943635

research-article2020
REA0010.1177/1747016120943635Research EthicsTambornino and Lanzerath

Research Ethics and Covid-19

Research Ethics

COVID-19 human challenge

2020, Vol. 16(3-4) 1–11
© The Author(s) 2020
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https://doi.org/10.1177/1747016120943635
DOI: 10.1177/1747016120943635

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Lisa Tambornino
European Network of Research Ethics Committees, Germany

Dirk Lanzerath
University of Bonn, Germany

Abstract
To reduce the global burden of the COVID-19 pandemic, there is an urgent need to develop
a safe vaccine. Vaccine development usually takes many years as it goes through several
different phases. To hasten COVID-19 vaccine development, it has been suggested that
the final stage could be replaced with a human challenge trial (HCT). Volunteers would
be intentionally infected with SARS-CoV-2 to see how the vaccine candidate works. To
intentionally infect a healthy human being with a potentially deadly virus is contrary to the
highest ethical standards in medical research. This article highlights the benefits and risks of
COVID-19 HCTs and summarises what research ethics committees (RECs) need to consider
during the ethical assessment of such trials including risk reduction, strict containment
measures, specific informed consent measures and avoiding high monetary inducements.

Keywords
COVID-19, human challenge trial, vaccine development, ethical review, research ethics
committees, ethical standards

Corresponding author:
Dirk Lanzerath, University of Bonn, Bonner Talweg 57, Bonn 53113, Germany.
Email: lanzerath@drze.de

Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative
Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which
permits non-commercial use, reproduction and distribution of the work without further permission provided the original work
is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
2 Research Ethics 16(3-4)

Introduction
The COVID-19 pandemic is a major challenge for billions of people and coun-
tries worldwide. Impacts upon health, the economy, society and everyday life
are extreme. The hope of returning to normalcy rests largely upon discovery of
a safe vaccine and/or effective treatments for severe cases of COVID-19.
Although more than 120 vaccine candidates are in development (BBC, 2020), it
could still take a long time until a safe vaccine is discovered and made available.
For the testing the effectiveness of a trial vaccine, vaccinated participants must
come into contact with the disease and usually, this is dependent upon a large
number of research participants having contact with persons who are infected.
However, the statistical chances of being infected with the SARS-CoV-2 virus
are currently very low. Even in countries with high infection rates, only a small
fraction of the population carries the virus and it is likely that most of those
infected are in quarantine, wearing masks or practising social distancing. This
poses a scientific dilemma. Human challenge trials (HCTs) have been posited as
a potential solution to this dilemma.

Human challenge studies involve the intentional infection of research participants and can
accelerate or improve vaccine development by rapidly providing estimates of vaccine safety
and efficacy. Human challenge studies of low virulence coronaviruses have been done in the
past and human challenge studies with severe acute respiratory syndrome coronavirus 2 have
been proposed (Jamrozik and Selgelid, 2020: 1).

The authors of 1Day Sooner a worldwide initiative, set up to find volunteers for
COVID-19 HCTs provide a brief timeline of challenge trials that were instrumen-
tal in the development of vaccines for deadly infectious diseases, for instance
smallpox, cholera and malaria (1Day Sooner, 2020). However, the history and
record of HCTs is not outstanding. Metzger et al. (2019) outline historical aspects
of HCTs. They explain how knowledge about infectious diseases has been gained
through experiments in humans going back to the 18th and 19th centuries.
Numerous fully unacceptable and unethical studies have been conducted in this
endeavour. In addition to the experiments of the Nazi concentration camps, others
include a study (1950–1965), in ‘Willowbrook’ a school for mentally disabled
children in the United States, where children were injected with hepatitis virus to
test passive vaccination. Parents were not truthfully informed about the risks of the
investigations, and children were involved with the prospect of harm rather than
benefit (Metzger et al., 2019: 1386). Furthermore, there is scant reliable informa-
tion available on vaccine HCTs, leading to successfully and extensively applied
vaccines. Taking this into account, the risks and benefits of COVID-19 HCTs need
to be reviewed very carefully.
Tambornino and Lanzerath 3

Human challenge trials and their benefits in

combatting COVID-19
During an HCT, a group of volunteers are intentionally infected with a contagious
agent to determine whether a vaccine candidate is effective or not. For the novel
coronavirus, two groups would be intentionally infected with the virus. First, those
who received the candidate vaccine, and second, those who are in the placebo-
controlled arm of the study. In cases where no vaccine is currently available for a
disease, a placebo-controlled study is considered the only way to obtain reliable
answers on the effectiveness of the candidate vaccine (Rid et al., 2014: 4709). This
approach has two advantages over the method of waiting for a random infection
(Eyal et al., 2020; Jamrozik and Selgelid, 2020; Shah et al., 2020):

(1) Researchers can determine whether a vaccine candidate is effective or not

more quickly, and
(2) a smaller group of participants is needed.

According to 1Day Sooner (2020), one day of speedier vaccine development

would save 7,120 lives. If they are correct, speeding up vaccine development by
three months would save over half a million lives.
The calculations of 1Day Sooner are based on two assumptions, which cannot
be taken for granted. First, the successful vaccine can be manufactured in large
enough numbers to satisfy demand. Second, people are willing to take the vaccine,
which depends largely on the question of how safe it appears and how communi-
cation with the public is handled. We shall leave these two issues aside for the
purpose of this paper.

Human challenge trials for COVID-19 – an overview

of the ethical issues
From an ethical perspective, infecting healthy individuals with a potentially fatal
disease for which there is no treatment is not justifiable. COVID-19 has led to a
large number of deaths worldwide, including unexplained deaths that cannot be
attributed to existing health conditions.1 It is estimated by the UK National Health
Service that of those who needed hospitalisation for COVID-19, 45% will require
additional, potentially long-term care after discharge from hospital; 4% will
require rehabilitation and 1% will require permanent nursing home care (NHS,
2020: 27). Hence, HCT involvement could be very dangerous for research partici-
pants; they could die or suffer permanent damage to lungs, brain or other organs.
This worst-case scenario of permanent damage or death cannot be ignored.
However, COVID-19 infections can also occur with very mild or even without
symptoms. Eyal et al. (2020) state that it may seem impermissible to allow people
4 Research Ethics 16(3-4)

to take the risk of severe, possibly long-term illness or even death, but they note
that such risk-taking is permissible in other life situations. For instance, we do not
stop firefighters from running into burning buildings and relatives are permitted to
donate organs, which could result in their death (Eyal et al., 2020). More impor-
tantly, according to Eyal et al. (2020), volunteers can autonomously give their
informed consent to take these risks. This aligns with the view of Chappell and
Singer (2020: 2), who write:
If it is permissible to expose some members of society (e.g. health workers or the economically
vulnerable) to a certain level of ex ante risk in order to minimize overall harm from the virus,
then it is permissible to expose fully informed volunteers to a comparable level of risk in the
context of promising research into the virus.

The question remains, however, of just how informed consent can be in a COVID-
19 HCT given that knowledge about the novel virus is scarce and constantly
changing. In particular, the long-term effects remain unclear. Therefore, volun-
teers cannot know the full extent of what they are consenting to. The risks of an
intentional infection are unpredictable and risk assessment is challenging. Those
arguing that consent is sufficient for exposing volunteers to a potentially deadly
virus would need to explain precisely how this informed consent will be obtained.
Furthermore, risks are not limited to research volunteers. If research partici-
pants are infected with the highly virulent SARS-CoV-2, they pose a risk to exter-
nals, i.e. those they are in contact with their relatives as well as health care staff
and researchers. However, this is not unique to HCTs; it also applies to other stud-
ies with serious pathogens.

What research ethics committees need to consider

when assessing COVID-19 HCTs
HCTs have been suggested for COVID-19 vaccine development (e.g. Chappell
and Singer, 2020; Eyal et al., 2020), which means that research ethics committees
(RECs) might have to review this kind of research in the near future.
Globally recognised standards and operational guidelines beyond legal require-
ments for ethical reviews are formulated for example in the Declaration of Helsinki
(WMA Declaration of Helsinki, 2013), the Good Clinical Practice Guideline (ICH
Topic E 8, 1998) and in the CIOMS guidelines (Council for International
Organizations of Medical Sciences (CIOMS), 2016). With these and other docu-
ments, such as institutional or national standards, RECs would have to decide
whether research proposals for COVID-19 HCTs should be rejected, or whether
special requirements can be formulated under which they can be conducted in an
ethically sound way.
Tambornino and Lanzerath 5

On the one hand, the accelerated development of a safe vaccine could lead to
benefits like significantly fewer COVID-19 deaths, and significantly lower social
and economic burdens globally. On the other hand, the risks to research partici-
pants are uncertain with a possibility of being extremely grievous, plus additional
risks might be encountered by third parties (e.g. relatives of research participants,
health care workers or researchers). This divergence between very high potential
benefits for society and very high potential risks to research participants/third par-
ties makes the ethical review of COVID-19 HCTs extremely challenging. Three
essential points must be addressed:

•• Minimising risks
•• Appropriate informed consent
•• Avoiding high monetary inducements

Minimising risks
Three groups have to be considered when minimising risks. First, the research
participants who receive an active vaccine candidate, second, the research partici-
pants who receive a placebo and third, all third parties who are in direct contact
with the first two groups.
The three main physiological risks for the vaccine group are side-effects of a
candidate vaccine, infection with COVID-19 and vaccine-enhanced COVID-19.2
The placebo group will not suffer from side-effects or vaccine-enhanced COVID-
19, since they will not receive the vaccine candidate. However, they will be
infected with SARS-CoV-2 and therefore, the chances are high that they will
develop some form of COVID-19. What this infection means for each research
participant remains unclear with possibilities ranging from no symptoms at all to
death. Finally, there is a third group that is at risk of contracting COVID-19 from
direct contact with research participants.
To reduce risks to third parties associated with the research participants, RECs
can consider restricting studies to inpatient settings for the time during which virus
transmission can occur (Jamrozik and Selgelid, 2020). In this case, it would be
important to ensure that early withdrawal from a study and leaving the inpatient
unit does not create risks for third parties. In addition, RECs must insist on full
protective equipment for health care workers and researchers.
To minimise risks for both groups of research participants, there are at least
three strategies that RECs need to be aware of:

1) Inclusion and exclusion criteria must be stipulated such that only partici-
pants who belong to a low-risk group can be included.
2) Measures could be taken to infect volunteers with an attenuated3 challenge
strain or a low viral load, which might reduce overall risks.
6 Research Ethics 16(3-4)

3) Early diagnosis and access to immediate high-quality medical care could

reduce risks further.

In addition, compensation for harm incurred during a study must be available for
all research participants.

Include only participants that belong to a low-risk group.  Experiences during the pan-
demic and early research studies have shown that older people, and people of all
ages with pre-existing medical conditions (such as diabetes, high blood pressure,
heart disease, obesity, lung disease or cancer) appear to develop serious symptoms
more often than others (World Health Organization (WHO), 2020a). It has also
been shown that the vast majority of young persons, without previous illnesses,
who are infected with COVID-19, develop no or only weak symptoms of the dis-
ease (Bialek et al., 2020). Early estimates of infection fatality risk in 20- to 29-year-
olds set it at 0.007–0.031% (Jamrozik and Selgelid, 2020). Hence, young people,
without health issues or background conditions, seem best suited to be involved in
HCTs. However, given that research into COVID-19 is still in its infancy, many
features of the disease are not fully understood, and it is currently not possible to
define a low-risk group with certainty. Unexplained cases of young, healthy peo-
ple dying from COVID-19, while rare, have been reported (Proto, 2020). At the
time of writing this paper, there is insufficient evidence to draw firm conclusions
about why some groups are symptom-free and others are not. Research findings
from studies of low-risk groups must be monitored to ensure that discovered risk
factors for seemingly young and healthy people are immediately accounted for
with regard to exclusion and inclusion criteria. Importantly, potential volunteers
must undergo thorough health checks before inclusion in an HCT.
At the same time, this approach has inherent weaknesses. Even if a vaccine is
shown to effective in one age group, it cannot be guaranteed that this vaccine will
be effective in all other age groups (Bialek et al., 2020). Hence, a stepped approach
would be needed to test the vaccine candidate, which proved effective in young
volunteers, in other age groups.

Consider lower risk trials.  There are two main ways of lowering risks in HCTs that can
be built into the design. First, attenuated, weakened strains of SARS-CoV-2 could be
developed and used in the HCT. Second, HCT volunteers could be infected with low
viral loads. Developing attenuated challenge strains is highly time-intensive (Jamro-
zik and Selgelid, 2020) and could invalidate the reason for running HCTs in the first
place. Hence, they are not given further consideration here. Alternatively, volunteers
could be exposed to such a small dose of the virus that they are unlikely to get ill or
only develop mild symptoms (as has been demonstrated in an influenza HCT by
Sherman (2019). The WHO recommends that initial challenges should be ‘con-
ducted one by one, with careful titration of viral dose’ (World Health Organization
Tambornino and Lanzerath 7

(WHO), 2020b: 8). To help minimise risks, close monitoring of the viral load and
related symptoms in the very first participants is required. Subsequent participants
can only proceed when there is sufficient confidence that the infection in the previ-
ous participants will gradually subside without unexpected or unacceptable adverse
events. Only when more is known about the pathophysiology of viral infection might
it be appropriate to proceed more expediently (World Health Organization (WHO),
2020b). However, there are two problems with this approach: First, it remains scien-
tifically unproven that a small SARS-CoV-2 viral load will cause only mild COVID-
19 symptoms (Caddy, 2020; Jones et al., 2020; Yu et al., 2020). Second, a high viral
load might be necessary to find out whether a vaccine candidate is fully effective.
Hence, whilst this approach will reduce risks to research participants, it might also
reduce the possibility of accelerating effective vaccine design, the main reason for
considering HCTs in the first place.

Access to early diagnosis and immediate high-quality medical care. Drugs for the
treatment of COVID-19 are being tested in clinical studies worldwide. The anti-
inflammatory drug Dexamethasone, the virus inhibitor Remdesivir and the can-
cer drug Ruxolitinib appear to be promising (European Medicines Agency
(EMA), 2020; Horby et al., 2020; Neubauer et al., 2020; Vfa. Die forschenden
Pharma-Unternehmen, 2020). They have shown, in individual cases, that the
treatment phase could be shortened, but there is currently still no cure in sight that
can preclude severe and/or fatal consequences for all. Nevertheless, immediate
access to diagnosis and high-quality medical care for all involved in the HCT is
likely to contribute to risk reduction. This being the case, HCT studies should be
undertaken predominantly in high-income countries and not in resource-poor set-
tings, where facilities are urgently needed for clinical care.

Appropriate informed consent

To date, more than 30,000 people have registered as volunteers for COVID-19
HCTs on 1Day Sooner. However, it is unlikely that all understand fully what they
volunteered for. HCT volunteers should receive a very detailed description of risks
that is fully up-to-date with current scientific knowledge. At present, this would
include these four essential points:

1) The long-term effects of a COVID-19 infection remain unclear.

2) COVID-19 infection can be fatal.
3) Research participants need to fully disclose their medical history to deter-
mine their risk exposure.
4) Research participants may not be able to withdraw immediately from a
study that is set in an inpatient setting.
8 Research Ethics 16(3-4)

Methods to evidence that potential research participants fully understand these

four points need to be developed by the researchers and reviewed by the RECs.

Avoiding high monetary inducements

Setting COVID-19 HCTs in high-income settings with high-quality inpatient med-
ical care facilities reduces the concern of undue inducement. However, it is essen-
tial that payments for time spent in the inpatient facility (if chosen) do not exceed
coverage for time lost (Gelinas et al., 2018; Grady, 2019; Resnik, 2015). Given the
uncertainty of risks, monetary incentives must be excluded. Otherwise, vulnerable
people will put themselves at risk for money.

Public engagement
In their ethical assessment of COVID-19 HCTs, Jamrozik and Selgelid (2020)
attribute high priority to public opinion and commitment of the community in
which such studies are to be conducted. This is to promote transparency but also
public acceptability. However, such an approach should be handled very carefully
from the perspective of ethics committees. As much as RECs are seen as interme-
diary bodies between science and society, for HCTs, they must focus on the pro-
tection of the healthy volunteers. Against the backdrop of a pandemic crisis, public
pressure is not always the best guide for well-considered ethical decisions. Public
majority opinion is important for societal discourse but cannot suffice as justifica-
tion for favourable opinion of an HCT by a REC.

Conclusion
In theory, COVID-19 HCTs could accelerate vaccine development when com-
pared with standard vaccine field trials. Furthermore, highly effective, traditional
public health measures (e.g. social distancing, masks, quarantine) pose a chal-
lenge for standard vaccine field trials as the numbers of participants needed would
be unfeasibly high. COVID-19 is a pandemic with gigantic health, social and
economic costs and delivering a vaccine earlier could yield significant societal
benefit. However, this cannot be done at any cost. The quest for a vaccine must
comply with established standards in research ethics, in particular, the principle
of do no harm.
It is often a challenge for RECs to decide whether the benefits of a medical trial
can justify the risks and whether the risks to research participants are acceptable.
However, even in the context of the most challenging REC work, the prospect of
COVID-19 HCTs stands out. Healthy volunteers are to be intentionally infected
with a potentially lethal agent for which no known treatment is available, also pos-
ing potential risks to third parties.
Tambornino and Lanzerath 9

The Council of Europe advises that a REC must be convinced that the participa-
tion of healthy volunteers in a research project does not lead to unacceptable risks
and burdens for the participants (Council of Europe, 2012: 6.C.4; Council for
International Organizations of Medical Sciences (CIOMS), 2016: 10). Given the
gaps in scientific understanding of COVID-19, at the time of writing this paper there
is no assured way of reducing the risks for participants appropriately. Consequently,
COVID-19 HCTs cannot currently be conducted in an ethically sound manner.
However, this might change in the light of new research and new risk minimising
options. The considerations of RECs should be guided by three aspects: the possibil-
ity of reducing risks through very specific inclusion/exclusion criteria; the consid-
eration of alternative study designs; and ensuring that the study is located in and
environment where there is immediate access to high-quality health care, preferably
in a high-income setting, where it does not constitute a drain on medical resources.

Acknowledgements
Thanks to Prof. Doris Schroeder and Dr Kate Chatfield for editorial input and reviewer com-
ments. Also, thanks to the members of the European Network of Research Ethics Committees
for sharing their views on HCTs; in particular, to Prof. Dr. Joerg Hasford.

Funding
All articles in Research Ethics are published as open access. There are no submission charges
and no Article Processing Charges as these are fully funded by institutions through Knowledge
Unlatched, resulting in no direct charge to authors. For more information about Knowledge
Unlatched please see here: http://www.knowledgeunlatched.org

ORCID iD
Dirk Lanzerath https://orcid.org/0000-0003-0652-8829

Notes
1. An analysis of figures from the National Health Service in the UK has shown that about
5% of patients who die from COVID-19 have no underlying health conditions (Duncan,
2020).
2. It has been shown that some vaccine research has worsened the severity of the disease
upon later infection. Hence, without the vaccine, the research participant would have had
a milder version of the disease (Jamrozik and Selgelid, 2020). It is unclear whether this
can happen with COVID-19, but it cannot be excluded.
3. An attenuated challenge strain is weaker and less virulent than the original strain.
Attenuated viruses can stimulate an immune response and create immunity, without caus-
ing illness.

References
1Day Sooner (2020) Available at: https://1daysooner.org/ (accessed 25 May 2020).
BBC (2020) Coronavirus: human trial of new vaccine begins in UK, 24 June 2020. Available
at: https://www.bbc.com/news/health-53061288 (accessed 26 June 2020).
10 Research Ethics 16(3-4)

Bialek S, Gierke R, Hughes M, et al. (2020) Coronavirus disease 2019 in children — United
States, February 12–April 2, 2020. Morbidity and Mortality Weekly Report 69(14): 422–426.
Caddy SL (2020) Coronavirus: does the amount of virus you are exposed to determine how
sick you’ll get? The Conversation, 7 April. Available at: https://theconversation.com/
coronavirus-does-the-amount-of-virus-you-are-exposed-to-determine-how-sick-youll-
get-135119 (accessed 26 June 2020).
Chappell RY and Singer P (2020) Pandemic ethics: the case for risky research. Research
Ethics. Epub ahead of print 2 June 2020. DOI: 10.1177%2F1747016120931920.
Council for International Organizations of Medical Sciences (CIOMS) (2016) International
ethical guidelines for health-related research involving humans. 4th edn. Available at:
https://cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf
(accessed 16 June 2020).
Council of Europe (2012) Guide for Research Ethics Committee Members. Steering Committee
on Bioethics. Available at: https://rm.coe.int/CoERMPublicCommonSearchServices/Disp
layDCTMContent?documentId=0900001680307e6c (accessed 27 June 2020).
Duncan P (2020) No underlying conditions in 5% of coronavirus deaths in English hospitals.
The Guardian, 17 April. Available at: https://www.theguardian.com/society/2020/apr/17/
no-underlying-conditions-coronavirus-deaths-english-hospitals (accessed 26 June 2020).
European Medicines Agency (EMA) (2020) Treatments and vaccines for COVID-19. Available
at: https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coro-
navirus-disease-covid-19/treatments-vaccines-covid-19 (accessed 26 June 2020).
Eyal N, Lipsitch M and Smith PG (2020) Human challenge studies to accelerate coronavirus
vaccine licensure. The Journal of Infectious Diseases 221(11): 1752–1756. DOI: 10.1093/
infdis/jiaa152.
Gelinas L, Largent EA, Cohen IG, et al. (2018) A framework for ethical payment to research
participants. The New England Journal of Medicine 378(8): 766–771. DOI: 10.1056/
NEJMsb1710591.
Grady C (2019) The continued complexities of paying research participants. The American
Journal of Bioethics 19(9): 5–7, DOI: 10.1080/15265161.2019.1643654
Horb P, Lim WS, Emberson J, et al. (2020) RECOVERY Collaborative Group, Effect of
Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report. medRxiv.
Epub ahead of print 22 June 2020. DOI: 10.1101/2020.06.22.20137273.
ICH Topic E 8 (1998) General considerations for clinical trials. Available at: https://www.
ema.europa.eu/en/documents/scientific-guideline/ich-e-8-general-considerations-clinical-
trials-step-5_en.pdf (accessed 16 June 2020).
Jamrozik E and Selgelid MJ (2020) COVID-19 human challenge studies: ethical issues. The
Lancet Infectious Diseases. Epub ahead of print 29 May 2020. DOI: 10.1016/.
Jones T, Mühlemann B, Veith T, et al. (2020) An analysis of COVID-19 viral load by patient
age. Available at: https://virologie-ccm.charite.de/fileadmin/user_upload/microsites/m_
cc05/virologie-ccm/dateien_upload/Weitere_Dateien/analysis-of-COVID-19-viral-load-
by-patient-age-v2.pdf (accessed 23 June 2020).
Metzger WG, Ehni HJ, Kremsner PG, et al. (2019) Experimental infections in humans — his-
torical and ethical reflections. Tropical Medicine and International Health 24(12): 1384–
1390. DOI: 10.1111/tmi.13320.
Neubauer A, Wiesmann T, Vogelmeier CF, et al. (2020) Ruxolitinib for the treatment of
COVID-19 induced acute respiratory distress syndrome (ARDS). Leukemia. Epub ahead
of print 17 June 2020. DOI: 10.1038/s41375-020-0907-9.
Tambornino and Lanzerath 11

NHS (2020) COVID-19 hospital discharge service requirements. Available at: https://
assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/
file/880288/COVID-19_hospital_discharge_service_requirements.pdf (accessed 26 June
2020).
Proto (2020) Why do young, healthy people die from COVID-19? Available at: http://pro-
tomag.com/articles/why-do-young-healthy-people-die-covid-19 (accessed 27 June 2020).
Resnik D (2015) Bioethical issues in providing financial incentives to research participants.
Medicolegal and Bioethics 5: 35–41. DOI: 10.2147/MB.S70416
Rid A, Saxena A, Baqui AH, et al. (2014) Placebo use in vaccine trials: recommendations of a
WHO expert panel. Vaccine 32(37): 4708–4712. DOI: 10.1016%2Fj.vaccine.2014.04.022.
Shah SK, Miller FG, Darton TC, et al. (2020) Ethics of controlled human infection to address
COVID-19. Science 368(6493): 832–834. DOI: 10.1126/science.abc1076.
Sherman AC (2019) The future of flu: a review of the human challenge model and systems
biology for advancement of influenza vaccinology. Frontiers in Cellular and Infection
Microbiology 9: 107. Epub ahead of print 17 April 2019. DOI: 10.3389/fcimb.2019.00107.
Vfa. Die forschenden Pharma-Unternehmen (2020) Therapeutic medicines against the coro-
navirus infection Covid-19, 7 April 2020. Available at: https://www.vfa.de/de/englische-
inhalte/therapeutic-medicines-coronavirus-covid-19 (accessed 23 June 2020).
WMA Declaration of Helsinki (2013) Ethical principles for medical research involving
human subjects. Available at: https://www.wma.net/policies-post/wma-declaration-of-
helsinki-ethical-principles-for-medical-research-involving-human-subjects (accessed 16
June 2020).
World Health Organization (WHO) (2020a) Q&A: older people and COVID-19. Available at:
https://www.who.int/news-room/q-a-detail/q-a-on-on-covid-19-for-older-people (accessed
16 June 2020).
World Health Organization (WHO) (2020b) Key criteria for the ethical acceptability of
COVID-19 human challenge studies. WHO reference number: WHO/2019-nCoV/Ethics_
criteria/2020.1. Available at: https://apps.who.int/iris/bitstream/handle/10665/331976/
WHO-2019-nCoV-Ethics_criteria-2020.1-eng.pdf?ua=1 (accessed 27 June 2020).
Yu X, Sun S, Shi Y, et al. (2020) COVID-19 viral load in sputum correlates with risk of
COVID-19 progression. Critical Care 24(170). DOI: 10.1186/s13054-020-02893-8.