Limited antigenic diversity of Plasmodium falciparum apical membrane antigen 1 supports the development of effective multi-allele vaccines

BackgroundPolymorphism in antigens is a common mechanism for immune evasion used by many important pathogens, and presents major challenges in vaccine development. In malaria, many key immune targets and vaccine candidates show substantial polymorphism. However, knowledge on antigenic diversity of key antigens, the impact of polymorphism on potential vaccine escape, and how sequence polymorphism relates to antigenic differences is very limited, yet crucial for vaccine development. Plasmodium falciparum apical membrane antigen 1 (AMA1) is an important target of naturally-acquired antibodies in malaria immunity and a leading vaccine candidate. However, AMA1 has extensive allelic diversity with more than 60 polymorphic amino acid residues and more than 200 haplotypes in a single population. Therefore, AMA1 serves as an excellent model to assess antigenic diversity in malaria vaccine antigens and the feasibility of multi-allele vaccine approaches. While most previous research has focused on sequence diversity and antibody responses in laboratory animals, little has been done on the cross-reactivity of human antibodies.MethodsWe aimed to determine the extent of antigenic diversity of AMA1, defined by reactivity with human antibodies, and to aid the identification of specific alleles for potential inclusion in a multi-allele vaccine. We developed an approach using a multiple-antigen-competition enzyme-linked immunosorbent assay (ELISA) to examine cross-reactivity of naturally-acquired antibodies in Papua New Guinea and Kenya, and related this to differences in AMA1 sequence.ResultsWe found that adults had greater cross-reactivity of antibodies than children, although the patterns of cross-reactivity to alleles were the same. Patterns of antibody cross-reactivity were very similar between populations (Papua New Guinea and Kenya), and over time. Further, our results show that antigenic diversity of AMA1 alleles is surprisingly restricted, despite extensive sequence polymorphism. Our findings suggest that a combination of three different alleles, if selected appropriately, may be sufficient to cover the majority of antigenic diversity in polymorphic AMA1 antigens. Antigenic properties were not strongly related to existing haplotype groupings based on sequence analysis.ConclusionsAntigenic diversity of AMA1 is limited and a vaccine including a small number of alleles might be sufficient for coverage against naturally-circulating strains, supporting a multi-allele approach for developing polymorphic antigens as malaria vaccines

Impact of Empowering Leadership on Antimicrobial Stewardship: A Single Center Study in a Neonatal and Pediatric Intensive Care Unit and a Literature Review

Background: Antimicrobial stewardship (AMS) is an important strategy of quality improvement for every hospital. Leadership is an important factor for implementation of quality improvement and AMS programs. Recent publications show successful AMS programs in children's hospitals, but successful implementation is often difficult to achieve and literature of AMS in neonatal and pediatric intensive care units (NICU/PICU) is scarce. Lack of resources and prescriber opposition are reported barriers. A leadership style focusing on empowering frontline staff to take responsibility is one approach to implement changes in health care institutions.Aim: Literature review regarding empowering leadership and AMS in health care and assessment of the impact of such a leadership style on AMS in a NICU/PICU over 3 years.Methods: Assessment of the impact of a leadership change September 1, 2015 from control-driven to an empowering leadership style on antibiotic use and hospital acquired infections. Prospective analysis and annual comparison of antibiotic use, rate of suspected and confirmed ventilator-associated pneumonia (VAP) and central-line associated blood stream infection (CLABSI) including antibiotic use overall, antibiotic therapy for culture-negative and culture-proven infections including correct initial choice and streamlining of antibiotics in the NICU/PICU of the Children's Hospital of Lucerne between January 1, 2015 and December 31, 2017.Results: Five articles were included in the literature review. All five studies concluded that an empowering leadership style may lead to a higher engagement of physicians. Three out of five studies reported improved AMS as reduced rate in hospital-acquired infections and improved prevention of MRSA infections. From 2015 to 2017, antibiotic days overall and antibiotic days for culture-negative situations (suspected infections and prophylaxis) per 1000 patient days declined significantly from 474.1 to 403.9 and from 418.2 to 309.4 days, respectively. Similar, the use of meropenem and vancomycin declined significantly. Over the 3 years, suspected and proven VAP- and CLABSI-episodes decreased with no confirmed episodes in 2017.Conclusion: An empowering leadership style which focuses on enabling frontline physicians to take direct responsibilities for their patients may be a successful strategy of antimicrobial stewardship allowing to overcome reported barriers of AMS implementation

Impact of Empowering Leadership on Antimicrobial Stewardship: A Single Center Study in a Neonatal and Pediatric Intensive Care Unit and a Literature Review

Antimicrobial stewardship (AMS) is an important strategy of quality improvement for every hospital. Leadership is an important factor for implementation of quality improvement and AMS programs. Recent publications show successful AMS programs in children's hospitals, but successful implementation is often difficult to achieve and literature of AMS in neonatal and pediatric intensive care units (NICU/PICU) is scarce. Lack of resources and prescriber opposition are reported barriers. A leadership style focusing on empowering frontline staff to take responsibility is one approach to implement changes in health care institutions. Literature review regarding empowering leadership and AMS in health care and assessment of the impact of such a leadership style on AMS in a NICU/PICU over 3 years. Assessment of the impact of a leadership change September 1, 2015 from control-driven to an empowering leadership style on antibiotic use and hospital acquired infections. Prospective analysis and annual comparison of antibiotic use, rate of suspected and confirmed ventilator-associated pneumonia (VAP) and central-line associated blood stream infection (CLABSI) including antibiotic use overall, antibiotic therapy for culture-negative and culture-proven infections including correct initial choice and streamlining of antibiotics in the NICU/PICU of the Children's Hospital of Lucerne between January 1, 2015 and December 31, 2017. Five articles were included in the literature review. All five studies concluded that an empowering leadership style may lead to a higher engagement of physicians. Three out of five studies reported improved AMS as reduced rate in hospital-acquired infections and improved prevention of MRSA infections. From 2015 to 2017, antibiotic days overall and antibiotic days for culture-negative situations (suspected infections and prophylaxis) per 1000 patient days declined significantly from 474.1 to 403.9 and from 418.2 to 309.4 days, respectively. Similar, the use of meropenem and vancomycin declined significantly. Over the 3 years, suspected and proven VAP- and CLABSI-episodes decreased with no confirmed episodes in 2017. An empowering leadership style which focuses on enabling frontline physicians to take direct responsibilities for their patients may be a successful strategy of antimicrobial stewardship allowing to overcome reported barriers of AMS implementation

The malaria vaccine candidate Apical Membrane Antigen 1 – antigenic diversity and its potential as effective multi-allele vaccine

© 2016 Dr. Ulrich TerheggenUnderstanding naturally acquired immunity to malaria and how human antibodies protect against clinical malaria is essential for vaccine development. Antibodies against Plasmodium falciparum apical membrane antigen 1 (AMA1), a leading vaccine candidate, can inhibit merozoite invasion of erythrocytes and protect from P. falciparum malaria. However, polymorphism in antigens like AMA1 is a common mechanism for immune evasion and presents major challenges in vaccine development. This study aims to understand antigenic diversity of AMA1, the correlation between sequence polymorphism and antigenic differences, the impact of polymorphism on potential vaccine escape, and the structural differences of the protein amongst various alleles, with the goal to ultimately ascertain which AMA1 alleles should be included in an effective multi-allele vaccine

Clinical manifestations of Q fever in adults and children

Q fever is a common zoonosis with almost a worldwide distribution caused by Coxiella burnetii. Farm animals and pets are the main reservoirs of infection and transmission to humans is usually via inhalation of contaminated aerosols, which may be carried by the wind far from the original source of infection. Occupational groups with close association with farm or wild animals are most at risk, however travellers occasionally become infected. The disease is associated with a wide spectrum of clinical manifestations and symptoms, ranging from asymptomatic infection to fatal disease. Awareness of the disease and newer diagnostic methods led to increase of recognition and detection in cases with various or multiple symptoms in adults and children. However, children seem to be less frequently symptomatic and may have milder disease. This review of Q fever cases examines clinical manifestations and symptoms of Q fever in both adults and children and shows that certain symptoms and their severity have altered presentation in children with acute and chronic Q fever when compared to adults.\ud Article Outlin

European consensus recommendations for neonatal and paediatric retrievals of positive or suspected COVID-19 patients

BACKGROUND: The 2020 novel coronavirus (SARS-Cov-2) pandemic necessitates tailored recommendations addressing specific procedures for neonatal and paediatric transport of suspected or positive COVID-19 patients. The aim of this consensus statement is to define guidelines for safe clinical care for children needing inter-facility transport while making sure that the clinical teams involved are sufficiently protected from SARS-CoV-2. METHODS: A taskforce, composed of members of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC) Transport section and the European Society for Paediatric Research (ESPR), reviewed the published literature and used a rapid, two-step modified Delphi process to formulate recommendations regarding safety and clinical management during transport of COVID-19 patients. RESULTS: The joint taskforce consisted of a panel of 12 experts who reached an agreement on a set of 17 recommendations specifying pertinent aspects on neonatal and paediatric COVID-19 patient transport. These included: case definition, personal protective equipment, airway management, equipment and strategies for invasive and non-invasive ventilation, special considerations for incubator and open stretcher transports, parents on transport and decontamination of transport vehicles. CONCLUSIONS: Our consensus recommendations aim to define current best-practice and should help guide transport teams dealing with infants and children with COVID-19 to work safely and effectively. IMPACT: We present European consensus recommendations on pertinent measures for transporting infants and children in times of the coronavirus (SARS-Cov-2 /COVID-19) pandemic. A panel of experts reviewed the evidence around transporting infants and children with proven or suspected COVID-19. Specific guidance on aspects of personal protective equipment, airway management and considerations for incubator and open stretcher transports is presented. Based on scant evidence, best-practice recommendations for neonatal and paediatric transport teams are presented, aiming for the protection of teams and patients. We highlight gaps in knowledge and areas of future research

A novel approach to identifying patterns of human invasion-inhibitory antibodies guides the design of malaria vaccines incorporating polymorphic antigens

Background: The polymorphic nature of many malaria vaccine candidates presents major challenges to achieving highly efficacious vaccines. Presently, there is very little knowledge on the prevalence and patterns of functional immune responses to polymorphic vaccine candidates in populations to guide vaccine design. A leading polymorphic vaccine candidate against blood-stage Plasmodium falciparum is apical membrane antigen 1 (AMA1), which is essential for erythrocyte invasion. The importance of AMA1 as a target of acquired human inhibitory antibodies, their allele specificity and prevalence in populations is unknown, but crucial for vaccine design. Methods: P. falciparum lines expressing different AMA1 alleles were genetically engineered and used to quantify functional antibodies from two malaria-exposed populations of adults and children. The acquisition of AMA1 antibodies was also detected using enzyme-linked immunosorbent assay (ELISA) and competition ELISA (using different AMA1 alleles) from the same populations. Results: We found that AMA1 was a major target of naturally acquired invasion-inhibitory antibodies that were highly prevalent in malaria-endemic populations and showed a high degree of allele specificity. Significantly, the prevalence of inhibitory antibodies to different alleles varied substantially within populations and between geographic locations. Inhibitory antibodies to three specific alleles were highly prevalent (FVO and W2mef in Papua New Guinea; FVO and XIE in Kenya), identifying them for potential vaccine inclusion. Measurement of antibodies by standard or competition ELISA was not strongly predictive of allele-specific inhibitory antibodies. The patterns of allele-specific functional antibody responses detected with our novel assays may indicate that acquired immunity is elicited towards serotypes that are prevalent in each geographic location. Conclusions These findings provide new insights into the nature and acquisition of functional immunity to a polymorphic vaccine candidate and strategies to quantify functional immunity in populations to guide rational vaccine design.Damien R. Drew, Danny W. Wilson, Salenna R. Elliott, Nadia Cross, Ulrich Terheggen, Anthony N. Hodder, Peter M. Siba, Kiprotich Chelimo, Arlene E. Dent, James W. Kazura, Ivo Mueller and James G. Beeso

Additional file 1: of A novel approach to identifying patterns of human invasion-inhibitory antibodies guides the design of malaria vaccines incorporating polymorphic antigens

Detailed methods and additional analysis of antibody data. (DOCX 1576 kb