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Not in my backyard: COVID‐19 vaccine development requires someone to be infected somewhere

Authors:
MJA 2021
1
Perspective
Not in my backyard: COVID-19 vaccine
development requires someone to be infected
somewhere
We must consider how we can support communities hosting vaccine efficacy trials
Since the beginning of the coronavirus disease
2019 (COVID-19) pandemic, Australia has pursued
a strategy of “aggressive suppression”,1 or the
attempt to maintain the number of incident infections
as low as possible through diagnostic testing, contact
tracing, quarantine, and societal shutdowns. This
choice places Australia among a small group of
wealthy island communities (notably, New Zealand,
Hong Kong, Singapore and Taiwan) attempting to
avoid the consequences of the large waves of infection
seen in other parts of the world. As a strategy,
epidemic suppression is not itself a complete solution
to COVID-19, but instead an epidemiological gambit,
employed while waiting for the development of a safe
and effective vaccine.2
At the time of writing (August 2020), none of the
more than 100 severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) vaccines under
development3 have demonstrated efficacy against
SARS-CoV-2 infection in humans. Seven registered
phase 3 field trials of four candidate vaccines are
currently recruiting participants in the United States,
the United Kingdom, Brazil, Indonesia, Bahrain, the
United Arab Emirates and South Africa.4 The only
mechanism by which these trials can demonstrate
the efficacy of a vaccine in the prevention or
modification of COVID-19 is through the infection of
trial participants and members of their surrounding
communities. Wealthy countries successfully
suppressing COVID-19 are therefore reliant on
infections and morbidity occurring
elsewhere to deliver an effective
vaccine. The risks and obligations
of this strategy must be carefully
considered.
Where and when can vaccine
trials be conducted for epidemic
diseases?
Unlike trials of therapies for non-
communicable diseases or vaccines
against endemic diseases, the event
rate (here the incidence of SARS-
CoV-2 infection) in trials conducted
during epidemics is unstable, subject
to public health policy, and difficult
to predict. Box 1 provides an
illustration of the consequences of
various public health strategies and
the timing of trial commencement
relative to the time of peak epidemic
transmission. In brief, vaccine
trials only accrue events during
periods of active transmission, which can be slowed or
stopped by either transmission control measures or the
depletion of susceptible members of the population.
Aggressive epidemic suppression may render local
vaccine efficacy trials infeasible due to low average
daily incidence. In contrast, rapid epidemics offer
the opportunity for rapid demonstration of vaccine
efficacy but delays to trial commencement can result
in trial failure due to declining incidence of infection.
Delays also erode the benefit of an effective vaccine
for the population hosting a vaccine trial due to the
accumulated prevalence of (initial) infection.
How many people must be infected for a vaccine
trial?
Due to the large effect sizes seen in vaccine trials,
the required number of infections occurring among
trial participants for the demonstration of efficacy is
relatively small. Larger trials require lower incidence
of infection. However, where a vaccine trial enrols a
random sample of an epidemiologically contiguous
population, the incidence of infection in the general
population will match the required incidence among
the trial participants (Supporting Information). Box 2
presents the minimum number of infections required
in a population the size of the Australian state of
Victoria5 to achieve 90% statistical power with an α
error of 5% and a minimum desirable vaccine efficacy
of 30%.6 Curves in the figure present estimates relating
1 Monash U niversit y,
Melbourne, VIC.
2 Monash Bioethics
Centr e,Monas h
University,
Melbourne, VIC.
3 Wellcome Centre
for Ethi cs and the
Humani ties,Ethox
Centr e,Universit y
of Oxf ord, Oxfo rd,
United Kingdom.
george.heriot@
monash.edu
doi: 10.5694/mja2.50930
George S Herio t1
Euzebiusz
Jamrozik2,3
1 The consequence of the incidence of infection during an epidemic on the
duration of vaccine efficacy trials. Equal shaded areas represent the
number of population infections required for the demonstration of
vaccine efficacy for trials commencing during suppression, before peak
transmission, and after peak transmission
2
Perspective
MJA 2021
2
to the vaccine efficacy of three established vaccines7,8
and also the World Health Organization minimum
standard for a SARS-CoV-2 vaccine.9
Demonstration of the efficacy of an inactivated or
component SARS-CoV-2 vaccine in a Victorian-
sized population is likely to require at least as many
infections during the trial period as have occurred
to date in Victoria (18822 at the time of writing),10
unless the trial were substantially larger than any
currently recruiting. Moreover, trials conducted in
larger communities would be accompanied by a
correspondingly larger number of infections because
the number of population infections is a function of
the proportional incidence in the trial.
These estimates represent the minimum number
of infections, as incomplete event ascertainment
(ie, insensitive or missed diagnostic testing of trial
participants), losses to follow-up, and delays to data
availability or analysis (during which infections
continue to accumulate) will all serve to increase the
number of infections occurring in the population
before the completion of the trial. These inefficiencies
result in a much larger number of these infections
occurring before trial reporting in settings with rapid
disease transmission or large numbers of infectious
individuals due to the momentum of the epidemic.
The restriction of trial enrolment to health care
workers or other groups whose incidence of infection
exceeds that of the population may serve to reduce the
required contemporaneous population infections but
would require recruiting thousands of participants
within these groups. Moreover, as health care settings
become better equipped and organised to minimise
transmission, vaccine efficacy trials with health care
workers become less feasible. Trials conducted in
quarantined subpopulations with more rapid epidemic
growth (eg, workers dormitories in Singapore) might
be considered ethically problematic, although such
strategies are analogous to the general reliance of low
incidence populations on vaccines developed in high
incidence populations.
Relying on other populations for vaccine
development
A public health strategy that aims to prevent local
infections while waiting for an efficacious vaccine
is inescapably reliant on infectious morbidity and
mortality occurring in other populations. From a
narrow perspective, this strategy could be seen as
ideal in that it minimises the local consequence of
disease before a vaccine becomes available. However,
this isolationist strategy also involves risks: trial
failures may lead to long vaccine development delays
(and extension of suppressive measures and border
closures), vaccine manufacturers may prioritise
distribution to countries involved in trials, and the
global public may object to the perceived exploitation
of already burdened populations by isolationist
holdouts.
For obvious reasons, all registered phase 3 vaccine
trials actively recruiting at the time of writing are
being conducted in countries with substantial ongoing
disease transmission. If experimental vaccines prove
efficacious, participation in these trials may be
beneficial to at least some trial participants. Even so,
the conduct of trials in these locations can be seen
as exploitative on a global level, as the burdens of
research are confined to populations hosting the trials
yet the benefits of an effective vaccine will largely
2 Infectious cost of coronavirus disease 2019 (COVID-19) vaccine trials
UAE=United Arab Emirates; UK=United Kingdom; US=United States; VE=vaccine efficac y; WHO=World Health Organization. *Total
participants are t he group size multiplied by the number of groups.
MJA 2021
3
Perspective
MJA 2021
3
flow elsewhere, particularly to countries successfully
maintaining suppression, such as Australia. Moreover,
if higher levels of herd immunity are reached in
countries after large epidemics during which trials
are conducted, little to no post-trial benefit from host
community vaccination will remain.11
Finally, should the first round of overseas vaccine
trials fail (due to lack of efficacy, safety concerns, or
insufficient infections in trial participants) while the
COVID-19 pandemic continues to evolve, Australia
risks being left marooned with a highly susceptible
population behind closed borders. In the worst-case
scenario, a rapid decline in infection rates elsewhere
may leave few locations able to successfully conduct
vaccine efficacy trials (as was seen with trials for the
Zika virus vaccine late in the 2015–2016 epidemic)12
and be associated with declining global motivation to
make the attempt. In such a situation, Australia would
have little choice but to swallow the sunk economic
and social costs of a suppression strategy and accept
the necessary infectious morbidity associated with
local vaccine efficacy testing.
An important alternative strategy is the use of
human challenge studies, in which volunteers
would be infected with SARS-CoV-2 after being
given experimental vaccines.13 These studies remain
controversial and Australia has not yet developed
facilities with relevant experience in respiratory
viral challenge. Controlled infection of quarantined
participants means that challenge studies can be
conducted during tight suppression without causing
infections in the surrounding community and can be
conducted with a small number of participants (eg,
74 total participants for a vaccine with 69% vaccine
efficacy assuming 90% successful inoculation). As
demonstrating vaccine efficacy requires someone to
be infected somewhere, it is arguable that challenge
studies should not be viewed as an option of last
resort, but instead as an option available to nations
with candidate vaccines but few active infections.
Conclusions
Demonstrating efficacy of a COVID-19 vaccine
requires trial participants and members of their
surrounding community to acquire infection in
numbers currently deemed unacceptable in countries
opting for epidemic suppression. Unless a change
in strategy occurs, these countries will remain
dependent on trials being performed in other
populations whose potential benefit from vaccination
is progressively diminishing. The unpredictability
of trial outcomes and the progress of the pandemic
elsewhere mean that this strategy is not only
potentially exploitative but also uncertain.
Island nations relying on other communities to resolve
this emergent occasion should acknowledge that
every COVID-19 death diminishes us, and reflect on
the obligations owed to, and not just by,14 populations
in which vaccine trials are being conducted. Recent
additional contributions to the Coalition for Epidemic
Preparedness Innovation15 are a welcome start, but we
must also consider how we can support communities
hosting vaccine efficacy trials, and what we are
prepared to contribute to the search for an effective
vaccine.
Competing interests: No relevant disclosures.
Provenance: Not commissione d; externally peer reviewed.
The unedited versio n of this artic le was published as a prepr int on mja.
com.au on 21 Oc tober 2020.
© 2021 AMP Co Pty Ltd
References are available online.
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Perspective
MJA 2021
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... Second, Australia's national strategy of so-called aggressive suppression involved the early application of strict lockdown restrictions when community transmission was observed. 13,14 As a consequence, the nexus between the introduction of lockdowns and very high community rates of COVID-19 cases was weaker in Australia than in most other countries. The third reason is the geographical specificity of the lockdown. ...
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Background Many studies have examined population mental health during the COVID-19 pandemic but have been unable to isolate the direct effect of lockdowns. The aim of this study was to examine changes in the mental health of Australians aged 15 years and older during the COVID-19 pandemic using a quasi-experimental design to disentangle the lockdown effect. Methods We analysed data from ten annual waves (2011–20) of the longitudinal Household, Income and Labour Dynamics in Australia (HILDA) Survey to identify changes in the mental health of respondents from the pre-COVID-19 period (2011–19) to the COVID-19 period (2020). Difference-in-differences models were used to compare these changes between respondents in the state of Victoria who were exposed to lockdown at the time of the 2020 interviews (treatment group) and respondents living elsewhere in Australia (who were living relatively free of restrictions; control group). The models included state, year (survey wave), and person-specific fixed effects. Mental health was assessed using the five-item Mental Health Inventory (MHI-5), which was included in the self-complete questionnaire administered during the survey. Findings The analysis sample comprised 151 583 observations obtained from 20 839 individuals from 2011 to 2020. The treatment group included 3568 individuals with a total of 37 578 observations (34 010 in the pre-COVID-19 and 3568 in the COVID-19 period), and the control group included 17 271 individuals with 114 005 observations (102 867 in the pre-COVID-19 and 11 138 in the COVID-19 period). Mean MHI-5 scores did not differ between the treatment group (72·9 points [95% CI 72·8–73·2]) and control group (73·2 points [73·1–73·3]) in the pre-COVID-19 period. In the COVID-19 period, decreased mean scores were seen in both the treatment group (69·6 points [69·0–70·2]) and control group (70·8 points [70·5–71·2]). Difference-in-differences estimation showed a small but statistically significant effect of lockdown on MHI-5 scores, with greater decline for residents of Victoria in 2020 than for those in the rest of Australia (difference –1·4 points [95% CI –1·7 to –1·2]). Stratified analyses showed that this lockdown effect was larger for females (−2·2 points [–2·6 to –1·7]) than for males (−0·6 [–0·8 to –0·5]), and even larger for women in couples with children younger than 15 years (−4·4 points [–5·0 to –3·8]), and for females who lived in flats or apartments (−4·1 points [–5·4 to –2·8]) or semi-detached houses, terraced houses, or townhouses (−4·8 points [–6·4 to –3·2]). Interpretation The imposition of lockdowns was associated with a modest negative change in overall population mental health. The results suggest that the mental health effects of lockdowns differ by population subgroups and for some might have exaggerated existing inequalities in mental health. Although lockdowns have been an important public health tool in suppressing community transmission of COVID-19, more research is needed into the potential psychosocial impacts of such interventions to inform their future use. Funding US National Institutes of Health.
... However, because VED does not occur until a person is exposed to a subsequent infection, which might occur only in late phase research and/or after a considerable time has passed since vaccination. VED can therefore remain a safety concern and area of uncertainty during phase III (efficacy) testing, which necessarily involves participants being exposed to infection with the pathogen in question 45 . Safety concerns about VED may also remain relevant (or be first identified) in post-licensure surveillance, as demonstrated in the case studies of measles and dengue. ...
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Vaccination is a cornerstone of global public health. Although licensed vaccines are generally extremely safe, both experimental and licensed vaccines are sometimes associated with rare serious adverse events. Vaccine-enhanced disease (VED) is a type of adverse event in which disease severity is increased when a person who has received the vaccine is later infected with the relevant pathogen. VED can occur during research with experimental vaccines and/or after vaccine licensure, sometimes months or years after a person receives a vaccine. Both research ethics and public health policy should therefore address the potential for disease enhancement. Significant VED has occurred in humans with vaccines for four pathogens: measles virus, respiratory syncytial virus, Staphylococcus aureus, and dengue virus; it has also occurred in veterinary research and in animal studies of human coronavirus vaccines. Some of the immunological mechanisms involved are now well-described, but VED overall remains difficult to predict with certainty, including during public health implementation of novel vaccines. This paper summarises the four known cases in humans and explores key ethical implications. Although rare, VED has important ethical implications because it can cause serious harm, including death, and such harms can undermine vaccine confidence more generally – leading to larger public health problems. The possibility of VED remains an important challenge for current and future vaccine development and deployment. We conclude this paper by summarising approaches to the reduction of risks and uncertainties related to VED, and the promotion of public trust in vaccines.
... Second, either a low-dosage challenge or a conventional challenge study should be deemed cumulatively safe enough for study cohorts, insofar as their cumulative risk is on a par with that of vaccine field trials, which are widely accepted. In particular, vaccine field trials vaccinate >100 times more participants than conventional challenge studies, and require more viral exposures (Heriot and Jamrozik, 2020). Further, vaccine field trials include risks of other adverse events from vaccine side-effects and from increased risk behavior. ...
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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 to a conventional vaccine challenge, a low-dosage vaccine challenge would be likelier to start, and start earlier. A low-dosage challenge would also be less likely to rule out a vaccine candidate which would have been potentially effective in target usage. A key ethical advantage of a low-dosage challenge over conventional challenge is that both it and its dose escalation process are safer for each participant. Low-dosage studies usually 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.
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The global response to the recent coronavirus pandemic has revealed an ethical crisis in public health. This article analyses key pandemic public health policies in light of widely accepted ethical principles: the need for evidence, the least restrictive/harmful alternative, proportionality, equity, reciprocity, due legal process, and transparency. Many policies would be considered unacceptable according to pre-pandemic norms of public health ethics. There are thus significant opportunities to develop more ethical responses to future pandemics. This paper serves as the introduction to this Special Issue of Monash Bioethics Review and provides background for the other articles in this collection.
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During the Covid-19 pandemic, ethicists and researchers proposed human challenge studies as a way to speed development of a vaccine that could prevent disease and end the global public health crisis. The risks to healthy volunteers of being deliberately infected with a deadly and novel pathogen were not low, but the benefits could have been immense. This essay is a history of the three major efforts to set up a challenge model and run challenge studies in 2020 and 2021. The pharmaceutical company Johnson and Johnson, the National Institutes of Health in the United States, and a private-public partnership of industry, university, and government partners in Britain all undertook preparations. The United Kingdom’s consortium began their Human Challenge Programme in March of 2021. Beyond documenting each effort, the essay puts these scientific and ethical debates in dialogue with the social, epidemiological, and institutional conditions of the pandemic as well as the commercial, intellectual, and political systems in which medical research and Covid-19 challenge studies operated. It shows how different institutions understood risk, benefit, and social value depending on their specific contexts. Ultimately the example of Covid-19 challenge studies highlights the constructedness of such assessments and reveals the utility of deconstructing them retrospectively so as to better understand the interplay of medical research and research ethics with larger social systems and historical contexts.
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COVID-19 poses an extraordinary threat to global public health and an effective vaccine could provide a key means of overcoming this crisis. 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. These studies of coronaviruses could provide considerable benefits to public health; for instance, by improving and accelerating vaccine development. However, human challenge studies of severe acute respiratory syndrome coronavirus 2 in particular might be controversial, in part, for ethical reasons. The ethical issues raised by such studies thus warrant early consideration involving, for example, broad consultation with the community. This Personal View provides preliminary analyses of relevant ethical considerations regarding human challenge studies of severe acute respiratory syndrome coronavirus 2, including the potential benefits to public health and to participants, the risks and uncertainty for participants, and the third-party risks (ie, to research staff and the wider community). We argue that these human challenge studies can reasonably be considered ethically acceptable insofar as such studies are accepted internationally and by the communities in which they are done, can realistically be expected to accelerate or improve vaccine development, have considerable potential to directly benefit participants, are designed to limit and minimise risks to participants, and are done with strict infection control measures to limit and reduce third-party risks.
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We analyzed the effects of the timing of vaccine distribution in 11 U.S. states during the 2009 H1N1 influenza pandemic. By using reported data on the fraction of patients presenting with flu-related symptoms, we developed a transformation that allowed estimation of the state-specific temporal flu wave curve, representing the number of new infections during each week. We also utilized data describing the weekly numbers of vaccine doses delivered and administered. By using a simple difference equations model of flu progression, we developed two influenza wave curves: first, an "observable" curve that included the beneficial effects of vaccinations, and second, an unobservable curve that depicted how the flu would have progressed with no vaccine administered. We fit the observable curve to match the estimated epidemic curve and early exponential growth associated with R0, the reproductive number. By comparing the number of infections in each scenario, we estimated the infections averted by the administration of vaccine. Southern states experienced peak infection several weeks before northern states, and most of the vaccine was delivered well after the peak of the southern flu wave. Our models suggest that the vaccine had minimal ameliorative impact in the southern states and measurable positive impact in the northern states. Vaccine delivery after peak also results in a smaller fraction of the population's seeking the vaccine. Our analysis suggests that current Centers for Disease Control and Prevention policy of allocating flu vaccine over time in direct proportion to states' populations may not be best in terms of averting nationally the maximum possible number of infections.
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No published meta-analyses have assessed efficacy and effectiveness of licensed influenza vaccines in the USA with sensitive and highly specific diagnostic tests to confirm influenza. We searched Medline for randomised controlled trials assessing a relative reduction in influenza risk of all circulating influenza viruses during individual seasons after vaccination (efficacy) and observational studies meeting inclusion criteria (effectiveness). Eligible articles were published between Jan 1, 1967, and Feb 15, 2011, and used RT-PCR or culture for confirmation of influenza. We excluded some studies on the basis of study design and vaccine characteristics. We estimated random-effects pooled efficacy for trivalent inactivated vaccine (TIV) and live attenuated influenza vaccine (LAIV) when data were available for statistical analysis (eg, at least three studies that assessed comparable age groups). We screened 5707 articles and identified 31 eligible studies (17 randomised controlled trials and 14 observational studies). Efficacy of TIV was shown in eight (67%) of the 12 seasons analysed in ten randomised controlled trials (pooled efficacy 59% [95% CI 51-67] in adults aged 18-65 years). No such trials met inclusion criteria for children aged 2-17 years or adults aged 65 years or older. Efficacy of LAIV was shown in nine (75%) of the 12 seasons analysed in ten randomised controlled trials (pooled efficacy 83% [69-91]) in children aged 6 months to 7 years. No such trials met inclusion criteria for children aged 8-17 years. Vaccine effectiveness was variable for seasonal influenza: six (35%) of 17 analyses in nine studies showed significant protection against medically attended influenza in the outpatient or inpatient setting. Median monovalent pandemic H1N1 vaccine effectiveness in five observational studies was 69% (range 60-93). Influenza vaccines can provide moderate protection against virologically confirmed influenza, but such protection is greatly reduced or absent in some seasons. Evidence for protection in adults aged 65 years or older is lacking. LAIVs consistently show highest efficacy in young children (aged 6 months to 7 years). New vaccines with improved clinical efficacy and effectiveness are needed to further reduce influenza-related morbidity and mortality. Alfred P Sloan Foundation.
CODIV-19: phase 2 and 3 vaccine trials. US National Library of Medicine
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