Controlled Human Infection Models To Accelerate Vaccine Development

Choy, Robert K. M.; Bourgeois, A. Louis; Ockenhouse, Christian F.; Walker, Richard I.; Sheets, Rebecca; Flores, Jorge

doi:10.1128/cmr.00008-21

Cited by 18 publications

(8 citation statements)

References 819 publications

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“…The prevalence of immunizations against infectious illnesses is on the rise and is very effective. In order to ensure the effectiveness of vaccines, the preclinical and clinical stages of vaccine development need the use of intricate, time-consuming, and costly in vivo and in vitro methodologies [ 19 , 20 ].…”

Section: Discussionmentioning

confidence: 99%

A novel chimeric vaccine containing multiple epitopes for simulating robust immune activation against Klebsiella pneumoniae

Hakimian,

Doosti,

Sharifzadeh

2024

BMC Immunol

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Background Due to antibiotic resistance, the Klebsiella genus is linked to morbidity and death, necessitating the development of a universally protective vaccine against Klebsiella pathogens. Methods Core sequence analysis prioritized non-redundant host molecules and expected lipid bilayer peptides from fully sequenced Klebsiella genomes. These proteins were refined to identify epitopes, examining their immunogenicity, toxicity, solubility, and interaction with MHC alleles. Epitopes were linked to CPG ODN C274 via EAAAK, HEYGAEALERAG, and GGGS linkers to enhance immunological responses. The vaccine’s tertiary structure was modelled and docked with MHC-I and MHC-II. Results Fifty-five proteins were recognized in the Vaxign collection as having remarkable features. Twenty-three proteins with potential pathogenicity were then identified. Eight options for vaccines emerged after the immunogenicity of proteins was examined. The best antigens were three proteins: MrkD, Iron-regulated lipid membrane polypeptides, and RmpA. These compounds were selected for their sensitivity. The structural protein sequences of K. pneumoniae were utilized to identify seven CTL epitopes, seven HTL epitopes, and seven LBL epitopes, respectively. The produced immunization displayed a stable contact with the receptors, based on molecular dynamic simulations lasting 250 nanoseconds. Intermolecular binding free energies also indicated the dominance of the van der Waals and electrostatic energies. Conclusion In summary, the results of this study might help scientists develop a novel vaccine to prevent K. pneumoniae infections.

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Section: Discussionmentioning

confidence: 99%

A novel chimeric vaccine containing multiple epitopes for simulating robust immune activation against Klebsiella pneumoniae

Hakimian,

Doosti,

Sharifzadeh

2024

BMC Immunol

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“…Controlled human infection models (CHIMs) have a strong track record in accelerating vaccine development, particularly for enteric pathogens. 12 13 For example, the live attenuated cholera vaccine CVD 103-HgR was licensed as a travel vaccine on the basis of safety, immunogenicity and efficacy data arising from CHIM studies. 14 More recently, a programme of typhoidal Salmonella CHIM studies demonstrated efficacy of a Vi-tetanus toxoid (Vi-TT) conjugate vaccine against S .…”

Section: Introductionmentioning

confidence: 99%

Protocol for the challenge non-typhoidalSalmonella(CHANTS) study: a first-in-human, in-patient, double-blind, randomised, safety and dose-escalation controlled human infection model in the UK

Smith,

Rydlova

et al. 2024

BMJ Open

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IntroductionInvasive non-typhoidalSalmonella(iNTS) serovars are a major cause of community-acquired bloodstream infections in sub-Saharan Africa (SSA). In this setting,Salmonella entericaserovar Typhimurium accounts for two-thirds of infections and is associated with an estimated case fatality rate of 15%–20%. Several iNTS vaccine candidates are in early-stage assessment which—if found effective—would provide a valuable public health tool to reduce iNTS disease burden. The CHANTS study aims to develop a first-in-humanSalmonellaTyphimurium controlled human infection model, which can act as a platform for future vaccine evaluation, in addition to providing novel insights into iNTS disease pathogenesis.Methods and analysisThis double-blind, safety and dose-escalation study will randomise 40–80 healthy UK participants aged 18–50 to receive oral challenge with one of two strains ofS. Typhimurium belonging to the ST19 (strain 4/74) or ST313 (strain D23580) lineages. 4/74 is a global strain often associated with diarrhoeal illness predominantly in high-income settings, while D23580 is an archetypal strain representing invasive disease-causing isolates found in SSA. The primary objective is to determine the minimum infectious dose (colony-forming unit) required for 60%–75% of participants to develop clinical or microbiological features of systemic salmonellosis. Secondary endpoints are to describe and compare the clinical, microbiological and immunological responses following challenge. Dose escalation or de-escalation will be undertaken by continual-reassessment methodology and limited within prespecified safety thresholds. Exploratory objectives are to describe mechanisms of iNTS virulence, identify putative immune correlates of protection and describe host–pathogen interactions in response to infection.Ethics and disseminationEthical approval has been obtained from the NHS Health Research Authority (London—Fulham Research Ethics Committee 21/PR/0051; IRAS Project ID 301659). The study findings will be disseminated in international peer-reviewed journals and presented at national/international stakeholder meetings. Study outcome summaries will be provided to both funders and participants.Trial registration numberNCT05870150

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“…High-resolution immune profiling of the host peripheral immunity after pathogen exposure, particularly during the pre-symptomatic phase, has largely been limited to human challenge studies (7)(8)(9). Controlled human infection models pose several limitations to understanding the host response during natural infections (10).…”

Section: Introductionmentioning

confidence: 99%

“…High-frequency longitudinal profiling of host peripheral immunity, particularly during extremely early presymptomatic phases, has largely been conducted in the setting of human challenge studies 7-9 . Controlled human infection models pose limitations to understanding the host response during natural infections 10,11 . Restricted by ethical and regulatory considerations, these models often employ use of a limited set of challenge strains, a uniform viral challenge dose, and are performed on low-risk, healthy volunteers (young adults), thus limiting their broad applicability to contemporaneously circulating variants and to the heterogeneity of population-wide immunologic backgrounds that are shaped by individual susceptibilities, and by prior vaccination and infection 11 .…”

Section: Introductionmentioning

confidence: 99%

homeRNA self-blood collection enables high-frequency temporal profiling of presymptomatic host immune kinetics to respiratory viral infection: a prospective cohort study

Lim,

Lea,

Dostie

et al. 2023

Preprint

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BackgroundHost 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 (homeRNA) 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.MethodsWe prospectively recruited non-symptomatic adults with recent exposure to ARVIs who subsequently tested negative (exposed uninfected) and positive for respiratory pathogens. Study participants performed self-collection of blood and nasal swabs across a 4-week observation window. Daily monitoring of symptoms, viral load, and blood transcriptional responses was performed for the first week followed by weekly monitoring of blood transcriptional responses and symptoms. Nasal swabs were assayed for respiratory pathogens including SARS- CoV-2. Immune kinetics from 132 longitudinal blood samples (8 SARS-CoV-2 infected and 4 exposed uninfected) were profiled at high temporal resolution for 773 host response genes.Findings68 participants across 26 U.S. states completed the study between June 2021 – April 2022, with 97.6% of scheduled longitudinal blood collections (n=691), 97.9% of nasal swabs (n=466) and 97.2% of symptom surveys (n=688) returned. SARS-CoV-2 infection was confirmed in 25% of the participants (n=17) Expression of host immediate early genes (IEGs) involved in AP-1 transcriptional complex and prostaglandin biosynthesis along with genes encoding the early T-cell activation antigen (CD69), pyrogenic cytokines (IL-6, MIP-1β, and IFN-γ), cytotoxic cell receptors and granule proteins, and interferon-induced GTPases were detected in the periphery prior to onset of viral shedding in the nasal passage. Upon onset of viral shedding, robust induction of interferon stimulated genes (ISGs) were observed. We also observed elevated expression of the host defense peptidesDEFA4,LCN2,LTF,BPI(HDPs) in exposed uninfected individuals.InterpretationSignatures of T-cell responses prior to nasal viral shedding followed by robust induction of innate ISGs upon onset of viral shedding suggests that T-cell derived immune memory may play a role in pathogen control during early phases of the infection. Elevated levels of HDPs in exposed uninfected individuals suggest a potential role for neutrophil-mediated immunity in host defense during pathogen exposure. Finally, we demonstrated that unsupervised self-collection and stabilization of blood usinghomeRNA can be used to study early host immune kinetics to natural ARVIs at a temporal resolution comparable to that of human challenge studies.

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Controlled Human Infection Models To Accelerate Vaccine Development

Cited by 18 publications

References 819 publications

A novel chimeric vaccine containing multiple epitopes for simulating robust immune activation against Klebsiella pneumoniae

A novel chimeric vaccine containing multiple epitopes for simulating robust immune activation against Klebsiella pneumoniae

Protocol for the challenge non-typhoidalSalmonella(CHANTS) study: a first-in-human, in-patient, double-blind, randomised, safety and dose-escalation controlled human infection model in the UK

homeRNA self-blood collection enables high-frequency temporal profiling of presymptomatic host immune kinetics to respiratory viral infection: a prospective cohort study

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