Experimental infection of human volunteers Roestenberg, Meta; Hoogerwerf, Marie-Astrid; Ferreira, Daniela M ...
Lancet. Infectious diseases/The Lancet. Infectious diseases,
October 2018, 2018-10-00, 20181001, Volume:
18, Issue:
10
Journal Article
Peer reviewed
Open access
Controlled human infection (CHI) trials, in which healthy volunteers are experimentally infected, can accelerate the development of novel drugs and vaccines for infectious diseases of global ...importance. The use of CHI models is expanding from around 60 studies in the 1970s to more than 120 publications in this decade, primarily for influenza, rhinovirus, and malaria. CHI trials have provided landmark data for several registered drugs and vaccines, and have generated unprecedented scientific insights. Because of their invasive nature, CHI studies demand critical ethical review according to established frameworks. CHI-associated serious adverse events are rarely reported. Novel CHI models need standardised safety data from comparable CHI models to facilitate evidence-based risk assessments, as well as funds to produce challenge inoculum according to regulatory requirements. Advances such as the principle of controlled colonisation, the expansion of models to endemic areas, and the use of genetically attenuated strains will further broaden the scope of CHI trials.
Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with moderate disease is unknown.
To ...determine the efficacy of 5 or 10 days of remdesivir treatment compared with standard care on clinical status on day 11 after initiation of treatment.
Randomized, open-label trial of hospitalized patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (pulmonary infiltrates and room-air oxygen saturation >94%) enrolled from March 15 through April 18, 2020, at 105 hospitals in the United States, Europe, and Asia. The date of final follow-up was May 20, 2020.
Patients were randomized in a 1:1:1 ratio to receive a 10-day course of remdesivir (n = 197), a 5-day course of remdesivir (n = 199), or standard care (n = 200). Remdesivir was dosed intravenously at 200 mg on day 1 followed by 100 mg/d.
The primary end point was clinical status on day 11 on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7). Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicates difference in clinical status distribution toward category 7 for the remdesivir group vs the standard care group.
Among 596 patients who were randomized, 584 began the study and received remdesivir or continued standard care (median age, 57 interquartile range, 46-66 years; 227 39% women; 56% had cardiovascular disease, 42% hypertension, and 40% diabetes), and 533 (91%) completed the trial. Median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group. On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; 95% CI, 1.09-2.48; P = .02). The clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not significantly different (P = .18 by Wilcoxon rank sum test). By day 28, 9 patients had died: 2 (1%) in the 5-day remdesivir group, 3 (2%) in the 10-day remdesivir group, and 4 (2%) in the standard care group. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more frequent among remdesivir-treated patients compared with standard care.
Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance.
ClinicalTrials.gov Identifier: NCT04292730.
In controlled human infection (CHI) studies, investigators deliberately infect healthy individuals with pathogens in order to study mechanisms of disease or obtain preliminary efficacy data on ...investigational vaccines and medicines. CHI studies offer a fast and cost‐effective way of generating new scientific insights, prioritizing investigational products for clinical testing, and reducing the risk that large numbers of people are exposed to ineffective or harmful substances in research or in practice. Yet depending on the pathogen, CHI studies can involve significant risks or burdens for participants, pose risks to individuals or communities not involved in the research, and lead to public controversy. It is therefore essential to ensure that the risks of CHI studies are justified by their social value—that is, their potential to generate benefits for society—and that public trust can be maintained. In this paper, we aim to clarify how research sponsors, research ethics committees and other reviewers should judge the social value of CHI studies. We develop a list of relevant considerations for making social value judgments based on the standard view of social value. We then use this list to discuss the example of potentially conducting dengue virus CHI studies in endemic settings. We argue that dengue virus CHI studies in endemic settings would fall on the higher end of the spectrum of social value, mostly because of their potential to redirect all fields of future dengue research. Drawing on this discussion, we derive several general recommendations for how reviewers should judge the social value of CHI studies.
Malaria is one of the most frequently occurring infectious diseases worldwide, with almost 1 million deaths and an estimated 243 million clinical cases annually. Several candidate malaria vaccines ...have reached Phase IIb clinical trials, but results have often been disappointing. As an alternative to these Phase IIb field trials, the efficacy of candidate malaria vaccines can first be assessed through the deliberate exposure of participants to the bites of infectious mosquitoes (sporozoite challenge) or to an inoculum of blood-stage parasites (blood-stage challenge). With an increasing number of malaria vaccine candidates being developed, should human malaria challenge models be more widely used to reduce cost and time investments? This article reviews previous experience with both the sporozoite and blood-stage human malaria challenge models and provides future perspectives for these models in malaria vaccine development.
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. We review the track record of human challenge trials contributing to the development of vaccines for 19 different pathogens and discuss relevant limitations, barriers, and pitfalls. This Review also highlights opportunities for efforts to broaden the scope and boost the effects of human challenge trials, to accelerate all vaccine development.
Summary Background We have shown that immunity to infection with Plasmodium falciparum can be induced experimentally in malaria-naive volunteers through immunisation by bites of infected mosquitoes ...while simultaneously preventing disease with chloroquine prophylaxis. This immunity was associated with parasite-specific production of interferon γ and interleukin 2 by pluripotent effector memory cells in vitro. We aim to explore the persistence of protection and immune responses in the same volunteers. Methods In an open-label study at the Radboud University Nijmegen Medical Centre (Nijmegen, Netherlands), from November to December, 2009, we rechallenged previously immune volunteers (28 months after immunisation) with the bites of five mosquitoes infected with P falciparum . Newly recruited malaria-naive volunteers served as infection controls. Our primary outcome was the detection of blood-stage parasitaemia by microscopy. We assessed the kinetics of parasitaemia with real-time quantitative PCR (rtPCR) and recorded clinical signs and symptoms. In-vitro production of interferon γ and interleukin 2 by effector memory T cells was studied after stimulation with sporozoites and red blood cells infected with P falciparum . Differences in cellular immune responses between the study groups were assessed with the Mann-Whitney test. This study is registered with ClinicalTrials.gov , number NCT00757887. Findings Four of six immune volunteers were microscopically negative after rechallenge. rtPCR-based detection of blood-stage parasites in these individuals was negative throughout follow-up. Patent parasitaemia was delayed in the remaining two immunised volunteers. In-vitro assays showed the long-term persistence of parasite-specific pluripotent effector memory T-cell responses in protected volunteers. The four protected volunteers reported several mild to moderate adverse events, of which the most commonly reported symptom was headache (one to three episodes per volunteer). The two patients with delayed patency had adverse events similar to those in the control group. Interpretation Artificially induced immunity lasts longer than generally recorded after natural exposure; providing a new avenue of research into the mechanisms of malaria immunity. Funding Dioraphte Foundation.
•Controlled human infection (CHI) models are diverse but face similar challenges.•CHI are increasingly used to select products for downstream development.•A CHI platform for researchers would be ...instrumental to share best practices.
The principle of deliberately infecting humans with infectious agents in a controlled setting, so-called controlled human infections (CHI), is not novel. Many CHI models have a long history and were established decades ago such as the intentional exposure to yellow fever and dengue performed in the 1900’s (Reed, 1902) 2. In these times bioethics and scientific reasoning were in their infancy. Nowadays, clinical trials are highly regulated and CHI are executed worldwide. Controlled human malaria infections and influenza infections are the two most frequently practiced. Others are experiencing a revival or are being carefully developed. Because CHI models test the efficacy of promising vaccine or drug candidates early in clinical development, they offer the potential to decrease the number of failing phase 2 and 3 trials, reducing risks for patients and saving costs and efforts.
In addition, CHI models provide unprecedented opportunities to dissect the physiological, immunological and metabolic changes that occur upon infection. However, it is clear that controlled infections require careful deliberation of safety, ethics, quarantine, scientific output and the production of infectious material.
An independent international workshop was hosted by the Leiden University Medical Centre in The Netherlands, bringing together clinical investigators, basic scientists, regulators, funders and policy makers from 22 different countries to discuss the opportunities and challenges in CHI. The aim of the workshop was to discuss CHI as a tool to advance science, drug and vaccine development, share the challenges of establishing a CHI model with specific focus on neglected tropical diseases and the possibilities to transfer models to endemic sites. Noticeably, among the 128 participants were clinical investigators from ten different countries in Sub-Saharan Africa. An important dimension of the meeting was to give the floor to young established clinicians and scientists to voice their perspective on the future of CHI models.
To quantitatively investigate the motivations, decision-making and experience of participants in controlled human infection (CHI) studies.
Cross-sectional descriptive survey study.
Previous ...participants of CHI studies at the Leiden Controlled Human Infection Center, control group of students from Leiden University.
61 previous participants and 156 controls.
Ranking of motivational and decisional factors, risk propensity score and multiple-choice questions on experience of trial participation and ethical aspects of CHI studies.
Motivating factors for participants were contributing to science (81%), contributing to research that may benefit developing countries (72%) and the financial compensation (63%). For 51% of participants, a reason other than financial compensation was the most important motivational factor. Participants considered trust in the study team (70%), time investment (63%), severity of symptoms (54%), chance of developing symptoms (54%) and whether it is an easy way to make money (54%) in their decision to participate. Most CHI participants (84%) were proud of their participation, would advise others to participate (89%) and would participate in a similar trial again (85%). CHI participants had a higher risk propensity score than students (estimated difference 0.9, p<0.001).
Although financial compensation is important, the motivations for participants in a CHI study are diverse and participants make a balanced appraisal of risks and burden before participating.
Abstract
Background
Schistosomiasis is a major global health problem caused by blood-dwelling parasitic worms, which is currently tackled primarily by mass administration of the drug praziquantel. ...Appropriate drug treatment strategies are informed by diagnostics that establish the prevalence and intensity of infection, which, in regions of low transmission, should be highly sensitive.
Methods
To identify sensitive new serological markers of Schistosoma mansoni infections, we have compiled a recombinant protein library of parasite cell-surface and secreted proteins expressed in mammalian cells.
Results
Together with a time series of sera samples from volunteers experimentally infected with a defined number of male parasites, we probed this protein library to identify several markers that can detect primary infections with as low as 10 parasites and as early as 5 weeks postinfection.
Conclusions
These new markers could be further explored as valuable tools to detect ongoing and previous S mansoni infections, including in endemic regions where transmission is low.
A library of recombinant S mansoni cell-surface and secreted proteins was produced in mammalian cells for functional and epidemiological studies. Using human and mouse sera from experimentally controlled infections, we identified molecular markers of infection as early as 5 weeks.
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