Few studies of biomarkers as predictors of outcome in infection have been performed in tropical, low- and middle-income countries where the burden of sepsis is highest. We evaluated whether selected biomarkers could predict 28-day mortality in infected patients in rural Thailand. Four thousand nine hundred eighty-nine adult patients admitted with suspected infection to a referral hospital in northeast Thailand were prospectively enrolled within 24 h of admission. In a secondary analysis of 760 patients, interleukin-8 (IL-8), soluble tumor necrosis factor receptor 1 (sTNFR-1), angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and soluble triggering receptor expressed by myeloid cells 1 (sTREM-1) were measured in the plasma. Association with 28-day mortality was evaluated using regression; a parsimonious biomarker model was selected using the least absolute shrinkage and selection operator (LASSO) method. Discrimination of mortality was assessed by receiver operating characteristic curve analysis and verified by multiple methods. IL-8, sTNFR-1, Ang-2, and sTREM-1 concentrations were strongly associated with death. LASSO identified a three-biomarker model of sTREM-1, Ang-2, and IL-8, but sTREM-1 alone provided comparable mortality discrimination (p = 0.07). sTREM-1 alone was comparable to a model of clinical variables (area under receiver operating characteristic curve [AUC] 0.81, 95% confidence interval [CI] 0.77-0.85 vs AUC 0.79, 95% CI 0.74-0.84; p = 0.43). The combination of sTREM-1 and clinical variables yielded greater mortality discrimination than clinical variables alone (AUC 0.83, 95% CI 0.79-0.87; p = 0.004). sTREM-1 predicts mortality from infection in a tropical, middle-income country comparably to a model derived from clinical variables and, when combined with clinical variables, can further augment mortality prediction. The Ubon-sepsis study was registered on ClinicalTrials.gov ( NCT02217592
), 2014. Read the full article here!
KAF156 is a novel antimalarial drug that is active against both liver- and blood- stage Plasmodium
parasites, including drug-resistant strains. Here, we investigated the causal prophylactic efficacy of KAF156 in a controlled human malaria infection (CHMI) model. In Part 1, healthy, malaria-naïve participants received 800 mg KAF156 or placebo three hr before CHMI with Pf-infected mosquitoes. In Part 2, KAF156 was administered as single doses of 800, 300, 100, 50, or 20 mg 21 hr post-CHMI. All participants received atovaquone/proguanil treatment if blood-stage infection was detected or on day 29. For each cohort, 7-14 subjects were enrolled to KAF156 treatment and up to four subjects to placebo. KAF156 at all dose levels was safe and well tolerated. Two serious adverse events were reported - both resolved without sequelae and neither was considered related to KAF156. In Part 1, all participants treated with KAF156 and none of those randomized to placebo were protected against malaria infection. In Part 2, all participants treated with placebo or 20 mg KAF156 developed malaria infection. In contrast, 50 mg KAF156 protected 3/14 participants from infection, and doses of 800, 300, and 100 mg KAF156 protected all subjects against infection. An exposure-response analysis suggested that a 24-hr post-dose concentration of KAF156 of 21·5 ng/mL (90% CI 17.66 to 25.32 ng/mL) would ensure a 95% chance of protection from malaria parasite infection. KAF156 was safe and well tolerated and demonstrated high levels of pre- and post-CHMI protective efficacy. Read the full article here!
Eyal contends that the expected social value of controlled human infection studies (CHIs) conducted in an effort to find vaccines and treatment for coronavirus disease 2019 (COVID-19) will be high enough to justify the risks to participants. We are concerned that Eyal and others (1) underestimate the uncertainties inherent in making such a determination. CHIs could take too long to be sufficiently valuable or may even hinder vaccine uptake and introduce risks that are not well understood. Because of these uncertainties, our Policy Forum supports laying the groundwork for CHIs but not deploying them to address COVID-19 until there is greater confidence that their value can justify the risks.
Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) CHIs can be integrated into a highly dynamic vaccine development pipeline is an open question. It takes months to develop a challenge strain (2), even under a highly compressed schedule, and additional time to establish an appropriate challenge model. If SARS-CoV-2 transmission continues at a relatively high rate, other vaccine trials might speed ahead and produce efficacy data before CHIs could be launched (3). On the other hand, if field trials are not feasible because of declining transmission, SARS-CoV-2 CHIs could provide crucial efficacy data about candidate vaccines and would have much higher and clearer social value... Read the full response here
We sought to determine whether donor-derived HHV-6B-specific CD4+ T cell abundance correlates with HHV-6B detection after allogeneic hematopoietic cell transplant (aHCT). We identified 33 patients who received HLA-matched, non-T cell depleted, myeloablative aHCT and had weekly plasma PCR testing for HHV-6B for 100 days thereafter. We tested donor peripheral blood mononuclear cells for HHV-6B-specific CD4+ T cells. Patients with HHV-6B detection >median (200 copies/mL) received approximately 10-fold fewer donor-derived total or HHV-6B-specific CD4+ T cells compared to those with <median or no HHV-6B detection. These data suggest the importance of donor-derived immunity for controlling HHV-6B reactivation. Read the full article here!
We tested for associations between single-nucleotide polymorphisms within the Angiopoietin-1, Angiopoietin-2, and Tumor Necrosis Factor Receptor 1A genes and AKI- SP2 in 421 critically ill subjects of European ancestry. Top performing single-nucleotide polymorphisms (FDR < 0.05) were tested for cis-biomarker expression and whether genetic risk for AKI-SP2 is mediated through circulating biomarkers. We also completed in vitro studies using human kidney microvascular endothelial cells. Finally, we calculated the renal clearance of plasma biomarkers using 20 different timed urine collections. A genetic variant, rs2920656C > T, near ANGPT2 was associated with reduced risk of AKI-SP2 (odds ratio, 0.45; 95% CI, 0.31-0.66; adjusted FDR = 0.003) and decreased plasma angiopoietin-2 (p = 0.002). Causal inference analysis showed that for each minor allele (T) the risk of developing AKI-SP2 decreases by 16%. Plasma angiopoietin-2 mediated 41.5% of the rs2920656 related risk for AKI-SP2. Human kidney microvascular endothelial cells carrying the T allele of rs2920656 produced numerically lower levels of angiopoietin-2 although this was not statistically significant (p = 0.07). Finally, analyses demonstrated that angiopoietin-2 is minimally renally cleared in critically ill subjects. Genetic mediation analysis provides supportive evidence that angiopoietin-2 plays a causal role in risk for AKI-SP2. Read the full article here!
The human malaria parasite Plasmodium vivax
remains vastly understudied, mainly due to the lack of suitable laboratory models. Here, we report a humanized mouse model to test interventions that block P. vivax
parasite transition from liver stage infection to blood stage infection. Human liver-chimeric FRGN huHep mice infected with P. vivax
sporozoites were infused with human reticulocytes, allowing transition of exo-erythrocytic merozoites to reticulocyte infection and development into all erythrocytic forms, including gametocytes, in vivo
. In order to test the utility of this model for preclinical assessment of interventions, the invasion blocking potential of a monoclonal antibody targeting the essential interaction of the P. vivax
Duffy Binding Protein with the Duffy antigen receptor was tested by passive immunization. This antibody inhibited invasion by over 95%, providing unprecedented in vivo evidence that PvDBP constitutes a promising blood stage vaccine candidate and proving our model highly suitable to test blood stage interventions. Read the full article here!
The coronavirus disease 2019 (COVID-19) pandemic, caused by infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is having a deleterious impact on health services and the global economy, highlighting the urgent need for an effective vaccine. Such a vaccine would need to rapidly confer protection after one or two doses and would need to be manufactured using components suitable for scale up. Here, we developed an Alphavirus-derived replicon RNA vaccine candidate, repRNA-CoV2S, encoding the SARS-CoV-2 spike (S) protein. The RNA replicons were formulated with lipid inorganic nanoparticles (LIONs) that were designed to enhance vaccine stability, delivery, and immunogenicity. We show that a single intramuscular injection of the LION/repRNA-CoV2S vaccine in mice elicited robust production of anti-SARS-CoV-2 S protein IgG antibody isotypes indicative of a type 1 T helper cell response. A prime/boost regimen induced potent T cell responses in mice including antigen-specific responses in the lung and spleen. Prime-only immunization of aged (17 months old) mice induced smaller immune responses compared to young mice, but this difference was abrogated by booster immunization. In nonhuman primates, prime-only immunization in one intramuscular injection site or prime/boost immunizations in five intramuscular injection sites elicited modest T cell responses and robust antibody responses. The antibody responses persisted for at least 70 days and neutralized SARS-CoV-2 at titers comparable to those in human serum samples collected from individuals convalescing from COVID-19. These data support further development of LION/repRNA-CoV2S as a vaccine candidate for prophylactic protection against SARS-CoV-2 infection. Read the full article here!
Bumped kinase inhibitors (BKIs) are effective against a variety of apicomplexan parasites. Fifteen BKIs with promising in vitro
efficacy against Neospora caninum
tachyzoites, low cytotoxicity in mammalian cells, and no toxic effects in non-pregnant BALB/c mice were assessed in pregnant mice. Drugs were emulsified in corn oil and were applied by gavage for 5 days. Five BKIs did not affect pregnancy, five BKIs exhibited ~15-35% neonatal mortality and five compounds caused strong effects (infertility, abortion, stillbirth and pup mortality). Additionally, the impact of these compounds on zebrafish (Danio rerio) embryo development was assessed by exposing freshly fertilised eggs to 0.2-50 μM of BKIs and microscopic monitoring of embryo development in a blinded manner for 4 days. We propose an algorithm that includes quantification of malformations and embryo deaths, and established a scoring system that allows the calculation of an impact score (Si) indicating at which concentrations BKIs visibly affect zebrafish embryo development. Comparison of the two models showed that for nine compounds no clear correlation between Si and pregnancy outcome was observed. However, the three BKIs affecting zebrafish embryos only at high concentrations (≥40 μM) did not impair mouse pregnancy at all, and the three compounds that inhibited zebrafish embryo development already at 0.2 μM showed detrimental effects in the pregnancy model. Thus, the zebrafish embryo development test has limited predictive value to foresee pregnancy outcome in BKI-treated mice. We conclude that maternal health-related factors such as cardiovascular, pharmacokinetic and/or bioavailability properties also contribute to BKI-pregnancy effects. Read the full article here!
An effective drug to treat cryptosporidial diarrhea in HIV-infected individuals is a global health priority. Promising drugs need to be evaluated in endemic areas which may be challenged by both lack of resources and experience to conduct International Committee of Harmonisation-Good Clinical Practice (ICH-GCP)-compliant clinical trials. We present the challenges and lessons learned in implementing a phase 2A, randomized, double-blind, placebo-controlled trial of clofazimine, in treatment of cryptosporidiosis
among HIV-infected adults at a single site in Malawi. Primary challenges are grouped under study initiation, study population, study implementation, and cultural issues. The lessons learned primarily deal with regulatory system and operational barriers, and recommendations can be applied to other human experimental trials in low- and middle-income countries, specifically in sub-Saharan Africa. This study demonstrated that initiating and implementing human experimental trials in sub-Saharan Africa can be challenging. However, solutions exist and successful execution requires careful planning, ongoing evaluation, responsiveness to new developments, and oversight of all trial operations. The study's results and data can be found for open-source viewing on the Van Voorhis lab page
. Read the full article here
Controlled human infection (CHI) models have been developed for numerous pathogens in order to better understand disease processes and accelerate drug and vaccine testing. In the past, some researchers conducted highly controversial CHIs with vulnerable populations, including children. Ethical frameworks for CHIs now recommend vulnerable populations be excluded because they cannot consent to high risk research. In this paper we argue that CHI studies span a wide spectrum of benefit and risk, and that some CHI studies may involve minimal risk. The categorical exclusion of children from CHIs therefore departs from the standard approach to evaluating research risks, as international regulations and ethical guidance for pediatric research generally permit non-beneficial research with low risks. The paradigm in research ethics has also shifted from focusing on protecting vulnerable participants to recognizing that inclusion can be important as a matter of justice, providing new reasons to question this default exclusion of children from CHIs. Recognizing that pediatric CHIs can raise complex ethical issues and are easy to sensationalize in ways that may threaten the public's trust in research and sponsor institutions, we conclude by describing additional complexities that must be addressed before pediatric CHIs beyond licensed vaccine studies might be ethically acceptable. Read the full article here!
In low transmission settings early diagnosis is the main strategy to reduce adverse outcomes of malaria
in pregnancy; however, microscopy and rapid diagnostic tests (RDTs) are inadequate for detecting low-density infections. We studied the performance of the highly sensitive-RDT (hsRDT) and the loop mediated isothermal DNA amplification (LAMP) for the detection of P. falciparum in pregnant women. A cross-sectional study was conducted in two malaria-endemic municipalities in Colombia. We screened pregnant women in the context of an antenatal care program in health facilities and evaluated five tests (microscopy, conventional RDT, hsRDT, LAMP and nested polymerase chain reaction-PCR) for the detection of P. falciparum
in peripheral blood, using a quantitative reverse transcription PCR (qRT-PCR) as the reference standard. Diagnostic performance of hsRDT and LAMP were compared with routine testing. The prevalence of P. falciparum
was 4.5% by qRT-PCR, half of those infections were subpatent. The sensitivity of the hsRDT (64.1%) was slightly better compared to microscopy and cRDT (59 and 53.8% respectively). LAMP had the highest sensitivity (89.7%) for detecting P. falciparum
and the ability to detect very low-density infections (minimum parasite density detected 0.08 p/μL). There is an underestimation of Plasmodium spp.
infections by tests routinely used in pregnant women attending antenatal care visits. LAMP methodology can be successfully implemented at local hospitals in malaria-endemic areas. The relevance of detecting and treating this sub-patent P. falciparum
infections in pregnant women should be evaluated. Trial registration: ClinicalTrials.gov, Identifier: NCT03172221
, Date of registration: May 29, 2017. Read the full article here!