Vacuna Eficacia Fase 4
Vacuna Eficacia Fase 4
Vacuna Eficacia Fase 4
The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused more than Lancet Infect Dis 2021;
1 million deaths in the first 6 months of the pandemic and huge economic and social upheaval internationally. An 21: e26–35
efficacious vaccine is essential to prevent further morbidity and mortality. Although some countries might deploy Published Online
October 27, 2020
COVID-19 vaccines on the strength of safety and immunogenicity data alone, the goal of vaccine development is
https://doi.org/10.1016/
to gain direct evidence of vaccine efficacy in protecting humans against SARS-CoV-2 infection and COVID-19 so S1473-3099(20)30773-8
that manufacture of efficacious vaccines can be selectively upscaled. A candidate vaccine against SARS-CoV-2 The Jenner Institute
might act against infection, disease, or transmission, and a vaccine capable of reducing any of these elements (S H Hodgson DPhil),
could contribute to disease control. However, the most important efficacy endpoint, protection against severe University of Oxford Clinical
Medical School, Medical
disease and death, is difficult to assess in phase 3 clinical trials. In this Review, we explore the challenges in
Sciences Division
assessing the efficacy of candidate SARS-CoV-2 vaccines, discuss the caveats needed to interpret reported efficacy (K Mansatta BA, G Mallett BA),
endpoints, and provide insight into answering the seemingly simple question, “Does this COVID-19 vaccine and Oxford Vaccine Group
work?” (K R W Emary BM BCh,
Prof A J Pollard FMedSci),
University of Oxford, Oxford,
Introduction primary endpoints for vaccine efficacy studies, with an UK; Nuffield Department of
The novel coronavirus, severe acute respiratory syndrome endpoint estimate of at least 50% for placebo-controlled Primary Care Health Sciences,
coronavirus 2 (SARS-CoV-2), has caused more than efficacy trials.6 However, protection against severe disease Radcliffe Primary Care Building,
Radcliffe Observatory Quarter,
1 million deaths in the first 6 months of the pandemic1 and death is difficult to assess in phase 3 clinical trials due
Oxford, UK (V Harris PhD); and
and huge economic and social upheaval internationally.2 to the unfeasibly large numbers of participants required. NIHR Oxford Biomedical
An efficacious vaccine is considered essential to prevent Instead, data to address this endpoint might be available Research Centre, Oxford, UK
further morbidity and mortality.3 To date, 44 candidate only from large phase 4 trials or epidemiological studies (K R W Emary, Prof A J Pollard)
COVID-19 vaccines are in clinical development and done after widespread deployment of a vaccine. In this Correspondence to:
Dr Susanne H Hodgson,
151 are in preclinical development, by use of a range of Review, we explore the challenges in assessing the efficacy
The Jenner Institute, University
vaccine platforms.4 In this unprecedented pandemic, of candidate SARS-CoV-2 vaccines and discuss the caveats of Oxford, Oxford OX3 7DQ, UK
vaccine development is time-dependent, and considerable needed to interpret reported efficacy endpoints. [email protected].
collaborative efforts are being expended to expedite ac.uk
preclinical and clinical assessment of candidate vaccines.5 Defining vaccine efficacy
The cost to manu facture and internationally deploy Many different endpoints are used in vaccine research to
an efficacious COVID-19 vaccine will be vast, and define efficacy depending on the pathogen, consequences
the process will be at risk of politicisation.3 Although of infection, and transmission dynamics. Often, out
some countries might deploy COVID-19 vaccines on the come data from randomised controlled trials (RCTs) are
strength of safety and immunogenicity data alone, the presented as a proportional reduction in disease between
goal of vaccine development is to gain direct evidence participants who were vaccinated and control partici
of vaccine efficacy in protecting humans against pants to calculate the reduction that is attributable to the
SARS-CoV-2 infection and COVID-19.6 vaccine.9 Outcomes might include reduction in infection
In their target product profile for COVID-19 vaccines, (ie, assessing sterilising immunity), severity of resultant
WHO suggested that a “clear demonstration of efficacy clinical disease (ie, assessing disease-modifying immu
(on a population basis) ideally with ~50% point estimate” nity),9 or duration of infectivity.10 Such RCTs represent
should be a minimum criterion for any acceptable best-case scenarios of vaccine efficacy under idealised
COVID-19 vaccine, and that efficacy can be assessed conditions in particular populations and pro vide key
against “disease, severe disease, and/or shedding/trans data necessary for vaccine licensure. However, vaccine
mission” endpoints.7 This definition is necessarily non- efficacy does not always predict vaccine effectiveness—
specific and reflects the complexities of assessing the ie, the protection attributable to a vaccine administered
clinical efficacy of candidate vaccines in the context of non-randomly under field conditions.11 For example, the
a novel pathogen. Indeed, a COVID-19 vaccine capable of effectiveness of rotavirus vaccines in children in low-
reducing any of these elements might contribute to income and middle-income settings was lower than the
disease control where there are no efficacious prophylactic efficacy observed in children in high-income countries.12
medications and few treatments.8 The US Food and Drug RCTs might not predict protection gained indirectly
Administration (FDA) suggested that laboratory-confirmed from herd protection (sometimes called herd immunity)
COVID-19 or SARS-CoV-2 infection are appropriate following widespread vaccine deployment. Equally, RCTs
done in a particular age group or geographical setting an unvaccinated comparator group in an RCT is the most
might not predict effectiveness if the vaccine is more efficient study design to show vaccine efficacy.6 Although
widely deployed. It is possible that alternative vaccine vaccine candidates can be assessed in isolation,4 WHO
platforms or the addition of adjuvants are required for and the US FDA suggest that an adaptive trial design,
adequate immunogenicity in older age groups, as for evaluating multiple vaccine candidates in parallel against
influenza vaccines.13 For this reason, prospective studies a single placebo group, could be an acceptable method to
of vaccine effective ness in real-world scenarios post increase efficiency, provided that the trials are sufficiently
licensure are routinely needed. powered.6,16
In the case of SARS-CoV-2, an efficacious vaccine Studies that rely on natural exposure to SARS-CoV-2
might prevent infection, disease, or transmission are vulnerable to multiple variables that influence
(figure 1). The outcome of SARS-CoV-2 infection in whether a vaccinee is exposed to SARS-CoV-2 and
individuals is heterogeneous and dependent on multiple then whether exposure leads to infection (figure 2). For
variables, inclu ding age, sex, ethnicity, and comor example, older participants could be more likely to avoid
bidities.14 On an indivi dual level, the consequence of social gatherings or use of public transport, reducing
infection can range from paucisymptomatic states to their likelihood of exposure to SARS-CoV-2. However,
hospital admission, requirement for respiratory support, health-care workers might not only be more likely to be
and death.14 Transmission dynamics of SARS-CoV-2 are exposed to SARS-CoV-2 but also might receive higher
not yet fully understood but the ability of infected infecting doses than would other participants in the
individuals to transmit infection when asymptomatic or study. Alternatively, by virtue of their recognised high-
in a presymptomatic period means that infection control risk occupations, health-care workers might have better
strategies that focus solely on preventing transmission access to protective strategies, such as personal protec
from symptomatic individuals will be insufficient alone tive equipment, than other partici pants, reducing the
to interrupt the transmission of SARS-CoV-2.15 likelihood of infection following exposure. These com
The effect of an efficacious vaccine on the course of the plex behavioural variables are diffi cult to control;
SARS-CoV-2 pandemic is complex and there are many therefore, it is important that participants are randomly
potential scenarios after deployment. The ability of a assigned between vaccine and comparator groups, by use
vaccine to protect against severe disease and mortality is of a concealed method, to ensure reliable assessment of
the most important efficacy endpoint, as hospital and efficacy outcomes.
critical-care admissions place the greatest burden on Efficacy studies should be adequately powered to meet
health-care systems. However, the beneficial effects of efficacy endpoints, and multiple variables inform these
such a vaccine on a population can be observed only if calculations, including local transmission rates and
the vaccine is efficacious in older adults (eg, approximately participant characteristics. For example, the severity of
>60 years) and widespread distribution of the vaccine COVID-19 and mortality rates vary according to age, sex,
exists, including to people who are most susceptible to and ethnicity, with higher rates of hospital admissions,
COVID-19. High coverage among these groups who are critical-care admissions, and death in older individuals,
at high risk of severe COVID-19 would have the greatest men, and individuals of Black, Asian, and minority
effect against disease endpoints. Alternatively, vaccines ethnic groups.14 For example, if a phase 3 efficacy study
that do not affect the clinical course, but reduce the enrolled participants aged only 20–29 years, the expected
transmissibility of SARS-CoV-2, could still be valuable low mortality rate in this population would require an
interventions on a population level. unfeasibly large sample size to adequately power the
study to assess mortality as an endpoint, and the study
Study design of SARS-CoV-2 vaccine efficacy trials would be reliant on a high rate of transmission to meet
Provided SARS-CoV-2 is circulating, comparison of other efficacy endpoints (table 1). Selection of older
clinical endpoints between vaccinated participants and participants with high rates of mortality, for example
few are validated (appendix p 1). Classical measures of vaccines might be deployed in the early post-marketing See Online for appendix
disease severity, such as admission to hospital, require period to large populations over a short timeframe, it will
ment for respiratory support, or admission to intensive be important that robust, ongoing pharmacovigilance is
care, represent the clinical phenotypes that place the in place post licensure to identify safety signals that
most burden on health-care systems and are important large-scale RCTs might not capture.6
endpoints.39 However, these phenotypes might represent
only a proportion of those with disease.40 SARS-CoV-2 infection
It is unclear whether previous exposure to SARS-CoV-2 SARS-CoV-2 infection can cause only mild, non-specific
provides protection against subsequent infection. Some symptoms in many individuals, which do not result in
studies to date have excluded participants who are sero contact with a health-care professional.14 Asymptomatic
positive for SARS-CoV-2. However, the US FDA recom infections are well recognised48 but difficult to capture.
mends that participants in vaccine efficacy studies are Serial sampling of vaccinees, for example via diagnostic
not screened or excluded if they have a previous history testing once per week, could ensure that all infected
or laboratory evidence of previous SARS-CoV-2 infection, individuals are identified, regardless of symptoms, and
as prevaccination screening is unlikely to occur in give an indication of the duration of infectivity. Ideally,
practice with deployment of a licensed COVID-19 vaccinees would be informed of their test results in real
vaccine.6 Stratification analysis will, therefore, be import time to allow appropriate isolation. However, it is worth
ant to establish the effect of pre-existing immunity on considering that such a sys tem could introduce an
efficacy outputs. unavoidable bias toward clinical endpoints, as partici
A syndrome of vaccine-associated enhanced respiratory pants might be more likely to report symptoms meeting
disease has been reported in preclinical studies of some clinical criteria for COVID-19 if they know that they
viral vaccines, in which immunised animals had are infected. This monitoring strategy requires a
increased likelihood of infection or severe disease when considerable commitment from vac cinees over an
subsequently challenged with the target patho gen. extended period, which is likely to result in an ever-
Murine, ferret, and non-human primate animal data for reducing number of samples collected. Asking vaccinees
candidate vaccines against severe acute respiratory to self-sample by, for example, posting self-collected
syndrome coronavirus 1 and Middle East respiratory oronasal swabs once per week for quantitative RT-PCR
syndrome have shown this effect, which is thought to be testing could help to increase the number of samples
mediated by non-neutralising antibodies or by T-helper- obtained; however, this process could be logistically
2-cell skewed response.47 difficult to implement, with considerable costs and an
A risk exists for SARS-CoV-2 vaccine-associated ever-reducing return rate.
enhanced respiratory disease, and it is unknown how it Following infection with SARS-CoV-2, antibody re
might manifest in humans.6 If vaccine-associated sponses are formed against key viral antigens, including
enhanced respiratory disease were to increase the the nucleoprotein and spike protein, typically peaking
likelihood of severe disease, then its relative risk could be 14–21 days after onset of symptoms.49 Most SARS-CoV-2
calculated by comparing the incidence of severe disease vaccine candidates seek to induce neutralising anti-spike
and mortality between vaccinees and recipients of a protein antibodies50 and several assays have been described
comparator vaccine. How ever, if detection of vaccine- as methods of assessing evidence of infection.43 Vaccine
associated enhanced respiratory disease is dependent on efficacy studies that screen and exclude participants who
the occurrence of disease, then this dependency would are seropositive for SARS-CoV-2 could use seroconversion
provide a null-biased estimate of the relative risk. Regular of vaccinees post vaccination as a surrogate for infection
screening of study participants for asymptomatic (appendix p 2), provided that the antibody assayed is
infections after vaccination and testing of symptomatic specific to infection and not induced by the candidate
participants allows calculation of the true incidence of vaccine.51 Seroconversion might allow detection of ongoing
infection in groups. This denominator allows accurate or recovered infection in vaccinees with minimal symp
calculation of the relative and absolute risk of vaccine- toms who do not present for quantitative RT-PCR testing51
associated enhanced respiratory disease, which are and increase the likelihood of diagnosis when combined
important safety data that are of public interest. with quantitative RT-PCR testing.52 Furthermore, given
Clinical trials might not be sufficiently powered to that the duration of seropositivity exceeds that for which
detect vaccine-associated enhanced respiratory disease or RNA can be detected, serological testing offers a substantial
serious adverse events related to the vaccine, if they are operational advantage over quantitative RT-PCR, with a
uncommon. The US FDA recommends that follow-up of larger time window to capture the endpoint (appendix p 2).43
study participants should continue for as long as is However, US FDA guidance that participants in vaccine
feasible, ideally for at least 1–2 years, to assess the efficacy studies should not be excluded if they have a
duration of protection and potential for vaccine-asso history or laboratory evidence of previous SARS-CoV-26
ciated enhanced respiratory disease as the immune means that the value of this endpoint is unclear, particularly
response to the vaccine wanes.6 Given that COVID-19 in populations with high baseline seropositivity to
Surrogate endpoints
Panel 2: Key considerations for the use of serological If an immunological correlate of protection is known,
markers of infection as a vaccine efficacy endpoint then the protective efficacy of a vaccine can be assessed
• Sensitivity and specificity of any serological assay for by measuring the proportion of vaccinees who generate a
SARS-CoV-2 disease are unknown given the absence particular immune response, without having to measure
of a validated gold standard for diagnosis.41 clinical outcomes.63 This technique facilitates the rapid
• Reported sensitivity and specificity of antibody tests screening and deselection of candidate vaccines. A
for SARS-CoV-2 vary widely53 and are most likely potential surrogate endpoint for a SARS-CoV-2 vaccine
influenced by timing of sampling in relation to would most likely depend on the characteristics of the
infection.49,52,53 vaccine, including antigen structure, method of delivery,
• Assays need to be able to distinguish antibodies induced and antigen processing and presentation in vaccines.6
by infection from those induced by vaccination. Not all individuals exposed to SARS-CoV-2 become
• The kinetics of antibody responses following infection are infected64 and heterogeneity is seen in clinical outcomes.14
incompletely described and might wane substantially However, the immunological mechanisms underlying
within months.54 protection or susceptibility to natural infection are un
• Individuals can be seronegative for antibodies post known. Seroconversion of antibodies against SARS-CoV-2
infection, as evidenced by the detection of is a marker of exposure, but whether the presence of
memory T-cell responses to SARS-CoV-2 in the neutralising antibodies is sufficient to provide protection
absence of antibodies.55 against subsequent infection or disease is unclear.49 More
over, if these antibodies are sufficient, we do not know the
titre that would be needed for protection or the diverse
SARS-CoV-2. Additionally, key caveats further decrease the range of innate immune effector functions that can be
usefulness of seroconversion as an efficacy endpoint relied on for antibody action, such as antibody-dependent
(panel 2). complement deposition and antibody-dependent neutro
phil phagocytosis.65 Cellular immune responses have also
Transmission been described in response to infection and are likely to
SARS-CoV-2 is readily transmitted between individuals, be an important component of a protective adaptive
predominantly via droplet transmission. However, immune response.66 Indeed, individuals have been des
aerosol and faeco–oral routes of transmission might cribed who were seronegative and had T-cell responses to
also take place.56 Individuals are also known to transmit the SARS-CoV-2 spike protein.55 However, the particular
SARS-CoV-2 in the asymptomatic and presymptomatic cellular signature that is required for protection is
period.48 During convalescence, patients can shed viral unknown, and whether protective T cells can be measured
RNA for many weeks,57,58 and even longer if immuno in peripheral blood samples is unclear. Additionally, an
suppressed.59 However, there is an unclear association efficacious SARS-CoV-2 vaccine might provide protection
between detectable RNA by quantitative RT-PCR and by a mechanism that is distinct from the mechanism
the ability to culture SARS-CoV-2 in vitro.60 induced following natural infection. Distin guishing
It is possible that a SARS-CoV-2 vaccine could reduce immuno logical markers of infection from mec hanistic
severity of disease but lead to prolonged shedding correlates of protection is difficult but important to inform
of infectious virus, which could have important conse rational design of a vaccine.
quences for public health if shedding resulted in If a SARS-CoV-2 vaccine were to show efficacy, a
increased transmission. Therefore, it might be important priority would be to identify an in-vitro correlate or
for investigators to consider not only the duration of surrogate of protection.67 Other vaccine candidates could
RNA positivity in regularly collected samples but also then be deemed efficacious and licensed if they induced
whether these samples include replication-competent similar levels of immune responses in non-inferiority
live virus. Nested quantitative RT-PCR targeting sub studies, which would circumvent the need for large
genomic RNA that encodes conserved structural pro efficacy studies. Evidence of effectiveness against disease
teins has been suggested as a measure of active would be needed in post-licensure studies, however, this
SARS-CoV-2 replication.60 As the transcription of these approach could markedly accelerate development of
RNAs is reliant on translation of the ORF1 gene within multiple SARS-CoV-2 vaccines. This approach relies on
the host cell and the subsequent assembly of an RNA- collaboration and standardisation of in-vitro assays to
dependent RNA polymerase, the detection of sub allow meaningful comparison of immunological outputs
genomic RNAs can help to identify replication-competent from different laboratories.68
and therefore transmissible virus.61 However, emerging In the absence of data for humans, animal studies can
evidence suggests that subgenomic RNAs might be help to identify potential correlates of protection. Indeed,
more stable than previously purported and so could be non-human primate studies are being widely used to
detectable for a period beyond the disap pearance of understand SARS-CoV-2.69 Protection against reinfection
actively replicating virus.62 with SARS-CoV-2 has been observed in rhesus monkeys,
Controlled human infection model NA=not applicable. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.
*The risk of infection in a controlled human infection model trial could be lower
Controlled human infection model (CHIM) studies, in than naturally acquired infection as individuals who are at low risk of severe
which human volunteers are exposed to infectious disease can be selected (eg, aged 18–25 years), the minimum dose of virus needed
pathogens (also known as challenge agents), are an to acquire infection can be administered, individuals can be carefully monitored,
and rescue therapies can be given if needed.
important com ponent of pathology, immunology, and
vaccine research. Microbial challenge studies are useful for Table 2: A comparison of the key factors for clinical trials that are reliant
providing proof of concept for therapeutic interventions on natural exposure to, or a direct challenge with, SARS-CoV-2
and can substantially reduce the time needed to reach
phase 3 studies, as has been shown for malaria and typhoid
vaccine development.74–76 CHIM studies could provide valuable immunological
Administration of a known dose of SARS-CoV-2 in a insights. For example, re-exposing individuals to
carefully controlled setting has been suggested as SARS-CoV-2 who have recovered from naturally acquired
a model to allow rapid initial assessment of vaccine infection could help to identify a surrogate marker of
efficacy and early deselection of vaccine candidates.77 protection, which would inform vaccine design. Provided
A COVID-19 CHIM model has several advantages over CHIM studies can be done safely, the information gained
studies that are reliant on naturally occurring community can be viewed as complementary to traditional RCTs,
transmission, which is difficult to predict and dependent both to guide resources for large-scale phase 3 studies
on changes in behaviour and public health interventions and in the efficacy evaluation of existing vaccines.
(table 2). CHIM studies require controlled delivery of a stan
Development of vaccines for COVID-19 has proceeded dardised inoculum, ideally made to good manufacturing
at an unprecedented rate to date, with some candidates practices, and meticulous care to prevent community
beginning phase 3 studies within 4 months of the start transmission of the challenge strain (appendix p 2).79
of vaccine development.4 If done, SARS-CoV-2 CHIM These studies can be logistically difficult and costly
studies are likely to include carefully selected young per participant, although the number of participants
volunteers at low risk of severe disease, who are exposed required is far lower than in large phase 3 studies.
to low doses of SARS-CoV-2 with the aim of establishing Although there are challenges to setting up a CHIM of
only asymp tomatic or mild infection. It is unclear SARS-CoV-2, there might also be substantial value in
whether efficacy shown in such a model will predict the doing so, even in the context of a licensed product. Use
key efficacy measure of protection against severe disease of this ethically complex and controversial approach for
and death in the target older population who are at risk of vaccine assessment will require multi disciplinary,
severe disease.78 international oversight to ensure that outputs are
18 Verity R, Okell LC, Dorigatti I, et al. Estimates of the severity 41 Watson J, Whiting PF, Brush JE. Interpreting a COVID-19 test
of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis result. BMJ 2020; 369: m1808.
2020; 20: 669–77. 42 van Kasteren PB, van der Veer B, van den Brink S, et al.
19 Office for National Statistics. All data related to coronavirus Comparison of seven commercial RT-PCR diagnostic kits
(covid-19). https://www.ons.gov.uk/peoplepopulationandcommunity/ for COVID-19. J Clin Virol 2020; 128: 104412.
healthandsocialcare/conditionsanddiseases/datalist (accessed 43 Younes N, Al-Sadeq DW, Al-Jighefee H, et al. Challenges in
July 25, 2020). laboratory diagnosis of the novel coronavirus SARS-CoV-2.
20 Allsup SJ, Gosney MA. Difficulties of recruitment for a randomised Viruses 2020; 12: 126.
controlled trial involving influenza vaccination in healthy older 44 He X, Lau EHY, Wu P, et al. Temporal dynamics in viral shedding
people. Gerontology 2002; 48: 170–73. and transmissibility of COVID-19. Nat Med 2020; 26: 672–75.
21 Cassidy EL, Baird E, Sheikh JI. Recruitment and retention 45 La Scola B, Le Bideau M, Andreani J, et al. Viral RNA load
of elderly patients in clinical trials: issues and strategies. as determined by cell culture as a management tool for discharge
Am J Geriatr Psychiatry 2001; 9: 136–40. of SARS-CoV-2 patients from infectious disease wards.
22 Demicheli V, Jefferson T, Ferroni E, Rivetti A, Di Pietrantonj C. Eur J Clin Microbiol Infect Dis 2020; 39: 1059–61.
Vaccines for preventing influenza in healthy adults. 46 Lachenbruch PA. Sensitivity, specificity, and vaccine efficacy.
Cochrane Database Syst Rev 2018; 2: CD001269. Control Clin Trials 1998; 19: 569–74.
23 Demicheli V, Jefferson T, Di Pietrantonj C, et al. Vaccines for 47 Lambert P-H, Ambrosino DM, Andersen SR, et al. Consensus
preventing influenza in the elderly. Cochrane Database Syst Rev summary report for CEPI/BC March 12–13, 2020 meeting:
2018; 2: CD004876. assessment of risk of disease enhancement with COVID-19
24 Raheja D, Davila EP, Johnson ET, Deović R, Paine M, Rouphael N. vaccines. Vaccine 2020; 38: 4783–91.
Willingness to participate in vaccine-related clinical trials among 48 Oran DP, Topol EJ. Prevalence of asymptomatic SARS-CoV-2
older adults. Int J Environ Res Public Health 2018; 15: 158. infection: a narrative review. Ann Intern Med 2020; 173: 362–67.
25 McMurdo ME, Roberts H, Parker S, et al. Improving recruitment 49 Long QX, Liu BZ, Deng HJ, et al. Antibody responses to
of older people to research through good practice. Age Ageing 2011; SARS-CoV-2 in patients with COVID-19. Nat Med 2020; 26: 845–48.
40: 659–65. 50 Thanh Le T, Andreadakis Z, Kumar A, et al. The COVID-19 vaccine
26 Velavan TP, Pollard AJ, Kremsner PG. Herd immunity and development landscape. Nat Rev Drug Discov 2020; 19: 305–06.
vaccination of children for COVID-19. Int J Infect Dis 2020; 98: 14–15. 51 Lipsitch M, Kahn R, Mina MJ. Antibody testing will enhance the
27 Petkova E, Antman EM, Troxel AB. pooling data from individual power and accuracy of COVID-19-prevention trials. Nat Med 2020;
clinical trials in the COVID-19 era. JAMA 2020; 324: 543–45. 26: 818–19.
28 Bangdiwala SI, Bhargava A, O’Connor DP, et al. Statistical 52 Zhao J, Yuan Q, Wang H, et al. Antibody responses to SARS-CoV-2
methodologies to pool across multiple intervention studies. in patients of novel coronavirus disease 2019. Clin Infect Dis 2020;
Transl Behav Med 2016; 6: 228–35. published online March 28. https://doi.org/10.1093/cid/ciaa344.
29 Vesikari T, Matson DO, Dennehy P, et al. Safety and efficacy 53 Whitman JD, Hiatt J, Mowery CT, et al. Test performance evaluation
of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. of SARS-CoV-2 serological assays. medRxiv 2020; published online
N Engl J Med 2006; 354: 23–33. May 17. https://doi.org/10.1101/2020.04.25.20074856 (preprint).
30 Soares-Weiser K, Maclehose H, Bergman H, et al. Vaccines for 54 Seow J, Graham C, Merrick B, et al. Longitudinal evaluation
preventing rotavirus diarrhoea: vaccines in use. and decline of antibody responses in SARS-CoV-2 infection.
Cochrane Database Syst Rev 2012; 11: CD008521. medRxiv 2020; published online July 11. https://doi.
31 WHO. Rotavirus vaccines. WHO position paper—January 2013. org/10.1101/2020.07.09.20148429 (preprint).
Wkly Epidemiol Rec 2013; 88: 49–64. 55 Sekine T, Perez-Potti A, Rivera-Ballesteros O, et al. Robust T cell
32 Bar-Zeev N, King C, Phiri T, et al. Impact of monovalent rotavirus immunity in convalescent individuals with asymptomatic or mild
vaccine on diarrhoea-associated post-neonatal infant mortality COVID-19. Cell 2020; published online Aug 14. https://doi.
in rural communities in Malawi: a population-based birth cohort org/10.1101/ 2020.06.29.174888.
study. Lancet Glob Health 2018; 6: e1036–44. 56 Khan S, Liu J, Xue M. Transmission of SARS-CoV-2, required
33 Auranen K, Rinta-Kokko H, Goldblatt D, et al. Colonisation developments in research and associated public health concerns.
endpoints in Streptococcus pneumoniae vaccine trials. Vaccine Front Med (Lausanne) 2020; 7: 310.
2013; 32: 153–58. 57 Zheng S, Fan J, Yu F, et al. Viral load dynamics and disease severity
34 Hitchings MD, Grais RF, Lipsitch M. Using simulation to aid trial in patients infected with SARS-CoV-2 in Zhejiang province, China,
design: ring-vaccination trials. PLoS Negl Trop Dis 2017; January–March 2020: retrospective cohort study. BMJ 2020;
11: e0005470. 369: m1443.
35 Henao-Restrepo AM, Camacho A, Longini IM, et al. Efficacy 58 To KK-W, Tsang OT-Y, Leung W-S, et al. Temporal profiles of viral
and effectiveness of an rVSV-vectored vaccine in preventing Ebola load in posterior oropharyngeal saliva samples and serum antibody
virus disease: final results from the Guinea ring vaccination, responses during infection by SARS-CoV-2: an observational
open-label, cluster-randomised trial (Ebola Ça Suffit!). Lancet cohort study. Lancet Infect Dis 2020; 20: 565–74.
2017; 389: 505–18. 59 Zhu L, Gong N, Liu B, et al. Coronavirus disease 2019 pneumonia
36 Mercatelli D, Giorgi FM. Geographic and genomic distribution in immunosuppressed renal transplant recipients: a summary
of SARS-CoV-2 mutations. Front Microbiol 2020; 11: 1800. of 10 confirmed cases in Wuhan, China. Eur Urol 2020; 77: 748–54.
37 Dearlove B, Lewitus E, Bai H, et al. A SARS-CoV-2 vaccine 60 Wölfel R, Corman VM, Guggemos W, et al. Virological assessment
candidate would likely match all currently circulating strains. of hospitalised patients with COVID-2019. Nature 2020; 581: 465–69.
bioRxiv 2020; published online April 27. https://doi. 61 Kim D, Lee J-Y, Yang J-S, Kim JW, Kim VN, Chang H. The
org/10.1101/2020.04.27.064774 (preprint). architecture of SARS-CoV-2 transcriptome. Cell 2020; 181: 914–21.
38 D’Cruz RJ, Currier AW, Sampson VB. Laboratory testing methods 62 Alexandersen S, Chamings A, Bhatta TR. SARS-CoV-2 genomic
for novel severe acute respiratory syndrome-coronavirus-2 and subgenomic RNAs in diagnostic samples are not an indicator
(SARS-CoV-2). Front Cell Dev Biol 2020; 8: 468. of active replication. medRxiv 2020; published online Aug 16.
39 Loeliger E, Chaudhari A, Coalition for Epidemic Preparedness https://doi.org/10.1101/2020.06.01.20119750 (preprint).
Innovations COVID-19 Clinical Working Group. COVID-19 efficacy 63 WHO. Correlates of vaccine-induced protection: methods and
endpoints in interventional trials: what constitutes an incident implications. Geneva: World Health Organization, 2013.
clinical disease case and what triggers diagnostic work-up. 64 Bi Q, Wu Y, Mei S, et al. Epidemiology and transmission
June 25, 2020. https://media.tghn.org/articles/COVID-19_Clinical_ of COVID-19 in 391 cases and 1286 of their close contacts in
Endpoint_Case_Definition_V2.0.pdf (accessed July 23, 2020). Shenzhen, China: a retrospective cohort study. Lancet Infect Dis
40 Zhu J, Ji P, Pang J, et al. Clinical characteristics of 3062 COVID-19 2020; 20: 911–19.
patients: a meta-analysis. J Med Virol 2020; published online 65 Yu J, Tostanoski LH, Peter L, et al. DNA vaccine protection against
April 15. https://doi.org/10.1002/jmv.25884. SARS-CoV-2 in rhesus macaques. Science 2020; 369: 806–11.
66 Vabret N, Britton GJ, Gruber C, et al. Immunology of COVID-19: 74 Academy of Medical Sciences. Microbial challenge studies. 2005.
current state of the science. Immunity 2020; 52: 910–41. https://acmedsci.ac.uk/policy/policy/microbial-challenge-studies
67 Plotkin SA. Correlates of protection induced by vaccination. (accessed Aug 5, 2020).
Clin Vaccine Immunol 2010; 17: 1055–65. 75 Cooper MM, Loiseau C, McCarthy JS, Doolan DL. Human
68 Vekemans J, Crofts J, Baker CJ, et al. The role of immune correlates challenge models: tools to accelerate the development of malaria
of protection on the pathway to licensure, policy decision and use vaccines. Expert Rev Vaccines 2019; 18: 241–51.
of group B Streptococcus vaccines for maternal immunisation: 76 Meiring JE, Giubilini A, Savulescu J, Pitzer VE, Pollard AJ.
considerations from World Health Organization consultations. Generating the evidence for typhoid vaccine introduction:
Vaccine 2019; 37: 3190–98. considerations for global disease burden estimates and vaccine
69 Lakdawala SS, Menachery VD. The search for a COVID-19 animal testing through human challenge. Clin Infect Dis 2019;
model. Science 2020; 368: 942–43. 69 (suppl 5): S402–07.
70 Chandrashekar A, Liu J, Martinot AJ, et al. SARS-CoV-2 infection 77 Eyal N, Lipsitch M, Smith PG. Human challenge studies
protects against rechallenge in rhesus macaques. Science 2020; to accelerate coronavirus vaccine licensure. J Infect Dis 2020;
369: 812–17. 221: 1752–56.
71 Yu J, Tostanoski LH, Peter L, et al. DNA vaccine protection against 78 Baay M, Neels P. SARS-CoV-2 controlled human infection
SARS-CoV-2 in rhesus macaques. Science 2020; 369: 806–11. models: ethics, challenge agent production and regulatory issues.
72 US Department of Health and Human Services: Food and Drug Biologicals 2020; published online Aug 15. https://doi.org/10.1016/j.
Administration. Product development under the animal rule: biologicals.2020.08.006.
guidance for industry. November, 2015. https://www.fda.gov/ 79 WHO. Feasibility, potential value and limitations of establishing
regulatory-information/search-fda-guidance-documents/product- a closely monitored challenge model of experimental COVID-19
development-under-animal-rule (accessed Aug 12, 2020). infection and illness in healthy young adult volunteers—final
73 European Medicines Agency. New vaccine for prevention report draft for public consultation. Geneva: World Health
of Ebola virus disease recommended for approval in the European Organization, 2020.
Union. May 29, 2020. https://www.ema.europa.eu/en/news/new- © 2020 Elsevier Ltd. All rights reserved.
vaccine-prevention-ebola-virus-disease-recommended-approval-
european-union (accessed Aug 2, 2020).