POLICY FORUM

Cite as: L. Corey et al., Science

10.1126/science.abc5312 (2020).

A strategic approach to COVID-19 vaccine R&D

By Lawrence Corey1,2, John R. Mascola3, Anthony S. Fauci4, Francis S. Collins5
1
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. 2Departments of Medicine and Lab Medicine,
University of Washington, Seattle, WA 98195, USA. 3Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health,
Bethesda, MD 20892, USA. 4National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. 5National Institutes of
Health, Bethesda, MD 20892, USA.
Email: [email protected]

A public-private partnership and platform for harmonized clinical trials aims to accelerate licensure and
distribution.

There is an unprecedented need to manufacture and dis- ies to the spike protein, have been shown to be protective

Downloaded from http://science.sciencemag.org/ on May 16, 2020

tribute enough safe and effective vaccine to immunize an against experimental infection (2, 3). Endpoints vary from
extraordinarily large number of individuals in order to pro- protection of infection to modification of viral replication
tect the entire global community from the continued threat and disease. These data bring optimism that a highly im-
of morbidity and mortality from severe acute respiratory munogenic vaccine will elicit the magnitude and quality of
syndrome–coronavirus 2 (SARS-CoV-2). The global need for antibody responses required for protection. The role that T
vaccine and the wide geographic diversity of the pandemic cell immunity plays in preventing acquisition or ameliora-
require more than one effective vaccine approach. Collabo- tion of early disease, either in animal challenge models or in
ration will be essential among biotechnology and pharma- human coronavirus disease, is unclear (4); this constitutes
ceutical companies, many of which are bringing forward a another reason why a diversity of vaccine approaches must
variety of vaccine approaches (1). The full development be pursued.
pathway for an effective vaccine for SARS-CoV-2 will require A high degree of safety is a primary goal for any widely
that industry, government, and academia collaborate in un- used vaccine, and there is theoretical risk that vaccination
precedented ways, each adding their individual strengths. could make subsequent SARS-CoV-2 infection more severe.
We discuss one such collaborative program that has recently This has been reported for feline coronaviruses and has
emerged: the ACTIV (Accelerating COVID-19 Therapeutic been observed in some vaccine-challenge animal models of
Interventions and Vaccines) public-private partnership. SARS-CoV-1 (5). These preclinical data suggest that the syn-
Spearheaded by the U.S. National Institutes of Health drome of vaccine-associated enhanced respiratory disease
(NIH), this effort brings together the strengths of all sectors results from a combination of poorly protective antibodies
at this time of global urgency. We further discuss a collabo- that produce immune complex deposition together with a T
rative platform for conducting harmonized, randomized helper cell 2 (TH2)–biased immune response. The potential
controlled vaccine efficacy trials. This mechanism aims to mechanism behind vaccine-induced immune enhancement
generate essential safety and efficacy data for several candi- and the means to minimize this risk have recently been re-
date vaccines in parallel, so as to accelerate the licensure viewed (6). It will be important to construct conformational-
and distribution of multiple vaccine platforms and vaccines ly correct antigens to elicit functionally effective
to protect against COVID-19 (coronavirus disease 2019). antibodies—a lesson learned from vaccine-induced en-
We currently know little about what constitutes a pro- hanced lower respiratory illness among infants receiving a
tective immune response against COVID-19. Data from formalin-inactivated respiratory syncytial virus (RSV) vac-
SARS-CoV-1 patients as well as recently infected SARS-CoV- cine. Animal models of SARS-CoV-2 infection are currently
2 patients document relatively high levels of immune re- being developed, and these models can be used to better
sponses after infection, especially antibody responses to the understand the immune responses associated with protec-
surface (spike) protein that mediates entry into host cells. tion (7).
However, in vivo data on the type or level of immunity re-
quired to protect from subsequent re-infection, and the like- CLINICAL AND IMMUNOLOGICAL ENDPOINTS
ly duration of that protection, are currently unknown. In The primary endpoint for defining the effectiveness of a
animal models of SARS-CoV-1, immunization with recombi- COVID vaccine also requires discussion. The two most
nant subunit proteins and viral- and nucleic acid–vectored commonly mentioned are (i) protection from infection as
vaccines, as well as passive transfer of neutralizing antibod- defined by seroconversion, and (ii) prevention of clinically

First release: 11 May 2020 www.sciencemag.org (Page numbers not final at time of first release) 1
symptomatic disease, especially amelioration of disease se- been suggested. Such experiments, if designed to define po-
verity, including the frequency of disease requiring high- tential immune correlates or winnow out less effective vac-
intensity medical care with some assessment of a decrease cine approaches, may have utility. However, this approach
in hospitalization. This requires the close evaluation of the has shortcomings with respect to pathophysiology and safe-
effect of vaccination on the severity of COVID-19 disease in ty (12). Although the risk of severe disease or death in young
a wide variety of epidemiological and medical settings healthy individuals from COVID-19 is quite low, it is not
among both younger and elderly populations as well as un- zero, and we do not yet have proven effective therapies for
derserved minorities. All of these issues need to be evaluat- COVID-19 to rescue volunteers with complications from
ed in the context of these initial efficacy trials. Achieving such a challenge. It is likely that a SARS-CoV-2 challenge
these endpoints could also be associated with reduced strain will, by design, cause mild illness in most volunteers
transmissibility on a population basis. and thus may not recapitulate the pulmonary pathophysiol-
Primary endpoints that involve reduction of disease re- ogy seen in some patients. Moreover, partial efficacy in
quire greater numbers of enrollees into trials, given that young healthy adults does not predict similar effectiveness
asymptomatic infection is estimated to be 20 to 40% of total among older adults with major cofactors associated with
cases of COVID-19 (8). Initial efficacy trials may then re- COVID-19 disease, nor would it prove reduction of transmis-

Downloaded from http://science.sciencemag.org/ on May 16, 2020

quire a large initial enrollment, with ongoing monitoring of sibility to major susceptibility groups. Whether such exper-
both serologic and clinical endpoints. A major challenge iments may be worthy of pursuit or would have a beneficial
leading to a degree of complexity in developing clinical trial impact on timelines for vaccine development needs careful
protocols for serological endpoints is the lack of precise evaluation by an independent panel of ethicists, clinical
knowledge of incidence rates (9). A critical requirement for trialists, and experts on vaccine development.
such a multi-trial strategy is the establishment of independ-
ent laboratories with similar or identical validated serologic VACCINE PLATFORMS
assays to provide a harmonizing bridge between multiple It is encouraging that vaccine development efforts have
vaccine products and multiple vaccine efficacy trials. The moved swiftly, and several major vaccine platforms are mov-
use of these laboratories for each clinical trial, or the shar- ing toward clinical evaluation. These include traditional
ing of critical specimens from a trial, should be required. recombinant protein, replicating and nonreplicating viral
Parameters that would distinguish the immune response vectors, and nucleic acid DNA and mRNA approaches. Each
resulting from vaccination versus from infection are under of these vaccine platforms has advantages and limitations.
intense investigation, and there is an immediate need to Important characteristics include speed and flexibility of
develop assays to address this issue. manufacture, safety and reactogenicity, the profile of hu-
Efficacy trials need to be evaluated for both benefit and moral and cellular immunogenicity, durability of immunity,
harm. The likelihood of SARS-CoV-2 reexposure is much scale and cost of manufacturing, vaccine stability, and cold
higher than that of SARS-CoV-1, which has disappeared chain requirements. No single vaccine or vaccine platform
from community circulation, and hence longer-term evalua- alone is likely to meet the global need, and so a strategic
tion of potential enhancement with reexposure is needed. approach to the multi-pronged endeavor is absolutely criti-
This requirement does not preclude licensure based on the cal.
endpoints outlined above; however, it does indicate that Several companies are developing nucleic acid–based
more prolonged follow-up of the initial vaccine cohorts vaccines, including Moderna, BioNTech/Pfizer, CureVac
should be undertaken. The durability of clinical and sero- (mRNA-based), and Inovio (DNA-based). DNA- and mRNA-
logic endpoints will also need to be explored, as waning of based vaccines can be generated quickly on the basis of viral
immunity is common with human coronavirus infections sequence, which allows a rapid pathway to the clinic (13,
(10). Coronaviruses have a single-stranded RNA genome 14). Currently, optimal immunogenicity of DNA requires an
with a relatively high mutation rate. Although there has electroporation or an injector delivery device to facilitate
been some genetic drift during the evolution of the SARS- DNA entry into cells. mRNA vaccines use lipid nanoparticles
CoV-2 epidemic, major alterations in the spike protein are to protect and deliver the mRNA and effectively adjuvant
not extensive to date, especially in the regions thought to be the immunogen. The scalability of these lipid nanoparticles
important for neutralization; this enables cautious opti- and their temperature stability are issues that need to be
mism that vaccines designed now will be effective against addressed. Although there is a wide body of early-phase
circulating strains 6 to 12 months in the future (11). clinical experience with nucleic acid vaccines, none are li-
The possibility of performing controlled human chal- censed for widespread usage. As such, the path forward is
lenge trials, in which a small number of volunteers are vac- filled with optimism, but some uncertainty remains, requir-
cinated and subsequently challenged with SARS-CoV-2, has ing rapid assessment of these products’ immunogenicity and

First release: 11 May 2020 www.sciencemag.org (Page numbers not final at time of first release) 2
safety while addressing the lack of commercial experience of generating surrogate markers that ultimately speed licen-
with them. sure and an overall comparison of efficacy. A common Insti-
Traditional recombinant protein technology can be used tutional Review Board as well as a common cross-trial Data
to express the spike protein (e.g., Sanofi, Novavax), and alt- and Safety Monitoring Board (DSMB) should be used so
hough the time to establish cell lines needed for manufac- that the regulatory framework for the entire enterprise is
turing is longer than for nucleic acid vaccines, there is a coordinated and the regulatory agencies and the public can
robust commercial experience with protein and protein par- make objective assessment of the effect sizes between ap-
ticle vaccines, including licensed vaccines for hepatitis B, proaches. As vaccine candidates are poised to enter phase 1,
human papillomavirus, varicella zoster, and influenza. Pro- the collective planning for phase 3 must be undertaken. Alt-
tein vaccines will require a potent adjuvant, which can be hough much of this focus is on trials in the United States,
critical for inducing a predominantly TH1-type immune re- the COVID-19 Prevention Networks established under the
sponse; however, the availability of certain adjuvants may ACTIV program have a global focus, and coordination with
be limited. Viral vector vaccines encode the viral gene of the World Health Organization, Coalition for Epidemic Pre-
interest into one of several well-characterized vectors, in- paredness Innovations, and other global philanthropic part-
cluding adenovirus (Ad) and vesicular stomatitis virus ners must also occur.

Downloaded from http://science.sciencemag.org/ on May 16, 2020

(VSV). The replication-defective adenovirus 26 (rAd26), re- Harmonized master protocols will be needed to enable
cently shown to be safe and immunogenic in preventing transparent evaluation of the relative effectiveness of each
Ebola virus infection (15), is being developed by Janssen vaccine approach. This harmonization can best be achieved
Pharmaceuticals for COVID-19. This platform has the poten- through public-private partnerships such as ACTIV, in
tial to be manufactured at large scale. Preexisting immunity which government-supported central laboratories and inde-
to the specific viral vector can attenuate immunogenicity, pendent biostatisticians serve as key resources for efficacy
and this needs to be addressed in early-stage trials. A re- trials, thereby providing a standardized way to assess the
combinant chimpanzee Ad vector (ChAdOx1), developed by relative immune responses of different types of vaccines (see
the University of Oxford and AstraZeneca, has also entered the figure). Such laboratories enhance the ability to define
clinical trials. Similar versions of ChAd vaccine products correlates of protection, which would speed licensure for all
have been tested in prior clinical trials and shown to be safe vaccines as well as define populations that will achieve pro-
and immunogenic. The VSV vector vaccine platform is repli- tective immunity. Data should be shared among companies
cation-competent and thus induces a robust, likely durable and be provided to independent statistical evaluation, allow-
immune response with a single dose. A licensed VSV Ebola ing the early evaluation of a potential surrogate marker of
vaccine made by Merck is highly effective after a single protection, which would markedly speed licensure and dis-
dose, although its reactogenicity may be limiting in some tribution. Such data can only be obtained from harmoniza-
populations. These diverse approaches provide the potential tion and collaboration early on, during the planning of
for scalable production required for widespread population efficacy trials and the implementation of the collaboration
use. described in the figure: the use of collaborating clinical trial
sites, the monitoring of these efficacy trials through a com-
STRATEGIC COLLABORATIONS mon DSMB, independent statisticians having access to
Under the ACTIV public-private partnership, NIH has part- cross-trial data in real time, and centralized immune moni-
nered with its sister agencies in the Department of Health toring laboratories. These innovations in the process of vac-
and Human Services, including the Food and Drug Admin- cine development are required to achieve the rapid
istration, Centers for Disease Control and Prevention, and development of the platform technologies entering clinical
Biomedical Advanced Research and Development Authority; trials. Global effort, global cooperation, and transparency
other U.S. government departments including the Depart- are needed to maximize the speed, veracity, and decision-
ments of Defense and Veterans Affairs; the European Medi- making required to deliver scientific advances to the global
cines Agency; and representatives from academia, population in a timely fashion. Models for all of these pro-
philanthropic organizations, more than 15 biopharmaceuti- grams exist, and rapid implementation of these ideas is es-
cal companies, and the Foundation for NIH. This forum al- sential if we are to succeed in the timelines required to
lows for discussions and consensus on vaccine trial designs, return us to pre–COVID-19 social interactions.
rapid data sharing, and close collaborations between the
public and private sectors to rapidly and efficiently conduct SCALE UP
vaccine efficacy studies. There is an emerging consensus The ability to manufacture hundreds of millions to billions
that vaccine trials need to either use common independent of doses of vaccine requires the vaccine-manufacturing ca-
laboratories or contribute samples and data for the purpose pacity of the entire world. Although new technologies and

First release: 11 May 2020 www.sciencemag.org (Page numbers not final at time of first release) 3
factories can be developed to sustain production, there is an 9. S. M. Kissler, C. Tedijanto, E. Goldstein, Y. H. Grad, M. Lipsitch, Projecting the
immediate need to fund the necessary biomanufacturing transmission dynamics of SARS-CoV-2 through the postpandemic period.
Science 368, eabb5793 (2020). doi:10.1126/science.abb5793 Medline
infrastructure, including the fill/finish steps that provide
10. W. Liu, A. Fontanet, P.-H. Zhang, L. Zhan, Z.-T. Xin, L. Baril, F. Tang, H. Lv, W.-C.
vialed vaccine products for distribution. Cost, distribution Cao, Two-year prospective study of the humoral immune response of patients
system, cold chain requirements, and delivery of widespread with severe acute respiratory syndrome. J. Infect. Dis. 193, 792–795 (2006).
coverage are all potential constriction points in the eventual doi:10.1086/500469 Medline
delivery of vaccines to individuals and communities. All of 11. T. Bedford et al., Cryptic transmission of SARS-CoV-2 in Washington State.
these issues require global cooperation among organizations medRxiv 2020.04.02.20051417 [preprint]. 16 April 2020.
involved in health care delivery and economics. 12. S. K. Shah, F. G. Miller, T. D. Darton, D. Duenas, C. Emerson, H. Fernandez Lynch,
E. Jamrozik, N. S. Jecker, D. Kamuya, M. Kapulu, J. Kimmelman, D. MacKay, M. J.
To return to a semblance of previous normality, the de- Memoli, S. C. Murphy, R. Palacios, T. L. Richie, M. Roestenberg, A. Saxena, K.
velopment of SARS-CoV-2 vaccines is an absolute necessity. Saylor, M. J. Selgelid, V. Vaswani, A. Rid, Ethics of controlled human infection to
To achieve this goal, all the resources in the public, private, study COVID-19. Science 10.1126/science.abc1076 (2020).
and philanthropic sectors need to participate in a strategic doi:10.1126/science.abc1076
manner. The ACTIV public-private partnership and collabo- 13. K. A. Dowd, S.-Y. Ko, K. M. Morabito, E. S. Yang, R. S. Pelc, C. R. DeMaso, L. R.
Castilho, P. Abbink, M. Boyd, R. Nityanandam, D. N. Gordon, J. R. Gallagher, X.
rative harmonized efficacy trials are enabling models to
Chen, J.-P. Todd, Y. Tsybovsky, A. Harris, Y. S. Huang, S. Higgs, D. L.

Downloaded from http://science.sciencemag.org/ on May 16, 2020

achieve our common goal. Vanlandingham, H. Andersen, M. G. Lewis, R. De La Barrera, K. H. Eckels, R. G.
Jarman, M. C. Nason, D. H. Barouch, M. Roederer, W.-P. Kong, J. R. Mascola, T.
C. Pierson, B. S. Graham, Rapid development of a DNA vaccine for Zika virus.
REFERENCES AND NOTES Science 354, 237–240 (2016). doi:10.1126/science.aai9137 Medline
1. N. Lurie, M. Saville, R. Hatchett, J. Halton, Developing Covid-19 Vaccines at 14. N. Pardi, M. J. Hogan, R. S. Pelc, H. Muramatsu, H. Andersen, C. R. DeMaso, K. A.
Pandemic Speed. N. Engl. J. Med. 10.1056/NEJMp2005630 (2020). Dowd, L. L. Sutherland, R. M. Scearce, R. Parks, W. Wagner, A. Granados, J.
doi:10.1056/NEJMp2005630 Medline Greenhouse, M. Walker, E. Willis, J.-S. Yu, C. E. McGee, G. D. Sempowski, B. L.
2. J. ter Meulen, A. B. H. Bakker, E. N. van den Brink, G. J. Weverling, B. E. E. Martina, Mui, Y. K. Tam, Y.-J. Huang, D. Vanlandingham, V. M. Holmes, H. Balachandran,
B. L. Haagmans, T. Kuiken, J. de Kruif, W. Preiser, W. Spaan, H. R. Gelderblom, J. S. Sahu, M. Lifton, S. Higgs, S. E. Hensley, T. D. Madden, M. J. Hope, K. Karikó, S.
Goudsmit, A. D. M. E. Osterhaus, Human monoclonal antibody as prophylaxis for Santra, B. S. Graham, M. G. Lewis, T. C. Pierson, B. F. Haynes, D. Weissman, Zika
SARS coronavirus infection in ferrets. Lancet 363, 2139–2141 (2004). virus protection by a single low-dose nucleoside-modified mRNA vaccination.
doi:10.1016/S0140-6736(04)16506-9 Medline Nature 543, 248–251 (2017). doi:10.1038/nature21428 Medline
3. H. Bisht, A. Roberts, L. Vogel, A. Bukreyev, P. L. Collins, B. R. Murphy, K. Subbarao, 15. I. D. Milligan, M. M. Gibani, R. Sewell, E. A. Clutterbuck, D. Campbell, E. Plested, E.
B. Moss, Severe acute respiratory syndrome coronavirus spike protein Nuthall, M. Voysey, L. Silva-Reyes, M. J. McElrath, S. C. De Rosa, N. Frahm, K. W.
expressed by attenuated vaccinia virus protectively immunizes mice. Proc. Natl. Cohen, G. Shukarev, N. Orzabal, W. van Duijnhoven, C. Truyers, N. Bachmayer, D.
Acad. Sci. U.S.A. 101, 6641–6646 (2004). doi:10.1073/pnas.0401939101 Splinter, N. Samy, M. G. Pau, H. Schuitemaker, K. Luhn, B. Callendret, J. Van
Medline Hoof, M. Douoguih, K. Ewer, B. Angus, A. J. Pollard, M. D. Snape, Safety and
4. J. Huang, Y. Cao, J. Du, X. Bu, R. Ma, C. Wu, Priming with SARS CoV S DNA and Immunogenicity of Novel Adenovirus Type 26- and Modified Vaccinia Ankara-
boosting with SARS CoV S epitopes specific for CD4+ and CD8+ T cells promote Vectored Ebola Vaccines: A Randomized Clinical Trial. JAMA 315, 1610–1623
cellular immune responses. Vaccine 25, 6981–6991 (2007). (2016). doi:10.1001/jama.2016.4218 Medline
doi:10.1016/j.vaccine.2007.06.047 Medline
5. M. Bolles, D. Deming, K. Long, S. Agnihothram, A. Whitmore, M. Ferris, W.
Funkhouser, L. Gralinski, A. Totura, M. Heise, R. S. Baric, A double-inactivated ACKNOWLEDGMENTS
severe acute respiratory syndrome coronavirus vaccine provides incomplete We thank C. Dieffenbach and E. Erbelding for insightful discussion and comments,
protection in mice and induces increased eosinophilic proinflammatory and M. Miner for editorial assistance.
pulmonary response upon challenge. J. Virol. 85, 12201–12215 (2011).
doi:10.1128/JVI.06048-11 Medline Published online 11 May 2020
6. B. S. Graham, Rapid COVID-19 vaccine development. Science 10.1126/science.abc5312
10.1126/science.abb8923 (2020). doi:10.1126/science.abb8923
7. B. Rockx, T. Kuiken, S. Herfst, T. Bestebroer, M. M. Lamers, B. B. Oude Munnink, D.
de Meulder, G. van Amerongen, J. van den Brand, N. M. A. Okba, D. Schipper, P.
van Run, L. Leijten, R. Sikkema, E. Verschoor, B. Verstrepen, W. Bogers, J.
Langermans, C. Drosten, M. Fentener van Vlissingen, R. Fouchier, R. de Swart, M.
Koopmans, B. L. Haagmans, Comparative pathogenesis of COVID-19, MERS, and
SARS in a nonhuman primate model. Science 368, eabb7314 (2020).
doi:10.1126/science.abb7314 Medline
8. T. M. McMichael, D. W. Currie, S. Clark, S. Pogosjans, M. Kay, N. G. Schwartz, J.
Lewis, A. Baer, V. Kawakami, M. D. Lukoff, J. Ferro, C. Brostrom-Smith, T. D. Rea,
M. R. Sayre, F. X. Riedo, D. Russell, B. Hiatt, P. Montgomery, A. K. Rao, E. J.
Chow, F. Tobolowsky, M. J. Hughes, A. C. Bardossy, L. P. Oakley, J. R. Jacobs, N.
D. Stone, S. C. Reddy, J. A. Jernigan, M. A. Honein, T. A. Clark, J. S. Duchin,
Epidemiology of Covid-19 in a Long-Term Care Facility in King County,
Washington. N. Engl. J. Med. 10.1056/NEJMoa2005412 (2020).
doi:10.1056/NEJMoa2005412 Medline

First release: 11 May 2020 www.sciencemag.org (Page numbers not final at time of first release) 4
 Downloaded from http://science.sciencemag.org/ on May 16, 2020
The ACTIV model for SARS-CoV-2 vaccine development.

First release: 11 May 2020 www.sciencemag.org (Page numbers not final at time of first release) 5
A strategic approach to COVID-19 vaccine R&D
By Lawrence Corey, John R. Mascola, Anthony S. Fauci and Francis S. Collins

published online May 11, 2020originally published online May 11, 2020

ARTICLE TOOLS http://science.sciencemag.org/content/early/2020/05/12/science.abc5312

Downloaded from http://science.sciencemag.org/ on May 16, 2020

RELATED http://stm.sciencemag.org/content/scitransmed/12/541/eabb5883.full
CONTENT
http://stm.sciencemag.org/content/scitransmed/12/534/eabb1469.full
http://stm.sciencemag.org/content/scitransmed/11/499/eaat0360.full
http://stm.sciencemag.org/content/scitransmed/9/396/eaal3653.full
REFERENCES This article cites 14 articles, 7 of which you can access for free
http://science.sciencemag.org/content/early/2020/05/12/science.abc5312#BIBL

PERMISSIONS http://www.sciencemag.org/help/reprints-and-permissions

Use of this article is subject to the Terms of Service

Science (print ISSN 0036-8075; online ISSN 1095-9203) is published by the American Association for the Advancement of
Science, 1200 New York Avenue NW, Washington, DC 20005. The title Science is a registered trademark of AAAS.
Copyright © 2020, American Association for the Advancement of Science