"human challenge"

Human challenge experiments could greatly accelerate the development of a tuberculosis (TB) vaccine. Human challenge for tuberculosis requires a strain that can both replicate in the host and be reliably cleared. To accomplish this, we designed Mycobacterium tuberculosis (Mtb) strains featuring up to three orthogonal kill switches, tightly regulated by exogenous tetracyclines and trimethoprim. The resultant strains displayed immunogenicity and antibiotic susceptibility similar to wild-type Mtb under permissive conditions...

Cabamiquine is a novel antimalarial agent that demonstrates the potential for chemoprevention and treatment of malaria. In this article, the dose-exposure-response relationship of cabamiquine was characterized using a population pharmacokinetic (PK)/pharmacodynamic (PD) model, incorporating the effects of cabamiquine on parasite dynamics at the liver and blood stages of malaria infection. Modeling was performed sequentially. First, a three-compartmental population PK model was developed, comprising linear elimination, a transit absorption model in combination with first-order absorption, and a recirculation model...

BACKGROUND: Host immunity is critical in determining outcomes of acute respiratory viral infections (ARVIs). However, detailed kinetics of host immune responses following natural exposures are poorly understood. Investigating the host response during the pre-symptomatic phase of viral infection is challenging, and prior work has largely relied on human challenge studies. In this prospective longitudinal study, we utilized a self-blood collection tool ( hom eRNA) to profile the host response during pre-symptomatic ARVIs in recently exposed adults and present a study framework for the conduct of large-scale longitudinal mechanistic studies...

Infectious diseases continue to account for a significant portion of global deaths despite the use of vaccines for several centuries. Immunization programs around the world are a testament to the great success of multiple vaccines, yet there are still diseases without vaccines and others that require safer more effective ones. Addressing uncontrolled and emerging disease threats is restrained by the limitations and bottlenecks encountered with traditional vaccine development paradigms. Recent advances in modern molecular biology technologies have enhanced the interrogation of host pathogen interaction and deciphered complex pathways, thereby uncovering the myriad interplay of biological events that generate immune protection against foreign agents...

No abstract text is available yet for this article.

Streptococcus pyogenes (also known as group A Streptococcus , Strep A) is an obligate human pathogen with significant global morbidity and mortality. Transmission is believed to occur primarily between individuals via respiratory droplets, but knowledge about other potential sources of transmission via aerosols or the environment is limited. Such knowledge is required to design optimal interventions to control transmission, particularly in endemic settings. We aim to detail an experimental methodology to assess the transmission potential of Strep A in a clinical environment...

Invasive non-typhoidal Salmonella disease (iNTS) is a major cause of morbidity and mortality globally, particularly as a cause of bloodstream infection in children and immunocompromised adults in sub-Saharan Africa. Vaccines to prevent non-typhoidal Salmonella (NTS) would represent a valuable public health tool in this setting to avert cases and prevent expansion of antimicrobial resistance. Several NTS and combination typhoidal-NTS vaccine candidates are in early-stage development, although the pathway to licensure is unclear due to challenges in conducting large phase III field trials...

The DENV envelope (E) and pre-membrane (prM) glycoproteins are primary targets of serologic immunity after infection and vaccination. Of these, serotype-specific (TS) antibodies typically target E domains, while serotype cross-reactive (CR) antibodies typically the target prM protein and conserved E regions. To identify and quantify E-domain TS neutralizing antibody responses in polyclonal sera, we developed a panel of chimeric DENV4/2 viruses that incorporate DENV2 envelope domain I, II, and III (DENV4/2-EDI, EDII, EDIII) into the DENV4 E glycoprotein...

Background Noroviruses (NoVs) are a leading cause of non-bacterial gastroenteritis in young children and adults worldwide. Snow Mountain Virus (SMV) is the prototype of NoV GII genotype 2 (GII.2) that has been developed as a viral model for human challenge models, an important tool for studying pathogenesis and immune response of NoV infections and for evaluating NoV vaccine candidates. Previous studies have identified blockade antibodies that block the binding of NoV virus-like particles (VLPs) to histo-blood group antigens (HBGAs) as a surrogate for neutralization in human Norwalk virus and GII...

All four serotypes of dengue virus (DENV) cause the full spectrum of disease. Therefore, vaccines must protect against all serotypes. To evaluate candidate vaccines, a human challenge model of dengue serotype 3 (rDEN30Δ30) was developed. All challenge virus recipients safely met the primary endpoint of viremia and secondary endpoints of rash and seroconversion to DENV-3.

The alarming rise of antibiotic resistance and the emergence of new vaccine technologies have increased the focus on vaccination to control gonorrhea. Neisseria gonorrhoeae strains FA1090 and MS11 have been used in challenge studies in human males. We used negative-ion MALDI-TOF MS to profile intact lipooligosaccharide (LOS) from strains MS11mkA, MS11mkC, FA1090 A23a, and FA1090 1-81-S2. The MS11mkC and 1-81-S2 variants were isolated from male volunteers infected with MS11mkA and A23a, respectively. LOS profiles were obtained after purification using the classical phenol water extraction method and by microwave-enhanced enzymatic digestion, which is more amenable for small-scale work...

Background:  This article is one of a series aiming to inform analytical methods to improve comparability of estimates of ethnic health disparities based on different sources. This article explores the quality of ethnicity data and identifies potential sources of bias when ethnicity information is collected in three key NHS data sources. Future research can build on these findings to explore analytical methods to mitigate biases. Methods:  Thematic analysis of semi-structured qualitative interviews to explore potential sources of error and bias in the process of collecting ethnicity information across three NHS data sources: General Practice Extraction Service (GPES) Data for Pandemic Planning and Research (GDPPR), Hospital Episode Statistics (HES) and Improving Access to Psychological Therapies (IAPT)...

Enteric fever, caused by oral infection with typhoidal Salmonella serovars, presents as a non-specific febrile illness preceded by an incubation period of 5 days or more. The enteric fever human challenge model provides a unique opportunity to investigate the innate immune response during this incubation period, and how this response is altered by vaccination with the Vi polysaccharide or conjugate vaccine. We find that on the same day as ingestion of typhoidal Salmonella , there is already evidence of an immune response, with 199 genes upregulated in the peripheral blood transcriptome 12 hours post-challenge (false discovery rate <0...

The COVID-19 pandemic has necessitated rapid research to aid in the understanding of the disease and the development of novel therapeutics. One option is to conduct controlled human infection trials (CHITs). In this article I examine the history of deliberate human infection and CHITs and their utilization prior to the COVID-19 pandemic, key ethical considerations of CHITs in the COVID-19 setting, an analysis of the World Health Organization's (WHO) Key criteria for the ethical acceptability of COVID-19 human challenge studies, and a review of the two COVID-19 CHITs that have already commenced, their compliance with the WHO criteria and other ethical considerations...

Human challenge studies (HCS) are controlled clinical trials in which participants are deliberately infected with a pathogen. Such trials are being developed for an increasing number of diseases. Partly as a result of the COVID-19 pandemic, there has been a recent ethical debate about the reasons for and against HCS in general, or rather, about the requirements that individual HCS must fulfill to be ethically acceptable. A systematic review was conducted to categorize and summarize such requirements and the reasons given for them...

BACKGROUND: The effect of childhood pneumococcal conjugate vaccine implementation in Malawi is threatened by absence of herd effect. There is persistent vaccine-type pneumococcal carriage in both vaccinated children and the wider community. We aimed to use a human infection study to measure 13-valent pneumococcal conjugate vaccine (PCV13) efficacy against pneumococcal carriage. METHODS: We did a double-blind, parallel-arm, randomised controlled trial investigating the efficacy of PCV13 or placebo against experimental pneumococcal carriage of Streptococcus pneumoniae serotype 6B (strain BHN418) among healthy adults (aged 18-40 years) from Blantyre, Malawi...

Effective bioinspiration requires dialogue between designers and biologists, and this dialogue must be rooted in a shared scientific understanding of living systems. To support learning from "nature's overarching design lessons" the Biomimicry Institute has produced ten "Unifying Patterns of Nature". These patterns have been developed to engage with those interested in finding biologically inspired solutions to human challenges. Yet, although well-intentioned and appealing, they are likely to dishearten biologists...

Haemophilus ducreyi is a causative agent of cutaneous ulcers in children who live in the tropics and of the genital ulcer disease chancroid in sexually active persons. In the anaerobic environment of abscesses and ulcers, anaerobic respiration and mixed acid fermentation (MAF) can be used to provide cellular energy. In Escherichia coli , MAF produces formate, acetate, lactate, succinate, and ethanol; however, MAF has not been studied in H. ducreyi . In human challenge experiments with H. ducreyi 35000HP, transcripts of the formate transporter FocA and pyruvate formate lyase (PflB) were upregulated in pustules compared to the inocula...

The unprecedented speed of delivery of SARS-CoV-2 pandemic vaccines has redefined the limits for all vaccine development. Beyond the aspirational 100-day timeline for tomorrow's hypothetical pandemic vaccines, there is a sense of optimism that development of other high priority vaccines can be accelerated. Early in the COVID-19 pandemic, an intense and polarised academic and public discourse arose concerning the role of human challenge trials for vaccine development. A case was made for human challenge trials as a powerful tool to establish early proof-of-concept of vaccine efficacy in humans, inform vaccine down selection, and address crucial knowledge gaps regarding transmission, pathogenesis, and immune protection...

Rationale: Pneumococcal pneumonia remains a global health problem. Pneumococcal colonization increases local and systemic protective immunity, suggesting that nasal administration of live attenuated Streptococcus pneumoniae (Spn) strains could help prevent infections. Objectives: We used a controlled human infection model to investigate whether nasopharyngeal colonization with attenuated S. pneumoniae strains protected against recolonization with wild-type (WT) Spn (SpnWT). Methods: Healthy adults aged 18-50 years were randomized (1:1:1:1) for nasal administration twice (at a 2-wk interval) with saline solution, WT Spn6B (BHN418), or one of two genetically modified Spn6B strains, SpnA1 ( Δfhs/piaA ) or SpnA3 ( ΔproABC/piaA ) (Stage I)...