Two cases of long-lasting, sub-microscopic Plasmodium malariae infections in adults from coastal Tanzania

Malaria is endemic in Tanzania with majority of clinical cases caused by Plasmodium falciparum. Additionally, Plasmodium malariae and Plasmodium ovale spp. are also present and clinical manifestations caused by these infections are not well described. Clinical episodes caused by P. malariae infections are often characterized by a relatively mild illness with a low number of parasites, which can persist for long periods. In this report, two cases of P. malariae infections that were identified during a clinical trial evaluating the P. falciparum malaria vaccine candidate, PfSPZ Vaccine are described. The two participants were followed up and monitored for clinical and laboratory parameters to assess vaccine safety providing the opportunity to study clinical manifestations of P. malariae over 4 months.; Two young, healthy Tanzanian men infected with low density asexual blood stage P. malariae diagnosed by quantitative polymerase chain reaction (qPCR) are described. Retrospective analysis of collected and stored blood samples revealed that the two volunteers had constant asexual blood stage parasitaemia for more than 4 months. During the 132 days of infection, the volunteers' vital signs, body temperature and serum biochemistry all remained within normal ranges. Haematological abnormalities, which were transiently outside normal ranges, were regarded as not clinically significant. During this time period, four consecutive evaluations of blood samples by thick blood smear microscopy conducted by an experienced microscopist were all negative, indicating the presence of low-density sub-microscopic infections.; The two cases of P. malariae infections presented here confirm the ability of this Plasmodium species to persist at low density in the human host for extended time periods without causing clinical symptoms. The presented data also demonstrate that clinical study sites in malaria endemic regions need to have a strong malaria diagnostic infrastructure, including the ability of capturing sub-microscopic parasitaemia and differentiation of Plasmodium species. Trial registration ClinicalTrials.gov: NCT02613520, https://clinicaltrials.gov/ct2/show/NCT02613520 , Registered: November 24th 2015, Enrolment of the first participant to the trial: December 15th 2015, Trial was registered before the first participant was enrolled

Baseline exposure, antibody subclass, and hepatitis B response differentially affect malaria protective immunity following RTS,S/AS01E vaccination in African children

Background: The RTS,S/AS01E vaccine provides partial protection against malaria in African children, but immune responses have only been partially characterized and do not reliably predict protective efficacy. We aimed to evaluate comprehensively the immunogenicity of the vaccine at peak response, the factors affecting it, and the antibodies associated with protection against clinical malaria in young African children participating in the multicenter phase 3 trial for licensure. Methods: We measured total IgM, IgG, and IgG1–4 subclass antibodies to three constructs of the Plasmodium falciparum circumsporozoite protein (CSP) and hepatitis B surface antigen (HBsAg) that are part of the RTS,S vaccine, by quantitative suspension array technology. Plasma and serum samples were analyzed in 195 infants and children from two sites in Ghana (Kintampo) and Mozambique (Manhiça) with different transmission intensities using a case-control study design. We applied regression models and machine learning techniques to analyze immunogenicity, correlates of protection, and factors affecting them. Results: RTS,S/AS01E induced IgM and IgG, predominantly IgG1 and IgG3, but also IgG2 and IgG4, subclass responses. Age, site, previous malaria episodes, and baseline characteristics including antibodies to CSP and other antigens reflecting malaria exposure and maternal IgGs, nutritional status, and hemoglobin concentration, significantly affected vaccine immunogenicity. We identified distinct signatures of malaria protection and risk in RTS,S/AS01E but not in comparator vaccinees. IgG2 and IgG4 responses to RTS,S antigens post-vaccination, and anti-CSP and anti-P. falciparum antibody levels pre-vaccination, were associated with malaria risk over 1-year follow-up. In contrast, antibody responses to HBsAg (all isotypes, subclasses, and timepoints) and post-vaccination IgG1 and IgG3 to CSP C-terminus and NANP were associated with protection. Age and site affected the relative contribution of responses in the correlates identified. Conclusions: Cytophilic IgG responses to the C-terminal and NANP repeat regions of CSP and anti-HBsAg antibodies induced by RTS,S/AS01E vaccination were associated with malaria protection. In contrast, higher malaria exposure at baseline and non-cytophilic IgG responses to CSP were associated with disease risk. Data provide new correlates of vaccine success and failure in African children and reveal key insights into the mode of action that can guide development of more efficacious next-generation vaccines

Strong off-target antibody reactivity to malarial antigens induced by RTS,S/AS01E vaccination is associated with protection

Contains fulltext : 250956.pdf (Publisher’s version ) (Open Access

ELIMU-MDx: a web-based, open-source platform for storage, management and analysis of diagnostic qPCR data

The Electronic Laboratory Information and Management Utensil for Molecular Diagnostics (ELIMU-MDx) is a user-friendly platform designed and built to accelerate the turnaround time of diagnostic qPCR assays. ELIMU-MDx is compliant with Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines and has extensive data-import capabilities for all major qPCR instruments by using the RDML data standard. This platform was designed as an open-source software tool and can be accessed through the web browser on all major operating systems

Molecular monitoring of the diversity of human pathogenic malaria species in blood donations on Bioko Island, Equatorial Guinea

Abstract Background Malaria can be transmitted by blood transfusion from human to human and it is responsible for the majority of transfusion-transmitted infectious diseases worldwide. In sub-Saharan Africa, it had been estimated that almost a quarter of blood donations contain malaria parasites. Since rapid diagnostic tests and thick blood smear microscopy lack sensitivity for low density parasitaemia, particularly in asymptomatic adults, the most reliable method to assess the problem of transfusion-transmitted malaria are nucleic acid-based molecular approaches such as quantitative polymerase chain reaction. The study was undertaken to determine the prevalence of sub-microscopic malaria parasite infection among blood donors in Malabo, Equatorial Guinea. Methods Between July and August 2017, a total of 200 individual blood samples from blood donors at the Malabo Blood Bank were collected and screened by rapid diagnostic tests and thick blood smear microscopy. Retrospectively, the same samples were analysed for the presence of undetected, low-density malaria parasites using quantitative polymerase chain reaction. Results In comparison to 6.5% (13/200) by rapid diagnostic test and 2.0% (4/200) by microscopy, the proportion of Plasmodium falciparum positive blood donations analysed by quantitative polymerase chain reaction was significantly higher (26%, 52/200). Densities of P. falciparum positive blood donations were ranging from 0.06 to 3707.0 parasites/µL with 79.6% below 100 parasites/µL and therefore not detectable by non-molecular malaria diagnostic tests. qPCR based species identification revealed that P. falciparum was the dominating species responsible for 88.1% (52/59) of positive blood donations, followed by Plasmodium malariae (15.3%, 9/59) and Plasmodium ovale (3.4%, 2/59). Conclusions This study confirms that in malaria endemic settings, sub-patent malaria infections among blood donors are prevalent. In blood collected from healthy donors living in Malabo, P. falciparum, P. malariae and P. ovale parasites were identified. Currently widely used malaria diagnostic tools have missed more than 75% of P. falciparum containing blood donations, demonstrating the value of quantitative polymerase chain reaction to reliably detect low density P. falciparum infections. Since the availability of molecular diagnostic methods in malaria endemic countries is still limited, the blood recipients living in malaria endemic countries should be treated following WHO recommendations

Assessment of the novel T-cell activation marker-tuberculosis assay for diagnosis of active tuberculosis in children : a prospective proof-of-concept study

The diagnosis of paediatric tuberculosis is complicated by non-specific symptoms, difficult specimen collection, and the paucibacillary nature of the disease. We assessed the accuracy of a novel immunodiagnostic T-cell activation marker-tuberculosis (TAM-TB) assay in a proof-of-concept study to identify children with active tuberculosis.; Children with symptoms that suggested tuberculosis were prospectively recruited at the NIMR-Mbeya Medical Research Center in Mbeya, and the Ifakara Health Institute in Bagamoyo, Tanzania, between May 10, 2011, and Sept 4, 2012. Sputum and peripheral blood mononuclear cells were obtained for Mycobacterium tuberculosis culture and performance assessment of the TAM-TB assay. The children were assigned to standardised clinical case classifications based on microbiological and clinical findings.; Among 290 children screened, we selected a subgroup of 130 to ensure testing of at least 20 with culture-confirmed tuberculosis. 17 of 130 children were excluded because of inconclusive TAM-TB assay results. The TAM-TB assay enabled detection of 15 of 18 culture-confirmed cases (sensitivity 83·3%, 95% CI 58·6-96·4). Specificity was 96·8% (95% CI 89·0-99·6) in the cases that were classified as not tuberculosis (n=63), with little effect from latent tuberculosis infection. The TAM-TB assay identified five additional patients with highly probable or probable tuberculosis, in whom M tuberculosis was not isolated. The median time to diagnosis was 19·5 days (IQR 14-45) for culture.; The sputum-independent TAM-TB assay is a rapid and accurate blood test that has the potential to improve the diagnosis of active tuberculosis in children.; European and Developing Countries Clinical Trials Partnership, German Federal Ministry of Education and Research, and Swiss National Science Foundation

Strong off-target antibody reactivity to malarial antigens induced by RTS,S/AS01E vaccination is associated with protection.

The RTS,S/AS01E vaccine targets the circumsporozoite protein (CSP) of the Plasmodium falciparum (P. falciparum) parasite. Protein microarrays were used to measure levels of IgG against 1000 P. falciparum antigens in 2138 infants (age 6-12 weeks) and children (age 5-17 months) from 6 African sites of the phase III trial, sampled before and at 4 longitudinal visits after vaccination. One month postvaccination, IgG responses to 17% of all probed antigens showed differences between RTS,S/AS01E and comparator vaccination groups, whereas no prevaccination differences were found. A small subset of antigens presented IgG levels reaching 4- to 8-fold increases in the RTS,S/AS01E group, comparable in magnitude to anti-CSP IgG levels (~11-fold increase). They were strongly cross-correlated and correlated with anti-CSP levels, waning similarly over time and reincreasing with the booster dose. Such an intriguing phenomenon may be due to cross-reactivity of anti-CSP antibodies with these antigens. RTS,S/AS01E vaccinees with strong off-target IgG responses had an estimated lower clinical malaria incidence after adjusting for age group, site, and postvaccination anti-CSP levels. RTS,S/AS01E-induced IgG may bind strongly not only to CSP, but also to unrelated malaria antigens, and this seems to either confer, or at least be a marker of, increased protection from clinical malaria

Effects of Aerosols and Clouds on the Levels of Surface Solar Radiation and Solar Energy in Cyprus

Cyprus plans to drastically increase the share of renewable energy sources from 13.9% in 2020 to 22.9% in 2030. Solar energy can play a key role in the effort to fulfil this goal. The potential for production of solar energy over the island is much higher than most of European territory because of the low latitude of the island and the nearly cloudless summers. In this study, high quality and fine resolution satellite retrievals of aerosols and dust, from the newly developed MIDAS climatology, and information for clouds from CM SAF are used in order to quantify the effects of aerosols, dust, and clouds on the levels of surface solar radiation for 2004–2017 and the corresponding financial loss for different types of installations for the production of solar energy. Surface solar radiation climatology has also been developed based on the above information. Ground-based measurements were also incorporated to study the contribution of different species to the aerosol mixture and the effects of day-to-day variability of aerosols on SSR. Aerosols attenuate 5–10% of the annual global horizontal irradiation and 15–35% of the annual direct normal irradiation, while clouds attenuate 25–30% and 35–50% respectively. Dust is responsible for 30–50% of the overall attenuation by aerosols and is the main regulator of the variability of total aerosol. All-sky annual global horizontal irradiation increased significantly in the period of study by 2%, which was mainly attributed to changes in cloudiness

Concentration and avidity of antibodies to different circumsporozoite epitopes correlate with RTS,S/AS01E malaria vaccine efficacy

RTS,S/AS01E has been tested in a phase 3 malaria vaccine study with partial efficacy in African children and infants. In a cohort of 1028 subjects from one low (Bagomoyo) and two high (Nanoro, Kintampo) malaria transmission sites, we analysed IgG plasma/serum concentration and avidity to CSP (NANP-repeat and C-terminal domains) after a 3-dose vaccination against time to clinical malaria events during 12-months. Here we report that RTS,S/AS01E induces substantial increases in IgG levels from pre- to post-vaccination (p\xE2\x80\x89<\xE2\x80\x890.001), higher in NANP than C-terminus (2855 vs 1297 proportional change between means), and higher concentrations and avidities in children than infants (p\xE2\x80\x89<\xE2\x80\x890.001). Baseline CSP IgG levels are elevated in malaria cases than controls (p\xE2\x80\x89<\xE2\x80\x890.001). Both, IgG magnitude to NANP (hazard ratio [95% confidence interval] 0.61 [0.48-0.76]) and avidity to C-terminus (0.07 [0.05-0.90]) post-vaccination are significantly associated with vaccine efficacy. IgG avidity to the C-terminus emerges as a significant contributor to RTS,S/AS01E-mediated protection

Baseline exposure, antibody subclass, and hepatitis B response differentially affect malaria protective immunity following RTS,S/AS01E vaccination in African children

Background: The RTS,S/AS01E vaccine provides partial protection against malaria in African children, but immune responses have only been partially characterized and do not reliably predict protective efficacy. We aimed to evaluate comprehensively the immunogenicity of the vaccine at peak response, the factors affecting it, and the antibodies associated with protection against clinical malaria in young African children participating in the multicenter phase 3 trial for licensure. Methods: We measured total IgM, IgG, and IgG1–4 subclass antibodies to three constructs of the Plasmodium falciparum circumsporozoite protein (CSP) and hepatitis B surface antigen (HBsAg) that are part of the RTS,S vaccine, by quantitative suspension array technology. Plasma and serum samples were analyzed in 195 infants and children from two sites in Ghana (Kintampo) and Mozambique (Manhiça) with different transmission intensities using a case-control study design. We applied regression models and machine learning techniques to analyze immunogenicity, correlates of protection, and factors affecting them. Results: RTS,S/AS01E induced IgM and IgG, predominantly IgG1 and IgG3, but also IgG2 and IgG4, subclass responses. Age, site, previous malaria episodes, and baseline characteristics including antibodies to CSP and other antigens reflecting malaria exposure and maternal IgGs, nutritional status, and hemoglobin concentration, significantly affected vaccine immunogenicity. We identified distinct signatures of malaria protection and risk in RTS,S/AS01E but not in comparator vaccinees. IgG2 and IgG4 responses to RTS,S antigens post-vaccination, and anti-CSP and anti-P. falciparum antibody levels pre-vaccination, were associated with malaria risk over 1-year follow-up. In contrast, antibody responses to HBsAg (all isotypes, subclasses, and timepoints) and post-vaccination IgG1 and IgG3 to CSP C-terminus and NANP were associated with protection. Age and site affected the relative contribution of responses in the correlates identified. Conclusions: Cytophilic IgG responses to the C-terminal and NANP repeat regions of CSP and anti-HBsAg antibodies induced by RTS,S/AS01E vaccination were associated with malaria protection. In contrast, higher malaria exposure at baseline and non-cytophilic IgG responses to CSP were associated with disease risk. Data provide new correlates of vaccine success and failure in African children and reveal key insights into the mode of action that can guide development of more efficacious next-generation vaccines