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Despite their clearly demonstrated safety and effectiveness, approved vaccines against COVID-19 are commonly mistrusted. Nations should find and implement effective ways to boost vaccine confidence. But the implications for ethical vaccine development are less straightforward than some have assumed. Opponents of COVID-19 vaccine challenge trials, in particular, made speculative or empirically implausible warnings on this matter, some of which, if applied consistently, would have ruled out most COVID-19 vaccine trials and many non-pharmaceutical responses., Competing Interests: Competing interests: NE serves on the Advisory Board of challenge trial volunteer organisation 1DaySooner (a non-profit promoting human challenge trials in COVID-19), an unpaid position., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

In many countries, the COVID-19 pandemic varied starkly between different racial and ethnic groups. Before vaccines were approved, some considered assigning priority access to worse-hit racial groups. That debate can inform rationing in future pandemics and in some of the many areas outside COVID-19 that admit of racial health disparities. However, concerns were raised that "race-responsive" prioritizations would be ruled unlawful for allegedly constituting wrongful discrimination. This legal argument relies on an understanding of discrimination law as demanding color-blindness. We argue that a, color-blind understanding of discrimination would be hostile only to one of two rationales for prioritizing the relevant racial minorities in settings of racial health disparities. We also propose a method for incorporating appropriate race-responsive concerns that is in many ways ethically and legally superior to ones suggested thus far. That method turns artificial intelligence, thanks precisely to its artificial and "black box" nature (features that underlie recent concerns about artificial intelligence's discriminatory potential), into an instrument of social justice., (© 2023 The Authors. Bioethics published by John Wiley & Sons Ltd.)

Notwithstanding the success of conventional field trials for vaccines against COVID-19, human challenge trials (HCTs) that could obtain more information about these and about other vaccines and further strategies against it are about to start in the UK. One critique of COVID-19 HCTs is their distinct paucity of information on crucial population groups. For safety reasons, these HCTs will exclude candidate participants of advanced age or with comorbidities that worsen COVID-19, yet a vaccine should (perhaps especially) protect such populations. We turn this cliché on its head. The truth is that either an HCT or a field trial has intrinsic generalisability limitations, that an HCT can expedite protection of high-risk participants even without challenging them with the virus, and that an important route to obtaining results generalisable to high-risk groups under either strategy is facilitated by HCTs., Competing Interests: Competing interests: NE serves on the Board of Advisor of 1DaySooner, an unpaid position., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

In high-income countries that were first to roll out coronavirus disease 2019 (COVID-19) vaccines, older adults have thus far usually been prioritized for these vaccines over younger adults. Age-based priority primarily resulted from interpreting evidence available at the time, which indicated that vaccinating the elderly first would minimize COVID-19 deaths and hospitalizations. The World Health Organization counsels a similar approach for all countries. This paper argues that some low- and middle-income countries that are short of COVID-19 vaccine doses might be justified in revising this approach and instead prioritizing certain younger persons when allocating current vaccines or future variant-specific vaccines., Competing Interests: Potential conflicts of interest. N. E. received payment or honoraria from Oxford University Press and held an unpaid, volunteer position with 1 Day Sooner. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Early into COVID, human challenge trials were considered, but usually as alternatives to conventional randomized controlled trials. Instead, assessment of authorized COVID vaccines, of further COVID vaccines, and of vaccines against future pandemics should combine both designs, in five different ways, including a wholly novel one that we elaborate, Viz., combining data from both designs to answer a single question., (© 2022 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Although vaccines against severe acute respiratory syndrome coronavirus 2 have now been found safe and efficacious, there remains an urgent global health need to test both these vaccines and additional vaccines against the same virus. Under variable conditions, either standard or unusual designs would for both familiar and often-missed reasons make continued testing possible and ethical., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Some HIV remission studies include a treatment interruption that seriously risks infecting participants' sex partners with HIV. What, ethically, is owed to these nonparticipants? Until greater certainty emerges on what protections should be afforded nonparticipants of research studies, what I call a "low-hanging fruit" approach may help researchers and review bodies determine how to address infection risks to nonparticipants in these studies., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

This commentary considers an extreme idea for protecting against human immunodeficiency virus (HIV) transmission to sex partners of individuals participating in HIV remission studies with an analytical treatment interruption (ATI). Other human challenge studies, such as studies of influenza, commonly isolate participants during the trial, to protect their contacts and the community against infection. Why should HIV studies with a treatment interruption be any different, one might wonder? This article concludes that isolation should not be used in HIV remission studies with an ATI but also shows that the matter is complex., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Only a few of the recommendations made in this supplement are implemented in ongoing HIV remission studies that involve an analytical treatment interruption. The absence of these recommendations in protocols puts sexual partners of study participants at serious risk. This paper addresses one possible barrier to implementation: a certain misunderstanding among sponsors and research entities., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

In a Policy Forum, Marc Lipsitch and colleagues discuss trial design issues in infectious disease outbreaks., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: ML has received consulting fees/honoraria from Pfizer, Merck, Affinivax, and Antigen Discovery and research grants from Pfizer and PATH Vaccine Solutions.

During the 2014-2015 Ebola outbreak in Guinea, Liberia and Sierra Leone, many opposed the use of individually randomised controlled trials to test candidate Ebola vaccines. For a raging fatal disease, they explained, it is unethical to relegate some study participants to control arms. In Zika and future emerging infections, similar opposition may hinder urgent vaccine research, so it is best to address these questions now. This article lays out the ethical case for individually randomised control in testing vaccines against many emerging infections, including lethal infections in low-income countries, even when at no point in the trial do the controls receive the countermeasures being tested. When individual randomisation is feasible-and it often will be-it tends to save more lives than alternative designs would. And for emerging infections, individual randomisation also tends as such to improve care, access to the experimental vaccine and prospects for all participants relative to their opportunities absent the trial, and no less than alternative designs would. That obtains even under placebo control and without equipoise-requiring which would undermine individual randomisation and the alternative designs that opponents proffered. Our arguments expound four often-neglected factors: benefits to non-participants, benefits to participants once a trial is over including post-trial access to the study intervention, participants' prospects before randomisation to arms and the near-inevitable disparity between arms in any randomised controlled trial., Competing Interests: Competing interests: ML served on the Scientific Advisory Group for the Ebola ça Suffit vaccine efficacy trial (unpaid position) and has received consulting fees or honoraria from Merck, Pfizer, Antigen Discovery and Affinivax. His research has received funding (through his employer) from Pfizer and PATH Vaccine Solutions., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Unprecedented global effort is under way to facilitate the testing of countermeasures in infectious disease emergencies. Better understanding of the various options for trial design is needed in advance of outbreaks, as is preliminary global agreement on the most suitable designs for the various scenarios. What would enhance the speed, validity, and ethics of clinical studies of such countermeasures? Focusing on studies of vaccine efficacy and effectiveness in emergencies, we highlight three needs: for formal randomized trials-even in most emergencies; for individually randomized trials-even in many emergencies; and for six areas of innovation in trial methodology. These needs should inform current updates of protocols and roadmaps., (Copyright © 2017, American Association for the Advancement of Science.)

A vaccine trial with a conventional challenge design can be very fast once it starts, but it requires a long prior process, in part to grow and standardize challenge virus in the laboratory. This detracts somewhat from its overall promise for accelerated efficacy testing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine candidates, and from the ability of developing countries and small companies to conduct it. We set out to identify a challenge design that avoids this part of the long prior process. Literature in trial design (including a proof of concept flu challenge trial by B. Killingley et al.), vaccinology, medical ethics, and various aspects of COVID response. A challenge design with deliberate natural viral exposure avoids the need to grow culture. This new design is described and compared both to a conventional challenge design and to a conventional phase III field trial. In comparison, the proposed design has ethical, scientific, and feasibility strengths. The proposed new design should be considered for future vaccine trials. [ABSTRACT FROM AUTHOR]

Human challenge trials to test the efficacy of vaccine candidates against SARS‐CoV‐2, the novel coronavirus behind Covid‐19, could save considerable time and many lives. But they may initially seem unethical because they expose healthy volunteers to a live virus that is killing many people and for which no cure exists. This article argues that this is not the correct test of their ethics. The correct test is comparative. And in the special circumstances of the Covid‐19 pandemic, human challenge trials meet the correct test better than standard efficacy testing would. [ABSTRACT FROM AUTHOR]

Controlled human challenge trials of SARS-CoV-2 vaccine candidates could accelerate the testing and potential rollout of efficacious vaccines. By replacing conventional phase 3 testing of vaccine candidates, such trials may subtract many months from the licensure process, making efficacious vaccines available more quickly. Obviously, challenging volunteers with this live virus risks inducing severe disease and possibly even death. However, we argue that such studies, by accelerating vaccine evaluation, could reduce the global burden of coronavirus-related mortality and morbidity. Volunteers in such studies could autonomously authorize the risks to themselves, and their net risk could be acceptable if participants comprise healthy young adults, who are at relatively low risk of serious disease following natural infection, if they have a high baseline risk of natural infection, and if during the trial they receive frequent monitoring and, following any infection, the best available care. [ABSTRACT FROM AUTHOR]

• 'Low-dosage' challenge studies use comparably lower doses per participant. • They have scientific, pragmatic and ethical advantages: they are faster, have safer dose escalation, are a safer challenge, and have fewer type II errors. • Low-dosage challenges are worth considering for COVID-19 challenges and future uses. The design of human challenge studies balances scientific validity, efficiency and study safety. This Perspective explores some advantages and disadvantages of 'low-dosage' challenge studies, in the setting of testing second-generation vaccines against COVID-19. Compared with a conventional vaccine challenge, a low-dosage vaccine challenge would be more likely to start, and start earlier. A low-dosage challenge would also be less likely to rule out a vaccine candidate that would have potentially been effective, particularly in certain target uses. A key ethical advantage of a low-dosage challenge over a conventional challenge is that both it and its dose escalation process are safer for each participant. Low-dosage studies would require larger numbers of participants than conventional challenges, but this and other potential disadvantages are less serious than they may initially appear. Overall, low-dosage challenges should be considered for certain roles such as prioritizing between second-generation vaccines against COVID-19. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]