Herd immunity to endemic diseases: Historical concepts and implications for public health policy.

BACKGROUND: "Herd immunity" became a contested term during the COVID-19 pandemic. Although the term "herd immunity" is often used to refer to thresholds at which some diseases can be eliminated (e.g., due to mass vaccination), the term has multiple referents. Different concepts of herd immunity have been relevant throughout the history of immunology and infectious disease epidemiology. For some diseases, herd immunity plays a role in the development of an endemic equilibrium, rather than elimination via threshold effects. METHODS: We reviewed academic literature from 1920 to 2022, using historical and philosophical analysis to identify and develop relevant concepts of herd immunity. RESULTS: This paper analyses the ambiguity surrounding the concept of herd immunity during the pandemic. We argue for the need to recapture a long-standing interpretation of this concept as one of the factors that leads to a dynamic endemic equilibrium between a host population and a mutating respiratory pathogen. CONCLUSIONS: Informed by the history of infectious disease epidemiology, we argue that understanding the concept in this way will help us manage both SARS-CoV-2 and hundreds of other seasonal respiratory pathogens with which we live but which have been disrupted due to sustained public health measures/non-pharmaceutical interventions targeting SARS-CoV-2.

Ethical approval for controlled human infectious model clinical trial protocols - A workshop report.

Controlled Human Infectious Model studies (CHIM) involve deliberately exposing volunteers to pathogens. To discuss ethical issues related to CHIM, the European Vaccine Initiative and the International Alliance for Biological Standardization organised the workshop "Ethical Approval for CHIM Clinical Trial Protocols", which took place on May 30-31, 2023, in Brussels, Belgium. The event allowed CHIM researchers, regulators, ethics committee (EC) members, and ethicists to examine the ethical criteria for CHIM and the role(s) of CHIM in pharmaceutical development. The discussions led to several recommendations, including continued assurance that routine ethical requirements are met, assurance that participants are well-informed, and that preparation of study documents must be both ethically and scientifically sound from an early stage. Study applications must clearly state the rationale for the challenge compared to alternative study designs. ECs need to have clear guidance and procedures for evaluating social value and assessing third-party risks. Among other things, public trust in research requires minimisation of harm to healthy volunteers and third-party risk. Other important considerations include appropriate stakeholder engagement, public education, and access to health care for participants after the study.

A Scalar Approach to Vaccination Ethics.

Should people get vaccinated for the sake of others? What could ground-and limit-the normative claim that people ought to do so? In this paper, we propose a reasons-based consequentialist account of vaccination for the benefit of others. We outline eight harm-based and probabilistic factors that, we argue, give people moral reasons to get vaccinated. Instead of understanding other-directed vaccination in terms of binary moral duties (i.e., where people either have or do not have a moral duty to get vaccinated), we develop a scalar approach according to which people can have stronger or weaker moral reasons to get vaccinated in view of the moral good of vaccination. One advantage of our approach is that it can capture why a person might have strong moral reasons to get vaccinated with Vaccine A, but only weak moral reasons to get vaccinated with Vaccine B. We discuss theoretical strengths of our approach and provide a case study of vaccination against COVID-19 to demonstrate its practical significance.

The Ethical Obligation for Research During Public Health Emergencies: Insights From the COVID-19 Pandemic.

In times of crises, public health leaders may claim that trials of public health interventions are unethical. One reason for this claim can be that equipoise-i.e. a situation of uncertainty and/or disagreement among experts about the evidence regarding an intervention-has been disturbed by a change of collective expert views. Some might claim that equipoise is disturbed if the majority of experts believe that emergency public health interventions are likely to be more beneficial than harmful. However, such beliefs are not always justified: where high quality research has not been conducted, there is often considerable residual uncertainty about whether interventions offer net benefits. In this essay we argue that high-quality research, namely by means of well-designed randomized trials, is ethically obligatory before, during, and after implementing policies in public health emergencies (PHEs). We contend that this standard applies to both pharmaceutical and non-pharmaceutical interventions, and we elaborate an account of equipoise that captures key features of debates in the recent pandemic. We build our case by analyzing research strategies employed during the COVID-19 pandemic regarding drugs, vaccines, and non-pharmaceutical interventions; and by providing responses to possible objections. Finally, we propose a public health policy reform: whenever a policy implemented during a PHE is not grounded in high-quality evidence that expected benefits outweigh harms, there should be a planned approach to generate high-quality evidence, with review of emerging data at preset time points. These preset timepoints guarantee that policymakers pause to review emerging evidence and consider ceasing ineffective or even harmful policies, thereby improving transparency and accountability, as well as permitting the redirection of resources to more effective or beneficial interventions.

Controlled human infection trials: Legitimacy and conditions of implementation in France.

This round table is the result of an observation. The observation being that controlled human infection clinical trials (also called "infectious challenge" trials or "Controlled Human Infection Models", "CHIM") recommended or even encouraged in the context of vaccine developments in particular, are not carried out in France. However, there are no formal prohibitions within regulations or ethical principles, which point to the prior assessment of risks and benefits for individuals and for society. The participants in this Round Table thus wished to examine, through the prism of their respective disciplines, the scientific and medical relevance of conducting such trials in France and, if possible, to imagine the conditions under which they would be carried out, thus resulting in recommendations on (1) the advisability of their conduct in France (2), the conditions under which they would be implemented in terms of logistics and regulations, and (3) their social acceptability. The recommendations on which the participants of the Round Table came to an agreement are presented as the analysis progresses.

Ethical issues in Nipah virus control and research: addressing a neglected disease.

Nipah virus is a priority pathogen that is receiving increasing attention among scientists and in work on epidemic preparedness. Despite this trend, there has been almost no bioethical work examining ethical considerations surrounding the epidemiology, prevention, and treatment of Nipah virus or research that has already begun into animal and human vaccines. In this paper, we advance the case for further work on Nipah virus disease in public health ethics due to the distinct issues it raises concerning communication about the modes of transmission, the burdens of public health surveillance, the recent use of stringent public health measures during epidemics, and social or religious norms intersecting with preventive measures. We also advance the case for further work on Nipah virus disease in research ethics, given ethical issues surrounding potential vaccine trials for a high-fatality disease with sporadic spillover events, the different local contexts where trials may occur, and the potential use of unproven therapeutics during outbreaks. Further bioethics work may help to ensure that research and public health interventions for Nipah virus disease are ethically acceptable and more likely to be effective.

Strategic and scientific contributions of human challenge trials for vaccine development: facts versus fantasy.

The unprecedented speed of delivery of SARS-CoV-2 pandemic vaccines has redefined the limits for all vaccine development. Beyond the aspirational 100-day timeline for tomorrow's hypothetical pandemic vaccines, there is a sense of optimism that development of other high priority vaccines can be accelerated. Early in the COVID-19 pandemic, an intense and polarised academic and public discourse arose concerning the role of human challenge trials for vaccine development. A case was made for human challenge trials as a powerful tool to establish early proof-of-concept of vaccine efficacy in humans, inform vaccine down selection, and address crucial knowledge gaps regarding transmission, pathogenesis, and immune protection. We review the track record of human challenge trials contributing to the development of vaccines for 19 different pathogens and discuss relevant limitations, barriers, and pitfalls. This Review also highlights opportunities for efforts to broaden the scope and boost the effects of human challenge trials, to accelerate all vaccine development.

Public health use of HIV phylogenetic data in sub-Saharan Africa: ethical issues.

Phylogenetic analyses of HIV are an increasingly accurate method of clarifying population-level patterns of transmission and linking individuals or groups with transmission events. Viral genetic data may be used by public health agencies to guide policy interventions focused on clusters of transmission or segments of the population in which transmission is concentrated. Analyses of HIV phylogenetics in high-income countries have often found that clusters of transmission play a significant role in HIV epidemics. In sub-Saharan Africa, HIV phylogenetic analyses to date suggest that clusters of transmission play a relatively minor role in local epidemics. Such analyses could nevertheless be used to guide priority setting and HIV public health programme design in Africa for sub-populations in which transmission events are more concentrated. Phylogenetic analysis raises ethical issues, in part due to the range of potential benefits and potential harms (ie, risks). Potential benefits include (1) improving knowledge of transmission patterns, (2) informing the design of focused public health interventions for subpopulations in which transmission is concentrated, (3) identifying and responding to clusters of transmission, (4) reducing stigma (in some cases) and (5) informing estimates of the (cost-)effectiveness of HIV treatment programmes. Potential harms include (1) privacy infringements, (2) increasing stigma (in some cases), (3) reducing trust in public health programmes, and (4) increased prosecution of legal cases where HIV transmission, homosexuality or sex work is criminalised. This paper provides analysis of relevant issues with a focus on sub-Saharan Africa in order to inform consultations regarding ethical best practice for HIV phylogenetics.

Herd immunity, vaccination and moral obligation.

The public health benefits of herd immunity are often used as the justification for coercive vaccine policies. Yet, 'herd immunity' as a term has multiple referents, which can result in ambiguity, including regarding its role in ethical arguments. The term 'herd immunity' can refer to (1) the herd immunity threshold, at which models predict the decline of an epidemic; (2) the percentage of a population with immunity, whether it exceeds a given threshold or not; and/or (3) the indirect benefit afforded by collective immunity to those who are less immune. Moreover, the accumulation of immune individuals in a population can lead to two different outcomes: elimination (for measles, smallpox, etc) or endemic equilibrium (for COVID-19, influenza, etc). We argue that the strength of a moral obligation for individuals to contribute to herd immunity through vaccination, and by extension the acceptability of coercion, will depend on how 'herd immunity' is interpreted as well as facts about a given disease or vaccine. Among other things, not all uses of 'herd immunity' are equally valid for all pathogens. The optimal conditions for herd immunity threshold effects, as illustrated by measles, notably do not apply to the many pathogens for which reinfections are ubiquitous (due to waning immunity and/or antigenic variation). For such pathogens, including SARS-CoV-2, mass vaccination can only be expected to delay rather than prevent new infections, in which case the obligation to contribute to herd immunity is much weaker, and coercive policies less justifiable.

Ethics of antibiotic allergy.

Antibiotic allergies are commonly reported among patients, but most do not experience reactions on rechallenge with the same agents. These reported allergies complicate management of infections in patients labelled as having penicillin allergy, including serious infections where penicillin-based antibiotics are the first-line (most effective and least toxic) treatment option. Allergy labels are rarely questioned in clinical practice, with many clinicians opting for inferior second-line antibiotics to avoid a perceived risk of allergy. Reported allergies thereby can have significant impacts on patients and public health, and present major ethical challenges. Antibiotic allergy testing has been described as a strategy to circumvent this dilemma, but it carries limitations that often make it less feasible in patients with acute infections or in community settings that lack access to allergy testing. This article provides an empirically informed ethical analysis of key considerations in this clinical dilemma, using Staphylococcus aureus bacteraemia in patients with penicillin allergies as a case study. We argue that prescribing first-line penicillin-based antibiotics to patients with reported allergies may often present a more favourable ratio of benefits to risks, and may therefore be more ethically appropriate than using second-line drugs. We recommend changes to policy-making, clinical research and medical education, in order to promote more ethically acceptable responses to antibiotic allergies than the status quo.

Quantifying the impact of individual and collective compliance with infection control measures for ethical public health policy.

Infectious disease control measures often require collective compliance of large numbers of individuals to benefit public health. This raises ethical questions regarding the value of the public health benefit created by individual and collective compliance. Answering these requires estimating the extent to which individual actions prevent infection of others. We develop mathematical techniques enabling quantification of the impacts of individuals or groups complying with three public health measures: border quarantine, isolation of infected individuals, and prevention via vaccination/prophylaxis. The results suggest that (i) these interventions exhibit synergy: They become more effective on a per-individual basis as compliance increases, and (ii) there is often substantial "overdetermination" of transmission. If a susceptible person contacts multiple infectious individuals, an intervention preventing one transmission may not change the ultimate outcome (thus, risk imposed by some individuals may erode the benefits of others' compliance). These results have implications for public health policy during epidemics.

A Systematic Review of Human Challenge Trials, Designs, and Safety.

BACKGROUND: Few studies have assessed participant safety in human challenge trials (HCTs). Key questions regarding HCTs include how risky such trials have been, how often adverse events (AEs) and serious adverse events (SAEs) occur, and whether risk mitigation measures have been effective. METHODS: A systematic search of PubMed and PubMed Central for articles reporting on results of HCTs published between 1980 and 2021 was performed and completed by 7 October 2021. RESULTS: Of 2838 articles screened, 276 were reviewed in full. A total of 15 046 challenged participants were described in 308 studies that met inclusion criteria; 286 (92.9%) of these studies reported mitigation measures used to minimize risk to the challenge population. Among 187 studies that reported on SAEs, 0.2% of participants experienced at least 1 challenge-related SAE. Among 94 studies that graded AEs by severity, challenge-related AEs graded "severe" were reported by between 5.6% and 15.8% of participants. AE data were provided as a range to account for unclear reporting. Eighty percent of studies published after 2010 were registered in a trials database. CONCLUSIONS: HCTs are increasingly common and used for an expanding list of diseases. Although AEs occur, severe AEs and SAEs are rare. Reporting has improved over time, though not all papers provide a comprehensive report of relevant health impacts. We found very few severe symptoms or SAEs in studies that reported them, but many HCTs did not report relevant safety data. This study was preregistered on PROSPERO as CRD42021247218.

Public health ethics: critiques of the "new normal".

The global response to the recent coronavirus pandemic has revealed an ethical crisis in public health. This article analyses key pandemic public health policies in light of widely accepted ethical principles: the need for evidence, the least restrictive/harmful alternative, proportionality, equity, reciprocity, due legal process, and transparency. Many policies would be considered unacceptable according to pre-pandemic norms of public health ethics. There are thus significant opportunities to develop more ethical responses to future pandemics. This paper serves as the introduction to this Special Issue of Monash Bioethics Review and provides background for the other articles in this collection.

Moralization and Mismoralization in Public Health.

Moralization is a social-psychological process through which morally neutral issues take on moral significance. Often linked to health and disease, moralization may sometimes lead to good outcomes; yet moralization is often detrimental to individuals and to society as a whole. It is therefore important to be able to identify when moralization is inappropriate. In this paper, we offer a systematic normative approach to the evaluation of moralization. We introduce and develop the concept of 'mismoralization', which is when moralization is metaethically unjustified. In order to identify mismoralization, we argue that one must engage in metaethical analysis of moralization processes while paying close attention to the relevant facts. We briefly discuss one historical example (tuberculosis) and two contemporary cases related to COVID-19 (infection and vaccination status) that we contend to have been mismoralized in public health. We propose a remedy of de-moralization that begins by identifying mismoralization and that proceeds by neutralizing inapt moral content. De-moralization calls for epistemic and moral humility. It should lead us to pull away from our tendency to moralize-as individuals and as social groups-whenever and wherever moralization is unjustified.

The unintended consequences of COVID-19 vaccine policy: why mandates, passports and restrictions may cause more harm than good.

Vaccination policies have shifted dramatically during COVID-19 with the rapid emergence of population-wide vaccine mandates, domestic vaccine passports and differential restrictions based on vaccination status. While these policies have prompted ethical, scientific, practical, legal and political debate, there has been limited evaluation of their potential unintended consequences. Here, we outline a comprehensive set of hypotheses for why these policies may ultimately be counterproductive and harmful. Our framework considers four domains: (1) behavioural psychology, (2) politics and law, (3) socioeconomics, and (4) the integrity of science and public health. While current vaccines appear to have had a significant impact on decreasing COVID-19-related morbidity and mortality burdens, we argue that current mandatory vaccine policies are scientifically questionable and are likely to cause more societal harm than good. Restricting people's access to work, education, public transport and social life based on COVID-19 vaccination status impinges on human rights, promotes stigma and social polarisation, and adversely affects health and well-being. Current policies may lead to a widening of health and economic inequalities, detrimental long-term impacts on trust in government and scientific institutions, and reduce the uptake of future public health measures, including COVID-19 vaccines as well as routine immunisations. Mandating vaccination is one of the most powerful interventions in public health and should be used sparingly and carefully to uphold ethical norms and trust in institutions. We argue that current COVID-19 vaccine policies should be re-evaluated in light of the negative consequences that we outline. Leveraging empowering strategies based on trust and public consultation, and improving healthcare services and infrastructure, represent a more sustainable approach to optimising COVID-19 vaccination programmes and, more broadly, the health and well-being of the public.

Against COVID-19 vaccination of healthy children.

COVID-19 vaccination of children has begun in a number of countries with provisional regulatory approval and public support. This article provides an ethical analysis of COVID-19 vaccination of healthy children. Specifically, we present three of the strongest arguments that might justify COVID-19 vaccination of children: (a) an argument from paternalism, (b) an argument from indirect protection and altruism, and (c) an argument from global eradication. We offer a series of objections to each of these arguments to show that none of them is currently tenable. Given the minimal direct benefit of COVID-19 vaccination for healthy children, the potential for rare risks to outweigh these benefits and to undermine vaccine confidence, the substantial evidence that COVID-19 vaccination confers adequate protection to risk groups whether or not healthy children are vaccinated and that current vaccines do not provide sterilizing immunity, and given that eradication of the virus is neither feasible nor a high priority for global health, we argue that routine COVID-19 vaccination of healthy children is currently ethically unjustified. Since mandates for children have already been implemented in some places (e.g., California) and may be considered elsewhere, we also present two additional arguments explicitly against making COVID-19 vaccination mandatory for children.

Ethics review of COVID-19 human challenge studies: A joint HRA/WHO workshop.

This report of a joint World Health Organization (WHO) and United Kingdom (UK) Health Research Authority (HRA) workshop discusses the ethics review of the first COVID-19 human challenge studies, undertaken in the midst of the pandemic. It reviews the early efforts of international and national institutions to define the ethical standards required for COVID-19 human challenge studies and create the frameworks to ensure rigorous and timely review of these studies. This report evaluates the utility of the WHO's international guidance document Key criteria for the ethical acceptability of COVID-19 human challenge studies (WHO Key Criteria) as a practical resource for the ethics review of COVID-19 human challenge studies. It also assesses the UK HRA's approach to these complex ethics reviews, including the formation of a Specialist Ad-Hoc Research Ethics Committee (REC) for COVID-19 Human Challenge Studies to review all current and future COVID-19 human challenge studies. In addition, the report outlines the reflections of REC members and researchers regarding the ethics review process of the first COVID-19 human challenge studies. Finally, it considers the potential ongoing scientific justification for COVID-19 human challenge studies, particularly in relation to next-generation vaccines and optimisation of vaccination schedules. Overall, there was broad agreement that the WHO Key Criteria represented an international consensus document that played a powerful role in setting norms and delineating the necessary conditions for the ethical acceptability of COVID-19 human challenge studies. Workshop members suggested that the WHO Key Criteria could be practically implemented to support researchers and ethics reviewers, including in the training of ethics committee members. In future, a wider audience may be engaged by the original document and potential additional materials, informed by the experiences of those involved in the first COVID-19 human challenge studies outlined in this document.

Ethics and antibiotic resistance.

INTRODUCTION OR BACKGROUND: Antibiotic resistance raises ethical issues due to the severe and inequitably distributed consequences caused by individual actions and policies. SOURCES OF DATA: Synthesis of ethical, scientific and clinical literature. AREAS OF AGREEMENT: Ethical analyses have focused on the moral responsibilities of patients to complete antibiotic courses, resistance as a tragedy of the commons and attempts to limit use through antibiotic stewardship. AREAS OF CONTROVERSY: Each of these analyses has significant limitations and can result in self-defeating or overly narrow implications for policy. GROWING POINTS: More complex analyses focus on ethical implications of ubiquitous asymptomatic carriage of resistant bacteria, non-linear outcomes within and between patients over time and global variation in resistant disease burdens. AREAS TIMELY FOR DEVELOPING RESEARCH: Neglected topics include the harms of antibiotic use, including off-target effects on the human microbiome, and the lack of evidence guiding most antibiotic prescription decisions.