Controlled human infection challenge studies (CHIs) involve intentionally exposing research participants to, and/or thereby infecting them with, micro‐organisms. There have been increased calls for more CHIs to be conducted in low‐ and middle‐income countries (LMICs) where many relevant diseases are endemic. This article is based on a research project that identified and analyzed ethical and regulatory issues related to endemic LMIC CHIs via (a) a review of relevant literature and (b) qualitative interviews involving 45 scientists and ethicists (...) with relevant expertise. In this article we argue that though there is an especially strong case for conducting CHIs in endemic (LMIC) settings, certain ethical issues related to the design and conduct of such studies (in such settings) nonetheless warrant particularly careful attention. We focus on ethical implications of endemic LMIC CHIs regarding (a) potential direct benefits for participants, (b) risks to participants, (c) third‐party risks, (d) informed consent, (e) payment of participants, and (f) community engagement. We conclude that there is a strong ethical rationale to conduct (well‐designed) CHIs in endemic LMICs, that certain ethical issues warrant particularly careful consideration, and that ethical analyses of endemic LMIC CHIs can inform current debates in research ethics more broadly. (shrink)

A number of papers have appeared recently arguing for the conclusion that it is ethically acceptable to infect healthy volunteers with severe acute respiratory syndrome coronavirus 2 as part of research projects aimed at developing COVID-19 vaccines or treatments. This position has also been endorsed in a statement by a working group for the WHO. The papers generally argue that controlled human infection is ethically acceptable if the risks to participants are low and therefore acceptable, the scientific (...) quality of the research is high, the research has high social value, participants give full informed consent, and there is fair selection of participants. All five conditions are necessary premises in the overall argument that such research is ethically acceptable. The arguments concerning risk and informed consent have already been critically discussed in the literature. This paper therefore looks specifically at the arguments relating to condition 3 ‘high social value’ and condition 5 ‘fair selection of participants’ and shows that whereas they may be valid, they are not sound. It is highly unlikely that the conditions that are necessary for ethical CHI trials to take place will be fulfilled. Most, if not all, CHI trials will thus be well intentioned but unethical. (shrink)

Controlled human infection (CHI) studies involve the deliberate exposure of healthy research participants to infectious agents to study early disease processes and evaluate interventions under controlled conditions with high efficiency. Although CHI studies expose participants to the risk of infection, they are designed to offer investigators unique advantages for studying the pathogenesis of infectious diseases and testing potential vaccines or treatments in humans. One of the central challenges facing investigators involves the fair selection of research (...) subjects to participate in CHI studies. While there is widespread agreement that investigators have a duty to select research participants fairly, this principle also yields conflicting ethical imperatives, for example requiring investigators to both exclude potential participants with co‐morbidities since they face increased risks, but also to include them in order to ensure generalizability. In this paper we defend an account of fair subject selection that is tailored to the context of CHI studies. We identify the considerations of fairness that bear directly on selecting participants for CHI studies and provide investigators and members of IRBs and RECs with a principled way to navigate the conflicting imperatives to which these considerations give rise. (shrink)

In controlled human infection studies (CHIs), participants are deliberately exposed to infectious agents in order to better understand the mechanism of infection or disease and test therapies or vaccines. While most CHIs have been conducted in high‐income countries, CHIs have recently been expanding into low‐ and middle‐income countries (LMICs). One potential ethical concern about this expansion is the challenge of obtaining the voluntary informed consent of participants, especially those who may not be literate or have limited (...) education. In some CHIs in LMICs, researchers have attempted to address this potential concern by limiting access to literate or educated populations. In this paper, we argue that this practice is unjustified, as it does not increase the chances of obtaining valid informed consent and therefore unfairly excludes illiterate populations and populations with lower education. Instead, we recommend that investigators improve the informed consent process by drawing on existing data on obtaining informed consent in these populations and interventions aimed at improving their understanding. Based on a literature review, we provide concrete suggestions for how to follow this recommendation and ensure that populations with lower literacy or education are given a fair opportunity to protect their rights and interests in the informed consent process. (shrink)

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. (shrink)

In spring, summer and autumn 2020, one abiding argument against controlled human infection studies of SARS-CoV-2 vaccines has been their impact on local communities. Leading scientists and bioethicists expressed concern about undue usage of local residents’ direly needed scarce resources at a time of great need and even about their unintended infection. They recommended either avoiding CHI trials or engaging local communities before conducting any CHIs. Similar recommendations were not made for the alternative—standard phase III field (...) trials of these same vaccines. We argue that the health effects of CHI studies on local residents not participating in the study tend to be smaller and more positive than those of field trials. That is all the more so now that tested vaccines are being rolled out. Whether or not local community engagement is necessary for urgent vaccine studies in the pandemic, the case for its engagement is stronger prior to field trials than prior to CHI studies. (shrink)

Controlled human infection model (CHIM) studies involve the intentional exposure of healthy research volunteers to infectious agents. These studies contribute to knowledge about the cause or development of disease and to the advancement of vaccine research. But they also raise ethical questions about the kinds of risks that should be permissible and whether limits should be imposed on research risks in CHIM studies. Two possible risk thresholds have been considered for CHIM studies. The first suggests constraining ethically (...) permissible risks according to a minimal risk threshold and the second endorses a higher risk threshold that excludes irreversible or fatal infections. I argue that neither of these thresholds is persuasive and situate questions about risk thresholds in CHIM studies within a broader debate about permissible risks in research. I argue that risks in CHIM studies should be constrained according to limits on research risks that do not offer corresponding benefits in all studies rather than developing a unique risk threshold for CHIM studies. I then propose five recommendations for the ethical assessment of risk in CHIM studies. (shrink)

Research using Controlled Human Infection Models is yet to be attempted in India. This study was conducted to understand the perceptions of the lay public and key opinion makers prior to the possible introduction of such studies in the country. 110 respondents from urban and rural Bangalore district were interviewed using qualitative research methods of Focus Group Discussions and In-depth Interviews. The data was analyzed using grounded theory. Safety was a key concern of the lay public, expressed (...) in terms of fear of death. The notion of infecting a healthy volunteer, the possibility of continued effects beyond the study duration and the likelihood of vulnerable populations volunteering solely for monetary benefit, were ethical concerns. Public good outcomes such as effective treatments, targeted vaccines and prevention of diseases was necessary justification for such studies. However, the comprehension of this benefit was not clear among non-medical, non-technical respondents and suggestions to seek alternatives to CHIMs repeatedly arose. There was a great deal of deflection—with each constituency feeling that people other than themselves may be ideally suited as participants. Risk takers, those without dependents, the more health and research literate, financially sound and those with an altruistic bent of mind emerged as possible CHIM volunteers. While widespread awareness and advocacy about CHIM is essential, listening to plural voices is the first step in public engagement in ethically contentious areas. Continued engagement and inclusive deliberative processes are required to redeem the mistrust of the public in research and rebuild faith in regulatory systems. (shrink)

ABSTRACT 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. (shrink)

The right to withdraw from research without penalty is well established around the world. However, it has been challenged in some corners of bioethics based on concerns about various harms—to participants, to scientific integrity, and to research bystanders—that may stem from withdrawal. These concerns have become particularly salient in emerging debates about the ethics of controlled human infection (CHI) studies in which participants are intentionally infected with pathogens, often in inpatient settings with extensive follow‐up. In this article, (...) I provide support for preserving the right to withdraw from research without penalty and demonstrate that it is also typically justified in the specific context of CHI studies. The right is well aligned with individual freedoms outside the research setting, where autonomous individuals are permitted to engage in behaviors that will foreseeably cause them harm; where they cannot be compelled to satisfy contracts for their services, nor penalized for failure to do so; and where their behavior is not constrained by public health authorities except in extreme circumstances. These freedoms are supported by U.S. law, as well as by ethical analysis that is more globally relevant. The problems associated with the right to withdraw, however, remain. The best approach to addressing them is not to restrict the right but rather to avoid initiating research when withdrawal would be especially problematic. If research proceeds, steps can still be taken to minimize participant withdrawal without infringing the right. Investigators can avoid participant surprise through informed consent focused on a study’s most burdensome aspects and promote study completion through financial incentives. Should participants nonetheless seek to withdraw, investigators may attempt to persuade them not to do so by encouraging consideration of the range of potential harms that may result. Researchers conducting CHI studies and other research from which withdrawal might be especially problematic should prepare for the possibility of participant withdrawal, respect participant requests to withdraw without penalty, and incorporate various measures to avoid such requests. (shrink)

Risks and benefit evaluation for controlled human infection studies, where healthy volunteers are deliberately exposed to infectious agents to evaluate vaccine efficacy, should be explicit, systematic, thorough, and non‐arbitrary. Decision analysis promotes these qualities using four steps: (1) determining explicit criteria and measures for evaluation, (2) identifying alternatives to the study, (3) defining the models used to estimate the measures for each alternative, and (4) running the models to produce the estimates and compare the alternatives. In this (...) paper, we describe how decision analysis might be applied by funders and regulators, as well as by others contemplating the use of novel controlled human infection studies for vaccine development and evaluation. (shrink)

Issues related to controlled human infection studies using Schistosoma mansoni (CHI-S) were explored to ensure the ethical and voluntary participation of potential CHI-S volunteers in an endemic setting in Uganda. We invited volunteers from a fishing community and a tertiary education community to guide the development of informed consent procedures. Consultative group discussions were held to modify educational materials on schistosomiasis, vaccines and the CHI-S model and similar discussions were held with a test group. With both groups, (...) a mock consent process was conducted. Fourteen in-depth key informant interviews and three group discussions were held to explore perceptions towards participating in a CHI-S. Most of the participants had not heard of the CHI-S. Willingness to take part depended on understanding the study procedures and the consenting process. Close social networks were key in deciding to take part. The worry of adverse effects was cited as a possible hindrance to taking part. Volunteer time compensation was unclear for a CHI-S. Potential volunteers in these communities are willing to take part in a CHI-S. Community engagement is needed to build trust and time must be taken to share study procedures and ensure understanding of key messages. (shrink)

Controlled human infection studies (CHIs) involve the intentional infection of human subjects for a scientific aim. Though some past challenge trials have involved serious ethical abuses, in the last few decades, CHIs have had a strong track record of safety. Despite increased attention to the ethics of CHIs during the COVID‐19 pandemic, CHIs remain controversial, and there has been no in‐depth treatment of CHIs through the lens of virtue ethics. In this article, we argue that (...) virtue theory can be helpful for addressing CHIs that present a constellation of controversial, unresolved, and/or under‐regulated ethical issues. We begin with some brief background on virtue ethics. We then substantiate our claim that some CHIs raise a constellation of ethical issues that are unresolved in the ethics literature and/or lack adequate regulatory guidance by demonstrating that CHIs can present indeterminate social value, risks to third parties, limitations on the right to withdraw from research, and questions about the upper limit of allowable risk. We argue that the presence of a virtuous investigator, with virtues such as prudence, compassion, and integrity, is especially important when these unresolved research ethics issues arise, which is the case for certain types of controlled human infection studies. We use the historical example of Walter Reed and the Yellow Fever Commission to illustrate this claim, and we also highlight some contemporary examples. We end by sketching some practical implications of our view, such as ensuring that investigators with experience running CHIs are involved in novel CHI models. (shrink)

There is limited guidance on how to assess the ethical acceptability of research risks that extend beyond research participants to third parties (or “research bystanders”). Community or stakeholder engagement has been proposed as one way to address potential harms to community members, including bystanders. Despite widespread agreement on the importance of community engagement in biomedical research, this umbrella term includes many different goals and approaches, agreement on which is ethically required or recommended for a particular context. We analyse the case (...) of a potential Zika virus human challenge trial to assess whether and how community engagement can help promote the ethical acceptability of research posing risks to bystanders. We conclude that, in addition to having intrinsic value, community engagement can improve the identification of bystander risks, effective approaches to minimizing them, and transparency about bystander risks for host communities. (shrink)

The proposed framework by Lynch et al. (2021) for promoting ethical forms of payment in Human Infection Controlled Studies (HICS) in general and SARS-Cov-2 HICS in particular is an important contri...

Controlled human malaria infection (CHMI) studies involve the deliberate infection of healthy volunteers with malaria parasites under controlled conditions to study immune responses and/or test drug or vaccine efficacy. An empirical ethics study was embedded in a CHMI study at a Kenyan research programme to explore stakeholders’ perceptions and experiences of deliberate infection and moral implications of these. Data for this qualitative study were collected through focus group discussions, in‐depth interviews and non‐participant observation. Sixty‐nine (...) participants were involved, including CHMI study volunteers, community representatives and research staff. Data were managed using QSR Nvivo 10 and analysed using an inductive‐deductive approach, guided by ethics literature. CHMI volunteers had reasonable understanding of the study procedures. Decisions to join were influenced by study incentives, trust in the research institution, their assessment of associated burdens and motivation to support malaria vaccine development. However, deliberate malaria infection was a highly unusual research strategy for volunteers, community representatives and some study staff. Volunteers’ experiences of physical, emotional and social burdens or harms were often greater than anticipated initially, and fluctuated over time, related to specific procedures and events. Although unlikely to deter volunteers' participation in similar studies in furture, we argue that the dissonance between level of understanding of the burdens involved and actual experiences are morally relevant in relation to community engagement, informed consent processes, and ongoing support for volunteers and research staff. We further argue that ethics oversight of CHMI studies should take account of these issues in deciding whether consent, engagement and the balance of benefits and harms are reasonable in a given context. (shrink)

The COVID-19 pandemic touched off an unprecedented search for vaccines and treatments. Without question, the development of vaccines to prevent COVID-19 was an enormous scientific accomplishment. Further, the RECOVERY and Solidarity trials identified effective treatments for COVID-19. But all was not success. The urgent need for COVID-19 prevention and treatment fueled an embrace of risks—to research participants and to the reliability of the science itself—as allegedly necessary costs to speed scientific progress. Scientists and (even) ethicists supported overturning longstanding norms protecting (...) healthy volunteers in human challenge trials to speed vaccine development, but these trials led to no vaccines. Physicians, with the approval of research ethics committees, designed hundreds of unblinded, single-center clinical trials at high risk of bias to speed the identification of new treatments. But these clinical trials led to no treatments. The lesson for future pandemics is that the acceptance of greater risks to participants or science does not reliably lead to progress. We are better served by science that upholds the highest ethical and methodological standards. (shrink)

In this work, a co-infection model for human papillomavirus and Chlamydia trachomatis with cost-effectiveness optimal control analysis is developed and analyzed. The disease-free equilibrium of the co-infection model is shown not to be globally asymptotically stable, when the associated reproduction number is less unity. It is proven that the model undergoes the phenomenon of backward bifurcation when the associated reproduction number is less than unity. It is also shown that HPV re-infection induced the phenomenon of backward (...) bifurcation. Numerical simulations of the optimal control model showed that: focusing on HPV intervention strategy alone, in the absence of C. trachomatis control, leads to a positive population level impact on the total number of individuals singly infected with C. trachomatis, Concentrating on C. trachomatis intervention controls alone, in the absence of HPV intervention strategies, a positive population level impact is observed on the total number of individuals singly infected with HPV. Moreover, the strategy that combines and implements HPV and C. trachomatis prevention controls is the most cost-effective of all the control strategies in combating the co-infections of HPV and C. trachomatis. (shrink)

The maternal‐fetal HIV transmission trials, conducted in developing countries in the 1990s, undoubtedly generated one of the most intense, high profile controversies in international research ethics. They sparked off a prolonged acrimonious and public debate and deeply divided the scientific community. They also provided an impetus for the revision of the Declaration of Helsinki – the most widely known guideline for international research. In this paper, I provide a brief summary of the context, outline the arguments for and against the (...) controversial use of placebo controls, and focus on particular areas that I believe merit further discussion or clarification. On balance, I argue that the researchers failed in their duties to protect the best interests of their research subjects, and to promote distributive justice. I discuss the difficulties of obtaining valid consent in this research context, and argue that it is unethical to inform women of their HIV status without at least offering them prophylactic treatment for their unborn children. A global view of justice, which endorses international equity, cannot be squared with international research guidelines that allow ‘local conditions’ to define the scope of duty to the control group. Finally, I suggest that the heated debate reflects a tension, if not an outright war, between two conflicting meta‐ethical systems, or incommensurable paradigms, that underpin scientific research involving human subjects. (shrink)

Controlled Human Infection Model (CHIM) research involves the infection of otherwise healthy participants with disease often for the sake of vaccine development. The COVID-19 pandemic has emphasised the urgency of enhancing CHIM research capability and the importance of having clear ethical guidance for their conduct. The payment of CHIM participants is a controversial issue involving stakeholders across ethics, medicine and policymaking with allegations circulating suggesting exploitation, coercion and other violations of ethical principles. There are multiple approaches (...) to payment: reimbursement, wage payment and unlimited payment. We introduce a new Payment for Risk Model, which involves paying for time, pain and inconvenience and for risk associated with participation. We give philosophical arguments based on utility, fairness and avoidance of exploitation to support this. We also examine a cross-section of the UK public and CHIM experts. We found that CHIM participants are currently paid variable amounts. A representative sample of the UK public believes CHIM participants should be paid approximately triple the UK minimum wage and should be paid for the risk they endure throughout participation. CHIM experts believe CHIM participants should be paid more than double the UK minimum wage but are divided on the payment for risk. The Payment for Risk Model allows risk and pain to be accounted for in payment and could be used to determine ethically justifiable payment for CHIM participants.Although many research guidelines warn against paying large amounts or paying for risk, our empirical findings provide empirical support to the growing number of ethical arguments challenging this status quo. We close by suggesting two ways (value of statistical life or consistency with risk in other employment) by which payment for risk could be calculated. (shrink)

Purposeful infection of healthy volunteers with a microbial pathogen seems at odds with acceptable ethical standards, but is an important contemporary research avenue used to study infectious diseases and their treatments. Generally termed ‘controlled human infection studies’, this research is particularly useful for fast tracking the development of candidate vaccines and may provide unique insight into disease pathogenesis otherwise unavailable. However, scarce bioethical literature is currently available to assist researchers and research ethics committees in negotiating the (...) distinct issues raised by research involving purposefully infecting healthy volunteers. In this article, we present two separate challenge studies and highlight the ethical issues of human challenge studies as seen through a well-constructed framework. Beyond the same stringent ethical standards seen in other areas of medical research, we conclude that human challenge studies should also include: independent expert reviews, including systematic reviews; a publicly available rationale for the research; implementation of measures to protect the public from spread of infection beyond the research setting; and a new system for compensation for harm. We hope these additions may encourage safer and more ethical research practice and help to safeguard public confidence in this vital research alternative in years to come. (shrink)

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. (shrink)

The world’s first COVID-19 human challenge trial using the D614G strain of SARS-CoV-2 is underway in the United Kingdom. The Wellcome Trust is funding challenge stock preparation of the Beta variant (B.1.351) for a follow-up human challenge trial, and researchers at Imperial College London are considering conducting that trial. However, little has been written thus far about the ethical justifiability of human challenge trials with SARS-CoV-2 variants of concern. While vaccine resistance as such does not increase risks (...) for volunteers in COVID-19 challenge trials, we explore two specific characteristics of some variants that may initially be thought to make such trials unethical and conclude that SARS-CoV-2 variant challenge trials can remain ethical. (shrink)

ObjectiveTo investigate the association of pre-existing migraine in patients hospitalised and who recovered from severe acute respiratory syndrome coronavirus 2 infection with the presence of post-coronavirus disease symptoms.BackgroundNo study has investigated the role of migraine as a risk factor for development of post-COVID symptoms.MethodsA case-control study including individuals hospitalised during the first wave of the pandemic was conducted. Patients with confirmed previous diagnosis of migraine were considered cases. Two age- and sex-matched individuals without a history of headache per case (...) were also recruited as controls. Hospitalisation/clinical data were collected from hospital medical records. Patients were scheduled for a telephone interview. A list of post-COVID symptoms was systematically evaluated, but participants were invited to freely report any symptom. The Hospital Anxiety and Depression Scale and the Pittsburgh Sleep Quality Index were used to assess anxiety/depressive symptoms and sleep quality. Multivariable conditional logistic regression models were constructed.ResultsOverall, 57 patients with confirmed diagnosis of migraine and 144 non-migraine controls who had recovered from COVID-19 were assessed at 7.3 months after hospital discharge. The number of post-COVID symptoms in the migraine group was significantly greater than in the non-migraine group. Fatigue was significantly more prevalent in the migraine group. However, no between-groups difference in the prevalence of headache as a post-COVID symptom was detected.ConclusionPatients with a history of migraine who recovered from COVID-19 exhibited more long-term fatigue as post-COVID sequelae than those without migraine. Some of the pathophysiological changes associated with migraine could predispose to the occurrence of post-COVID symptoms. (shrink)

A mathematical model of the dynamics of the immune system is considered to illustrate the effect of its response to HIV infection, i.e. on viral growth and on T-cell dynamics. The specific immune response is measured by the levels of cytotoxic lymphocytes in a human body. The existence and stability analyses are performed for infected steady state and uninfected steady state. In order to keep infection under control, roles of drug therapies are analyzed in the presence of (...) efficient immune response. Numerical simulations are computed and exhibited to illustrate the support of the immune system to drug therapies, so as to ensure the decay of infection and to maintain the level of healthy cells. (shrink)

Schistosoma mansoni is one of several species of trematode helminths responsible for schistosomiasis, a major parasitic infection of man. Genetic analysis in mice has revealed that the protective immunity induced against this parasite by an attenuated larval vaccine is strongly influenced by genes regulating the activation of macrophage effector cells. The latter finding suggests that the induction of cell‐mediated immunity may be a successful strategy for a non‐living vaccine against the human infection.

To counter the pandemic caused by severe acute respiratory syndrome coronavirus 2, some have proposed accelerating SARS-CoV-2 vaccine development through controlled human infection trials. These trials would involve the deliberate exposure of relatively few young, healthy volunteers to SARS-CoV-2. We defend this proposal against the charge that there is still too much uncertainty surrounding the risks of COVID-19 to responsibly run such a trial.

A compartmental model is described for the spread of Gambian sleeping sickness in a spatially heterogeneous environment in which vector and human populations migrate between two "patches": the village and the plantations. The number of equilibrium points depends on two "summary parameters": gr the proportion removed among human infectives, and R0, the basic reproduction number. The origin is stable for R0 1. Control strategies are assessed by studying the mix of vector control between the two patches that bring (...) R0 below 1. The results demonstrate the importance of vector control in the plantations. For example if 20 percent of flies are in the village and the blood meal rate in the village is 10 percent, then a 20 percent added vector mortality in the village must be combined with a 9 percent added mortality in the plantations in order to bring R0 below 1. The results are quite insentive to the blood meal rate in the village. Optimal strategies (that minimize the total number of flies trapped in both patches) are briefly discussed. (shrink)

Grimwade et al highlight the current lack of a universal, standardised approach to the payment of participants taking part in controlled human infection model studies.1 As they discuss, payment for these studies is controversial, with many voicing arguments for and against higher payments, particularly for those studies which involve significant burdens to the participant. The main concerns about overpayment relate to the concepts of undue inducement or coercion, whereas underpayment raises concern about exploitation and unfair treatment. In (...) many healthy volunteer trials compensation for travel, time and inconvenience are generally accepted as fair payment, but payment for risk is less accepted, with a belief that non-therapeutic studies should only incur minimal risks, so payment for risk should not be necessary.2 This paper argues that payment for risk should be included for CHIM studies. Their findings among members of the UK public and CHIM experts from a variety of centres suggest that there is support for greater risks being associated with higher payments for participants. The amount of compensation offered by a trial has to be approved by an ethics committee/institutional review board, and some research suggests that IRB members have concerns about higher payments being offered, with only approximately one-third agreeing that payment should be offered for risk.3 Without agreement and clear guidance for calculating compensation for these types of trial, there is bound to be …. (shrink)

When payment is offered for controlled human infection model research, ethical concerns may be heightened due to unfamiliarity with this study design as well as perceptions—and misperceptions—regarding risk. Against this backdrop, we commend Grimwade et al 1 for their careful handling of the relevant issues, coupling empirical and conceptual approaches. We agree with foundational elements of the authors’ analysis, including the acceptability of payment for research risk.1 However, in our view, it is preferable to treat payment for (...) risk as a discretionary incentive to achieve adequate recruitment and retention, rather than compensation owed as a matter of fairness. Grimwade et al 1 note that although their ‘Payment for Risk Model’ was ‘created specifically in the context of CHIM research, it has the potential to inform payment in other areas of medical research.’ We agree and would go further: we do not need a special payment framework for CHIMs because there is nothing so novel about them compared with other types of research as to demand a distinct approach. Any successful payment framework must address the following ethical issues: preserving informed consent ; treating participants fairly ; encouraging adequate recruitment and retention; avoiding deception by participants; and preserving public trust.2 Some of these issues may have particular salience in the context of CHIMs, but this study design does not demand consideration of entirely distinct ethical factors when evaluating offers of payment.2 We also agree with Grimwade et al 1 about several other key points.2 Given the burdens involved and …. (shrink)

We largely agree with Grimwade et al ’s1 conclusion that challenge trial participants may ethically be paid, including for risk. Here, we add further arguments, clarify some points from the perspective of economics and indicate areas where economists can support the development of a framework for ethically justifiable payment. Our arguments apply to carefully constructed and monitored controlled human infection model trials that have been appropriately reviewed and approved. Participants in medical studies perform a service. Outside the (...) domain of research participation, there is nearly universal agreement that workers providing a service should be compensated fairly, and that work involving more discomfort and risk should be compensated more generously. Accordingly, labour regulations impose floors, not caps on compensation. Caps, even if intended to protect against undue inducement, also raise concerns about illegal price-fixing that disadvantages workers. Such limits on payment for egg donors have successfully been challenged in court.i Moreover, caps on compensation may harm everyone at risk of infection, not just potential participants. Insufficient compensation may impede the recruitment of enough suitable subjects, for example, when representativeness of the subject sample is required. Delays in vaccine development not only prolong disruption of social, educational and economic activity but also lead to excess infections and deaths. Unlike paid CHIM participants, individuals exposed to such infection do not accept it voluntarily, are not compensated for it, and are unlikely to receive the level of medical supervision afforded to closely monitored CHIM participants. Payment caps can lead to attempts to circumvent the regulation. For example, many countries …. (shrink)

This paper reassesses Robert Koch’s work on tropical infections of humans and cattle as being inspired by an underlying interest in epidemiology. Such an interest was developed from the early 1890s when it became clear that an exclusive focus on pathogens was insufficient as an approach to explain the genesis and dynamics of epidemics. Koch, who had failed to do so before, now highlighted differences between infection and disease and described the role of various sub-clinical states of disease in (...) the propagation and—consequently—in the control of epidemics. Studying pathologies of men and cattle in tropical countries eventually facilitated the application of such measures in Europe through the screening of healthy carriers of typhoid, which was carried out in 1902. The concept of the carrier state can be understood as a spin-off from tropical medicine into the study and control of infectious disease in Europe. With it travelled assumptions that were typical for colonial and veterinary medicine where the health of indigenous individuals or cattle would be a secondary objective compared to the control of diseases in populations. (shrink)

Significant attention has been given both to the ethics of Controlled Human Infection Model research and the ethics of payment for research participation. However, comparatively little attention has been given to the ethics of paying for participation specifically in CHIM research. Grimwade et al should be commended for thoughtfully addressing this topic and especially for the empirical data collection informing their work, which is too often lacking in discussions of payment for research participation. In what follows I (...) will discuss three relatively subtle factors that, I believe, make a difference to the ethical analysis of paying for research participation and raise what I intend to be constructive questions about the extent to which the survey instrument employed by the authors captures them. The authors focus on payment for risk in CHIM research. They correctly stress that compensating participants for risk is controversial and that “many general guidelines warn against paying for the risk in medical research”. While not all guidance documents share this scepticism,1 compensating for risk raises thorny issues and uncertainty over the topic among IRBs and regulatory bodies is likely to hinder the practice. Part of the difficulty in assessing payment for research risks stems from the way in which subtle variances in background assumptions influence the ethical assessment, which also complicates empirical attempts to measure attitudes on the topic. Most importantly, it is crucial to be precise about background assumptions concerning whether participants are protected from bearing the financial burdens of research risks that eventuate in actual harms. Protective mechanisms …. (shrink)

We thank the authors of the five commentaries for their careful and highly constructive consideration of our paper,1 which has enabled us to develop our proposal. Participation in research has traditionally been viewed as altruistic. Over time, payments for inconvenience and lost wages have been allowed, as have small incentives, usually in kind. The problem, particularly with controlled human infection model research or ‘challenge studies’, is that they are unpleasant and time-consuming. Researchers want to offer carrots to (...) incentivise participation. We are proposing that research participation be viewed as a job with the full suite of financial entitlements of fairly remunerated work, including payment for risk and labour law protections. This would be a significant shift from current practice and standards. Ambuehl, Ockenfels and Roth have grasped this basic point and have beautifully elaborated how a fair price could be arrived at using economic theory. They build on our proposal helpfully and suggest ‘ salary for time involvement that is adjusted to account for the amount of discomfort experienced during participation, insurance against ex post adverse outcomes and ex ante compensation for risks that cannot be compensated ex post.’3 This effectively addresses Fernandez Lynch and Largent’s2 concern that compensation for risk is inappropriate for harms which do not eventuate. However, because death cannot be compensated for, there must be payment for risk of death, as Ambuehl, Ockenfels and Roth convincingly argue.3 Indeed, the three-part model suggested by Ambuehl, Ockenfels and Roth makes us realise that job model would be a better title for our model than a payment for risk model. The alternative to a properly remunerated job model is the original altruistic model. However, this …. (shrink)

Drug‐resistant bacterial infections constitute a major threat to global public health. Several key bacteria that are becoming increasingly resistant are among those that are ubiquitously carried by human beings and usually cause no symptoms (i.e. individuals are asymptomatic carriers) until and/or unless a precipitating event leads to symptomatic infection (and thus disease). Carriers of drug‐resistant bacteria can also transmit resistant pathogens to others, thus putting the latter at risk of resistant infections. Accumulating evidence suggests that such transmission occurs (...) not only in hospital settings but also in the general community, although considerably more data are needed to assess the extent of this problem. Asymptomatic carriage of drug‐resistant bacteria raises important ethical questions regarding the appropriate public health response, including the degree to which it would be justified to impose burdens on asymptomatic carriers (and others) in order to prevent transmission. In this paper, we (i) summarize current evidence regarding the carriage of key drug‐resistant bacteria, noting important knowledge gaps; and (ii) explore the particular implications of existing public health ethics frameworks for policy‐making regarding asymptomatic carriers. Inter alia, we argue that the relative burdens imposed by public health measures on healthy carriers (as opposed to sick individuals) warrant careful consideration and should be proportionate to the expected public health benefits in terms of risks averted. We conclude that more surveillance and research regarding community transmission will be needed in order to clarify relevant risks and design proportionate policies, although extensive community surveillance itself would also require careful ethical consideration. (shrink)

Human contact networks constitute a multitude of individuals and pairwise contacts among them. However, the dynamic nature, which generates the evolution of human contact networks, of contact patterns is unknown yet. Here, we analyse three empirical datasets and identify two crucial mechanisms of the evolution of temporal human contact networks, i.e., the activity state transition laws for an individual to be socially active and the contact establishment mechanism that active individuals adopt. We consider both of the two (...) mechanisms to propose a temporal network model, the so-called memory-driven model, of human contact networks. Then, we study the susceptible-infected spreading processes on empirical human contact networks as well as four corresponding temporal network models and compare the full prevalence time of SI processes with various infection rates on the networks. The full prevalence time of SI processes in the MD model is the same as that in real-world human contact networks. Moreover, we find that the individual activity state transition promotes the spreading process, while the contact establishment of active individuals suppresses the prevalence. Besides, we observe that individuals who establish social ties with a small exploring rate are still able to induce an endemic which prevails in the networks. The study offers new insights to predict and control the diffusion processes on networks. (shrink)

In a recent article, Steel, Buchak and Eyal argue that current levels of uncertainty do not present a good reason to bar controlled human infection trials of COVID-19 vaccines from proceeding. We argue that their argumentation for this conclusion is flawed. SBE are mistaken about the effects which different forms of ignorance have on participants’ ability to provide valid informed consent. Decision-makers considering whether to allow such trials, we argue, must ultimately consider the likelihood that consent to (...) participation in such trials under current conditions would be valid, and whether this likelihood is high enough to permit such trials. This is a question that SBE completely ignore. We conclude that there indeed are valid concerns about conducting CHI trials given the current state of knowledge about COVID-19, concerns which SBE fail to address. (shrink)

BackgroundOver the past two decades, Uganda has experienced a significant increase in clinical research driven by both academia and industry. This has been combined with a broader spectrum of research proposals, with respect to methodologies and types of intervention that need evaluation by Research Ethics Committees (RECs) with associated increased requirement for expertise. We assessed the competencies of REC members regarding review of research protocols with complex and emerging research study designs. The aim was to guide development of a training (...) curriculum to improve the quality of scientific and ethical review.MethodsThis was a cross-sectional study design, with quantitative data collection methods. Research Ethics Committee members completed a structured pre-coded questionnaire on current competence with complex and emerging study design. REC members were asked to outline a list of additional topics for which they needed training. Data from coded questions were entered into Epidata Version 3.1 and then exported to STATA Version14.1 for analysis. Descriptive analysis was performed and findings are presented using percentages and frequencies.ResultsWe enrolled 55 REC members from 6 RECs who have a total of 97 members. The majority of whom were males (56.4%, n = 31/55). The level of competence for review of selected study design was lowest for Controlled Human Infection Model (10.9%, n = 6) and reverse pharmacology design (10.9%, n = 6), and highest for cluster randomized study design (52.7%, n = 29) and implementation science research (52.7%, n = 29).ConclusionCompetence for review of research protocols with complex and emerging study design was low among participating REC members. We recommend prioritising training of REC members on complex and emerging study designs to enhance quality of research protocol review. (shrink)

Indigenous knowledge is the dynamic information base of a society, facilitating communication and decision-making. It is the cornerstone of many modern-day innovations in science and technology. It is also a ready and valuable resource for sustainable and resilient livelihoods, and attracts increasing public interest due to its applications in bio-technology, health, bioprospecting, pharmaceuticals, agriculture, food preparation, mathematics and astronomy. INDIGENOUS KNOWLEDGE OF NAMIBIA is a fascinating compendium aimed at a wide readership of academics and students, government officials, policy makers, and (...) development partners. The 17 chapters examine the indigenous knowledge of medicinal plants for treating HIV/AIDS, malaria, cancer, and other microbial infections of humans and livestock; indigenous foods; coping and response strategies in dealing with human-wildlife conflicts, floods, gender, climate change and the management of natural resources. A new rationalisation of adolescent customary and initiation ceremonies is recommended in response to the HIV/AIDS pandemic; and a case study of the San people of Namibia speaks to the challenges of harmonising modern education with that of indigenous people. (shrink)

Vaccination, meaning induction of immunity through controlled exposure to antigens, has been mainly used as a prophylactic measure, but more recently as a therapeutic measure. As far as ethical dilemmas from therapeutic vaccines resemble those occurring for conventional treatment clinical trials, this chapter will focus only on prophylactic vaccines. Analogously, some of the ethical aspects of pre-exposure prophylaxis through medication or passive immunity are shared with prophylactic vaccines. This chapter will discuss the implications of having most vaccine trials not (...) conducted in combination with health care, the compensation of vaccine study participants, the preventive misconception, the need to keep participant commitment in vaccine studies, post-trial access in vaccine trials, controlled human infection models, studies in special populations, and vaccine community-based studies. (shrink)

The outbreak of COVID-19 at the end of 2019 has become the most devastating public health event of the 21st century. The different performances of governments and people in different countries and regions show that national values may play an important role in the prevention and control of COVID-19. Based on data from the seventh wave of World Values Survey and the Human Freedom Index report in 2020, three national value factors are extracted in this manuscript, including religious belief, (...) government satisfaction and individual freedom. Then ordinary least squares regression regression model is constructed to explore the influence of these three value factors on the prevention and control of COVID-19 and some heterogeneity analysis is implemented. The results show that religious belief and individual freedom significantly increased the COVID-19 infection rate, while government satisfaction significantly reduced the COVID-19 infection rate. The study findings have the ability to hold up after a range of robustness. For countries and regions with different COVID-19 testing policies, the influence of national values is different. Only in countries and regions with high testing rate policies and complete systems of the prevention and control of COVID-19, the influence of national values is significant. Based on these findings, a series of targeted policy recommendations for building national values in the post-epidemic era are proposed. (shrink)

Recent court decisions imposing liability on physicians who fail to inform patients that they carry the human immunodeficiency virus before performing invasive procedures create an urgent need for the Centers for Disease Control and Prevention to reopen the issuance of guidelines and to address authoritatively the question of the appropriate limits within which HIV-infected health care providers can treat patients.Public fear of HIV-infected physicians were kindled by reports, beginning in 1990, that Dr. David Acer, an HIV-infected dentist, had infected (...) a number of his patients. However, great skepticism has arisen as to whether Dr. Acer’s patients were infected as a result of procedures conducted in accordance with universal precautions against transmission. Moreover, look back studies have failed to identify even one patient, among the thousands who have undergone procedures administered by HIV-infected physicians, who contracted the virus directly from his/her physician. (shrink)

Recently, approach-avoidance tendencies and visual perception biases have been increasingly studied using bistable point-light walkers (PLWs). Prior studies have found a facing-the-viewer bias when one is primed with general threat stimuli (e.g. angry faces), explained by the “error management theory”, as failing to detect a threat as approaching is riskier than the opposite. Importantly, no study has explored how disease threat – linked to the behavioural immune system – might affect this bias. This study aimed to explore whether disease-signalling cues (...) can alter how we perceive the motion direction of ambiguous PLWs. Throughout 3 experiments, participants indicated the motion direction of a bistable PLW previously primed with a control or disease-signalling stimuli – that is, face with a surgical mask (Experiment 1), sickness sound (Experiment 2), or face with a disease cue (Experiment 3). Results showed that sickness cues do not significantly modulate the perception of approach-avoidance behaviours. However, a pattern emerged in Experiments 2 and 3, suggesting that sickness stimuli led to more facing away percepts. Unlike other types of threat, this implies that disease-related threat stimuli might trigger a distinct perceptual bias, indicating a preference to avoid a possible infection source. Nonetheless, this finding warrants future investigations. (shrink)

The main objective of Zika transmission studies is to work out the simplest approach to scale back human mortality and morbidity caused by the disease. Therefore, it is essential to spot the relative importance of the various factors contributing to the transmission and prevalence of the disease. Many mathematical models have been formulated incorporating vector-to-human transmission or human-to-human transmission. However, they do not take into consideration the mixture of both sorts of transmission. It raises the question (...) of the impact of both sorts of transmission on the disease dynamics. We develop a mathematical model of Zika with the vertical transmission in the vector population and human-to-human transmission to answer this question. It includes the immature phase of mosquitoes, adult mosquitoes, and human hosts. Results show that neglecting sexual transmission results in an understatement of the proportion of the infected population. Furthermore, it reduces the speed of disease spreading. On the other hand, vertical transmission in mosquitoes has a negligible effect on the dynamics of disease spread. We perform a sensitivity analysis of the reproductive number R 0 to raise to understand the parameters driving the dynamics of the disease. It appears that the most sensitive parameters in decreasing order are as follows: the adult mosquito death rate, the sting rate, the transmission probability of mosquito to human, and, therefore, the transmission probability of human to mosquito. Furthermore, the proportion at the equilibrium of infected humans is extremely sensitive to the transition rate from the immature vector stage to the adult stage, the human-to-human transmission rate, and, therefore, the human recovery rate. These results confirm that control policies targeting the vector population and, therefore, the recovery rate of people are pretty effective solutions. To validate the model and estimate the important parameters of the model and the prediction of the disease, we consider the real cases in Colombia from 2016. In a series of graphic maps, we presented the comparative study to estimate the disease scenarios and to predict the time limit of the epidemic control measure. (shrink)

Emergence of the novel pathogenic coronavirus SARS‐CoV‐2 and its rapid pandemic spread presents challenges that demand immediate attention. Here, we describe the development of a semi‐quantitative high‐content microscopy‐based assay for detection of three major classes (IgG, IgA, and IgM) of SARS‐CoV‐2 specific antibodies in human samples. The possibility to detect antibodies against the entire viral proteome together with a robust semi‐automated image analysis workflow resulted in specific, sensitive and unbiased assay that complements the portfolio of SARS‐CoV‐2 serological assays. Sensitive, (...) specific and quantitative serological assays are urgently needed for a better understanding of humoral immune response against the virus as a basis for developing public health strategies to control viral spread. The procedure described here has been used for clinical studies and provides a general framework for the application of quantitative high‐throughput microscopy to rapidly develop serological assays for emerging virus infections. (shrink)

Human infection challenge studies (HCS) involve intentionally infecting research participants with pathogens (or other micro-organisms). There have been recent calls for more HCS to be conducted in low-income and middle-income countries (LMICs), where many relevant diseases are endemic. HCS in general, and HCS in LMICs in particular, raise numerous ethical issues. This paper summarises the findings of a project that explored ethical and regulatory issues related to LMIC HCS via (i) a review of relevant literature and (ii) 45 (...) qualitative interviews with scientists and ethicists. Among other areas of consensus, we found that there was widespread agreement that LMIC HCS can be ethically acceptable, provided that they have a sound scientific rationale, are accepted by local communities and meet usual research ethics requirements. Unresolved issues include those related to (i) acceptable approaches to trade-offs between the scientific aim to produce generalisable results and the protection of participants, (iii) the sharing of benefits with LMIC populations, (iii) the acceptable limits to risks and burdens for participants, (iv) the potential for third-party risk and whether the degree of acceptable third-party risk is different in endemic settings, (v) the conditions under which (if any) it would be appropriate to recruit children for disease-causing HCS, (v) appropriate levels of payment to participants and (vi) appropriate governance of (LMIC) HCS. This paper provides preliminary analyses of these ethical considerations in order to (i) inform scientists and policymakers involved in the planning, conduct and/or governance of LMIC HCS and (ii) highlight areas warranting future research. Insofar as this article focuses on HCS in (endemic) settings where diseases are present and/or widespread, much of the analysis provided is relevant to HCS (in HICs or LMICs) involving pandemic diseases including COVID19. (shrink)

This survey aimed to illustrate factors that contribute to nurses' fear when faced with a possible human-to-human avian flu pandemic and their willingness to care for patients with avian flu in Taiwan. The participants were nursing students with a lesser nursing credential who were currently enrolled in a bachelor degree program in a private university in southern Taiwan. Nearly 42% of the nurses did not think that, if there were an outbreak of avian flu, their working hospitals would (...) have sufficient infection control measures and equipment to prevent nosocomial infection in their working environment. About 57% of the nurse participants indicated that they were willing to care for patients infected with avian influenza. Nurses' fear about an unknown infectious disease, such as the H5N1 influenza virus, could easily be heightened to levels above those occurring during the 2003 severe acute respiratory syndrome outbreak in Taiwan. (shrink)

BackgroundHIV cure research involving cell and gene therapy has intensified in recent years. There is a growing need to identify ethical standards and safeguards to ensure cell and gene therapy (CGT) HIV cure research remains valued and acceptable to as many stakeholders as possible as it advances on a global scale.MethodsTo elicit preliminary ethical and practical considerations to guide CGT HIV cure research, we implemented a qualitative, in-depth interview study with three key stakeholder groups in the United States: (1) biomedical (...) HIV cure researchers, (2) bioethicists, and (3) community stakeholders. Interviews permitted evaluation of informants’ perspectives on how CGT HIV cure research should ethically occur, and were transcribed verbatim. We applied conventional content analysis focused on inductive reasoning to analyze the rich qualitative data and derive key ethical and practical considerations related to CGT towards an HIV cure.ResultsWe interviewed 13 biomedical researchers, 5 community members, and 1 bioethicist. Informants generated considerations related to: perceived benefits of CGT towards an HIV cure, perceived risks, considerations necessary to ensure an acceptable benefit/risk balance, CGT strategies considered unacceptable, additional ethical considerations, and considerations for first-in-human CGT HIV cure trials. Informants also proposed important safeguards to developing CGT approaches towards an HIV cure, such as the importance of mitigating off-target effects, mitigating risks associated with long-term duration of CGT interventions, and mitigating risks of immune overreactions.ConclusionOur study identified preliminary considerations for CGT-based HIV cure across three key stakeholder groups. Respondents identified an ideal cure strategy as one which would durably control HIV infection, protect the individual from re-acquisition, and eliminate transmission to others. Known and unknown risks should be anticipated and perceived as learning opportunities to preserve and honor the altruism of participants. Preclinical studies should support these considerations and be transparently reviewed by regulatory experts and peers prior to first-in-human studies. To protect the public trust in CGT HIV cure research, ethical and practical considerations should be periodically revisited and updated as the science continues to evolve. Additional ethics studies are required to expand stakeholder participation to include traditionally marginalized groups and clinical care providers. (shrink)

Much of the fear and uncertainty around Zika epidemics stem from potential association between Zika virus complications on infected pregnant women and risk of their babies being born with microcephaly and other neurological abnormalities. However, much remains unknown about its mode of transmission, diagnosis and long-term pathogenesis. Worries of these unknowns necessitate the need for effective and efficient psychosocial programs and medical-legal strategies to alleviate and mitigate ZIKV related burdens. In this light, local and global efforts in maintaining fundamental health (...) principles of moral, medical and legal decision-making policies, and interventions to preserve and promote individual and collectiveHuman Rights, autonomy, protection of the most vulnerable, equity, dignity, integrity and beneficence that should not be confused and relegated by compassionate humanitarian assistance and support. This paper explores the potential medical and ethical-legal implications of ZIKV epidemics emergency response packages and strategies alongside optimizing reproductive and mental health policies, programs and best practice measures. Further long-term cross-borders operational research is required in elucidating Zika-related population-based epidemiology, ethical-medical and societal implications in guiding evidence-based local and global ZIKV maternal-child health complications related approaches and interventions. Core programs and interventions including future Zika safe and effective vaccines for global Zika immunization program in most vulnerable and affected countries and worldwide should be prioritized. (shrink)