Controlled human infection models in COVID-19 and tuberculosis: current progress and future challenges.

Controlled Human Infection Models (CHIMs) involve deliberately exposing healthy human volunteers to a known pathogen, to allow the detailed study of disease processes and evaluate methods of treatment and prevention, including next generation vaccines. CHIMs are in development for both tuberculosis (TB) and Covid-19, but challenges remain in their ongoing optimisation and refinement. It would be unethical to deliberately infect humans with virulent Mycobacteria tuberculosis (M.tb), however surrogate models involving other mycobacteria, M.tb Purified Protein Derivative or genetically modified forms of M.tb either exist or are under development. These utilise varying routes of administration, including via aerosol, per bronchoscope or intradermal injection, each with their own advantages and disadvantages. Intranasal CHIMs with SARS-CoV-2 were developed against the backdrop of the evolving Covid-19 pandemic and are currently being utilised to both assess viral kinetics, interrogate the local and systemic immunological responses post exposure, and identify immune correlates of protection. In future it is hoped they can be used to assess new treatments and vaccines. The changing face of the pandemic, including the emergence of new virus variants and increasing levels of vaccination and natural immunity within populations, has provided a unique and complex environment within which to develop a SARS-CoV-2 CHIM. This article will discuss current progress and potential future developments in CHIMs for these two globally significant pathogens.

A new day for human challenge trials?

Two years into the coronavirus disease 2019 (COVID-19) pandemic and following several hot debates, the world's first COVID-19 human challenge trial has recently been published by Killingley et al. We review its findings and explain why this particular juncture in time makes additional challenge trials for COVID-19 and for other diseases justified and important.

The Ethics of Human Challenge Trials Using Emerging Severe Acute Respiratory Syndrome 2 Variants.

The world's first coronavirus disease 2019 human challenge trial using the D614G strain of severe acute respiratory syndrome 2 (SARS-CoV-2) is underway in the United Kingdom. The Wellcome Trust is funding challenge stock preparation of the Beta and Delta variant for a follow-up human challenge trial, and researchers at hVIVO are considering conducting these trials. However, little has been written thus far about the ethical justifiability of human challenge trials with SARS-CoV-2 variants of concern. We explore 2 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.

Assessment of Risks Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Experimental Human Infection Studies.

Controlled human infection (CHI) models for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been proposed as a tool to accelerate the development of vaccines and drugs. Such models carry inherent risks. Participants may develop severe disease or complications after deliberate infection. Prolonged isolation may negatively impact their well-being. Through secondary infection of study personnel or participant household contacts, the experimental virus strain may cause a community outbreak. We identified risks associated with such a SARS-CoV-2 CHI model and assessed their likelihood and impact and propose strategies that mitigate these risks. In this report, we show that risks can be minimized with proper risk mitigation strategies; the residual risk, however, should be weighed carefully against the scientific and social values of such a CHI model.

Human Challenge Studies for Vaccine Development : Regulatory Aspects of Human Challenge Studies.

The traditional regulatory pathway for the evaluation of new vaccine candidates generally proceeds from preclinical through three successive phases of human trials, and the demonstration of efficacy is usually done through randomized-controlled clinical trials. However, human challenge trials or controlled human infection models have been used in vaccine clinical development to generate supportive data for establishment of correlates of protection, supportive data for licensure, as well as licensure in the case of Vaxchora® by the US FDA. Despite this, there are no codified regulations from national regulatory authorities (NRAs) that specifically address HCTs, nor guidance related to standardization of approaches to HCTs among regulators. NRAs may agree that HCTs are innovative, promising tools to accelerate vaccine development; however, a strong benefit/risk assessment is needed to ensure the safety of study participants. Lastly, it is important to consider the regulatory framework in which the human challenge trial may be conducted.

Human challenge trials in vaccine development.

The increasing recent interest in human challenge studies or controlled human infection model studies for accelerating vaccine development has been driven by the recognition of the unique ability of these studies to contribute to the understanding of response to infection and the performance of vaccines. With streamlining of ethical processes, conduct and supervision and the availability of new investigative tools from immunophenotyping to glycobiology, the potential to derive valuable data to inform vaccine testing and development has never been greater. However, issues of availability and standardization of challenge strains, conduct of studies in disease endemic locations and the iteration between clinical and laboratory studies still need to be addressed to gain maximal value for vaccine development.

Key criteria for the ethical acceptability of COVID-19 human challenge studies: Report of a WHO Working Group.

This report of the WHO Working Group for Guidance on Human Challenge Studies in COVID-19 outlines ethical standards for COVID-19 challenge studies. It includes eight Key Criteria related to scientific justification, risk-benefit assessment, consultation and engagement, co-ordination of research, site selection, participant selection, expert review, and informed consent. The document aims to provide comprehensive guidance to scientists, research ethics committees, funders, policymakers, and regulators in deliberations regarding SARS-CoV-2 challenge studies by outlining criteria that would need to be satisfied in order for such studies to be ethically acceptable.

Coronavirus Human Infection Challenge Studies: Assessing Potential Benefits and Risks.

Human infection challenge studies (HCS) have been proposed as a means to accelerate SARS-CoV2 vaccine development and thereby help to mitigate a prolonged global public health crisis. A key criterion for the ethical acceptability of SARS-CoV2 HCS is that potential benefits outweigh risks. Although the assessment of risks and benefits is meant to be a standard part of research ethics review, systematic comparisons are particularly important in the context of SARS-CoV2 HCS in light of the significant potential benefits and harms at stake as well as the need to preserve public trust in research and vaccines. In this paper we explore several considerations that should inform systematic assessment of SARS-CoV-2 HCS. First, we detail key potential benefits of SARS-CoV-2 HCS including, but not limited to, those related to the acceleration of vaccine development. Second, we identify where modelling is needed to inform risk-benefit (and thus ethical) assessments. Modelling will be particularly useful in (i) comparing potential benefits and risks of HCS with those of vaccine field trials under different epidemiological conditions and (ii) estimating marginal risks to HCS participants in light of the background probabilities of infection in their local community. We highlight interactions between public health policy and research priorities, including situations in which research ethics assessments may need to strike a balance between competing considerations.

A COVID-19 human viral challenge model. Learning from experience.

The controlled human infection model and specifically the human viral challenge model are not dissimilar to standard clinical trials while adding another layer of complexity and safety considerations. The models deliberately infect volunteers, with an infectious challenge agent to determine the effect of the infection and the potential benefits of the experimental interventions. The human viral challenge model studies can shorten the time to assess the efficacy of a new vaccine or treatment by combining this with the assessment of safety. The newly emerging SARS-CoV-2 virus is highly contagious, and an urgent race is on to develop a new vaccine against this virus in a timeframe never attempted before. The use of the human viral challenge model has been proposed to accelerate the development of the vaccine. In the early 2000s, the authors successfully developed a pathogenic human viral challenge model for another virus for which there was no effective treatment and established it to evaluate potential therapies and vaccines against respiratory syncytial virus. Experience gained in the development of that model can help with the development of a COVID-19 HVCM and the authors describe it here.

SARS-CoV-2 controlled human infection models: Ethics, challenge agent production and regulatory issues.

This second International Alliance for Biological Standardization COVID-19 webinar brought together a broad range of international stakeholders, including academia, regulators, funders and industry, with a considerable participation from low- and middle-income countries, to discuss the use of controlled human infection models to accelerate development and market authorization assessment of a vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Exploring the acceptability of controlled human infection with SARSCoV2-a public consultation.

Rapid development of an effective vaccine for SARSCoV2 is a global priority. A controlled human infection model (CHIM) would accelerate the efficacy assessment of candidate vaccines. This strategy would require deliberate exposure of volunteers to SARSCoV2 with no currently available treatment and a small but definite risk of serious illness or death. This raises complex questions about the social and ethical acceptability of risk to individuals, given the potential benefit to the wider population, and as such, a study cannot be done without public involvement. We conducted a structured public consultation with 57 individuals aged 20-40 years to understand public attitudes to a CHIM, and pre-requisites for enrolment. The overall response to this strategy was positive, and many would volunteer altruistically. Carefully controlled infection is viewed as safer than natural exposure to wild virus. The prolonged social isolation required for the proposed CHIM is considered an obstacle but not insurmountable, with reasonable compensation and supportive care. Given the significant level of public interest, a CHIM should be done as open science with regular, controlled dissemination of information into the public domain. Importantly, there was a strong view that the final decision whether to conduct a CHIM should be in the hands of qualified and experienced clinician-scientists and the authorities.

Evaluating Use Cases for Human Challenge Trials in Accelerating SARS-CoV-2 Vaccine Development.

Human challenge trials (HCTs) have been proposed as a means to accelerate SARS-CoV-2 vaccine development. We identify and discuss 3 potential use cases of HCTs in the current pandemic: evaluating efficacy, converging on correlates of protection, and improving understanding of pathogenesis and the human immune response. We outline the limitations of HCTs and find that HCTs are likely to be most useful for vaccine candidates currently in preclinical stages of development. We conclude that, while currently limited in their application, there are scenarios in which HCTs would be extremely beneficial. Therefore, the option of conducting HCTs to accelerate SARS-CoV-2 vaccine development should be preserved. As HCTs require many months of preparation, we recommend an immediate effort to (1) establish guidelines for HCTs for COVID-19; (2) take the first steps toward HCTs, including preparing challenge virus and making preliminary logistical arrangements; and (3) commit to periodically re-evaluating the utility of HCTs.