Human challenge trials in vaccine development, Rockville, MD, USA, September 28–30, 2017
Introduction
After the successful workshop on human challenge trials (HCTs), organized by the International Alliance for Biological Standardization (IABS) in Strasbourg, France, in 2014 [1], a follow-up meeting was held in Rockville, MD, USA, September 28–30, 2017. The objective of this second meeting was to examine and promote the use of HCTs or controlled human infections (CHI), in response to the continuing human suffering caused by infectious diseases around the globe, which should be preventable by the development of new and improved vaccines for which the approach of CHI could be valuable. As the term CHI more closely reflects the infectious nature of the experiment, the abbreviation CHI will be used throughout this document.
The agenda for the meeting was based on the principle that CHI can provide key safety, tolerability, immunogenicity, and efficacy data supporting vaccine research, and can be used to study host-pathogen biology. Unlike large field trials, CHI can generate these data with speed, efficiency and minimal expense, albeit without assurance that findings will accurately bridge to the field. Often, large field trials will still be required to generate pivotal data demonstrating safety and benefit to individuals and public health to satisfy regulatory requirements for product licensure. However, such trials are expensive, may require thousands of subjects, and can take years to complete. In contrast, CHI, despite not necessarily mimicking wild-type infection, generally involve only tens of subjects and require only a few months to complete. Incorporated wisely into a clinical development plan, CHI can support optimization or down-selection of new vaccine candidates, assuring that only the worthiest candidates progress to field testing. CHI may also provide pivotal efficacy data in support of licensure, particularly when field efficacy studies are not feasible, e.g. due to low attack rates.
Deliberate exposure of humans to infectious agents has been performed in the Western world since the early 18th century, when variolation, based on historical use of this approach in the Orient and Middle East, was tested for the first time in the UK as a prevention for smallpox. Early CHI studies, however, sometimes lacked adequate ethical justification. For example, some were performed in vulnerable populations, e.g., orphans and prisoners, and did not fully adhere to important ethical principles, as these had not been formally elucidated and their centrality to human research was not promulgated until the publication of the Belmont report in 1979 [2].
Since the 1970s, major changes have occurred in public opinion about CHI and the ethical and regulatory context in which CHI are performed. Studies now generally enroll healthy, non-disadvantaged volunteers from the local community, in compliance with ethical standards, assuring informed consent, under the oversight of institutional review boards (IRBs), and, increasingly, within the purview of regulatory authorities such as the United States Food & Drug Administration (FDA) and European Medicines Agency (EMA). Participants in CHI are well-informed of the risks, free to choose or decline participation, perceive (and are motivated by) societal benefit, and are compensated for their time. Key elements supporting the effective use of CHI are the development of well-characterized and quality-controlled challenge strains, standardized procedures for inoculation, formally approved clinical protocols, pre-selected outcome measures, dedicated human challenge facilities, access to adequate numbers of volunteers, and regulatory endorsement of the value of the data obtained. A landmark was achieved in 2016 with the licensure of the cholera vaccine Vaxchora™ by the FDA, based on demonstration of safety in healthy volunteers, and efficacy data obtained from CHI, supplemented by safety data collected in larger study populations.
Many aspects of CHI were examined by the participants who convened in Rockville. Altogether, the program comprised of 55 presentations, 5 panel discussions, and 3 point-counterpoint debates. A consensus was achieved that CHI, if ethically justified and performed with careful attention to safety and informed consent, should be pursued vigorously and with expanded applications aiming to promote and accelerate vaccine development. An important outcome was the proposal that vulnerable populations suffering a heavy disease burden might be considered for inclusion in CHI that significantly advance vaccine development, particularly when other populations cannot provide adequate surrogate data. This is a way to address the paucity of data in populations where vaccines are most needed, especially in endemic settings, stressing, however, the need to develop shared and appropriate ethical guidelines. This and additional concepts are listed for further exploration in future meetings. The momentum and enthusiasm generated by the meeting are being harnessed by IABS, which is planning a third HCT event in Oxford, UK, in 2019.
Section snippets
Regulatory framework for human challenge trials
The FDA requires that CHI are conducted under an Investigational New Drug (IND) application [3]. The purpose of regulatory oversight of human challenge models is to assure the safety and rights of subjects, by risk assessment, risk mitigation and risk communication. Furthermore, IRB review and informed consent are necessary. Clinical considerations for CHI may include the exclusion of children, elderly, pregnant women, immunocompromised individuals and other vulnerable populations;
Human challenge trials guidelines
In order to facilitate research, development and implementation of vaccines and biologicals, the World Health Organization (WHO) has prepared written standards, recommendations and guidelines, as well as measurement standards. The aim is to provide key principles for evaluation of biologicals, while leaving room for regulatory agencies to formulate additional requirements. Where possible, the WHO will assist in the implementation of the guidelines through workshops, training and advisory
Quality standards for challenge strains
The FDA demands that for the production of challenge strains, Chemistry Manufacturing and Controls guidance applies in regard to strain characterization, purity, potency, and stability/viability. Facilities for production of challenge agents should comply with cGMP appropriate to the phase of the clinical study. In the case of bacterial and parasitic diseases, safety of the challenge strain is ensured by verification that infection can be terminated by treatment, and the absence of genetic
Development of challenge strains
To be informative of protective efficacy against natural infection, CHI need to use adequate pathogen strains. Homologous challenge is defined as challenge with an organism that is genetically (or immunogenically) identical to the vaccine strain, while heterologous challenge uses an organism that differs immunogenically from the vaccine strain. Finally, strains used in challenge trials should be representative of field strains, particularly those originating from the same geographic region.
Development of new challenge models
Progress of development of several new challenge models was presented:
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Schistosoma. A CHI has been developed, based on the production of male cercariae under GMP conditions. A dose escalation study is being performed, to find the optimal dose. Most common adverse events were rash, headache and fever, which could last for several weeks, and rarely were grade 3. A dose-related increase of CAA could be observed, useful as a diagnostic marker, and to show effective treatment with praziquantel.
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Refining and optimizing existing controlled human infection models
Similarly, progress on refinement and optimization of several existing challenge models were presented:
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Controlled Human Hookworm Infection (CHHI). Studies are needed for vaccine validation. A vaccine based on a combination of recombinant proteins has been developed, and phase 1 trials have been performed, however, phase 3 trials can only be done after proof of concept has been established. Previous CHHI have been done in the 1980s, showing that infection is well-tolerated, has a predictable
Human challenge trials to support licensure
For some diseases, field trials of vaccines are nearly impossible due to the low incidence rate of the disease. So far, only one example exists where CHI supported licensure (cholera, described below), however, there are several other organisms where CHI might help to support licensure:
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Cholera, a non-invasive diarrheal disease, caused by the ingestion of Vibrio cholerae, leads to life-threatening loss of fluid and electrolytes induced by the cholera toxin subunit A. The oral live attenuated
Advancing the frontiers of human challenge research: the typhoid example
Every year, 22 million new cases of enteric fever caused by typhoid are estimated to occur, although they frequently go undetected due non-specific symptoms and lack of accurate diagnostics. There is a specific issue of increasing antimicrobial resistance in S. typhi, and so there is an acute need for improved control measures, such as better diagnostics and vaccines. The Vi polysaccharide vaccine shows an efficacy of 70%, but this decreases to 50% after three years [32]. A conjugate vaccine
What can we learn about human immunity from human challenge trials?
The level of detail obtained with a CHI is dependent on the organism under investigation, prior knowledge available on this organism, and how well CHMI reproduces the natural infection and predicts drug or vaccine efficacy. In more complex organisms, such as Campylobacter jejuni, CHI offer unparalleled opportunities to advance human immunology, especially if re-challenges are done, but basic immunologic data are needed from natural disease populations before a CHI can be started. Furthermore,
Dengue CHI: model of infection or disease?
In the dengue infection model, infection is the endpoint, verified by recovery of infectious virus from the blood, by PCR or culture. This is a reproducible endpoint requiring low participant numbers, is safe and ethical, with minimal risk to participants. The challenge strains used are recombinant viruses that were not attenuated compared with their wildtype parent viruses. They cause low viremia and mild disease. 3 log10 PFU induced viremia in more than 80% of the subjects, rash in 80–100% of
Safety in human challenge trials
When setting up an CHI, risk mitigation has to take place at multiple steps: the host, the pathogen and the environment. To be amenable for a CHI, a disease must lead to tolerable discomfort, and effective treatment of the disease must generally be available unless the agent is intrinsically self-limiting, and rapid recovery should be the norm. Precise endpoints must be defined, so treatment can be initiated once these are met. The infection should not lead to persistent illness, or
Ethical perspectives
Several ethical considerations need to be addressed in order to approve an CHI [48,49]:
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Are risks and discomforts identified, minimized, determined to be reasonable, and justified by social value?
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Does scientific rationale and design align with social value?
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Is there a system for compensation for research-related injury?
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Are vulnerable populations enrolled?
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Is the informed consent process adequate?
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Is the level of compensation appropriate?
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Can the right to withdraw be respected?
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Will appropriate
Use of human challenge trials in developing countries
CHMI had not been done in Africa in the modern era due to its reliance on mosquito bite inoculation and the fact that the vector used is Anopheles stephensi, a potent south Asian vector that could pose severe public health risk if introduced. With the development of the PfSPZ Challenge (see above), CHMIs can now be performed safely. Since the first African study in Tanzania [4], 11 more CHMIs have been performed in Tanzania (Jongo, AJTMH, in press, and NCT02613520), Gabon [52], Kenya [53], and
Use of human challenge trials in vulnerable populations
It is imperative to develop vaccines for children, pregnant women, and immunocompromised. This does not mean, however, that CHI can be performed in these vulnerable groups. The Declaration of Helsinki states that medical research on a vulnerable group is only justified if the research is responsive to the health needs or priorities of this group and the research cannot be carried out in a non-vulnerable group. The EC regulation 1901/2006 states that medicinal products for the pediatric
Recommendations
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When animal models do not exist, and field trials cannot be performed, within reasonable resource constraints, including cost and time, consideration should be given to the conduct of CHI, where the concept of ‘do harm to prevent greater harm’ is combined with the principle of non-maleficence.
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With respect to the proposed role of CHI throughout clinical development, a good discussion at an early stage between regulator and developer/investigator will streamline the regulatory process, avoiding
Funding
The meeting was organized with financial support from the Bill & Melinda Gates Foundation, the Wellcome Trust, Sanofi Pasteur and GlaxoSmithKline Vaccines.
Declaration of interest
Conflict of interest statement: T.L.R., is a salaried employee of Sanaria Inc., the developer and owner of PfSPZ Vaccine and PfSPZ Challenge. The other authors declare no conflict of interest.
Acknowledgements
The authors would like to thank Aaron Mendelsohn (P95, Epidemiology and Pharmacovigilance Consulting and Services) for careful review of this paper.
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