Vaccine 39 (2021) 6573–6584Contents lists available at ScienceDirect
Vaccine
journal homepage: www.elsevier .com/locate /vacc ineReviewA Research and Development (R&D) roadmap for influenza vaccines:
Looking toward the futureAbbreviations: ABS, Access and Benefit Sharing; ACT, Access to COVID-19 Tools; ADCC, antibody-dependent cellular cytotoxicity; CARB-X, biopharmaceutical ac
for combating antibiotic resistant bacteria; CEPI, Coalition for Epidemic Preparedness Innovations; CIDRAP, Center for Infectious Disease Research and Policy
Collaborative Influenza Vaccine Innovation Centers; COBRA, computationally optimized broadly reactive antigen; CHIVIM, controlled human influenza virus infectio
EU, European Union; FVVA, full value of vaccine assessment; GISRS, Global Influenza Surveillance and Response System; HAI, hemagglutination-inhibit
hemagglutinin; HVAC, heating, ventilation, and air conditioning; IIV, inactivated influenza vaccines; IVR, Influenza Vaccines Research and Development (R&D) R
LAIV, live-attenuated influenza vaccines; LMICs, low- and middle-income countries; ME&A, monitoring, evaluation, and adjustment; NA, neuraminidase; NIAID, US
Institute of Allergy and Infectious Diseases; R&D, Research and Development; SME, subject matter expert; WHO, World Health Organization.
⇑ Corresponding author at: Center for Infectious Disease Research and Policy, University of Minnesota, Minneapolis, MN, USA.
E-mail address: kamoore@umn.edu (K.A. Moore).
https://doi.org/10.1016/j.vaccine.2021.08.010
0264-410X/
 2021 The Authors. Published by Elsevier Ltd.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Kristine A. Moore a,b,⇑, Julia T. Ostrowsky a, Alison M. Kraigsley a, Angela J. Mehr a, Joseph S. Bresee c,
Martin H. Friede d, Bruce G. Gellin e, Josephine P. Golding f, Peter J. Hart f, Ann Moen d, Charlotte L. Weller f,
Michael T. Osterholm a, The Influenza Vaccines R&D Roadmap Taskforce William Ampofo g, Wendy
Barclay h, Marco Cavaleri i, Cheryl Cohen j, Benjamin Cowling k, Rebecca Cox l, Ian Gustm, Bruce Innis n,
Gagandeep Kang o, Jacqueline Katz p, Florian Krammer q, Punnee Pitisuttithum r, Diane Post s, Larisa
Rudenko t, Marilda Siqueira u, Jerry Weir v
aCenter for Infectious Disease Research and Policy, University of Minnesota, Minneapolis, MN, USA
bCenter for Infectious Disease Research and Policy, C315 Mayo Memorial Building, MMC 263, 420 Delaware Street, SE, Minneapolis, MN 55455, USA
c The Global Funders Consortium for Universal Influenza Vaccine Development, The Task Force for Global Health, and the US Centers for Disease Control and Prevention, Atlanta, GA,
USA
dWorld Health Organization, Geneva, Switzerland
e The Sabin Vaccine Institute, Washington, D.C., USA
fWellcome Trust, London, United Kingdom
gUniversity of Ghana, Accra, Ghana
h Imperial College London, London, United Kingdom
iEuropean Medicines Agency, Amsterdam, the Netherlands
jNational Institute for Communicable Diseases and University of the Witwatersrand, Johannesburg, South Africa
kUniversity of Hong Kong, Hong Kong
lUniversity of Bergen, Bergen, Norway
mUniversity of Melbourne, Melbourne, Australia
n PATH Center for Vaccine Innovation & Access, Washington, D.C., USA
oChristian Medical College, Vellore, India
pUS Centers for Disease Control & Prevention (Retired), Atlanta, GA, USA
q Icahn School of Medicine at Mount Sinai, New York City, NY, USA
rMahidol University, Bangkok, Thailand
sNational Institutes of Health, Bethesda, MD, USA
t Institute of Experimental Medicine, St. Petersburg, Russia
uOswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
v Food and Drug Administration, Silver Spring, MD, USA
a r t i c l e i n f oArticle history:
Received 4 May 2021
Received in revised form 30 July 2021
Accepted 3 August 2021
Available online 30 September 2021
Keywords:
Influenza
Pandemic preparednessa b s t r a c t
Improved influenza vaccines are urgently needed to reduce the burden of seasonal influenza and to
ensure a rapid and effective public-health response to future influenza pandemics. The Influenza
Vaccines Research and Development (R&D) Roadmap (IVR) was created, through an extensive interna-
tional stakeholder engagement process, to promote influenza vaccine R&D. The roadmap covers a 10-
year timeframe and is organized into six sections: virology; immunology; vaccinology for seasonal influ-
enza vaccines; vaccinology for universal influenza vaccines; animal and human influenza virus infection
models; and policy, finance, and regulation. Each section identifies barriers, gaps, strategic goals, mile-
stones, and additional R&D priorities germane to that area. The roadmap includes 113 specific R&Dcelerator
; CIVICs,
n model;
ion; HA,
oadmap;
National
K.A. Moore, J.T. Ostrowsky, A.M. Kraigsley et al. Vaccine 39 (2021) 6573–6584Seasonal influenza vaccines
Universal influenza vaccines
Broadly protective influenza vaccines
Roadmapmilestones, 37 of which have been designated high priority by the IVR expert taskforce. This report sum-
marizes the major issues and priority areas of research outlined in the IVR. By identifying the key issues
and steps to address them, the roadmap not only encourages research aimed at new solutions, but also
provides guidance on the use of innovative tools to drive breakthroughs in influenza vaccine R&D.

 2021 The Authors. Published by Elsevier Ltd. This is an openaccess article under the CCBY license (http://
creativecommons.org/licenses/by/4.0/).Contents1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6574
2. Roadmap development process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6575
3. Key issues for influenza vaccine R&D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65753.1. Virology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6575
3.2. Immunology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6578
3.3. Vaccinology for seasonal influenza vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6578
3.4. Vaccinology for universal influenza vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6579
3.5. Animal and human influenza virus infection models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6580
3.6. Policy, financing, and regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65804. Roadmap implementation and monitoring. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6581
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6581
CRediT authorship contribution statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6581
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6581
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6582
Funding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6582
Institutional Review Board Statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6582
Data Availability Statement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6582
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65821. Introduction
Influenza virus vaccines are the cornerstone of public-health
efforts to reduce the burden of seasonal influenza and to respond
to the unpredictable emergence of pandemic influenza [1]. Current
strategies for generating seasonal influenza vaccines and for influ-
enza vaccine pandemic preparedness, however, are far from opti-
mal. Seasonal influenza vaccines are strain-specific and not
designed to provide broad protection against the continual evolu-
tion of influenza viruses. Vaccine-induced immunity is short-
lived and researchers have yet to identify determinants of durable
protective immunity (i.e., lasting 5–10 years). Production of cur-
rent seasonal influenza vaccines requires up to 6 months and can-
not begin until vaccine seed strains are selected for the upcoming
season [2]. The lag time between annual vaccine strain selection
and vaccine production leaves ample time for changes to occur
in the circulation of different virus strains and lineages, which
can lead to antigenic distinctions between the vaccine and circulat-
ing viruses. Yet even in years when the vaccine is antigenically
well-matched with circulating strains, vaccine effectiveness can
be suboptimal, partly because of egg-adapted mutations (for vacci-
nes produced in eggs) or the influence of host factors (such as age)
on the immune response [3,4]. Furthermore, the need for annual
vaccinations is an important barrier to implementing influenza
vaccination programs in many low- and middle-income countries
(LMICs), leading to variable vaccine uptake around the globe [5]
and vulnerabilities in global influenza pandemic preparedness
[6]. Even incremental improvements in the efficacy of seasonal
influenza vaccines could have a significant impact on the global
annual burden of severe seasonal influenza disease (estimated at
3–5 million cases per year) and death (estimated at 290,000 to6574650,000 deaths annually) [7]. While public health authorities advo-
cate for annual influenza vaccination programs in all countries,
governments faced with many urgent health issues and limited
resources are unlikely to act without compelling health and eco-
nomic data to support this as a priority.
Durable, universal vaccines that protect against all current and
future strains of influenza and that are suitable for use in LMICs
would be a game-changing public-health breakthrough [8]. Fur-
thermore, this advancement would have a dramatic impact on
the entire influenza vaccination enterprise by improving vaccine
effectiveness, eliminating the need and cost for developing annual
reformulations and annual vaccination campaigns, and simplifying
the entire vaccine delivery system to allow broader global imple-
mentation and access.
In addition, the occurrence of a severe influenza pandemic
remains widely recognized as a critical biological threat, even fol-
lowing the emergence of SARS-CoV-2. Our current strategy of wait-
ing until the next pandemic is detected and then formulating a
strain-specific vaccine, primarily using reliable but time-
consuming egg-based production methods, is archaic. During the
2009–10 H1N1 pandemic, for example, vaccine arrived after the
pandemic peak in many areas, limiting the utility of vaccines dur-
ing the first year of the pandemic [9–12]. As the COVID-19 experi-
ence has shown, delays in vaccine availability during a severe
pandemic can have dire consequences.
In recent years, researchers have worked toward improving sea-
sonal influenza vaccines, accelerating development and production
of those vaccines, and generating broadly protective and more dur-
able vaccines. New programs have been initiated, such as the Col-
laborative Influenza Vaccine Innovation Centers (CIVICs) program
funded by the US National Institute of Allergy and Infectious
K.A. Moore, J.T. Ostrowsky, A.M. Kraigsley et al. Vaccine 39 (2021) 6573–6584Diseases [13], the European Union (EU)-India Joint Call [14], and
the Bill & Melinda Gates Foundation Grand Challenge for Universal
Influenza Vaccine Development [15]. In addition, in 2018, NIAID
published its strategic plan for universal influenza vaccine devel-
opment [16] and in 2019, the World Health Organization (WHO)
launched the Global Influenza Strategy 2019–2030 calling for the
development of better global tools, including improved, novel,
and universal influenza vaccines, by 2030 to benefit all countries
and instill public confidence and uptake [1]. Researchers are
exploring innovative technologies, including new vaccine plat-
forms (such as virus-like particles, nanoparticles, DNA-based,
mRNA-based, recombinant proteins, and viral vectors) and novel
constructs (such as chimeric hemagglutinin [HA] vaccines, ‘‘head-
less” HA vaccines, or computationally optimized broadly reactive
antigen [COBRA] vaccines) to stimulate broadly neutralizing anti-
bodies and cross-reactive T cell immune responses [17–22]. These
innovations hold promise toward creating next-generation influ-
enza vaccines and toward streamlining the development process
to enhance timeliness and efficiency.
In response to the COVID-19 pandemic, several vaccines against
SARS CoV-2 that use novel platforms have been developed and
authorized for use. To date, these include mRNA vaccines and
adenovirus-vectored vaccines. Other vaccines using additional
platforms, such as nanoparticle technology to create subunit vacci-
nes, are in advanced clinical development at the time of this report.
This recent experience is providing valuable information about
vaccine safety for novel platforms, use of adjuvants, regulatory
pathway speed and flexibility, creative funding strategies (such
as COVAX, which is the vaccine pillar of the WHO’s Access to
COVID-19 Tools [ACT] Accelerator), and the critical importance of
equitable global vaccine allocation and distribution. Researchers
are also exploring multivalent vaccines that combine antigens for
SARS-CoV-2 and influenza [23,24] to achieve protection against
both viruses as efficiently as possible. As we gain experience with
these new approaches, the influenza vaccine research and develop-
ment (R&D) landscape may change significantly in the near future.
While recent discoveries in immunology, structural biology, and
vaccinology have moved influenza vaccine R&D forward, the goal
of achieving universal or broadly protective influenza vaccines
remains elusive. Immune responses to influenza virus infection
and vaccination are highly complex and incompletely understood,
and the scientific barriers to creating broadly protective and more
durable vaccines are formidable. Furthermore, as noted by the
Sabin-Aspen Science and Policy Group, key R&D efforts are con-
strained by fragmentation and a lack of goal-oriented coordination
[25]. Overcoming these persistent issues will likely require innova-
tive, mission-driven collaboration to garner financial investment
from around the globe, and consensus-building among stakehold-
ers regarding high-priority activities and strategies. To address
these concerns, the Global Funders Consortium for Universal Influ-
enza Vaccine Development [26] called for the development of a
global influenza vaccines R&D roadmap. In 2019, the Wellcome
Trust established funding to develop the roadmap and identified
the Center for Infectious Disease Research and Policy (CIDRAP),
University of Minnesota, to coordinate the effort.2. Roadmap development process
The Influenza Vaccines R&D Roadmap (IVR) [27], is intended to
provide a framework for prioritizing global R&D activities, with the
goal of improving the production and effectiveness of
strain-specific influenza vaccines and advancing the development,
licensure, and manufacture of durable, broadly protective or uni-
versal influenza vaccines. The IVR lays out a 10-year timeline, with6575progress on the milestones to be tracked over time and adjust-
ments made to the roadmap as necessary.
In developing the IVR, CIDRAP relied heavily on global stake-
holder engagement, using several published methodologic models
for guidance [28,29], and theWHO Generic Methodology for Devel-
oping and Implementing R&D Roadmaps for Priority Pathogens
with Epidemic Potential (unpublished). CIDRAP formed a project
steering group that included representatives from the Bill &
Melinda Gates Foundation, the Global Funders Consortium for
Universal Influenza Vaccine Development, the Sabin Vaccine Insti-
tute, the Wellcome Trust, and WHO. Steering group members met
in February 2019 to identify experts for a global IVR taskforce and
outline a framework for project development. The inital taskforce,
which was comprised of experts from 12 countries, was formed in
April 2019. The group met several times during the course of the
project, provided technical expertise, reviewed roadmap drafts,
and identified priority milestones. In fall 2020, CIDRAP convened
four online consultations for invited international subject matter
experts (SMEs) to review and discuss different sections of the
IVR; SMEs represented different areas of expertise and sectors of
the influenza research community, including industry and regula-
tion. One hundred forty-seven SMEs, representing nearly 100 dif-
ferent organizations and 20 countries, participated in one or
more of the sessions. The last phase of stakeholder engagement
was a public comment period, which involved posting the draft
IVR online during January and February 2021 and inviting com-
ments, via email and social media, from a broad group of global
stakeholders. We received 109 sets of comments from stakeholders
in 26 countries; each comment was reviewed by CIDRAP staff and
adjudicated as deemed appropriate.3. Key issues for influenza vaccine R&D
The IVR is organized into six sections: virology, immunology,
vaccinology for seasonal influenza vaccines, vaccinology for uni-
versal influenza vaccines, animal and human influenza virus infec-
tion models, and policy, finance, and regulation. Each section
identifies barriers, gaps, strategic goals, milestones, and additional
R&D priorities germane to that topic. The IVR includes 113 mile-
stones across the six sections, with 37 identified as high priority
(Table 1). The strategic goals are intended to be relatively general,
whereas the milestones generally follow the SMART format (speci-
fic, measurable, achievable, realistic/relevant, and time-sensitive).
The sections below summarize the major issues for each of the
six sections, with a particular focus on areas considered high
priority.3.1. Virology
Global influenza virus surveillance tracks antigenic drift of
influenza viruses, providing essential data for annual reformula-
tion of seasonal influenza vaccines. The WHO Global Influenza
Surveillance and Response System (GISRS), an international net-
work of national influenza centers, WHO collaborating centers
and essential regulatory laboratories, and other groups, is respon-
sible for tracking influenza viruses around the globe [30]. The
GISAID Initiative is another key organization that promotes the
rapid sharing of virologic data to help researchers understand
how influenza viruses evolve and spread during epidemics and
pandemics [31]. Additional sequence data could also provide criti-
cal early information on an emerging pandemic virus. For example,
the first SARS-CoV-2 genetic sequences were made available on
GISAID’s EpiCoV platform on January 10, 2020, which allowed
manufacturers to begin the COVID-19 vaccine development pro-
cess [32]. Although these activities provide an essential function,
K.A. Moore, J.T. Ostrowsky, A.M. Kraigsley et al. Vaccine 39 (2021) 6573–6584
6576
Table 1
IVR High-Priority Milestones by Topic Area and Strategic Goal.
Strategic goal* Milestone*
Virology

 Strategic Goal 1.2: Enhance the ability to forecast viruses that are likely to circulate in the upcoming sea- 
 Milestone 1.2.e. By 2025, develop, standardize, and implement methods to improve antigenic characteri-
son to improve the antigenic match between circulating influenza viruses and viral strains selected for zation of H1N1 and H3N2 influenza viruses.
seasonal vaccine production.
Immunology and Immune Correlates of Protection

 Strategic Goal 2.2: Gain better understanding of human immunology to inform influenza vaccine devel- 
 Milestone 2.2.c. By 2027, determine key mechanisms of long-term protection following influenza infection
opment through basic research focused on the use of new tools and technologies. (i.e., immunity lasting at least several years), including the discovery of early biomarkers associated with
durable immune responses, to inform the development of durable vaccine-induced protection.

 Strategic Goal 2.4: Determine the impact of prior influenza virus infection or vaccination on the future 
 Milestone 2.4.b. By 2026, determine through prospective birth-year cohort studies how repeated influenza
immune responses to influenza viruses or vaccines. vaccinations affect the immune response to subsequent influenza vaccinations.

 Milestone 2.4.c. By 2028, determine how the initial encounter with an influenza virus (i.e., immune
imprinting) affects B and T cell responses including immunologic responses to subsequent influenza virus
infection or vaccination.

 Milestone 2.4.d. By 2029, determine if vaccination with IIV vs. LAIV of very young children before their first
encounter with influenza virus has a significant impact on future influenza vaccine responses.

 Strategic Goal 2.6: Improve understanding of the role of mucosal immunity in protecting against 
 Milestone 2.6.b. By 2023, further determine the role of mucosal antibodies in protecting against influenza
influenza. virus infection, disease, and transmission.

 Milestone 2.6.d. By 2026, determine the role of mucosal T cells in protecting against influenza virus infec-
tion, disease, and transmission.

 Strategic Goal 2.7: Develop novel correlates of protection for assessing seasonal influenza vaccines and 
 Milestone 2.7.a. By 2025, develop functional assays to accurately capture the breadth and range of protec-
broadly protective or universal influenza vaccines, as part of clinical studies that demonstrate efficacy tive responses other than virus neutralization, such as influenza virus-specific ADCC, antibody-dependent
against a disease endpoint. cellular phagocytosis, and complement dependent cytotoxicity.

 Milestone 2.7.b. By 2028, develop new measurement tools, including qualified correlates of protection, for
mucosal immunity, particularly for assessing LAIVs or other mucosal vaccines if developed.
Vaccinology for Seasonal Influenza Vaccines

 Strategic Goal 3.2: Identify strategies and policies to optimize seasonal influenza vaccines and improve 
 Milestone 3.2.b. By 2022, convene a workshop to review the development of novel platforms (e.g., mRNA-
vaccine effectiveness. based) for COVID-19 vaccines to identify how best to apply them to development of improved seasonal
influenza vaccines.

 Milestone 3.2.e. By 2024, determine optimum methods for assessing vaccine effectiveness of conventional
egg-based and cell culture-based vaccines in comparison to vaccines created using new technologies, in
coordination with regulatory agencies and using consistent endpoints, to allow data to be combined as
appropriate over multiple seasons and to allow better comparability of data across studies.

 Milestone 3.2.h. By 2028, evaluate the effectiveness of alternate routes of vaccine delivery (e.g., intranasal,
oral, intradermal needle-free administration, and topical routes) in preclinical and clinical studies, to iden-
tify new mechanisms of immune protection, such as enhancement of mucosal immunity.

 Strategic Goal 3.4: Further assess the role of existing and new adjuvants in creating next-generation 
 Milestone 3.4.b. By 2026, determine, through clinical studies, if any promising new adjuvant candidates
improved seasonal influenza vaccines, informed by recent R&D with adjuvants in new COVID-19 vaccines. under investigation can substantially improve the immune response to influenza vaccines in the elderly
and assess their safety profiles.

 Milestone 3.4.c. By 2026, determine, through clinical studies, if any existing adjuvants substantially
improve the immune response to influenza vaccines in the very young (e.g., as an initial vaccination fol-
lowed by non-adjuvanted vaccines) and assess their safety profiles.

 Strategic Goal 3.5: Determine the role of NA as a vaccine antigen for improving vaccine effectiveness and 
 Milestone 3.5.d. By 2025, determine if the presence of NA improves seasonal influenza vaccines, and, if so,
immunogenicity of seasonal influenza vaccines. establish the optimal dose of NA that improves immunogenicity and effectiveness.
Vaccinology for Broadly Protective or Universal Influenza Vaccines

 Strategic Goal 4.1: Identify the most promising broadly protective or universal influenza vaccine candi- 
 Milestone 4.1.d. By 2022, convene a workshop to review the development of novel platforms (e.g., mRNA-
dates that elicit durable protection against influenza viruses in preclinical studies, with a focus on target- based) for COVID-19 vaccines to identify how best to apply them to broadly protective or universal influ-
ing conserved regions of the virus. enza vaccines. (See similar milestone under Vaccinology for Seasonal Influenza Vaccines).

 Milestone 4.1.e. By 2024, identify the most promising influenza vaccine candidates that elicit robust and
broadly protective immunity.

 Strategic Goal 4.2: Evaluate the most promising broadly protective or universal influenza vaccine candi- 
 Milestone 4.2.e: By 2023, develop consensus on streamlining clinical research for evaluating broadly pro-
dates, using at least several different platforms, in clinical trials, informed by recent experience with tective influenza vaccines, drawing on COVID-19 vaccine experience.
SARS-CoV-2 vaccine trials. 
 Milestone 4.2.f: By 2024, identify several vaccine candidates that demonstrate broad—based immunity—
humoral, cell—mediated, or both—in preclinical research and assess them for safety and immunogenicity
in phase 1 clinical trials in healthy adults.
K.A. Moore, J.T. Ostrowsky, A.M. Kraigsley et al. Vaccine 39 (2021) 6573–6584
6577
Table 1 (continued)
Strategic goal* Milestone*

 Milestone 4.2.g: By 2024, determine correlates of protection for assessing broadly protective or universal
influenza vaccines that are appropriate for different stages of vaccine development.

 Milestone 4.2.h: By 2025, identify the most promising vaccine candidates from phase 1 trials and advance
them into phase 2 or directly to phase 3 clinical trials in at-risk populations.

 Milestone 4.2.i: By 2027, identify the most promising vaccine candidates from phase 2 trials for general
and pediatric populations that demonstrate broad protection and provide durable immunity (more than
1 year) and assess them for efficacy in phase 3 clinical trials.
Influenza Research in Animal Models and Human Viral Infection Models
Strategic Goal 5.1: Optimize animal models for influenza vaccine research. 
 Milestone 5.1.b. By 2022, ensure that validated reagents, updated viral stocks, and harmonized assays are
available to improve understanding of the innate and adaptive immune responses in ferrets and to facilitate
cross-comparison of different research studies across different laboratories.

 Milestone 5.1.e. By 2023, convene a workshop on the development of pre-exposure animal models to
address the fact that humans generally have pre-existing immunity to influenza.

 Milestone 5.1.f. By 2025, complete and publish a comprehensive analysis of the predictive value of differ-
ent animal models, including natural hosts such as pigs and horses, for influenza vaccine studies (both sea-
sonal and broadly protective vaccines).

 Milestone 5.1.g. By 2026, develop and validate novel animal models, as needed, for evaluating immune
responses—including durability—to broadly protective influenza vaccines.
Strategic Goal 5.2: Address steps needed to further develop and refine the CHIVIM. 
 Milestone 5.2.a. By 2022, determine the use cases for the CHIVIM and generate guidance, including ethical
and safety considerations, for using the model.

 Milestone 5.2.b. By 2023, ensure that reagents for the CHIVIM are broadly available.

 Milestone 5.2.c. By 2023, ensure that a biorepository of diverse, accessible, and well-characterized chal-
lenge stocks is generated and made available to investigators.

 Milestone 5.2.d. By 2024, further develop the CHIVIM to ensure that it can be widely operationalized by
different investigators.
Policy, Finance, and Regulation

 Strategic Goal 6.1: Catalyze broad support and sustained funding for developing improved seasonal influ- 
 Milestone 6.1.a. By 2022, develop and disseminate a full value of vaccine assessment (FVVA) for improved
enza vaccines and broadly protective or universal influenza vaccines. seasonal and broadly protective, universal influenza vaccines that addresses different vaccine use cases and
includes an assessment for LMICs.

 Milestone 6.1.b. By 2022, develop targeted and creative communications and advocacy strategies and nec-
essary communications tools that build on the FVVA and provide information on economic costs, the risks
of future influenza pandemics, and the need for investment in influenza vaccine R&D.

 Strategic Goal 6.2: Promote innovation for developing improved seasonal influenza vaccines and broadly 
 Milestone 6.2.a. By 2022, distill lessons learned from experience with COVID-19 vaccine R&D, including
protective or universal influenza vaccines. clinical research and study designs, manufacturing, distribution, advocacy, financing, and global
collaboration.
Milestone 6.2.b. By 2023, identify a set of strategies for accelerating the development of universal influenza
vaccines through innovative approaches.

 Strategic Goal 6.3: Promote information sharing aimed at moving influenza vaccine development 
 Milestone 6.3.c: By 2022, assess the impact of the Nagoya protocol, and possibly related national ABS leg-
forward. islation, on sharing of influenza isolates and gene sequences in relation to influenza vaccine R&D and deter-
mine strategies to address potential unintended consequences.

 Strategic Goal 6.4: Further explore regulatory challenges associated with development and manufactur- 
 Milestone 6.4.a: By 2022, conduct a workshop that includes regulators and vaccine manufacturers to: (1)
ing of improved seasonal and broadly protective or universal influenza vaccines. clarify regulatory processes related to the development and evaluation of broadly protective or universal
influenza vaccines, (2) develop a regulatory science agenda that anticipates the challenges of evaluating
and licensing these new vaccines, (3) review the regulatory experience with COVID-19 vaccines and iden-
tify ways to streamline the process for new influenza vaccines, and (4) generate additional recommenda-
tions regarding how best to provide guidance on vaccine development, manufacture, approval, and
delivery.

 Milestone 6.4.b. By 2023, identify a framework to address post-marketing assessment of safety and effec-
tiveness of new broadly protective or universal influenza vaccines.
Abbreviations: ABS, Access and Benefit Sharing; ADCC, antibody-dependent cellular cytotoxicity; CHIVIM, controlled human influenza virus infection model; FVVA, full value of vaccine assessment; IIV, inactivated influenza
vaccines; LAIV, live-attenuated influenza vaccines; NA, neuraminidase; R&D, research and development; SARS-CoV-2; severe acute respiratory syndrome coronavirus 2.
*The milestones identified above reflect only those that were deemed to be of high priority. They are organized by the order in which they appear in the Influenza Vaccines R&D Roadmap and reflect the numbering scheme of the
roadmap. To see all goals and milestones, please refer to the complete roadmap.
K.A. Moore, J.T. Ostrowsky, A.M. Kraigsley et al. Vaccine 39 (2021) 6573–6584surveillance is not uniformly distributed globally and there are
populations for which surveillance data are limited [33]. To
enhance understanding of influenza virus evolution and to
improve capabilities to predict changes over time (and thereby cre-
ate improved seasonal influenza vaccines), greater geographic
diversity of influenza virus sequence data and increased metadata
collection are needed. Efforts to increase global capacity for SARS-
CoV-2 surveillance align with and support this need. Additionally,
new tools (such as computational approaches and systems biology)
could be more broadly applied to facilitate understanding of influ-
enza virus evolution—particularly the emergence of novel influ-
enza viruses with pandemic potential [16,34]. In part because of
continuous viral evolution, antigenic mismatches between vaccine
strains and circulating influenza strains occur, particularly for the
H3N2 subtype; therefore, continuing efforts are needed to improve
methods for antigenic characterization of H3N2 viruses, despite
recent progress in this area [35].
To address these considerations, the IVR virology section high-
lights the following key activities relevant to influenza vaccine
R&D: (1) improving understanding of human and animal influenza
virus evolution, particularly using functional assays to identify rel-
evant epitopes, with the goal of enabling predictions of phenotypes
from genotypes [36,37]; (2) enhancing the ability to forecast the
range of viruses likely to circulate in the upcoming season to
improve the antigenic match between circulating influenza viruses
and viral strains selected for vaccine production; (3) developing,
standardizing, and implementing methods to improve antigenic
characterization of influenza A H1N1 and H3N2 viruses [38–40];
and (4) improving the ability to detect and understand the emer-
gence of novel influenza viruses with pandemic potential.
3.2. Immunology
The current lack of a comprehensive understanding of human
immunology and interactions among the many components of
the immune system limits the pace and direction of influenza vac-
cine R&D [41]; innovative new strategies needed for improved
influenza vaccines may result from discoveries not yet identified
in existing research. Furthermore, many critical issues remain
unresolved. For example, differences between immune responses
to influenza virus infection versus influenza vaccination are inade-
quately understood and require further research [42]. Second,
more information is needed on the immune factors required for
inducing broad protection against influenza viruses [16,43,44]
and the mechanisms that induce durable immunity, such as activa-
tion of long-lived plasma cells in the bone marrow [45]. This
involves improving scientific understanding of both the humoral
and cell-meditated immune responses to influenza virus infection
and vaccination, particularly regarding immunodominance hierar-
chies of the antibody response and how immunodominance can be
overcome [4,46–48]. Third, the role of mucosal immunity is a crit-
ical research topic for influenza vaccine development, including
determining the potential magnitude of mucosal immunity elicited
by influenza virus infection or vaccines and understanding the dri-
vers of myeloid and lymphoid cell differentiation and migration to
protect upper and lower respiratory airways [45,49,50]. Fourth, the
role of immune imprinting from early childhood exposure on influ-
encing subsequent immune responses to influenza virus infection
or vaccination requires further understanding [51–53]. A related
issue is the need to clarify the roles that repeated influenza virus
infection and/or annual seasonal vaccination play in determining
the immune response to subsequent vaccinations [54–57]. Finally,
efforts are needed to further clarify the role of the T-cell response
in protecting against severe influenza disease [58], since protection
against severe disease is of particular importance for vaccines for-
mulated for use in LMICs.6578To date, the most commonly used marker for immune response
to influenza virus infection or vaccination is the serum
hemagglutination-inhibition (HAI) antibody titer; however, HAI
titers have limitations in predicting vaccine effectiveness, particu-
larly for older adults, and do not provide a comprehensive assess-
ment of immunity [59,60]. Additional correlates of protection,
potentially involving multiple correlates or complex correlates,
are needed to evaluate immune responses from universal or
broadly protective influenza vaccine candidates [61–63]. A corre-
late of protection is also needed for assessing mucosal immunity
(e.g., through measurement of mucosal antibodies). Additionally,
reagents, and standardized, harmonized assays are needed to eval-
uate non-HA head immune responses [59,64] and to assess and
quantify T-cell immune responses [65,66]. Systems biology has
the potential to identify molecular predictors or correlates of pro-
tection and may be able to provide insights into some of the key
immunologic questions.
To address these issues, the IVR immunology section focuses
on: (1) ensuring availability of critical tools for immunologic
research involving next-generation influenza vaccines; (2) con-
ducting basic research aimed at achieving a more comprehensive
understanding of human immunology to inform influenza vaccine
development, including the use of new tools, such as systems biol-
ogy; (3) determining key mechanisms of long-term protection (i.e.,
lasting at least several years), including clarifying the roles of CD4
and CD8 T cells and antibodies to various epitopes (e.g., HA, NA
[neuraminidase], M2e, and epitopes in conserved internal proteins)
[64]; (4) determining the impact of prior influenza virus infection
or vaccination on future immune responses to influenza viruses
or vaccines [53,67–69]; (5) improving understanding of the B-cell
immune responses to influenza that are important for develop-
ment of broadly protective immunity, particularly in the context
of partial pre-existing immunity from continual exposure to influ-
enza viruses; (6) clarifying the role of T cells in generating or sup-
porting protective immunity to influenza virus infection and
vaccination (including prevention of severe disease); (7) determin-
ing the critical role of mucosal immune responses in protecting
against influenza virus infection, disease, and transmission; and
(8) developing novel correlates of protection for assessing next-
generation influenza vaccines, as part of randomized controlled
clinical trials that evaluate vaccine efficacy.
3.3. Vaccinology for seasonal influenza vaccines
Critical limitations with seasonal influenza vaccines are subop-
timal vaccine effectiveness (particularly in the elderly), variable
effectiveness from year to year, and long production times. From
2004 to 2018 in the United States, average annual estimates of
influenza vaccine effectiveness against medically attended illness
ranged from 10% to 60% [70]. Also, during the 2016–17 influenza
season, the overall vaccine effectiveness at six international sites
in Canada, Mexico, Russia, Spain, and Turkey was estimated at
27% [71]. Even a 10% to 15% improvement in vaccine effectiveness
for seasonal vaccines could have an important impact on the global
annual health burden of influenza as evidenced by a recent study
in the United States [72]. Potential strategies to incrementally
improve vaccine effectiveness of current seasonal influenza vacci-
nes include evaluating alternative platforms to deliver HA antigens
(e.g., mRNA-based vaccines) or combinations of licensed products
(potentially as part of prime-boost regimens), adjusting HA antigen
doses for different populations and age groups, expanding the use
of adjuvants, and determining the role of NA as a vaccine antigen
[17,73–76]. The development of alternative approaches to vaccine
delivery (such as microarray patches or other needle-free injection
systems) may also lead to significant advantages to enhance sea-
sonal vaccination programs in LMICs and pandemic-response
K.A. Moore, J.T. Ostrowsky, A.M. Kraigsley et al. Vaccine 39 (2021) 6573–6584capabilities. Second, current production methods lead to a long lag
time (i.e., 5–6 months) for annual seasonal influenza vaccine devel-
opment. New platforms, such as those applied to COVID-19 vacci-
nes, could reduce the production time significantly. Third, seasonal
influenza vaccines need to be more suitable for use in LMICs by
offering better protection against severe disease and providing
more durable protection to avoid the need for annual reformula-
tions and vaccinations [8].
With regard to optimizing seasonal influenza vaccine effective-
ness, key strategic goals outlined in the IVR include: (1) promoting
strategies that shorten the lag time from identification of candidate
vaccine viruses through the vaccine development and distribution
process, such as exploring use of new platforms (e.g., mRNA-
based); (2) determining strategies and policies to optimize vaccine
effectiveness, including identifying key lessons learned from the
COVID-19 pandemic; (3) improving the ability to assess the impact
of seasonal influenza vaccines on preventing severe disease (par-
ticularly for use in LMICs) and to support development of influenza
vaccines that protect against severe disease; (4) further assessing
the role of existing and new adjuvants for improving vaccine effec-
tiveness [76,77] and possibly offering cross-protection [78]; and
(5) clarifying the role of NA in improving vaccine effectiveness.
3.4. Vaccinology for universal influenza vaccines
The definitions for universal or broadly protective influenza
vaccines have not been standardized and several have been pro-
posed (Table 2) [15,22,25,26,75,79]. Most have suggested that a
truly universal vaccine should provide long-term (several years
to life-long) protection against all drifted and shifted influenza A
and B strains (including pandemic strains and zoonotic strains).
The US NIAID strategic plan for guiding research toward improved
influenza vaccines identified the goals for universal influenza vac-
cines as: (1) at least 75% effective against symptomatic influenzaTable 2
Universal Influenza Vaccines: Definitions and Key Features.
Source Definitions
Bill & Melinda Gates 
 Universal influenza vaccines: ‘‘protection from
Foundation Grand mortality caused by all subtypes of circulatin
Challenges Initiative [15] (drifted and shifted) influenza A subtype virus
B lineage viruses for at least 3–5 years.”
European Commission 
 Next-generation influenza vaccines: improve
European Union–India safety; improved duration of immunity; react
Collaboration for Next increased breadth of influenza strains and/or
Generation Influenza of a large-scale influenza pandemic; suitable fo
Vaccines [14] ulations and LMICs.
Global Funders Consortium for 
 Universal influenza vaccine: high efficacy; induc
Universal Influenza Vaccine a broad array of influenza A viruses (and perh
Development [26] viruses); prevents severe disease; confers more
nity than current vaccines; prevents seasona
influenza; cost-effective for low- and high-reso
National Institute of Allergy & 
 Universal influenza vaccine: goal of at least 7
Infectious Diseases against symptomatic influenza virus infection;
A Universal Influenza Groups 1 and Group 2 influenza A viruses (se
Vaccine: The Strategic Plan influenza B viruses); durable protection for at
for the NIAID [16] preferably through multiple seasons; suitab
groups.
Sabin-Aspen Vaccine Science & 
 Universal influenza vaccine: safe and highly eff
Policy Group groups, against any strain; confers lifelong imm
Accelerating the
Development of Universal
Influenza Vaccine [25]
World Health Organization 
 Universal-type influenza A vaccines: protection
Preferred Product influenza A virus illness for at least 5 years; su
Characteristics for Next- risk groups in LMICs.
Generation Influenza
Vaccines [8]
Abbreviations: LMICs, low- and middle-income countries; NIAID, US National Institute
6579virus infection, (2) protective against phylogenetic groups 1 and
2 influenza A viruses, (3) capable of providing durable protection
for at least 1 year, and (4) suitable for all age groups [16]. For the
purposes of the IVR, a universal influenza vaccine ‘‘is one that
offers protection against all influenza A and B viruses, including
seasonal viruses and existing or emerging zoonotic viruses with
pandemic potential.” A broadly protective influenza vaccine ‘‘offers
protection against multiple influenza viruses (i.e., is not strain-
specific) but does not meet the criteria for a universal vaccine.
For example, a broadly protective vaccine could confer protection
against all strains within a single HA subtype (subtype-specific),
multiple HA subtypes within a single group (multi-subtype), all
group 1 or group 2 influenza A viruses (pan-group), or all influenza
B viruses.”
To generate universal or broadly protective influenza vaccines,
new approaches are needed for immunogen design to achieve
robust immune responses to conserved regions of the influenza
virus [79–81]. This may require identifying successful strategies
for overcoming immunodominance of the HA globular head
domain [82,83]. Universal influenza vaccine constructs may also
need to include multiple antigenic targets to provide broadly pro-
tective and durable immunity against a wide range of influenza
viruses [84], particularly including conserved antigens targeted
by T cells, given that broad T-cell responses appear to be associated
with asymptomatic or mild disease [85].
While many promising vaccine candidates for broadly protec-
tive or universal influenza vaccines are under study, clinical devel-
opment requires overcoming a variety of significant logistical
challenges, such as conducting clinical trials over multiple seasons
with different circulating viruses and demonstrating immuno-
genicity without well-established correlates of protection [19,22].
Furthermore, resources for conducting large efficacy trials are lim-
ited, necessitating the selection of the most promising candidates
for advancement through clinical trials [50,63]. The strategic goalsTarget viruses Duration of Target population
protection
morbidity and All influenza A Minimum of 3– All age groups,
g and emerging viruses and 5 years especially in
es and influenza influenza B viruses developing
countries
d efficacy and Increased breadth Improved Different
ivity against an of influenza strains duration of populations and
from the outset immunity LMICs
r different pop-
es immunity to Influenza A viruses More durable All
aps influenza B and perhaps than current
durable immu- influenza B viruses influenza
l and pandemic vaccines
urce settings.
5% effectiveness Group 1 and Group Durable All age groups
protects against 2 influenza A protection for at
condary target, viruses least 1 year
least 1 year and
le for all age
ective in all age All influenza Lifelong All age groups
unity. viruses
against severe Influenza A viruses At least 5 years High-risk groups
itable for high- in LMICs
of Allergy and Infectious Diseases.
K.A. Moore, J.T. Ostrowsky, A.M. Kraigsley et al. Vaccine 39 (2021) 6573–6584and milestones in the universal vaccines section of the IVR, there-
fore, focus on identifying the most promising broadly protective or
universal influenza vaccine candidates that elicit durable protec-
tion against influenza viruses in preclinical studies [80,81,86] and
evaluating those candidates in phase 1 through phase 3 clinical tri-
als, with a particular focus on determination of efficacy rather than
just immunogenicity. Recent experience with COVID-19 vaccines
suggests that the clinical trial process could be streamlined to
move more quickly to phase 2/3 clinical trials or to run clinical tri-
als in parallel once vaccine safety is established.
3.5. Animal and human influenza virus infection models
Experimental animal models provide an important research
tool for evaluating influenza virus transmission, pathogenesis,
and immune responses to vaccination. Currently, a number of ani-
mal models exist for studying influenza (e.g., mice, ferrets, guinea
pigs, swine, horses, and nonhuman primates [NHPs]). While these
models provide valuable information, an ideal animal model for
influenza has not yet been identified and further efforts are needed
to bridge the gap between animal studies and human outcomes.
For example, influenza disease in certain animal models does not
accurately mimic disease in humans and the complex exposure
history to influenza virus in humans is difficult to recreate in ani-
mal models [87–90]. Key activities in the IVR for optimizing animal
models include: (1) ensuring that validated reagents, harmonized
assays, and updated viral stocks are available for use in key models
such as ferrets; (2) clarifying issues around development of pre-
exposure animal models [88]; (3) publishing a comprehensive
analysis of the predictive value of different animal models for
influenza vaccine studies; and (4) developing and validating novel
animal models, as needed, for evaluating immune responses and
durability to broadly protective influenza vaccines [88].
The controlled human influenza virus infection model (CHIVIM)
could be used to surmount certain important clinical research hur-
dles in developing broadly protective or universal influenza vac-
cines. Although much progress has been made recently in
moving the CHIVIM forward [91,92], important issues remain, such
as lack of standardization for certain key elements of the model,
limited access to challenge viruses, lack of harmonized protocols,
the need for better definition of endpoints (particularly for deter-
mining mucosal immunity), the need for agreed-upon criteria for
selection of challenge strains, regulatory challenges, and environ-
mental considerations (such as heating, ventilation, and air condi-
tioning [HVAC] systems) [91]. Key issues in the IVR for advancing
the CHIVIM include: (1) determining the use cases for the CHIVIM
and generating guidance (to include ethical and safety considera-
tions) for using the model; (2) ensuring that reagents for using
the CHIVIM are broadly available to investigators; (3) ensuring that
a biorepository of diverse, accessible, and well-characterized chal-
lenge stocks is generated and made available to investigators; and
(4) further developing the CHIVIM to ensure that it can be widely
operationalized by different investigators around the globe. Two
human infection studies for COVID-19 have recently been
launched in the United Kingdom [93,94]; these efforts may yield
important information applicable to the CHIVIM.
3.6. Policy, financing, and regulation
The majority of the estimated 1.48 billion doses of seasonal
influenza vaccine produced each year are manufactured using rel-
atively time-consuming but reliable conventional egg-based pro-
duction methods [95]. The size and scope of this existing global
market for influenza vaccines is a barrier to investment in new,
durable, and broadly protective influenza vaccines, since the com-
panies that profit from this commercial model may be resistant to6580change. Furthermore, bringing new vaccines to market requires
overcoming significant financial hurdles. For example, a new pro-
duct must cross the ‘‘valley of death” during the development pro-
cess. This period encompasses early clinical trials through phase 3
trials to the point of regulatory approval and early commercializa-
tion. During this time, substantial costs are incurred while out-
comes are uncertain and no revenue is generated [96]. A root
cause of the ‘‘valley of death” for new vaccines is that an asymme-
try of risk exists, where manufacturers take on much of the risk
and the public sector is not balancing that risk with sufficient com-
mitments and funding. Additional creative mechanisms (such as
push/pull incentives and non-dilutive funding [i.e., funding that
does not drain company equity]) are needed to further de-risk
influenza vaccine R&D [97,98].
Currently, a coordinated commitment to sustained funding for
developing next-generation or universal vaccines is lacking. Efforts
are needed to catalyze broad support and funding for developing
next-generation seasonal influenza vaccines and broadly protec-
tive or universal influenza vaccines. The IVR calls for development
of a full value of vaccine assessment (FVVA) [99] for improved
influenza vaccines that addresses different vaccine use cases for
preventing seasonal and pandemic influenza and includes an
assessment for LMICs. The IVR also advocates for targeted and cre-
ative communications and advocacy strategies that build on the
FVVA. These need to be explicitly designed to highlight the impact
of influenza, the urgency of the global need for a universal influ-
enza vaccine, and the social and economic costs of not developing
improved vaccines for seasonal and pandemic influenza. These
tools should be aimed at informing policy makers, funders,
researchers, healthcare providers, and the general public about
influenza-related health and economic costs, the risk of future
influenza pandemics, and the need for investment in influenza vac-
cine R&D [25,100]. One priority milestone in the IVR is to distill the
lessons learned from recent experience with COVID-19 vaccine
R&D to inform future work on influenza vaccines and to address
a number of these considerations.
The IVR also calls for efforts to explore the feasibility of creating a
newpublic-privateenterprisewithrobustfunding,aimedatmission-
driven R&D for universal influenza vaccines, similar to the biophar-
maceutical accelerator for combating antibiotic resistant bacteria
(known as CARB-X), which was established in July 2016 [101].
Anotherapproachis toaligntheworkof theIVRwiththatof theCoali-
tion for Epidemic Preparedness Innovations (CEPI) [102]. CEPI will
continue to focus on pandemic and epidemic preparedness in the
future,withanemphasisonglobalequitableaccess formedicalcoun-
termeasures; implementation of the IVR could potentially be folded
intothatwork.AsweemergefromtheCOVID-19pandemic,therewill
likelybeanevolvingglobalecosystemofvaccineR&Dwithneworga-
nizational coalitions forming that could also be engaged in moving
the IVRmilestones forward.
Another key issue is the need for improved data sharing around
the globe. While GISRS and GISAID have successfully fostered
international sharing of influenza virus isolates and gene
sequences for years, certain provisions of the Nagoya Protocol
[103] may restrict utilization of influenza viruses. Additionally,
mechanisms to improve data management and sharing among aca-
demic, industry, and government developers are needed. Also,
challenges with mapping (and potentially sharing) of intellectual
property and proprietary technologies continue to be barriers to
influenza vaccines R&D. Finally, improved innovation and coordi-
nation are needed to maximize the value of research on influenza
vaccines, such as exploring options for reuse of influenza vaccine
study data.
Clarity regarding regulatory requirements, potentially including
the use of innovative approval pathways, will be needed for licens-
ing broadly protective or universal influenza vaccines. Alternative
K.A. Moore, J.T. Ostrowsky, A.M. Kraigsley et al. Vaccine 39 (2021) 6573–6584pathways will likely require the development of additional tools,
such as new potency assays and new correlates of protection or
immune markers likely to predict protection. Different vaccine
goals (such as short- vs. long-term protection or protection against
severe vs. mild disease) may require different clinical trial designs,
which pose challenges for clinical evaluation. Key activities in the
IVR related to regulatory science include: (1) clarifying regulatory
processes for developing and evaluating broadly protective or uni-
versal influenza vaccines, (2) developing a regulatory science
agenda that anticipates the challenges of evaluating and licensing
new broadly protective or universal influenza vaccines and incor-
porates lessons learned from recent experience with COVID-19
vaccines, (3) promoting international regulatory harmonization,
and (4) developing a framework to improve post-marketing assess-
ment of safety and effectiveness of new broadly protective or uni-
versal influenza vaccines.4. Roadmap implementation and monitoring
In late July 2021, the IVR expert taskforce met virtually to begin
considering active strategies for implementing the IVR. This meet-
ing focused on developing ongoing structures and mechanisms to:
(1) promote ownership and ‘‘buy in” of the IVR by key R&D part-
ners, (2) enhance coordination of activities across the influenza
vaccine R&D ecosystem, (3) monitor and assess roadmap progress
over time, and (4) identify gaps in progress and create strategies to
address them. A website is being established at CIDRAP for moni-
toring, evaluation, and adjustment (ME&A) related to the IVR over
time; current and future versions of the IVR can be accessed
through this site [27]. The site will also contain a brief executive
summary and other communications tools to increase accessibility
of the roadmap. During the implementation meeting, taskforce
members discussed the most critical and immediate needs for
influenza vaccine R&D, using the high-priority milestones as a
starting point; during this discussion the taskforce developed con-
sensus on several issues. First, for immunology, the taskforce
agreed that a critical need is to determine the key mechanisms
of long-term protection following influenza infection to inform
the development of durable influenza vaccines. Second, for vacci-
nology, the taskforce agreed that an immediate need is to review
the novel platforms (e.g., mRNA-based) for COVID-19 vaccines to
determine how best to apply them to developing improved sea-
sonal vaccines and to enhance pandemic preparedness. A third
critical need, also under vaccinology, is to draw on the COVID-19
vaccine experience to streamline clinical research for evaluating
broadly protective or universal influenza vaccines. A fourth critical
need is to clarify regulatory processes for developing broadly pro-
tective or universal influenza vaccines, including developing a reg-
ulatory science agenda that anticipates and addresses challenges in
evaluating and licensing new products. Part of this process will be
to provide guidance to industry on vaccine development, manufac-
ture, approval, and delivery.5. Conclusion
The COVID-19 experience has clearly illustrated the global
impact of a severe pandemic respiratory virus and demonstrates
the value of rapid vaccine development and delivery in preventing
the potentially devastating health, social, and economic effects. A
preparedness mindset—in advance of a pandemic—could prevent
the catastrophic consequences that the global community has
endured since early 2020 and that will continue to impact global
health, social, and economic systems for years to come [104,105].
Furthermore, efforts to improve seasonal influenza vaccines and
to generate universal or broadly protective vaccines go hand-in-6581hand. For example, improving seasonal influenza vaccines will
enhance their usefulness in LMICs, leading to expansion of
country-based influenza vaccination programs, which will reduce
the burden of season influenza and also provide critical infrastruc-
ture for global pandemic preparedness. Development of universal
vaccines will dramatically enhance pandemic preparedness by
ensuring that vaccines are available at the onset of the next pan-
demic. Achieving the high-priority milestones identified in the
IVR, however, will require enhanced coordination and potentially
new public-private partnerships, including increased investment
by industry and sustained funding from government agencies
and philanthropic organizations.
By defining the specific barriers and gaps, the roadmap invites
not only current influenza investigators to generate new solutions,
but also provides initial direction for transdisciplinary innovators
to apply emerging tools that can drive breakthroughs in influenza
vaccine R&D. The IVR can also serve as an important catalyst for
generating and focusing the resources necessary to make improved
seasonal influenza vaccines and broadly protective or universal
influenza vaccines a reality before the next pandemic strikes.CRediT authorship contribution statement
Kristine A. Moore: Conceptualization, Writing – original draft,
Writing - review & editing. Julia T. Ostrowsky: Conceptualization,
Writing – original draft. Alison M. Kraigsley: Conceptualization,
Writing - review & editing. Angela J. Mehr: Conceptualization,
Writing - review & editing. Joseph S. Bresee: Conceptualization,
Writing - review & editing. Martin H. Friede: Conceptualization,
Writing - review & editing. Bruce G. Gellin: Conceptualization,
Writing - review & editing. Josephine P. Golding: Conceptualiza-
tion, Writing - review & editing. Peter J. Hart: Conceptualization,
Writing - review & editing. Ann Moen: Conceptualization, Writing
- review & editing. Charlotte L. Weller: Conceptualization, Writing
- review & editing.Michael T. Osterholm: Conceptualization, Writ-
ing - review & editing.Declaration of Competing Interest
The authors declare the following financial interests/personal
relationships which may be considered as potential competing
interests: [Kristine Moore, Julia Ostrowsky, Angela Mehr, Michael
Osterholm report financial support was provided by Wellcome
Trust. Kristine Moore, Michael Osterholm report a relationship with
Wellcome Trust that includes: funding grants.
Coauthor received grants to the organization from Sanofi Pas-
teur, received grants from US CDC, PATH, Wellcome Trust, South
African MRC. (CC)
Coauthor is a former Director of one of the WHO International
Reference Centres for influenza and was part of the biannual strain
selection group. His family superannuation fund holds some shares
in companies which produce vaccines, including Influenza vaccine
(Pfizer, Merck and CSL) and specific antiviral agents (Vaxart). (IG)
Coauthor is an independent Director of two organisations that
support vaccine development, the Coalition for Epidemic Prepared-
ness Innovations and MSD Wellcome Trust Hilleman Laboratories
Pvt; Ltd. Neither is working on influenza vaccines. (GK)
Coauthor has the following declarations: The Icahn School of
Medicine at Mount Sinai has filed patent applications relating to
universal influenza virus vaccines, SARS-CoV-2 serological assays
and NDV-based SARS-CoV-2 vaccines which name me as inventor.
I would also like to note the following, which could be perceived
as a conflict of interest: I have previously published work on influ-
enza virus vaccines with S. Gilbert (University of Oxford); have con-
sulted for Curevac, Merck and Pfizer (before 2020); I am currently
K.A. Moore, J.T. Ostrowsky, A.M. Kraigsley et al. Vaccine 39 (2021) 6573–6584consulting for Pfizer, Seqirus and Avimex; my laboratory is collabo-
rating with Pfizer on animal models of SARS-CoV-2 and with Dyna-
vax on influenza virus vaccines; my laboratory is collaborating with
N. Pardi at the University of Pennsylvania on mRNA vaccines against
SARS-CoV-2 and my laboratory was working in the past with
GlaxoSmithKline on the development of influenza virus vaccines
and two of my mentees have recently joined Moderna. (FK)].
Acknowledgements
The authors wish to acknowledge the contributions of Dr. Pad-
mini Srikantiah, Dr. Francesco Berlanda Scorza, and Ms. Janet
White of the Bill & Melinda Gates Foundation as past members
of the IVR Steering Group.
Funding
The work for this project was completed with generous support
from the Wellcome Trust.
Institutional Review Board Statement
Not applicable. Informed Consent Statement: Not applicable.
Data Availability Statement
Data sharing not applicable.
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