, three non-randomised trials, and one controlled before-after study). Twelve studies were conducted in the USA, while there was one study each from: Australia, Sweden, Tanzania, and the UK. Ten studies had unclear or high risk of bias. We categorised interventions as recipient-oriented, provider-oriented, or health systems-oriented. The interventions targeted adolescent boys or girls or both (seven studies), parents (four studies), and providers (two studies). Five studies had mixed participants that included adolescents and parents, adolescents and healthcare providers, and parents and healthcare providers. The outcomes included uptake of human papillomavirus (HPV) (11 studies); hepatitis B (three studies); and tetanus-diphtheria-acellular-pertussis (Tdap), meningococcal, HPV, and influenza (three studies) vaccines among adolescents. Health education improves HPV vaccine uptake compared to usual practice (RR 1.43, 95% CI 1.16 to 1.76; I² = 0%; 3 studies, 1054 participants; high-certainty evidence). In addition, one large study provided evidence that a complex multi-component health education intervention probably results in little to no difference in hepatitis B vaccine uptake compared to simplified information leaflets on the vaccine (RR 0.98, 95% CI 0.97 to 0.99; 17,411 participants; moderate-certainty evidence). Financial incentives may improve HPV vaccine uptake compared to usual practice (RR 1.45, 95% CI 1.05 to 1.99; 1 study, 500 participants; low-certainty evidence). However, we are uncertain whether combining health education and financial incentives has an effect on hepatitis B vaccine uptake, compared to usual practice (RR 1.38, 95% CI 0.96 to 2.00; 1 study, 104 participants; very low certainty evidence). Mandatory vaccination probably leads to a large increase in hepatitis B vaccine uptake compared to usual practice (RR 3.92, 95% CI 3.65 to 4.20; 1 study, 6462 participants; moderate-certainty evidence). Provider prompts probably make little or no difference compared to usual practice, on completion of Tdap (OR 1.28, 95% CI 0.59 to 2.80; 2 studies, 3296 participants), meningococcal (OR 1.09, 95% CI 0.67 to 1.79; 2 studies, 3219 participants), HPV (OR 0.99, 95% CI 0.55 to 1.81; 2 studies, 859 participants), and influenza (OR 0.91, 95% CI 0.61 to 1.34; 2 studies, 1439 participants) vaccination schedules (moderate-certainty evidence). Provider education with performance feedback may increase the proportion of adolescents who are offered and accept HPV vaccination by clinicians, compared to usual practice. Compared to adolescents visiting non-participating clinicians (in the usual practice group), the adolescents visiting clinicians in the intervention group were more likely to receive the first dose of HPV during preventive visits (5.7 percentage points increase) and during acute visits (0.7 percentage points for the first and 5.6 percentage points for the second doses of HPV) (227 clinicians and more than 200,000 children; low-certainty evidence). A class-based school vaccination strategy probably leads to slightly higher HPV vaccine uptake than an age-based school vaccination strategy (RR 1.09, 95% CI 1.06 to 1.13; 1 study, 5537 participants; moderate-certainty evidence). A multi-component provider intervention (including an education session, repeated contacts, individualised feedback, and incentives) probably improves uptake of HPV vaccine compared to usual practice (moderate-certainty evidence). A multi-component intervention targeting providers and parents involving social marketing and health education may improve HPV vaccine uptake compared to usual practice (RR 1.41, 95% CI 1.25 to 1.59; 1 study, 25,869 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: Various strategies have been evaluated to improve adolescent vaccination including health education, financial incentives, mandatory vaccination, and class-based school vaccine delivery. However, most of the evidence is of low to moderate certainty. This implies that while this research provides some indication of the likely effect of these interventions, the likelihood that the effects will be substantially different is high. Therefore, additional research is needed to further enhance adolescent immunisation strategies, especially in low- and middle-income countries where there are limited adolescent vaccination programmes. In addition, it is critical to understand the factors that influence hesitancy, acceptance, and demand for adolescent vaccination in different settings. This is the topic of an ongoing Cochrane qualitative evidence synthesis, which may help to explain why and how some interventions were more effective than others in increasing adolescent HPV vaccination coverage.

Cytomegalovirus infection is a risk factor for tuberculosis disease in infants.

Immune activation is associated with increased risk of tuberculosis (TB) disease in infants. We performed a case-control analysis to identify drivers of immune activation and disease risk. Among 49 infants who developed TB disease over the first 2 years of life, and 129 healthy matched controls, we found the cytomegalovirus-stimulated (CMV-stimulated) IFN-γ response to be associated with CD8+ T cell activation (Spearman's rho, P = 6 × 10-8). A CMV-specific IFN-γ response was also associated with increased risk of developing TB disease (conditional logistic regression; P = 0.043; OR, 2.2; 95% CI, 1.02-4.83) and shorter time to TB diagnosis (Log Rank Mantel-Cox, P = 0.037). CMV+ infants who developed TB disease had lower expression of NK cell-associated gene signatures and a lower frequency of CD3-CD4-CD8- lymphocytes. We identified transcriptional signatures predictive of TB disease risk among CMV ELISpot-positive (area under the receiver operating characteristic [AUROC], 0.98, accuracy, 92.57%) and -negative (AUROC, 0.9; accuracy, 79.3%) infants; the CMV- signature was validated in an independent infant study (AUROC, 0.71; accuracy, 63.9%). A 16-gene signature that previously identified adolescents at risk of developing TB disease did not accurately classify case and control infants in this study. Understanding the microbial drivers of T cell activation, such as CMV, could guide new strategies for prevention of TB disease in infants.

The global epidemiology of viral-induced acute liver failure: a systematic review protocol.

INTRODUCTION: The burden of viral-induced acute liver failure (ALF) around the world still remains unclear, with little to no data collected regarding the disease incidence in general and synthesised data on the relative contribution of different viruses to the aetiology of ALF is missing in the field. The aim of this review is to estimate the burden (prevalence, incidence, mortality, hospitalisation) of ALF following infection HAV, HBV, HCV, HDV, HEV, EBV), HSV1, HSV2, VZV, parvo-virus B19, HPIVs, YFV, HVV-6, CMV, CA16 and/or HAdVs. Establishing the common aetiologies of viral-induced ALF, which vary geographically, is important so that: (1) treatment can be initiated quickly, (2) contraindications to liver transplant can be identified, (3) prognoses can be deterined more accurately, and most importantly, (4) vaccination against viral ALF aetiologies can be prioritised especially in under-resourced regions with public health risks associated with the relevant attributable diseases. METHODS AND ANALYSIS: EBSCOhost, PubMed, ScienceDirect, Scopus and Web of Science databases will be searched for relevant literature published and grey literature from 2009 up to 2019. Published cross-sectional and cohort studies will be eligible for inclusion in this review. Qualifying studies will be formally assessed for quality and risk of bias using a standardised scoring tool. Following standardised data extraction, meta-analyses will be carried out using STATA. Depending on characteristics of included studies, subgroup analyses and meta-regression analyses will be performed. This review will be reported according to Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. ETHICS AND DISSEMINATION: No ethics approval is required as the systematic review will use only published data already in the public domain. Findings will be disseminated through publication in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42018110309.

A systematic review of the epidemiology of hepatitis A in Africa.

BACKGROUND: Hepatitis A, caused by the hepatitis A virus (HAV), is a vaccine preventable disease. In Low and Middle-Income Countries (LMICs), poor hygiene and sanitation conditions are the main risk factors contributing to HAV infection. There have been, however, notable improvements in hygiene and sanitation conditions in many LMICs. As a result, there are studies showing a possible transition of some LMICs from high to intermediate HAV endemicity. The World Health Organization (WHO) recommends that countries should routinely collect, analyse and review local factors (including disease burden) to guide the development of hepatitis A vaccination programs. Up-to-date information on hepatitis A burden is, therefore, critical in aiding the development of country-specific recommendations on hepatitis A vaccination. METHODS: We conducted a systematic review to present an up-to-date, comprehensive synthesis of hepatitis A epidemiological data in Africa. RESULTS: The main results of this review include: 1) the reported HAV seroprevalence data suggests that Africa, as a whole, should not be considered as a high HAV endemic region; 2) the IgM anti-HAV seroprevalence data showed similar risk of acute hepatitis A infection among all age-groups; 3) South Africa could be experiencing a possible transition from high to intermediate HAV endemicity. The results of this review should be interpreted with caution as the reported data represents research work with significant sociocultural, economic and environmental diversity from 13 out of 54 African countries. CONCLUSIONS: Our findings show that priority should be given to collecting HAV seroprevalence data and re-assessing the current hepatitis A control strategies in Africa to prevent future disease outbreaks.

Assessment of humoral and cell-mediated immune responses to pertussis vaccination: a systematic review protocol.

INTRODUCTION: Globally, some studies show a resurgence of pertussis. The risks and benefits of using whole-cell pertussis (wP) or acellular pertussis (aP) vaccines in the control of the disease have been widely debated. Better control of pertussis will require improved understanding of the immune response to pertussis vaccines. Improved understanding and assessment of the immunity induced by pertussis vaccines is thus imperative. Several studies have documented different immunological outcomes to pertussis vaccination from an array of assays. We propose to conduct a systematic review of the different immunological assays and outcomes used in the assessment of the humoraland cell-mediated immune response following pertussis vaccination. METHODS AND ANALYSIS: The primary outcomes for consideration are quality and quantity of immune responses (humoral and cell-mediated) post-pertussis vaccination. Of interest as secondary outcomes are types of immunoassays used in assessing immune responses post-pertussis vaccination, types of biological samples used in assessing immune responses post-pertussis vaccination, as well as the types of antigens used to stimulate these samples during post-pertussis vaccination immune response assessments. Different electronic databases (including PubMed, Cochrane, EBSCO Host, Scopus and Web of Science) will be accessed for peer-reviewed published and grey literature evaluating immune responses to pertussis vaccines between 1990 and 2019. The quality of included articles will be assessed using standardised risk and quality assessment tools specific to the study design used in each article. Data extraction will be done using a data extraction form. The extracted data will be analysed using STATA V.14.0 and RevMan V.5.3 software. A subgroup analysis will be conducted based on the study population, type of vaccine (wP or aP) and type of immune response (cell-mediated or humoral). Guidelines for reporting systematic reviews in the revised 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement will be used in this study. ETHICS AND DISSEMINATION: Ethics approval is not required for this study as it is a systematic review. We will only make use of data already available in the public space. Findings will be reported via publication in a peer-reviewed journal and presented at scientific meetings and workshops. TRIAL REGISTRATION NUMBER: CRD42018102455.

An update on trends in the types and quality of childhood immunization research outputs from Africa 2011-2017: Mapping the evidence base.

BACKGROUND: Strengthening immunisation programmes in Africa remains a key strategy of improving vaccine coverage. Research plays a vital role in the design and implementation of strategic immunisation plans for improving vaccination coverage, in turn providing context specific evidence to inform policy and practice. We therefore updated an evidence map describing the types and quality of available literature on childhood immunisation in Africa from 2011 to 2017. METHODS: PubMed and Africa Wide databases were searched for English studies on childhood immunisation in Africa published from January 2011 to September 2017. Studies had to be conducted in humans and the reported information needed to be on either: vaccines; immunisation programmes; immunisation policies; or epidemiology of vaccine preventable diseases targeted by Expanded Programme on Immunisation vaccines. RESULTS: Out of 5567 studies retrieved, 797 studies from 165 journals met the inclusion criteria. During 2011-2017, 42 African countries contributed to research on childhood immunisation. Most studies were carried out in multiple countries (15.1%). Five countries contributed 41% of the total research output. Nigeria and South Africa contributed the highest proportion of studies at 12% and 11.4% respectively. The quantity of research output increased progressively from 2011 to 2015 after which there was a significant decline. CONCLUSION: There was a remarkable increase in childhood immunisation research in the period 2011 to 2017 when compared to the initial assessment. However, the reason for decline in research output from 2015 requires further investigation. Most childhood immunisation research was still generated by five countries as previously observed, highlighting the critical need for strategic investment in research capacities and improved collaboration between countries in Africa.

Comparison of adverse events following immunisation with acellular and whole-cell pertussis vaccines: A systematic review.

INTRODUCTION: Two types of vaccines are currently licensed for use against pertussis: whole-cell (wP) and acellular pertussis (aP). There is evidence that wP confers more durable immunity than aP, however wP has been more frequently associated with adverse events following immunisation (AEFI). A comparison of the frequency of AEFI with the first doses of wP and aP has not yet been clearly documented. This must be done in light of recent considerations to move towards a wP prime-aP boost vaccination strategy in low and middle-income countries. OBJECTIVES: To compare the frequency of AEFI associated with the first dose of the wP and aP vaccines. We also compared the frequency of AEFI associated with subsequent doses of wP. METHODS: This systematic review was carried out in strict accordance with the published protocol. RESULTS: High heterogeneity amongst included one-armed studies did not allow for pooling of prevalence estimates. The prevalence estimates of AEFI at first vaccine dose of wP ranged from 0 to 75%, while the prevalence estimates of AEFI at first vaccine dose of aP ranges from 0 to 39%. The prevalence estimates of adverse events following second and third vaccine dose of wP ranged from 0 to 71% and 0 to 61%, respectively. Risk ratios among two-armed studies showed an increased risk of adverse events with first dose of wP compared to aP [local reaction RR 2.73 (2.33, 3.21), injection site pain RR 4.15 (3.24, 5.31), injection site swelling RR 4.38 (2.70, 7.12), fever over 38 °C RR 9.21 (5.39, 15.76), drowsiness RR 1.34 (1.18, 1.52) and vomiting RR 1.28 (0.91, 1.79)]. CONCLUSION: Our results confirm that, when comparing the first dose, wP is more reacotgenic than aP. The proposed wP prime followed by aP boost pertussis vaccine strategy should be approached with caution.

Pertussis in Africa: Findings and recommendations of the Global Pertussis Initiative (GPI).

Pertussis remains a major cause of morbidity and mortality, particularly in infants and young children, and despite the availability of vaccines and pertinent national and international guidelines. The disease burden is more severe in low- and middle-income countries (LMICs), especially in the African continent. Pertussis is more prevalent among young infants in Africa. Poor or no pertussis surveillance, lack of disease awareness, diagnostic limitations, and competing health priorities are considered key contributory factors for this high pertussis burden in Africa. Most African countries use whole-cell pertussis (wP) vaccines, but coverage with three primary doses of diphtheria-tetanus-pertussis vaccines falls short of the World Health Organization's recommended goal of >90%. The Global Pertussis Initiative (GPI) works toward developing recommendations through systematic evaluation and prioritization of strategies to prevent pertussis-related infant and child deaths, as well as reducing global disease burden to acceptable national, regional, and local levels. For countries using wP vaccines, the GPI recommends continuing to use wP to improve primary and toddler booster vaccination coverage. Vaccination during pregnancy is the next priority when acellular pertussis (aP) vaccines and other resources are available that directly protect newborns too young to be vaccinated, followed by, in order of priority, booster doses in older children, adolescents, healthcare workers and finally, all adults. Improved surveillance should be a high priority for African LMICs assessing true disease burden and vaccine effectiveness to inform policy. More research is warranted to evaluate the safety and efficacy of wP and aP vaccines and strategies, and to determine their optimal use.

Varicella zoster virus-associated morbidity and mortality in Africa - a systematic review.

BACKGROUND: Varicella zoster virus (VZV) causes varicella and herpes zoster. These vaccine preventable diseases are common globally. Most available data on VZV epidemiology are from industrialised temperate countries and cannot be used to guide decisions on the immunization policy against VZV in Africa. This systematic review aims to review the published data on VZV morbidity and mortality in Africa. METHODS: All published studies conducted in Africa from 1974 to 2015 were eligible. Eligible studies must have reported any VZV epidemiological measure (incidence, prevalence, hospitalization rate and mortality rate). For inclusion in the review, studies must have used a defined VZV case definition, be it clinical or laboratory-based. RESULTS: Twenty articles from 13 African countries were included in the review. Most included studies were cross-sectional, conducted on hospitalized patients, and half of the studies used varying serological methods for diagnosis. VZV seroprevalence was very high among adults. Limited data on VZV seroprevalence in children showed very low seropositivity to anti-VZV antibodies. Co-morbidity with VZV was common. CONCLUSION: There is lack of quality data that could be used to develop VZV control programmes, including vaccination, in Africa. TRIAL REGISTRATION: PROSPERO 2015: CRD42015026144 .