RESUMEN
At the height of the Covid pandemic, there was much discussion in the literature about using human challenge trials (HCTs) to expedite the development of effective Covid-19 vaccines. Historically, reluctance to fully accept HCTs has largely been due to potential conflicts with the principle of nonmaleficence in bioethics. Only a few commentators have explored this topic in depth. In this paper, we claim that to address ethical concerns regarding HCTs, two types of ethical reasons should be identified and investigated: first-order reasons that can be given to claim that a practice in itself is in direct conflict with the principles of bioethics; and second-order reasons that take into consideration how a practice is carried out and its consequences. We argue that understanding these ethical reasons is crucial for guiding the implementation of HCTs. We investigate a first-order reason against HCTs when the practice is in conflict with the principle of nonmaleficence, and when it is not. Following this argument and assuming there is no first-order reason based on nonmaleficence that hinders using HCTs, we argue there may be second-order reasons to guide implementation of this practice, such as difficulty in obtaining informed consent; protection of the weaker party; and trust in the scientific enterprise.
Asunto(s)
COVID-19 , Humanos , COVID-19/prevención & control , Vacunas contra la COVID-19 , Consentimiento Informado/ética , Ensayos Clínicos como Asunto/ética , SARS-CoV-2 , Pandemias/éticaRESUMEN
In a challenge trial, research subjects are purposefully exposed to some pathogen in a controlled setting, in order to test the efficacy of a vaccine or other experimental treatment. This is an example of medical effective altruism (MEA), where individuals volunteer to risk harms for the public good. Many bioethicists rejected challenge trials in the context of Covid-19 vaccine research on ethical grounds. After considering various grounds of this objection, I conclude that the crucial question is how much harm research subjects can permissibly risk. But we lack a satisfying way of making this judgment that does not appeal simply to the intuitions of doctors or bioethicists. I consider one recent and structurally plausible approach to critically evaluating the harm question. Alex London defends a social consistency test for research risks: we should compare the risks undertaken by research subjects to relevantly similar risks which are accepted in other spheres of society. I argue there is no good reason not to consider volunteer military service as a relevant social comparison. This implies there is essentially no cap on acceptable risks on the social consistency rationale. In short, if soldiers can be heroes, why can't research volunteers?
Asunto(s)
Altruismo , Vacunas contra la COVID-19 , COVID-19 , SARS-CoV-2 , Humanos , COVID-19/prevención & control , Vacunas contra la COVID-19/administración & dosificación , Sujetos de Investigación , VoluntariosRESUMEN
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.
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COVID-19 , Humanos , Pandemias , SARS-CoV-2RESUMEN
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.
Asunto(s)
Vacunas contra la COVID-19/administración & dosificación , COVID-19/prevención & control , Ética en Investigación , SARS-CoV-2/genética , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/inmunología , Ética , Humanos , Reino Unido , VacunasRESUMEN
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.
Asunto(s)
COVID-19 , Obtención de Tejidos y Órganos , Vacunas contra la COVID-19 , Humanos , Pandemias , SARS-CoV-2RESUMEN
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.
RESUMEN
In the midst of the ongoing Covid-19 pandemic, researchers across the globe are still working to develop effective vaccines. To expedite this process even further, human challenge trials have been proposed by the World Health Organization (WHO) as an alternative to conventional approaches. In such trials, healthy volunteers are deliberately infected with the pathogen of interest, enabling scientists to study the infection process and facilitate further research on treatments or prophylactics, including vaccines. While human challenge trials would offer a collective benefit to society, minimizing the risks is always difficult. Ethical controversy thus inevitably surrounds these trials. Typically, healthy young adults are recruited to serve as the first candidate subjects for human challenge trials because they are generally considered to represent a low-risk population. Here, we present three reasons for doubt about this healthy-young-adults-first criterion and give justification for also recruiting healthy older adults (or not-young adults), meaning those over 30 years of age, to participate in such trials for SARS-CoV-2.
Asunto(s)
COVID-19/terapia , Ensayos Clínicos como Asunto/ética , Selección de Paciente/ética , Adulto , Factores de Edad , Antivirales/uso terapéutico , COVID-19/mortalidad , COVID-19/prevención & control , Vacunas contra la COVID-19/uso terapéutico , Ensayos Clínicos como Asunto/métodos , Humanos , SARS-CoV-2 , Adulto Joven , Tratamiento Farmacológico de COVID-19RESUMEN
COVID-19 has generated a new and distinctive focus on the use of human challenge studies, also known as controlled human infection trials. The first such trial was authorised in England in February 2021. Although vaccines are now available for COVID-19, there remain multiple deficits in knowledge in respect of treatment and prevention of the infection and a powerful impetus for solutions given the level of its global morbidity and mortality. Thus, there are potent incentives for unorthodox acceleration of medical knowledge but against these must be balanced ethical and pragmatic considerations. This editorial adds to the literature on such issues by reflecting on the ethical principles that are applicable and identifying the arguments that have been mustered for and against human challenge studies in relation to COVID-19. It argues that, given the limited state of knowledge about the diverse and longer term risks from contraction of COVID-19, considerable care needs to be devoted to any assessment of the appropriateness of human challenge trials to test treatments for the disease or measures to prevent contracting the virus.
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COVID-19 , Inglaterra , Ética en Investigación , Humanos , Proyectos de Investigación , SARS-CoV-2RESUMEN
A vaccine for COVID-19 is urgently needed. Several vaccine trial designs may significantly accelerate vaccine testing and approval, but also increase risks to human subjects. Concerns about whether the public would see such designs as ethical represent an important roadblock to their implementation; accordingly, both the World Health Organization and numerous scholars have called for consulting the public regarding them. We answered these calls by conducting a cross-national survey (n = 5920) in Australia, Canada, Hong Kong, New Zealand, South Africa, Singapore, the United Kingdom, and the United States. The survey explained key differences between traditional vaccine trials and two accelerated designs: a challenge trial or a trial integrating a Phase II safety and immunogenicity trial into a larger Phase III efficacy trial. Respondents' answers to comprehension questions indicate that they largely understood the key differences and ethical trade-offs between the designs from our descriptions. We asked respondents whether they would prefer scientists to conduct traditional trials or one of these two accelerated designs. We found broad majorities prefer for scientists to conduct challenge trials (75%) and integrated trials (63%) over standard trials. Even as respondents acknowledged the risks, they perceived both accelerated trials as similarly ethical to standard trial designs. This high support is consistent across every geography and demographic subgroup we examined, including vulnerable populations. These findings may help assuage some of the concerns surrounding accelerated designs.
Asunto(s)
Vacunas contra la COVID-19/administración & dosificación , COVID-19/prevención & control , Toma de Decisiones , Pandemias/prevención & control , Proyectos de Investigación , SARS-CoV-2/inmunología , Vacunación/psicología , Asia/epidemiología , Australia/epidemiología , COVID-19/epidemiología , COVID-19/psicología , COVID-19/virología , Vacunas contra la COVID-19/biosíntesis , Vacunas contra la COVID-19/provisión & distribución , Conducta de Elección , Ensayos Clínicos como Asunto , Femenino , Humanos , Inmunidad Innata/efectos de los fármacos , Esquemas de Inmunización , Inmunogenicidad Vacunal , Masculino , América del Norte/epidemiología , Seguridad del Paciente , Salud Pública , SARS-CoV-2/patogenicidad , Encuestas y Cuestionarios , Factores de Tiempo , Reino Unido/epidemiología , Vacunación/métodosRESUMEN
If, as is alleged, challenge trials of vaccines against COVID-19 are likely to save thousands of lives and vastly diminish the economic and social harms of the pandemic while subjecting volunteers to risks that are comparable to kidney donation, then it would seem that the only sensible objection to such trials would be to deny that they have low risks or can be expected to have immense benefits. This essay searches for a philosophical rationale for rejecting challenge trials while supposing that they have huge benefits and relatively low risks. Although it finds some force in objections to challenge trials grounded in the obligations of researchers to limit the harms imposed on some individuals for the benefit of others, it argues that there is no compelling objection to challenge trials of vaccines for COVID-19-if they have the benefits and risks that have been claimed.
Asunto(s)
Investigación Biomédica/ética , Vacunas contra la COVID-19/administración & dosificación , COVID-19/epidemiología , COVID-19/prevención & control , Ensayos Clínicos como Asunto/ética , Ensayos Clínicos como Asunto/métodos , Vacunas contra la COVID-19/efectos adversos , Humanos , Pandemias , Filosofía Médica , SARS-CoV-2RESUMEN
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.
Asunto(s)
Comités de Ética en Investigación , Valores Sociales , Análisis Costo-Beneficio , Humanos , Proyectos de InvestigaciónRESUMEN
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.
Asunto(s)
Investigación Biomédica , Ética en Investigación , Niño , Humanos , Consentimiento Informado , Proyectos de Investigación , Investigadores , Poblaciones VulnerablesRESUMEN
Human challenge trials (HCTs) deliberately infect participants in order to test vaccines and treatments in a controlled setting, rather than enrolling individuals with natural exposure to a disease. HCTs are therefore potentially powerful tools to prepare for future outbreaks of emerging infectious diseases. Yet when an infectious disease is emerging, there is often substantial risk and uncertainty about its complications, and few available interventions, making an HCT ethically complex. In light of the need to consider ethical issues proactively as a part of epidemic preparedness, we use the case of a Zika virus HCT to explore whether and when HCTs might be ethically justified to combat emerging infectious diseases. We conclude that emerging infectious diseases could be appropriate candidates for HCTs and we identify relevant considerations and provide a case example to illustrate when they might be ethically acceptable.
Asunto(s)
Ensayos Clínicos como Asunto/ética , Enfermedades Transmisibles Emergentes/terapia , Epidemias/prevención & control , Experimentación Humana Terapéutica/ética , Infección por el Virus Zika/terapia , Enfermedades Transmisibles Emergentes/epidemiología , Enfermedades Transmisibles Emergentes/virología , Urgencias Médicas , Voluntarios Sanos , Humanos , Vacunas/uso terapéutico , Virus Zika/inmunología , Virus Zika/patogenicidad , Infección por el Virus Zika/epidemiología , Infección por el Virus Zika/virologíaRESUMEN
Vaccine efficacy and prophylactic treatment of infections are tested best when the vaccinated or treated individual is challenged through deliberate infection with the respective pathogen. However, this trial design calls for particular ethical caution. Awareness of the history of challenge trials is indispensable, including trials that were problematic or even connected to abuse. We briefly introduce historical aspects of experimental infections in humans and the ethical debate around them and give estimates of the numbers of volunteers participating in human experimental infection models. Challenge models can offer a great chance and benefit for the development of medical interventions to fight infectious diseases, but only when they are appropriately controlled and regulated.
L'efficacité des vaccins et le traitement prophylactique des infections sont mieux testés lorsque l'individu vacciné ou traité est exposé par le biais d'une infection délibérée par l'agent pathogène concerné. Cependant, cette conception d'essai appelle à une prudence éthique particulière. Il est indispensable de connaître l'histoire des essais cliniques, y compris des essais qui se sont avérés problématiques ou même liés à des abus. Nous présentons brièvement les aspects historiques des infections expérimentales chez l'homme et le débat éthique autour d'eux et donnons des estimations du nombre de volontaires participant à des modèles d'infection expérimentale humaine. Les modèles d'exposition peuvent offrir une grande chance et un avantage pour le développement d'interventions médicales pour lutter contre les maladies infectieuses, mais uniquement lorsqu'elles sont contrôlées et réglementées de manière appropriée.
Asunto(s)
Ensayos Clínicos como Asunto/historia , Experimentación Humana/historia , Ensayos Clínicos como Asunto/ética , Control de Enfermedades Transmisibles/historia , Historia del Siglo XX , Historia del Siglo XXI , Experimentación Humana/ética , HumanosRESUMEN
Salmonellosis caused by Salmonella Enteritidis is a widespread zoonosis and poultry products are an important source of infection. This study was carried out to evaluate the protection of different vaccination schedules in layers using a live commercial attenuated Salmonella Enteritidis vaccine based on strain Sm24/Rif12/Ssq (AviPro® Salmonella Vac E, ELANCO) during rearing and egg production. Three hundred and fifty Salmonella-free chickens were distributed into 7 vaccinated groups and 1 unvaccinated group. Different vaccination schedules were performed combining either 1, 2, or 3 oral gavage doses. Chickens from Group A, B, and C were vaccinated once, either at the first day, at 7 or 16 wk old, respectively. Chickens from Group D were vaccinated twice-at the first day and 7 wk old. Chickens from Group E were vaccinated twice-at the first day and 16 wk old. Chickens from Group F were vaccinated twice-at 7 and 16 wk old. Chickens from Group G were vaccinated 3 times, following the manufacturer's recommendation: at the first day, 7 and 16 wk old. Chickens from Group H remained unvaccinated. Five challenge trials numbered 1 to 5 were carried out at 8, 12, 16, 29, and 55 wk old, respectively. After challenge, chickens were sampled by cloacal swabbing and, after euthanasia, livers, ovaries, spleens, and cecal contents were cultured to isolate S. Enteritidis. Additionally, eggs were collected after challenge and cultured to isolate S. Enteritidis on egg shells (Trials 4 and 5). Protection against experimental infection with a virulent nalidixic acid resistant S. Enteritidis strain K285/94, was evaluated by measuring reduction of excretion, colonization, invasion into organs, eggshell contamination, and egg production. The live S. Enteritidis vaccine protected the hens by reducing S. Enteritidis excretion, isolation from organs, and egg contamination. Higher protection throughout laying period was afforded after administration of three vaccine doses during rearing period.
Asunto(s)
Pollos , Enfermedades de las Aves de Corral/prevención & control , Salmonelosis Animal/prevención & control , Vacunas contra la Salmonella/inmunología , Salmonella enteritidis/inmunología , Animales , Recuento de Colonia Microbiana/veterinaria , Femenino , Eliminación Intestinal , Óvulo/microbiología , Enfermedades de las Aves de Corral/inmunología , Enfermedades de las Aves de Corral/microbiología , Salmonelosis Animal/inmunología , Salmonelosis Animal/microbiología , Vacunas contra la Salmonella/administración & dosificación , Vacunación/veterinaria , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/inmunología , Vacunas de Productos Inactivados/administración & dosificación , Vacunas de Productos Inactivados/inmunologíaRESUMEN
Since its peak in early 2016, the incidence of Zika virus (ZIKV) cases has declined to such low levels that Phase 3 field efficacy trials may be infeasible. While great progress was made to rapidly advance several vaccine candidates into Phase 1 and 2 clinical trials, in the absence of sustained viral transmission it may be difficult to evaluate the effectiveness of ZIKV vaccine candidates by conducting traditional clinical disease endpoint efficacy studies. However, ZIKV is still circulating at low levels in some areas and is likely to re-emerge in naïve populations or in sites of prior epidemics once population immunity wanes. Therefore, the public health need for a ZIKV vaccine remains. To facilitate continued ZIKV vaccine development efforts, the World Health Organization's Initiative for Vaccine Research and the National Institutes of Health's National Institute of Allergy and Infectious Diseases co-hosted a meeting of experts in March 2018 to identify strategies to demonstrate vaccine effectiveness in view of waning ZIKV disease incidence. This paper outlines points for consideration for developers, regulators, and other stakeholders working towards a licensed ZIKV vaccine. These deliberations may also be applicable to development of vaccines for other emerging infections where the size, unpredictability, and ephemeral nature of outbreaks makes clinical disease endpoint efficacy trials to demonstrate vaccine effectiveness infeasible.
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Vacunación/legislación & jurisprudencia , Potencia de la Vacuna , Vacunas Virales/inmunología , Infección por el Virus Zika/prevención & control , Anticuerpos Antivirales/sangre , Ensayos Clínicos como Asunto , Brotes de Enfermedades/prevención & control , Humanos , National Institutes of Health (U.S.) , Estados Unidos , Vacunación/estadística & datos numéricos , Organización Mundial de la SaludRESUMEN
Human challenge trials (HCTs) deliberately infect participants in order to test vaccines and treatments in a controlled setting, rather than enrolling individuals with natural exposure to a disease. HCTs are therefore potentially powerful tools to prepare for future outbreaks of emerging infectious diseases. Yet when an infectious disease is emerging, there is often substantial risk and uncertainty about its complications, and few available interventions, making an HCT ethically complex. In light of the need to consider ethical issues proactively as a part of epidemic preparedness, we use the case of a Zika virus HCT to explore whether and when HCTs might be ethically justified to combat emerging infectious diseases. We conclude that emerging infectious diseases could be appropriate candidates for HCTs and we identify relevant considerations and provide a case example to illustrate when they might be ethically acceptable.
RESUMEN
Snakin-1 is a cysteine-rich antimicrobial peptide (AMP) isolated from potato tubers, with broad-spectrum activity. It belongs to the Snakin/GASA family, whose members have been studied because of their diverse roles in important plant processes, including defense. To analyze if this defensive function may lead to disease tolerance in lettuce, one of the most worldwide consumed leafy vegetable, we characterized three homozygous transgenic lines overexpressing Snakin-1. They were biologically assessed by the inoculation with the fungal pathogens Rhizoctonia solani and Sclerotinia sclerotiorum both in vitro and in planta at the greenhouse. When in vitro assays were performed with R. solani on Petri dishes containing crude plant extracts it was confirmed that the expressed Snakin-1 protein has antimicrobial activity. Furthermore, transgenic lines showed a better response than wild type in in vivo challenges against R. solani both in chamber and in greenhouse. In addition, two of these lines showed significant in vivo protection against the pathogen S. sclerotiorum in challenge assays on adult plants. Our results show that Snakin-1 is an interesting candidate gene for the selection/breeding of lettuce plants with increased fungal tolerance.
Asunto(s)
Lactuca/genética , Enfermedades de las Plantas/prevención & control , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Ascomicetos/patogenicidad , Resistencia a la Enfermedad , Lactuca/crecimiento & desarrollo , Lactuca/microbiología , Enfermedades de las Plantas/microbiología , Hojas de la Planta/genética , Hojas de la Planta/metabolismo , Plantas Modificadas Genéticamente/crecimiento & desarrollo , Plantas Modificadas Genéticamente/microbiología , Especies Reactivas de Oxígeno/metabolismo , Rhizoctonia/patogenicidadRESUMEN
The aquaculture industry is suffering from losses associated with bacterial infections by opportunistic pathogens. Vibrio anguillarum is one of the most important pathogens, causing vibriosis in fish and shellfish cultures leading to high mortalities and economic losses. Bacterial resistance to antibiotics and inefficient vaccination at the larval stage of fish emphasizes the need for novel approaches, and phage therapy for controlling Vibrio pathogens has gained interest in the past few years. In this study, we examined the potential of the broad-host-range phage KVP40 to control four different V. anguillarum strains in Atlantic cod (Gadus morhua L.) and turbot (Scophthalmus maximus L.) larvae. We examined larval mortality and abundance of bacteria and phages. Phage KVP40 was able to reduce and/or delay the mortality of the cod and turbot larvae challenged with V. anguillarum. However, growth of other pathogenic bacteria naturally occurring on the fish eggs prior to our experiment caused mortality of the larvae in the unchallenged control groups. Interestingly, the broad-spectrum phage KVP40 was able to reduce mortality in these groups, compared to the nonchallenge control groups not treated with phage KVP40, demonstrating that the phage could also reduce mortality imposed by the background population of pathogens. Overall, phage-mediated reduction in mortality of cod and turbot larvae in experimental challenge assays with V. anguillarum pathogens suggested that application of broad-host-range phages can reduce Vibrio-induced mortality in turbot and cod larvae, emphasizing that phage therapy is a promising alternative to traditional treatment of vibriosis in marine aquaculture.
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Testing the equality of 2 proportions for a control group versus a treatment group is a well-researched statistical problem. In some settings, there may be strong historical data that allow one to reliably expect that the control proportion is one, or nearly so. While one-sample tests or comparisons to historical controls could be used, neither can rigorously control the type I error rate in the event the true control rate changes. In this work, we propose an unconditional exact test that exploits the historical information while controlling the type I error rate. We sequentially construct a rejection region by first maximizing the rejection region in the space where all controls have an event, subject to the constraint that our type I error rate does not exceed α for any true event rate; then with any remaining α we maximize the additional rejection region in the space where one control avoids the event, and so on. When the true control event rate is one, our test is the most powerful nonrandomized test for all points in the alternative space. When the true control event rate is nearly one, we demonstrate that our test has equal or higher mean power, averaging over the alternative space, than a variety of well-known tests. For the comparison of 4 controls and 4 treated subjects, our proposed test has higher power than all comparator tests. We demonstrate the properties of our proposed test by simulation and use our method to design a malaria vaccine trial.