Controlled human malaria infection (CHMI) outcomes in Kenyan adults is associated with prior history of malaria exposure and anti-schizont antibody response

BACKGROUND: Individuals living in endemic areas acquire immunity to malaria following repeated parasite exposure. We sought to assess the controlled human malaria infection (CHMI) model as a means of studying naturally acquired immunity in Kenyan adults with varying malaria exposure. METHODS: We analysed data from 142 Kenyan adults from three locations representing distinct areas of malaria endemicity (Ahero, Kilifi North and Kilifi South) enrolled in a CHMI study with Plasmodium falciparum sporozoites NF54 strain (Sanaria® PfSPZ Challenge). To identify the in vivo outcomes that most closely reflected naturally acquired immunity, parameters based on qPCR measurements were compared with anti-schizont antibody levels and residence as proxy markers of naturally acquired immunity. RESULTS: Time to endpoint correlated more closely with anti-schizont antibodies and location of residence than other parasite parameters such as growth rate or mean parasite density. Compared to observational field-based studies in children where 0.8% of the variability in malaria outcome was observed to be explained by anti-schizont antibodies, in the CHMI model the dichotomized anti-schizont antibodies explained 17% of the variability. CONCLUSIONS: The CHMI model is highly effective in studying markers of naturally acquired immunity to malaria. Trial registration Clinicaltrials.gov number NCT02739763. Registered 15 April 2016

Controlled Human Malaria Infection in Semi-Immune Kenyan Adults (CHMI-SIKA): a study protocol to investigate in vivo Plasmodium falciparum malaria parasite growth in the context of pre-existing immunity [version 2; peer review: 2 approved]

Malaria remains a major public health burden despite approval for implementation of a partially effective pre-erythrocytic malaria vaccine. There is an urgent need to accelerate development of a more effective multi-stage vaccine. Adults in malaria endemic areas may have substantial immunity provided by responses to the blood stages of malaria parasites, but field trials conducted on several blood-stage vaccines have not shown high levels of efficacy. We will use the controlled human malaria infection (CHMI) models with malaria-exposed volunteers to identify correlations between immune responses and parasite growth rates in vivo. Immune responses more strongly associated with control of parasite growth should be prioritized to accelerate malaria vaccine development. We aim to recruit up to 200 healthy adult volunteers from areas of differing malaria transmission in Kenya, and after confirming their health status through clinical examination and routine haematology and biochemistry, we will comprehensively characterize immunity to malaria using >100 blood-stage antigens. We will administer 3,200 aseptic, purified, cryopreserved Plasmodium falciparum sporozoites (PfSPZ Challenge) by direct venous inoculation. Serial quantitative polymerase chain reaction to measure parasite growth rate in vivo will be undertaken. Clinical and laboratory monitoring will be undertaken to ensure volunteer safety. In addition, we will also explore the perceptions and experiences of volunteers and other stakeholders in participating in a malaria volunteer infection study. Serum, plasma, peripheral blood mononuclear cells and whole blood will be stored to allow a comprehensive assessment of adaptive and innate host immunity. We will use CHMI in semi-immune adult volunteers to relate parasite growth outcomes with antibody responses and other markers of host immunity. / Registration: ClinicalTrials.gov identifier NCT02739763

Global habitat suitability of Spodoptera frugiperda (JE Smith) (Lepidoptera, Noctuidae): key parasitoids considered for its biological control

Open Access Journal; Published online: 24 Mar 2021The present study is the first modeling effort at a global scale to predict habitat suitability of fall armyworm (FAW), Spodoptera frugiperda and its key parasitoids, namely Chelonus insularis, Cotesia marginiventris,Eiphosoma laphygmae,Telenomus remus and Trichogramma pretiosum, to be considered for biological control. An adjusted procedure of a machine-learning algorithm, the maximum entropy (Maxent), was applied for the modeling experiments. Model predictions showed particularly high establishment potential of the five hymenopteran parasitoids in areas that are heavily affected by FAW (like the coastal belt of West Africa from Côte d’Ivoire (Ivory Coast) to Nigeria, the Congo basin to Eastern Africa, Eastern, Southern and Southeastern Asia and some portions of Eastern Australia) and those of potential invasion risks (western & southern Europe). These habitats can be priority sites for scaling FAW biocontrol efforts. In the context of global warming and the event of accidental FAW introduction, warmer parts of Europe are at high risk. The effect of winter on the survival and life cycle of the pest in Europe and other temperate regions of the world are discussed in this paper. Overall, the models provide pioneering information to guide decision making for biological-based medium and long-term management of FAW across the globe

Dual Electron Spectrometer for Magnetospheric Multiscale Mission: Results of the Comprehensive Tests of the Engineering Test Unit

The Magnetospheric Multiscale mission (MMS) is designed to study fundamental phenomena in space plasma physics such as a magnetic reconnection. The mission consists of four spacecraft, equipped with identical scientific payloads, allowing for the first measurements of fast dynamics in the critical electron diffusion region where magnetic reconnection occurs and charged particles are demagnetized. The MMS orbit is optimized to ensure the spacecraft spend extended periods of time in locations where reconnection is known to occur: at the dayside magnetopause and in the magnetotail. In order to resolve fine structures of the three dimensional electron distributions in the diffusion region (reconnection site), the Fast Plasma Investigation's (FPI) Dual Electron Spectrometer (DES) is designed to measure three dimensional electron velocity distributions with an extremely high time resolution of 30 ms. In order to achieve this unprecedented sampling rate, four dual spectrometers, each sampling 180 x 45 degree sections of the sky, are installed on each spacecraft. We present results of the comprehensive tests performed on the DES Engineering & Test Unit (ETU). This includes main parameters of the spectrometer such as energy resolution, angular acceptance, and geometric factor along with their variations over the 16 pixels spanning the 180-degree tophat Electro Static Analyzer (ESA) field of view and over the energy of the test beam. A newly developed method for precisely defining the operational space of the instrument is presented as well. This allows optimization of the trade-off between pixel to pixel crosstalk and uniformity of the main spectrometer parameters

Factors influencing the implementation of cardiovascular risk scoring in primary care: a mixed-method systematic review

BACKGROUND:Cardiovascular disease (CVD) such as ischemic heart disease and stroke is the leading causes of death and disability globally with a growing burden in low and middle-income countries. A credible way of managing the incidence and prevalence of cardiovascular diseases is by reducing risk factors. This understanding has led to the development and recommendation for the clinical use of cardiovascular risk stratification tools. These tools enhance clinical decision-making. However, there is a lag in the implementation of these tools in most countries. This systematic review seeks to synthesise the current knowledge of the factors influencing the implementation of cardiovascular risk scoring in primary care settings. METHODS:We searched bibliographic databases and grey literature for studies of any design relating to the topic. Titles, abstracts and full texts were independently assessed for eligibility by two reviewers. This was followed by quality assessment and data extraction. We analysed data using an integrated and best fit framework synthesis approach to identify these factors. Quantitative and qualitative forms of data were combined into a single mixed-methods synthesis. The Consolidated Framework for Implementation Research was used as the guiding tool and template for this analysis. RESULTS:Twenty-five studies (cross-sectional n = 12, qualitative n = 9 and mixed-methods n = 4) were included in this review. Twenty (80%) of these were conducted in high-income countries. Only four studies (16%) included patients as participants. This review reports on a total of eleven cardiovascular risk stratification tools. The factors influencing the implementation of cardiovascular risk scoring are related to clinical setting and healthcare system (resources, priorities, practice culture and organisation), users (attributes and interactions between users) and the specific cardiovascular risk tool (characteristics, perceived role and effectiveness). CONCLUSIONS:While these findings bolster the understanding of implementation complexity, there exists limited research in the context of low and middle-income countries. Notwithstanding the need to direct resources in bridging this gap, it is also crucial that these efforts are in concert with providing high-quality evidence on the clinical effectiveness of using cardiovascular risk scoring to improve cardiovascular disease outcomes of mortality and morbidity. TRIAL REGISTRATION:PROSPERO registration number: CRD42018092679

Controlled human malaria infection (CHMI) outcomes in Kenyan adults is associated with prior history of malaria exposure and anti-schizont antibody response

Background Individuals living in endemic areas acquire immunity to malaria following repeated parasite exposure. We sought to assess the controlled human malaria infection (CHMI) model as a means of studying naturally acquired immunity in Kenyan adults with varying malaria exposure. Methods We analysed data from 142 Kenyan adults from three locations representing distinct areas of malaria endemicity (Ahero, Kilifi North and Kilifi South) enrolled in a CHMI study with Plasmodium falciparum sporozoites NF54 strain (Sanaria® PfSPZ Challenge). To identify the in vivo outcomes that most closely reflected naturally acquired immunity, parameters based on qPCR measurements were compared with anti-schizont antibody levels and residence as proxy markers of naturally acquired immunity. Results Time to endpoint correlated more closely with anti-schizont antibodies and location of residence than other parasite parameters such as growth rate or mean parasite density. Compared to observational field-based studies in children where 0.8% of the variability in malaria outcome was observed to be explained by anti-schizont antibodies, in the CHMI model the dichotomized anti-schizont antibodies explained 17% of the variability. Conclusions The CHMI model is highly effective in studying markers of naturally acquired immunity to malaria. Trial registration Clinicaltrials.gov number NCT02739763. Registered 15 April 201

Randomized, double-blinded, controlled non-inferiority trials evaluating the immunogenicity and safety of fractional doses of Yellow Fever vaccines in Kenya and Uganda

Introduction: Yellow fever is endemic in specific regions of sub-Saharan Africa and the Americas, with recent epidemics occurring on both continents. The yellow fever vaccine is effective, affordable and safe, providing life-long immunity following a single dose vaccination. However, the vaccine production process is slow and cannot be readily scaled up during epidemics. This has led the World Health Organization (WHO) to recommend the use of fractional doses as a dose-sparing strategy during epidemics, but there are no randomized controlled trials of fractional yellow fever vaccine doses in Africa. Methods and analysis: We will recruit healthy adult volunteers, adults living with HIV, and children to a series of randomized controlled trials aiming to determine the immunogenicity and safety of fractional vaccine doses in comparison to the standard vaccine dose. The trials will be conducted across two sites; Kilifi, Kenya and Mbarara, Uganda. Recruited participants will be randomized to receive fractional or standard doses of yellow fever vaccine. Scheduled visits will include blood collection for serum and peripheral blood mononuclear cells (PBMCs) before vaccination and on various days – up to 2 years – post-vaccination. The primary outcome is the rate of seroconversion as measured by the plaque reduction neutralization test (PRNT50) at 28 days post-vaccination. Secondary outcomes include antibody titre changes, longevity of the immune response, safety assessment using clinical data, the nature and magnitude of the cellular immune response and post-vaccination control of viremia by vaccine dose. Ethics and dissemination: The clinical trial protocols have received approval from the relevant institutional ethics and regulatory review committees in Kenya and Uganda, and the WHO Ethics Review Committee. The research findings will be disseminated through open-access publications and presented at relevant conferences and workshops. Registration: ClinicalTrials.gov NCT02991495 (registered on 13 December 2016) and NCT04059471 (registered on 15 August 2019)

Randomized, double-blinded, controlled non-inferiority trials evaluating the immunogenicity and safety of fractional doses of Yellow Fever vaccines in Kenya and Uganda

Introduction: Yellow fever is endemic in specific regions of sub-Saharan Africa and the Americas, with recent epidemics occurring on both continents. The yellow fever vaccine is effective, affordable and safe, providing life-long immunity following a single dose vaccination. However, the vaccine production process is slow and cannot be readily scaled up during epidemics. This has led the World Health Organization (WHO) to recommend the use of fractional doses as a dose-sparing strategy during epidemics, but there are no randomized controlled trials of fractional yellow fever vaccine doses in Africa. Methods and analysis: We will recruit healthy adult volunteers, adults living with HIV, and children to a series of randomized controlled trials aiming to determine the immunogenicity and safety of fractional vaccine doses in comparison to the standard vaccine dose. The trials will be conducted across two sites; Kilifi, Kenya and Mbarara, Uganda. Recruited participants will be randomized to receive fractional or standard doses of yellow fever vaccine. Scheduled visits will include blood collection for serum and peripheral blood mononuclear cells (PBMCs) before vaccination and on various days – up to 2 years – post-vaccination. The primary outcome is the rate of seroconversion as measured by the plaque reduction neutralization test (PRNT50) at 28 days post-vaccination. Secondary outcomes include antibody titre changes, longevity of the immune response, safety assessment using clinical data, the nature and magnitude of the cellular immune response and post-vaccination control of viremia by vaccine dose. Ethics and dissemination: The clinical trial protocols have received approval from the relevant institutional ethics and regulatory review committees in Kenya and Uganda, and the WHO Ethics Review Committee. The research findings will be disseminated through open-access publications and presented at relevant conferences and workshops. Registration: ClinicalTrials.gov NCT02991495 (registered on 13 December 2016) and NCT04059471 (registered on 15 August 2019).</p

Distinct kinetics of antibodies to 111 Plasmodium falciparum proteins identifies markers of recent malaria exposure

Strengthening malaria surveillance is a key intervention needed to reduce the global disease burden. Reliable serological markers of recent malaria exposure could improve current surveillance methods by allowing for accurate estimates of infection incidence from limited data. We studied the IgG antibody response to 111 Plasmodium falciparum proteins in 65 adult travellers followed longitudinally after a natural malaria infection in complete absence of re-exposure. We identified a combination of five serological markers that detect exposure within the previous three months with >80% sensitivity and specificity. Using mathematical modelling, we examined the antibody kinetics and determined that responses informative of recent exposure display several distinct characteristics: rapid initial boosting and decay, less inter-individual variation in response kinetics, and minimal persistence over time. Such serological exposure markers could be incorporated into routine malaria surveillance to guide efforts for malaria control and elimination

Immunogenicity and safety of fractional doses of yellow fever vaccines: a randomised, double-blind, non-inferiority trial

Background Stocks of yellow fever vaccine are insufficient to cover exceptional demands for outbreak response. Fractional dosing has shown efficacy, but evidence is limited to the 17DD substrain vaccine. We assessed the immunogenicity and safety of one-fifth fractional dose compared with standard dose of four WHO-prequalified yellow fever vaccines produced from three substrains. Methods We did this randomised, double-blind, non-inferiority trial at research centres in Mbarara, Uganda, and Kilifi, Kenya. Eligible participants were aged 18–59 years, had no contraindications for vaccination, were not pregnant or lactating, had no history of yellow fever vaccination or infection, and did not require yellow fever vaccination for travel. Eligible participants were recruited from communities and randomly assigned to one of eight groups, corresponding to the four vaccines at standard or fractional dose. The vaccine was administered subcutaneously by nurses who were not masked to treatment, but participants and other study personnel were masked to vaccine allocation. The primary outcome was proportion of participants with seroconversion 28 days after vaccination. Seroconversion was defined as post-vaccination neutralising antibody titres at least 4 times pre-vaccination measurement measured by 50% plaque reduction neutralisation test (PRNT50). We defined non-inferiority as less than 10% decrease in seroconversion in fractional compared with standard dose groups 28 days after vaccination. The primary outcome was measured in the per-protocol population, and safety analyses included all vaccinated participants. This trial is registered with ClinicalTrials.gov, NCT02991495. Findings Between Nov 6, 2017, and Feb 21, 2018, 1029 participants were assessed for inclusion. 69 people were ineligible, and 960 participants were enrolled and randomly assigned to vaccine manufacturer and dose (120 to Bio-Manguinhos-Fiocruz standard dose, 120 to Bio-Manguinhos-Fiocruz fractional dose, 120 to Chumakov Institute of Poliomyelitis and Viral Encephalitides standard dose, 120 to Chumakov Institute of Poliomyelitis and Viral Encephalitides fractional dose, 120 to Institut Pasteur Dakar standard dose, 120 to Institut Pasteur Dakar fractional dose, 120 to Sanofi Pasteur standard dose, and 120 to Sanofi Pasteur fractional dose). 49 participants had detectable PRNT50 at baseline and 11 had missing PRNT50 results at baseline or 28 days. 900 were included in the per-protocol analysis. 959 participants were included in the safety analysis. The absolute difference in seroconversion between fractional and standard doses by vaccine was 1·71% (95% CI −2·60 to 5·28) for Bio-Manguinhos-Fiocruz, −0·90% (–4·24 to 3·13) for Chumakov Institute of Poliomyelitis and Viral Encephalitides, 1·82% (–2·75 to 5·39) for Institut Pasteur Dakar, and 0·0% (–3·32 to 3·29) for Sanofi Pasteur. Fractional doses from all four vaccines met the non-inferiority criterion. The most common treatment-related adverse events were headache (22·2%), fatigue (13·7%), myalgia (13·3%) and self-reported fever (9·0%). There were no study-vaccine related serious adverse events. Interpretation Fractional doses of all WHO-prequalified yellow fever vaccines were non-inferior to the standard dose in inducing seroconversion 28 days after vaccination, with no major safety concerns. These results support the use of fractional dosage in the general adult population for outbreak response in situations of vaccine shortage. Funding The study was funded by Médecins Sans Frontières Foundation, Wellcome Trust (grant no. 092654), and the UK Department for International Development. Vaccines were donated in kind