Selecting participants fairly for controlled human infection studies

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.     

Ethical issues surrounding controlled human infection challenge studies in endemic low-and middle-income countries

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.     

What risks should be permissible in controlled human infection model studies?

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.     

Decision analysis approach to risk/benefit evaluation in the ethical review of controlled human infection studies

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.     

Deliberately infecting healthy volunteers with malaria parasites: Perceptions and experiences of participants and other stakeholders in a Kenyan-based malaria infection study

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.     

The right to withdraw from controlled human infection studies: Justifications and avoidance

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.     

The role of community engagement in addressing bystander risks in research: The case of a Zika virus controlled human infection study

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.     

Reexamining the categorical exclusion of pediatric participants from controlled human infection trials

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.     

Informed consent for controlled human infection studies in low- and middle-income countries: Ethical challenges and proposed solutions

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.     

Justifying the risks of COVID-19 challenge trials: The analogy with organ donation

In the beginning of the COVID pandemic, researchers and bioethicists called for human challenge trials to hasten the development of a vaccine for COVID. However, the fact that we lacked a specific, highly effective treatment for COVID led many to argue that a COVID challenge trial would be unethical and we ought to pursue traditional phase III testing instead. These ethical objections to challenge trials may have slowed the progress of a COVID vaccine, so it is important to evaluate their merit. One common way of doing so is to make an analogy to other social practices that are relevantly similar and which we currently sanction. We submit that non-directed live organ donation (NDLOD) is a promising analogy. After arguing that the risks to volunteers for each activity appear similar, we explore potential disanalogies that would undermine the comparison. We note that there are differences in both the kind and certainty of benefit secured by NDLOD compared to challenge trials. We conclude these differences are insufficient to make NDLOD permissible and challenge trials impermissible. Ultimately, if we think the risks associated with NDLOD are ethically permissible, then we should think the same of the risks associated with COVID challenge trials.     

Defending the social value of knowledge as a safeguard for public trust

The ‘socially valuable knowledge’ (SVK) principle has been widely acknowledged as one of the most important guiding principles for biomedical research involving human subjects. The principle states that the potential of producing socially valuable knowledge is a necessary requirement, although not sufficient, for the ethical conduct of research projects. This is due to the assumption that the social value of knowledge avoids exploitation of research subjects and justifies the use of health resources. However, more recently, several authors have started interrogating the validity of SVK in research and offered various lines of argument against the SVK principle as a necessary constraint to research. In this article, I will reconstruct the main arguments of this discussion between defenders and debunkers of the SVK principle and offer a third way to consider the social value of knowledge in research studies. I will argue that the social value of knowledge can be supported by an independent justification. This justification of the SVK principle addresses the rationality and common interest of researchers. Thus, I will introduce the SVK principle as a safeguarding principle for public trust based on a conceptual framework by Alex John London. My approach justifies keeping the principle as a precautionary and rational requirement for human health research that all rational stakeholders can agree upon.     

Opinions of researchers based in the UK on recruiting subjects from developing countries into randomized controlled trials

Background: Explaining technical terms in consent forms prior to seeking informed consent to recruit into trials can be challenging in developing countries, and more so when the studies are randomized controlled trials. This study was carried out to examine the opinions of researchers on ways of dealing with these challenges in developing countries. Methods: Recorded in‐depth interviews with 12 lecturers and five doctoral students, who had carried out research in developing countries, at a leading school of public health in the United Kingdom. A purposive, snowballing approach was used to identify interviewees. Results: Researchers were divided on the feasibility of explaining technical trials in illiterate populations; the majority of them held the view that local analogies could be used to explain these technical terms. Others were of the opinion that this could not be done since it was too difficult to explain technical trials, such as randomized controlled trials, even to people in developed countries. Conclusion: Researchers acknowledged the difficulty in explaining randomized controlled trials but it was also their perception that this was an important part of the ethics of the work of scientific research involving human subjects. These difficulties notwithstanding, efforts should be made to ensure that subjects have sufficient understanding to consent, taking into account the fact that peculiar situations in developing countries might compound this difficulty.     

Ethics of human genetic studies in sub-saharan Africa: the case of Cameroon through a bibliometric analysis

Many ethical concerns surrounding human genetics studies remain unresolved. We report here the situation in Cameroon. Objectives: To describe the profile of human genetic studies that used Cameroonian DNA samples, with specific focus on i) the research centres that were involved, ii) authorship, iii) population studied, iv) research topics and v) ethics disclosure, with the aim of raising ethical issues that emerged from these studies. Method: Bibliometric Studies; we conducted a PubMed-based systematic review of all the studies on human genetics that used Cameroonian DNA samples from 1989 to 2009. Results and Discussion: Fifty articles were identified, involving predominantly research centres from Europe (64%) and America (32%). Only 7 (14%) Cameroonian institutions and 14 (28%) Cameroonian authors were associated with these publications. At least 52% of publications were devoted to population genetics (variation/migration patterns) amongst 30 Cameroonian ethnic groups. Very few studies concerned public health related genetic issues and only 5 (10%) references were found for hemoglobinopathies like sickle cell anaemia. Almost all DNA samples are 'banked' outside of the African continent. Capacity building, rights to the genetic information and benefits to the individuals, communities and populations who contribute to these studies are addressed. Conclusions: 1) Our data suggests the need for a wider debate towards building capacity and addressing ethical issues related to human genomic research in sub-Saharan Africa and specifically in Cameroon; 2) National ethical guidelines and regulations concerning the collection, use and storage of human DNA are urgently needed in Cameroon.     

Safety testing of monoclonal antibodies in non-human primates: Case studies highlighting their impact on human risk assessment

Monoclonal antibodies (mAbs) are improving the quality of life for patients suffering from serious diseases due to their high specificity for their target and low potential for off-target toxicity. The toxicity of mAbs is primarily driven by their pharmacological activity, and therefore safety testing of these drugs prior to clinical testing is performed in species in which the mAb binds and engages the target to a similar extent to that anticipated in humans. For highly human-specific mAbs, this testing often requires the use of non-human primates (NHPs) as relevant species. It has been argued that the value of these NHP studies is limited because most of the adverse events can be predicted from the knowledge of the target, data from transgenic rodents or target-deficient humans, and other sources. However, many of the mAbs currently in development target novel pathways and may comprise novel scaffolds with multi-functional domains; hence, the pharmacological effects and potential safety risks are less predictable. Here, we present a total of 18 case studies, including some of these novel mAbs, with the aim of interrogating the value of NHP safety studies in human risk assessment. These studies have identified mAb candidate molecules and pharmacological pathways with severe safety risks, leading to candidate or target program termination, as well as highlighting that some pathways with theoretical safety concerns are amenable to safe modulation by mAbs. NHP studies have also informed the rational design of safer drug candidates suitable for human testing and informed human clinical trial design (route, dose and regimen, patient inclusion and exclusion criteria and safety monitoring), further protecting the safety of clinical trial participants.     

Optimal cell density and multiplicity of infection for the propagation of human rotavirus in monkey kidney cells

The human rotavirus titer was optimal at an infection cell density of about 4–8 × 10⁴ cells cm^–2 in monkey kidney cell cultures. The highest viral titers (3.8 × 10⁷ TCID₅₀ ml^–1 and 3.7 × 10⁷ TCID₅₀ ml^–1) were obtained at an multiplicity of infection of 0.05 in well plate and T-flask, respectively.     

Using social values in the prioritization of research: Quantitative examples and generalizations

1. Identifying critical uncertainties about ecological systems can help prioritize research efforts intended to inform management decisions. However, exclusively focusing on the ecological system neglects the objectives of natural resource managers and the associated social values tied to risks and rewards of actions.
2. I demonstrate how to prioritize research efforts for a harvested population by applying expected value of perfect information (EVPI) to harvest decisions made with a density‐independent matrix population model. Research priorities identified by EVPI diverge from priorities identified by matrix elasticity analyses that ignore social utility.
3. Using a density‐dependent harvest model, the value of information about the intrinsic productivity of a population is shown to be sensitive to the socially determined penalty for implementing a harvest rate that deviates from the goal because of imperfection in estimation.
4. Synthesis and applications. The effect of including social values into harvest decision‐making depends on the assumed population model, uncertainty in population vital rates, and the particular form of the utility function used to represent risk/reward of harvest. EVPI analyses that include perceived utility of different outcomes can be used by managers seeking to optimize monitoring and research spending. Collaboration between applied ecologists and social scientists that quantitatively measure peoples'' values is needed in many structured decision‐making processes.

     

LEEP术联合保妇康栓治疗CIN合并高危型HPV持续感染的临床疗效分析

目的 观察宫颈电环切除术(LEEP术)联合保妇康栓治疗宫颈上皮内瘤变(CIN)合并高危型人乳头瘤病毒(HPV)持续感染的疗效.方法 158例病例随机分为两组,对照组79例,治疗组79例.治疗组患者在LEEP术后于阴道内放置保妇康栓,对照组未放置任何药物.观察两组患者宫颈创面愈合时间、术后并发症的发生情况、CIN消退及高危型HPV持续感染的情况.结果 两组患者官颈创面愈合时间、并发症发生情况比较差异无统计学意义(P＞0.05);而CIN消退差异有统计学意义(P＜0.05);高危型HPV持续感染率差异有统计学意义(P＜0.01).结论 LEEP术联合保妇康栓治疗CIN合并高危型HPV持续感染疗效满意,是较为理想的方法.     

基于地形梯度的赣南地区生态系统服务价值对人为干扰的空间响应

赣南地区是我国南方山地丘陵带的重要组成部分,属于我国重要的生态屏障带,生态保护意义重大。以赣南为研究区域,基于1990—2015年间的6期遥感影像,利用遥感、地理信息技术和空间统计的方法,研究了赣南地区基于地形梯度变化的土地利用结构及生态系统服务价值的时空分异,基于网格法分析了全区人为干扰度空间分布及其与地形梯度的关系,并对人为干扰度与生态系统服务价值的空间相关性进行了分析。研究结果表明:(1)随着地形梯度的上升,赣南地区的林地面积比例逐渐上升,其他用地类型的面积比例逐渐下降;其中林地和耕地的变化最为显著;(2) 1990—2015年间赣南地区的生态系统服务价值均随着地形梯度的上升而下降;在地形位指数为0.2164—0.6826的梯度1区域下降最为显著;(3)人为干扰分析显示,90%的高人为干扰度网格分布在低海拔和低坡度的地形梯度1区域,在其他地形梯度分布较少;(4)赣南地区生态系统服务价值和人为干扰度值存在极为显著的空间集聚现象,高-低型集聚区主要分布在地形梯度1的大余县、南康市、赣州市区、信丰县、瑞金市、会昌县、兴国县、于都县等8个县市,低-高型集聚区主要分布在地形梯度较高的崇义县和上犹县。分析了赣南地区生态系统服务价值的地形梯度变化及其与人为干扰度的空间聚类效应,为合理布局和保护我国南方丘陵的生态用地,发挥赣南地区的生态屏障作用提供了理论依据和决策支持。     

Behavioural variation in 172 small-scale societies indicates that social learning is the main mode of human adaptation

The behavioural variation among human societies is vast and unmatched in the animal world. It is unclear whether this variation is due to variation in the ecological environment or to differences in cultural traditions. Underlying this debate is a more fundamental question: is the richness of humans’ behavioural repertoire due to non-cultural mechanisms, such as causal reasoning, inventiveness, reaction norms, trial-and-error learning and evoked culture, or is it due to the population-level dynamics of cultural transmission? Here, we measure the relative contribution of environment and cultural history in explaining the behavioural variation of 172 Native American tribes at the time of European contact. We find that the effect of cultural history is typically larger than that of environment. Behaviours also persist over millennia within cultural lineages. This indicates that human behaviour is not predominantly determined by single-generation adaptive responses, contra theories that emphasize non-cultural mechanisms as determinants of human behaviour. Rather, the main mode of human adaptation is social learning mechanisms that operate over multiple generations.     

Reproductive system,social organization,human disturbance and ecological dominance in native populations of the little fire ant,Wasmannia auropunctata

The invasive ant species Wasmannia auropunctata displays both ecologically dominant and non‐dominant populations within its native range. Three factors could theoretically explain the ecological dominance of some native populations of W. auropunctata: (i) its clonal reproductive system, through demographic and/or adaptive advantages; (ii) its unicolonial social organization, through lower intraspecific and efficient interspecific competition; (iii) the human disturbance of its native range, through the modification of biotic and abiotic environmental conditions. We used microsatellite markers and behavioural tests to uncover the reproductive modes and social organization of dominant and non‐dominant native populations in natural and human‐modified habitats. Microsatellite and mtDNA data indicated that dominant and non‐dominant native populations (supercolonies as determined by aggression tests) of W. auropunctata did not belong to different evolutionary units. We found that the reproductive system and the social organization are neither necessary nor sufficient to explain W. auropunctata ecological dominance. Dominance rather seems to be set off by unknown ecological factors altered by human activities, as all dominant populations were recorded in human‐modified habitats. The clonal reproductive system found in some populations of W. auropunctata may however indirectly contribute to its ecological dominance by allowing the species to expand its environmental niche, through the fixation over time of specific combinations of divergent male and female genotypes. Unicoloniality may rather promote the range expansion of already dominant populations than actually trigger ecological dominance. The W. auropunctata model illustrates the strong impact of human disturbance on species’ ecological features and the adaptive potential of clonal reproductive systems.