ABSTRACT
Many low- and middle-income countries have been slow to introduce the pneumococcal conjugate vaccine (PCV) into their routine childhood immunization schedules despite a high burden of disease. We estimated the global economic surplus of PCV, defined as the sum of the net value to 194 countries (i.e., monetized health benefits minus net costs) and to vaccine manufacturers (i.e., profits). We further explored the distribution of global economic surplus across country income groups and manufacturers and the effect of different pricing strategies based on cross-subsidization, pooled procurement, and various tiered pricing mechanisms. We found that current PCV pricing policies disproportionately benefit high-income countries and manufacturers. Based on the 2021 birth cohort, high-income countries and manufacturers combined received 76.5% of the net economic benefits generated by the vaccine. Over the two decades of PCV availability, low- and middle-income countries have not received the full economic benefits of PCV. Cross-subsidization of the vaccine price for low- and middle-income countries and pooled procurement policies that would relate the vaccine price to the value of economic benefits generated for each country could reduce these inequalities. This analysis offers important considerations that may improve the equitable introduction and use of new and under-utilized vaccines.
ABSTRACT
Neutralizing antibodies (NAbs) are considered the primary mechanism of vaccine-mediated protection against human papillomaviruses (HPV), the causative agent of cervical cancer. However, the minimum level of NAb needed for protection is currently unknown. The HPV pseudovirion-based neutralization assay (PBNA) is the gold standard method for assessing HPV antibody responses but is time-consuming and labor-intensive. With the development of higher valency HPV vaccines, alternative serological assays with the capacity for multiplexing would improve efficiency and output. Here we describe a multiplex bead-based immunoassay to characterize the antibody responses to the seven oncogenic HPV types (HPV16/18/31/33/45/52/58) contained in the current licensed nonavalent HPV vaccine. This assay can measure antibody isotypes and subclasses (total IgG, IgM, IgA1-2, IgG1-4), and can be adapted to measure other antibody features (e.g., Fc receptors) that contribute to vaccine immunity. When tested with serum samples from unvaccinated and vaccinated individuals, we found high concordance between HPV-specific IgG using this multiplex assay and NAbs measured with PBNA. Overall, this assay is high-throughput, sample-sparing, and time-saving, providing an alternative to existing assays for the measurement and characterization of HPV antibody responses.
Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , Immunoglobulin G , Papillomavirus Infections , Papillomavirus Vaccines , Humans , Antibodies, Viral/blood , Immunoassay/methods , Female , Papillomavirus Infections/diagnosis , Papillomavirus Infections/immunology , Papillomavirus Infections/virology , Papillomavirus Vaccines/immunology , Papillomavirus Vaccines/administration & dosage , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Immunoglobulin G/blood , Papillomaviridae/immunology , Human Papillomavirus VirusesABSTRACT
Background: Pneumonia is the leading cause of death in young children globally and is prevalent in the Papua New Guinea highlands. We investigated clinical predictors of hypoxic pneumonia to inform local treatment guidelines in this resource-limited setting. Methods: Between 2013 and 2020, two consecutive prospective observational studies were undertaken enrolling children 0-4 years presenting with pneumonia to health-care facilities in Goroka Town, Eastern Highlands Province. Logistic regression models were developed to identify clinical predictors of hypoxic pneumonia (oxygen saturation <90% on presentation). Model performance was compared against established criteria to identify severe pneumonia. Findings: There were 2067 cases of pneumonia; hypoxaemia was detected in 36.1%. The strongest independent predictors of hypoxic pneumonia were central cyanosis on examination (adjusted odds ratio [aOR] 5.14; 95% CI 3.47-7.60), reduced breath sounds (aOR 2.92; 95% CI 2.30-3.71), and nasal flaring or grunting (aOR 2.34; 95% CI 1.62-3.38). While the model developed to predict hypoxic pneumonia outperformed established pneumonia severity criteria, it was not sensitive enough to be clinically useful at this time. Interpretation: Given signs and symptoms are unable to accurately detect hypoxia, all health care facilities should be equipped with pulse oximeters. However, for the health care worker without access to pulse oximetry, consideration of central cyanosis, reduced breath sounds, nasal flaring or grunting, age-specific tachycardia, wheezing, parent-reported drowsiness, or bronchial breathing as suggestive of hypoxaemic pneumonia, and thus severe disease, may prove useful in guiding management, hospital referral and use of oxygen therapy. Funding: Funded by Pfizer Global and the Bill & Melinda Gates Foundation.
ABSTRACT
The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. When activated by increases in ADP:ATP and/or AMP:ATP ratios (signalling energy deficit), AMPK acts to restore energy balance. Binding of AMP to one or more of three CBS repeats (CBS1, CBS3, CBS4) on the AMPK-γ subunit activates the kinase complex by three complementary mechanisms: (i) promoting α-subunit Thr172 phosphorylation by the upstream kinase LKB1; (ii) protecting against Thr172 dephosphorylation; (iii) allosteric activation. Surprisingly, binding of ADP has been reported to mimic the first two effects, but not the third. We now show that at physiologically relevant concentrations of Mg.ATP2- (above those used in the standard assay) ADP binding does cause allosteric activation. However, ADP causes only a modest activation because (unlike AMP), at concentrations just above those where activation becomes evident, ADP starts to cause competitive inhibition at the catalytic site. Our results cast doubt on the physiological relevance of the effects of ADP and suggest that AMP is the primary activator in vivo. We have also made mutations to hydrophobic residues involved in binding adenine nucleotides at each of the three γ subunit CBS repeats of the human α2ß2γ1 complex and examined their effects on regulation by AMP and ADP. Mutation of the CBS3 site has the largest effects on all three mechanisms of AMP activation, especially at lower ATP concentrations, while mutation of CBS4 reduces the sensitivity to AMP. All three sites appear to be required for allosteric activation by ADP.
Subject(s)
AMP-Activated Protein Kinases , Adenosine Diphosphate , Adenosine Monophosphate , Adenosine Diphosphate/metabolism , Adenosine Monophosphate/metabolism , Humans , Allosteric Regulation , AMP-Activated Protein Kinases/metabolism , AMP-Activated Protein Kinases/genetics , AMP-Activated Protein Kinases/chemistry , Ligands , Phosphorylation , Adenosine Triphosphate/metabolism , Enzyme Activation , Protein BindingABSTRACT
Neuronal mitochondria play important roles beyond ATP generation, including Ca2+ uptake, and therefore have instructive roles in synaptic function and neuronal response properties. Mitochondrial morphology differs significantly between the axon and dendrites of a given neuronal subtype, but in CA1 pyramidal neurons (PNs) of the hippocampus, mitochondria within the dendritic arbor also display a remarkable degree of subcellular, layer-specific compartmentalization. In the dendrites of these neurons, mitochondria morphology ranges from highly fused and elongated in the apical tuft, to more fragmented in the apical oblique and basal dendritic compartments, and thus occupy a smaller fraction of dendritic volume than in the apical tuft. However, the molecular mechanisms underlying this striking degree of subcellular compartmentalization of mitochondria morphology are unknown, precluding the assessment of its impact on neuronal function. Here, we demonstrate that this compartment-specific morphology of dendritic mitochondria requires activity-dependent, Ca2+ and Camkk2-dependent activation of AMPK and its ability to phosphorylate two direct effectors: the pro-fission Drp1 receptor Mff and the recently identified anti-fusion, Opa1-inhibiting protein, Mtfr1l. Our study uncovers a signaling pathway underlying the subcellular compartmentalization of mitochondrial morphology in dendrites of neurons in vivo through spatially precise and activity-dependent regulation of mitochondria fission/fusion balance.
Subject(s)
Neurons , Pyramidal Cells , Neurons/metabolism , Pyramidal Cells/physiology , Hippocampus , Axons/metabolism , Mitochondria/metabolism , Dendrites/physiologyABSTRACT
IMPORTANCE: Streptococcus pneumoniae (the pneumococcus) is a bacterial pathogen with the greatest burden of disease in Asia and Africa. The pneumococcal capsular polysaccharide has biological relevance as a major virulence factor as well as public health importance as it is the target for currently licensed vaccines. These vaccines have limited valency, covering up to 23 of the >100 known capsular types (serotypes) with higher valency vaccines in development. Here, we have characterized a new pneumococcal serotype, which we have named 33G. We detected serotype 33G in nasopharyngeal swabs (n = 20) from children and adults hospitalized with pneumonia, as well as healthy children in Mongolia. We show that the genetic, serological, and biochemical properties of 33G differ from existing serotypes, satisfying the criteria to be designated as a new serotype. Future studies should focus on the geographical distribution of 33G and any changes in prevalence following vaccine introduction.
Subject(s)
Pneumococcal Infections , Streptococcus pneumoniae , Child , Humans , Streptococcus pneumoniae/genetics , Pneumococcal Infections/microbiology , Serogroup , Pneumococcal Vaccines , AsiaABSTRACT
The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status activated by increases in AMP or ADP relative to ATP. Once activated, it phosphorylates targets that promote ATP-generating catabolic pathways or inhibit ATP-consuming anabolic pathways, helping to restore cellular energy balance. Analysis of human cancer genome studies reveals that the PRKAA2 gene (encoding the α2 isoform of the catalytic subunit) is often subject to mis-sense mutations in cancer, particularly in melanoma and non-melanoma skin cancers, where up to 70 mis-sense mutations have been documented, often accompanied by loss of the tumour suppressor NF1. Recently it has been reported that knockout of PRKAA2 in NF1-deficient melanoma cells promoted anchorage-independent growth in vitro, as well as growth as xenografts in immunodeficient mice in vivo, suggesting that AMPK-α2 can act as a tumour suppressor in that context. However, very few of the mis-sense mutations in PRKAA2 that occur in human skin cancer and melanoma have been tested to see whether they cause loss-of-function. We have addressed this by making most of the reported mutations and testing their activity when expressed in AMPK knockout cells. Of 55 different mis-sense mutations (representing 75 cases), 9 (12%) appeared to cause a total loss of activity, 18 (24%) a partial loss, 11 (15%) an increase in phenformin-stimulated kinase activity, while just 37 (49%) had no clear effect on kinase activity. This supports the idea that AMPK-α2 acts as a tumour suppressor in the context of human skin cancer.
Subject(s)
Melanoma , Skin Neoplasms , Animals , Humans , Mice , Adenosine Triphosphate/metabolism , AMP-Activated Protein Kinases/genetics , AMP-Activated Protein Kinases/metabolism , Catalytic Domain , Melanoma/genetics , Mutation , Skin Neoplasms/geneticsABSTRACT
Importance: Multiple SARS-CoV-2 variants have emerged over the COVID-19 pandemic. The implications for COVID-19 severity in children worldwide are unclear. Objective: To determine whether the dominant circulating SARS-CoV-2 variants of concern (VOCs) were associated with differences in COVID-19 severity among hospitalized children. Design, Setting, and Participants: Clinical data from hospitalized children and adolescents (younger than 18 years) who were SARS-CoV-2 positive were obtained from 9 countries (Australia, Brazil, Italy, Portugal, South Africa, Switzerland, Thailand, UK, and the US) during 3 different time frames. Time frames 1 (T1), 2 (T2), and 3 (T3) were defined to represent periods of dominance by the ancestral virus, pre-Omicron VOCs, and Omicron, respectively. Age groups for analysis were younger than 6 months, 6 months to younger than 5 years, and 5 to younger than 18 years. Children with an incidental positive test result for SARS-CoV-2 were excluded. Exposures: SARS-CoV-2 hospitalization during the stipulated time frame. Main Outcomes and Measures: The severity of disease was assessed by admission to intensive care unit (ICU), the need for ventilatory support, or oxygen therapy. Results: Among 31â¯785 hospitalized children and adolescents, the median age was 4 (IQR 1-12) years and 16â¯639 were male (52.3%). In children younger than 5 years, across successive SARS-CoV-2 waves, there was a reduction in ICU admission (T3 vs T1: risk ratio [RR], 0.56; 95% CI, 0.42-0.75 [younger than 6 months]; RR, 0.61, 95% CI; 0.47-0.79 [6 months to younger than 5 years]), but not ventilatory support or oxygen therapy. In contrast, ICU admission (T3 vs T1: RR, 0.39, 95% CI, 0.32-0.48), ventilatory support (T3 vs T1: RR, 0.37; 95% CI, 0.27-0.51), and oxygen therapy (T3 vs T1: RR, 0.47; 95% CI, 0.32-0.70) decreased across SARS-CoV-2 waves in children 5 years to younger than 18 years old. The results were consistent when data were restricted to unvaccinated children. Conclusions and Relevance: This study provides valuable insights into the impact of SARS-CoV-2 VOCs on the severity of COVID-19 in hospitalized children across different age groups and countries, suggesting that while ICU admissions decreased across the pandemic in all age groups, ventilatory and oxygen support generally did not decrease over time in children aged younger than 5 years. These findings highlight the importance of considering different pediatric age groups when assessing disease severity in COVID-19.
Subject(s)
COVID-19 , Adolescent , Humans , Child , Male , Infant , Child, Preschool , Female , COVID-19/epidemiology , SARS-CoV-2 , Pandemics , OxygenABSTRACT
Introduction: Identifying SARS-CoV-2 infection risk factors allows targeted public health and social measures (PHSM). As new, more transmissible variants of concern (VoC) emerge, vaccination rates increase and PHSM are eased, it is important to understand any potential change to infection risk factors. The aim of this systematic literature review is to describe the risk factors for SARS-CoV-2 infection by VoC. Methods: A literature search was performed in MEDLINE, PubMed and Embase databases on 5 May 2022. Eligibility included: observational studies published in English after 1 January 2020; any age group; the outcome of SARS-CoV-2 infection; and any potential risk factors investigated in the study. Results were synthesized into a narrative summary with respect to measures of association, by VoC. ROBINS-E tool was utilized for risk of bias assessment. Results: Of 6,197 studies retrieved, 43 studies were included after screening. Common risk factors included older age, minority ethnic group, low socioeconomic status, male gender, increased household size, occupation/lower income level, inability to work from home, public transport use, and lower education level. Most studies were undertaken when the ancestral strain was predominant. Many studies had some selection bias due to testing criteria and limited laboratory capacity. Conclusion: Understanding who is at risk enables the development of strategies that target priority groups at each of the different stages of a pandemic and helps inform vaccination strategies and other interventions which may also inform public health responses to future respiratory infection outbreaks. While it was not possible to determine changes to infection risk by recent VoC in this review, the risk factors identified will add to the overall understanding of the groups who are at greatest risk of infection in the early stages of a respiratory virus outbreak. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022330706, PROSPERO [CRD42022330706].
Subject(s)
COVID-19 , Humans , Male , Bias , COVID-19/epidemiology , COVID-19/prevention & control , Pandemics/prevention & control , Risk Factors , SARS-CoV-2ABSTRACT
COVID-19 vaccines have been introduced in children and adolescents in many countries. However, high levels of community transmission and infection-derived immunity make the decision to introduce COVID-19 vaccination of children in countries yet to do so particularly challenging. For example, other vaccine preventable diseases, including measles and polio, generally have far higher childhood morbidity and mortality in low-income and middle-income countries (LMICs) than COVID-19, and coverage with these vaccines has declined during the pandemic. Many countries are yet to introduce pneumococcal conjugate and rotavirus vaccines for children, which prevent common causes of childhood death, or human papillomavirus vaccine for adolescents. The Pfizer and Moderna COVID-19 vaccines that have been widely tested in children and adolescents have a positive risk-benefit profile. However, the benefit is less compared with other life-saving vaccines in this age group, particularly in LMICs and settings with widespread infection-derived immunity. The resources required for rollout may also pose a considerable challenge in LMICs. In this paper, we describe COVID-19 in children, with a focus on LMICs, and summarise the published literature on safety, efficacy and effectiveness of COVID-19 vaccination in children and adolescents. We highlight the complexity of decision-making regarding COVID-19 vaccination of children now that most of this low-risk population benefit from infection-derived immunity. We emphasise that at-risk groups should be prioritised for COVID-19 vaccination; and that if COVID-19 vaccines are introduced for children, the opportunity should be taken to improve coverage of routine childhood vaccines and preventative healthcare. Additionally, we highlight the paucity of epidemiological data in LMICs, and that for future epidemics, measures need to be taken to ensure equitable access to safe and efficacious vaccines before exposure to infection.
Subject(s)
COVID-19 , Adolescent , Humans , Child , COVID-19 Vaccines , Vaccination , 2019-nCoV Vaccine mRNA-1273 , PandemicsABSTRACT
Background: In 2008/9, Fiji vaccinated >30,000 girls aged 9-12 years with the quadrivalent human papillomavirus (4vHPV) vaccine coverage for at least one dose was >60% (one dose only was 14%, two dose only was 13%, three doses was 35%). We calculated vaccine effectiveness (VE) of one, two and three doses of 4vHPV against oncogenic HPV genotypes 16/18, eight years following vaccination. Methods: A retrospective cohort study was undertaken (2015-2019) in pregnant women ≤23 years old, eligible to receive 4vHPV in 2008/9, with confirmed vaccination status. The study was restricted to pregnant women due to the cultural sensitivity of asking about sexual behavior in Fiji. For each participant a clinician collected a questionnaire, vaginal swab and genital warts examination, a median eight (range 6-11) years post vaccination. HPV DNA was detected by molecular methods. Adjusted VE (aVE) against the detection of vaccine HPV genotypes (16/18), the comparison group of non-vaccine genotypes (31/33/35/39/45/51/52/56/58/59/66/68), and genital warts were calculated. Covariates included in the adjusted model were: age, ethnicity and smoking, according to univariate association with any HPV detection. Findings: Among 822 participants the prevalence of HPV 16/18 in the unvaccinated, one, two and three-dose groups were 13.3% (50/376), 2.5% (4/158), 0% (0/99) and 1.6% (3/189), respectively; and for the non-vaccine high-risk genotypes, the detection rate was similar across dosage groups (33.2%-40.4%, p = 0.321). The aVE against HPV 16/18 for one, two and three doses were 81% (95% CI; 48-93%), 100% (95% CI; 100-100%), and 89% (95% CI; 64-96%), respectively. Prevalence of HPV 16/18 was lower among women with longer time since vaccination. Interpretations: A single dose 4vHPV vaccine is highly effective against HPV genotypes 16 and 18 eight years following vaccination. Our results provide the longest duration of protection for reduced dose 4vHPV schedule in a low- or middle-income country in the Western Pacific region. Funding: This study was supported by the Bill & Melinda Gates Foundation and the Department of Foreign Affairs and Trade of the Australian Government and Fiji Health Sector Support Program (FHSSP). FHSSP is implemented by Abt JTA on behalf of the Australian Government.
ABSTRACT
Background: In 2021, the Australian Government Department of Health commissioned a consortium of modelling groups to generate evidence assisting the transition from a goal of no community COVID-19 transmission to 'living with COVID-19', with adverse health and social consequences limited by vaccination and other measures. Due to the extended school closures over 2020-21, maximizing face-to-face teaching was a major objective during this transition. The consortium was tasked with informing school surveillance and contact management strategies to minimize infections and support this goal. Methods: Outcomes considered were infections and days of face-to-face teaching lost in the 45 days following an outbreak within an otherwise COVID-naïve school setting. A stochastic agent-based model of COVID-19 transmission was used to evaluate a 'test-to-stay' strategy using daily rapid antigen tests (RATs) for close contacts of a case for 7 days compared with home quarantine; and an asymptomatic surveillance strategy involving twice-weekly screening of all students and/or teachers using RATs. Findings: Test-to-stay had similar effectiveness for reducing school infections as extended home quarantine, without the associated days of face-to-face teaching lost. Asymptomatic screening was beneficial in reducing both infections and days of face-to-face teaching lost and was most beneficial when community prevalence was high. Interpretation: Use of RATs in school settings for surveillance and contact management can help to maximize face-to-face teaching and minimize outbreaks. This evidence supported the implementation of surveillance testing in schools in several Australian jurisdictions from January 2022.
Subject(s)
COVID-19 , Humans , COVID-19/epidemiology , COVID-19/prevention & control , Quarantine , SARS-CoV-2 , Pandemics/prevention & control , Australia/epidemiologyABSTRACT
BACKGROUND: High pneumococcal carriage density has been associated with severe pneumonia in some settings. The impact of pneumococcal conjugate vaccines (PCVs) on pneumococcal carriage density has been variable. The aim of this systematic literature review is to describe the effect of PCV7, PCV10 and PCV13 on pneumococcal colonisation density in children under five years old. METHODS: We included peer reviewed English literature published between 2000 and 2021 to identify relevant articles using Embase, Medline and PubMed. Original research articles of any study design in countries where PCV has been introduced/studied were included. Quality (risk) assessment was performed using tools developed by the National Heart Brain and Lung Institute for inclusion in this review. We used a narrative synthesis to present results. RESULTS: Ten studies were included from 1941 articles reviewed. There were two randomised controlled trials, two cluster randomised trials, one case control study, one retrospective cohort study and four cross sectional studies. Three studies used semiquantitative culture methods to determine density while the remaining studies used quantitative molecular techniques. Three studies reported an increase in density and three studies found a decrease in density among vaccinated compared with unvaccinated children. Four studies found no effect. There was considerable heterogeneity in the study populations, study design and laboratory methods. CONCLUSION: There was no consensus regarding the impact of PCV on pneumococcal nasopharyngeal density. We recommend the use of standardised methods to evaluate PCV impact on density.
Subject(s)
Carrier State , Pneumococcal Infections , Humans , Child , Infant , Child, Preschool , Vaccines, Conjugate/therapeutic use , Cross-Sectional Studies , Case-Control Studies , Retrospective Studies , Streptococcus pneumoniae , Pneumococcal Vaccines/therapeutic use , Nasopharynx , Pneumococcal Infections/prevention & controlABSTRACT
Background: A systematic review in 2019 found reductions in antimicrobial resistance (AMR) of pneumococcal vaccine serotypes following pneumococcal conjugate vaccine (PCV) introduction. However, few low- or middle-income countries were included as not many had introduced higher valent PCVs (PCV10 or PCV13). The aim of our review is to describe AMR rates in these samples following the introduction of PCV10 or PCV13. Methods: We conducted a systematic literature review of published papers that compared AMR for invasive pneumococcal disease (IPD), otitis media (OM) and nasopharyngeal carriage (NPC) samples following introduction of PCV10 or PCV13 to the pre-PCV period. Included studies published from July 2017 to August 2020 had a post-licensure observational study design and reported on our defined outcomes: IPD, OM, NPC and other (sputum or mixed invasive and non-invasive pneumococcal) isolates from people of all ages. Rates of AMR in the pre- and post-period were extracted. Results: Data were extracted from 31 studies. Among IPD isolates, penicillin AMR rates following PCV10 or PCV13 introduction declined in 32% (n = 9/29) of included studies, increased in 34% (n = 10/29) and showed no change in 34% (n = 10/29). Cephalosporins AMR declined in 32% (n = 6/19) of studies, increased in 21% (n = 4/19) and showed no change in 47% (n = 9/19). Macrolides AMR declined in 33% (n = 4/12) of studies, increased in 50% (n = 6/12), and showed no change in 17% (n = 2/12). AMR to other antibiotics (including multidrug resistance) declined in 23% (n = 9/39) of studies, increased in 41% (n = 16/39) and showed no change in AMR in 36% (n = 14/39). There were no obvious differences between AMR; in setting which used PCV10 vs PCV13, according to time since PCV introduction or by World Bank income status of the respective country. The only study including OM isolates found no change in penicillin resistance. There were few studies on AMR in NPC (four studies), OM (one study) or other isolates (five studies). The results followed similar patterns to IPD isolates. Conclusions: We observed considerable heterogeneity in the findings between and within studies, e.g. no evidence of reduction in amoxicillin AMR with an increase in macrolides AMR. Reasons for such diverse findings include the period covered by different studies and variation in other pressures towards AMR.
Subject(s)
Anti-Infective Agents , Otitis Media , Pneumococcal Infections , Humans , Infant , Vaccines, Conjugate/therapeutic use , Pneumococcal Infections/epidemiology , Pneumococcal Infections/prevention & control , Streptococcus pneumoniae , Pneumococcal Vaccines , Serogroup , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Otitis Media/prevention & control , Observational Studies as TopicABSTRACT
Background: There is an ongoing need to assess the impact of pneumococcal conjugate vaccines (PCVs) to guide the use of these potentially valuable but under-utilized vaccines against pneumonia, which is one of the most common causes of post-neonatal mortality. Methods: We conducted a systematic review of the literature on PCV10 and PCV13 impact on all-cause, radiologically confirmed and severe pneumonia hospitalisation rates as well as all-cause and pneumonia-specific mortality rates. We included studies that were published from 2003 onwards, had a post-licensure observational study design, and reported on any of our defined outcomes in children aged between 0-9 years. We derived incidence rates (IRs), incidence rate ratios (IRRs) or percent differences (%). We assessed all studies for risk of bias using the Effective Public Health Practice Project (EPHPP) quality assessment tool. Results: We identified a total of 1885 studies and included 43 comparing one or more of the following hospitalised outcomes of interest: all-cause pneumonia (n = 27), severe pneumonia (n = 6), all-cause empyema (n = 8), radiologically confirmed pneumonia (n = 8), pneumococcal pneumonia (n = 7), and pneumonia mortality (n = 10). No studies evaluated all-cause mortality. Studies were conducted in all WHO regions except South East Asia Region (SEAR) and low- or middle-income countries (LMICs) in the Western Pacific Region (WPR). Among children <5 years old, PCV impact ranged from 7% to 60% for all-cause pneumonia hospitalisation, 8% to 90% for severe pneumonia hospitalisation, 12% to 79% for radiologically confirmed pneumonia, and 45% to 85% for pneumococcal confirmed pneumonia. For pneumonia-related mortality, impact was found in three studies and ranged from 10% to 78%. No obvious differences were found in vaccine impact between PCV10 and PCV13. One study found a 17% reduction in all-cause pneumonia among children aged 5-9 years, while another found a reduction of 81% among those aged 5-17 years. A third study found a 57% reduction in all-cause empyema among children 5-14 years of age. Conclusion: We found clear evidence of declines in hospitalisation rates due to all-cause, severe, radiologically confirmed, and bacteraemic pneumococcal pneumonia in children aged <5 years, supporting ongoing use of PCV10 and PCV13. However, there were few studies from countries with the highest <5-year mortality and no studies from SEAR and LMICs in the WPR. Standardising methods of future PCV impact studies is recommended.
Subject(s)
Pneumococcal Infections , Pneumonia, Pneumococcal , Infant, Newborn , Child , Humans , Infant , Child, Preschool , Adolescent , Pneumonia, Pneumococcal/epidemiology , Pneumonia, Pneumococcal/prevention & control , Vaccines, Conjugate/therapeutic use , Pneumococcal Infections/epidemiology , Pneumococcal Infections/prevention & control , Pneumococcal Vaccines/therapeutic use , Hospitalization , Observational Studies as TopicABSTRACT
AMP-activated protein kinase (AMPK) is the central component of a signalling pathway that senses energy stress and triggers a metabolic switch away from anabolic processes and towards catabolic processes. There has been a prolonged focus in the pharmaceutical industry on the development of AMPK-activating drugs for the treatment of metabolic disorders such as Type 2 diabetes and non-alcoholic fatty liver disease. However, recent findings suggest that AMPK inhibitors might be efficacious for treating certain cancers, especially lung adenocarcinomas, in which the PRKAA1 gene (encoding the α1 catalytic subunit isoform of AMPK) is often amplified. Here, we study two potent AMPK inhibitors, BAY-3827 and SBI-0206965. Despite not being closely related structurally, the treatment of cells with either drug unexpectedly caused increases in AMPK phosphorylation at the activating site, Thr172, even though the phosphorylation of several downstream targets in different subcellular compartments was completely inhibited. Surprisingly, the two inhibitors appear to promote Thr172 phosphorylation by different mechanisms: BAY-3827 primarily protects against Thr172 dephosphorylation, while SBI-0206965 also promotes phosphorylation by LKB1 at low concentrations, while increasing cellular AMP:ATP ratios at higher concentrations. Due to its greater potency and fewer off-target effects, BAY-3827 is now the inhibitor of choice for cell studies, although its low bioavailability may limit its use in vivo.
Subject(s)
Benzamides , Diabetes Mellitus, Type 2 , Lung Neoplasms , Pyrimidines , Humans , Phosphorylation , Protein Kinase Inhibitors/pharmacology , AMP-Activated Protein KinasesABSTRACT
INTRODUCTION: Infections are a leading cause of neonatal mortality globally and can be transmitted from mother-to-child vertically or horizontally. Fiji has higher rates of serious neonatal infections and infant skin and soft tissue infections (SSTIs) than high-income countries. Research from the Gambia found that a single dose of oral azithromycin in labour decreased bacterial carriage and infections in mothers and infants, particularly infant skin infections. The Bulabula MaPei clinical trial evaluates the safety and efficacy of a single dose of azithromycin in labour in reducing the incidence of maternal and infant SSTIs and other infections and the impact on bacterial carriage. It will also describe the effect of azithromycin on antimicrobial (AMR) resistance, the maternal and infant microbiome, and infant dysbiosis. METHODS AND ANALYSIS: We are conducting a blinded, placebo-controlled randomised clinical trial administering 2 g of oral azithromycin, or placebo, given to healthy, pregnant women (≥18 years) in labour in Suva, Fiji. The primary outcome is the cumulative incidence of SSTIs in infants by 3 months of age. Secondary outcomes include the incidence of other infant and maternal infections, and safety and tolerability of azithromycin in mother and infant. Following informed consent, 2110 pregnant women will be randomised in a 1:1 ratio, with all study staff and participants masked to group allocation. Mother/infant pairs will be followed up for 12 months over six visits collecting clinical data on infections, antimicrobial use, safety and anthropometrics, in addition to nasopharyngeal, oropharyngeal, rectovaginal and vaginal swabs, maternal breastmilk and infant stool samples, in order to compare bacterial carriage, AMR rates and microbiome. Recruitment for Bulabula MaPei started in June 2019. ETHICS AND DISSEMINATION: This trial was approved and is being conducted according to the protocol approved by The Royal Children's Hospital Human Research Ethics Committee, Australia, and the Fiji National Health Research and Ethics Review Committee. The findings of this study will be disseminated in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: NCT03925480.