Available online at www.sciencedirect.com
ScienceDirect
Broadly protective influenza vaccines: design and
production platforms
Husni Elbahesh, Giulietta Saletti, Thomas Gerlach and
Guus F Rimmelzwaan
Effective vaccines are the cornerstone of our defenses against and patients with chronic diseases, vaccination against
acute influenza virus infections that result in 500 000 annual influenza is recommended [4]. Thus, the availability of
deaths worldwide. For decades, an on-going concerted effort efficacious vaccines is important in mitigating the potential
has been to develop a universal influenza vaccine to combat impact of seasonal and future pandemic outbreaks. This
the looming threat of potentially pandemic emerging and re- was exemplified in 2009, when a novel swine origin qua-
emerging influenza viruses. To address the need for rapid druple reassortant virus of the H1N1 subtype caused a
efficacious vaccines that could mitigate the impact of seasonal pandemic outbreak.Despite huge efforts, vaccines became
and future pandemics, multiple platforms are under available after the peak of the pandemic in many countries,
development and/or investigation. What is clear is that any which is obviously an unwanted scenario.
universal vaccine must provide long-lasting cross-protective
immunity that can induce both B and T cell responses. This Although IAV of the H1N1 subtype circulated in the
review will explore some of the universal influenza vaccine human population before 2009, these viruses were anti-
platforms in the contexts of their ability to induce long-lasting genically different from the pandemic strain and conse-
and cross-protective T cell immunity. quently, the majority of individuals did not have virus
neutralizing (VN) antibodies to the H1N1pdm09 strain.
In contrast however, H1N1 viruses that circulated
Address
between 1918 and 1957 resemble the 2009 pandemic
University of Veterinary Medicine (TiHo), Research Center for Emerging
Infections and Zoonoses (RIZ), Bu¨ nteweg 17, 30559 Hannover, Germany strain antigenically. Consequently, individuals born
before 1957 had been exposed to these viruses and
Corresponding author:
developed antibodies that cross-reacted with the
Rimmelzwaan, Guus F ([email protected])
2009 pandemic strain and were spared from infection
to a certain extent [5–8].
Current Opinion in Virology 2019, 34:1–9
Current vaccine strategies typically aim at the induction
This review comes from a themed issue on Emerging viruses: inter-
species transmission of VN antibodies that are directed to epitopes located in
close vicinity of the receptor binding site of hemaggluti-
Edited by Adolfo Garcı´a-Sastre and Juergen A Richt
nin (HA), the receptor binding protein of influenza
For a complete overview see the Issue and the Editorial
viruses. However, update of the vaccine strains is
Available online 27th November 2018
required almost annually to match the epidemic strains
https://doi.org/10.1016/j.coviro.2018.11.005 antigenically. Furthermore, the seasonal vaccine will offer
little protection against pandemic or zoonotic influenza
1879-6257/ã 2018 Elsevier B.V. All rights reserved.
viruses with an antigenically distinct HA, often of an
alternative subtype. In contrast, IAV infections induce
a certain level of immunity against IAVs of other subtypes
(heterosubtypic immunity) (reviewed in Ref. [9 ]) and
experiments in both mouse and primate models of infec-
Introduction tion demonstrated that cross-reactive virus-specific CD8+
Influenza viruses are major cause of acute respiratory tract T-cells in particular contribute to this type of protective
infections. Both influenza A and B viruses (IAV or IBV, immunity [10–14]. In humans, it was also shown that the
respectively) cause annual epidemics in humans with sub- presence of virus-specific CD8+ T-cells induced by infec-
stantial morbidity and mortality. In addition, IAV have tion with seasonal IAV strains correlated with protection
caused pandemic outbreaks of variable severity [1]. While against pandemic and zoonotic viruses [15,16 ,17].
seasonal IAV are currently of the H1N1 and H3N2 sub- Therefore, developing vaccines that can induce potent
types, zoonotic infections with IAV of other subtypes, like T cell responses could overcome limitations of antibody-
H5N1 and H7N9, continue to be detected. It has been mediated immunity by providing heterotypic cross-pro-
demonstrated that some avian viruses only require a few tection through recognition of highly conserved internal
adaptive mutations to become transmissible between proteins. In this review, we discuss current and future
mammals and therefore pose a pandemic threat [2,3]. To universal vaccine platforms (Figure 1) with consideration
protect selected high risk groups, like children, the elderly to induction of lasting and cross-reactive T cell responses.
www.sciencedirect.com Current Opinion in Virology 2019, 34:1–9
2 Emergining virus: intraspecies transmission
Figure 1
LAIV
Broadly Protective IIV Immunity
RNA Vaccine Recombinant/VLP (mRNA/SAM-mRNA) DNA Vaccine
Influenza virus gene
Cellular correlates Vectored-Vaccine Antibody correlates of protection of protection
Influenza virus gene
Expression of Expression of internal proteins surface proteins (M1, NP) (HA, NA, M2e)
Current Opinion in Virology
Schematic of current and future ‘universal’ influenza vaccine platforms under investigation with respective consideration of the type of lasting
immunity and correlates of protection induced.
Current vaccines Both inactivated influenza virus (IIV) and live attenu-
Design and production ated influenza virus (LAIV) vaccines make up the
The global influenza vaccination program is a major effort majority of IV vaccines being used, both of which are
with more than 400 million doses administered every largely produced in embryonated chicken eggs. Vaccine
year [18]. Because seasonal influenza viruses undergo strains used for vaccine production are typically
antigenic drift, the vaccine composition requires frequent obtained by genetic reassortment. The gene segments
updates for the vaccine to maintain efficacy. The recom- encoding HA and NA of defined antigenicity are com-
mendation of strains to be used for vaccine production bined with those obtained from an egg adapted strain
relies on a vast global network of surveillance, the and confer a high yield phenotype or for LAIV, with
WHO’s Global Influenza Surveillance and Response gene segments that confer the vaccine strains an atten-
System (GISR). Together with national centers in more uated cold-adapted and temperature-sensitive pheno-
than 100 countries, GISR is tasked with identifying type. The production and characterization of high yield
circulating strains, their global distribution patterns and reassortant strains is time-consuming. In addition, dur-
most importantly, their antigenic similarity to previous ing passaging in embryonated chicken eggs the vaccine
vaccine strains. strains may acquire adaptive changes in the HA, which
Current Opinion in Virology 2019, 34:1–9 www.sciencedirect.com
Development of universal influenza vaccines Elbahesh et al. 3
may affect its antigenicity and consequently its effec- are typically used in children. Reports of reduced vac-
tiveness [19–23]. Egg-independent vaccine production cine efficacy in children between 2 and 17 years old
using mammalian cell-culture is an attractive alterna- prompted the American Centers for Disease Control and
tive [24–27] and the production of recombinant HA in Prevention to recommend that LAIV should not be used
insect cells by a baculovirus expression system has also in this age group during the 2016/2017 and 2017/2018
received FDA approval [24–28]. Regardless of the seasons. However, the CDC did recommend the Flu-
vaccine production system, the major antigenic target Mist LIAV for the 2018/2019 season after manufacturers
of these vaccines is the viral HA; specifically the glob- showed increased efficacy by replacing the H1N1 vac-
ular head of the HA which contains at least 5 antigenic cine component with a different strain (A/Slovenia/2903/
sites that surround the receptor binding site [29]. HA- 2015) [49–51].
specific antibodies directed to these antigenic sites can
neutralize the virus by preventing binding of the virus Considering the above, there is a clear need for alterna-
to its receptor, provided that they match the virus tive influenza vaccines that can induce broadly protec-
antigenically. The acquisition of amino acid changes tive immunity. During a pandemic outbreak, the prior
at these positions can result in evasion from recognition use of these vaccines would reduce morbidity and mor-
by VN antibodies. tality in the population and would buy some time until
tailor made vaccines against the emerging pandemic
Challenges and limitations strains become available. The development of such
The emergence of viruses with novel HA and/or NA ‘universal’ influenza vaccines has been high on the
genes derived from animal influenza viruses is of great research agenda for some years now and some advance-
concern, because these reassortant viruses are well ments have been made [52].
adapted to replicate in humans and VN antibodies to
their membrane glycoproteins are virtually absent in the
human population. Consequently these viruses have the Universal vaccines
potential to cause a pandemic outbreak, which has indeed Design and limitations
occurred four times in the last century, in 1918 (H1N1), The largest efforts in designing a ‘universal’ influenza
1957 (H2N2), 1968 (H3N2) and 2009 (H1N1). In addi- vaccine have largely concentrated on HA, specifically the
tion, zoonotic human infections by avian IAV of various stalk-domain, which exhibits great conservation across
subtypes, including H9N2, H5N1, H7N7 and H7N9 IAV subtypes [53 ,54,55 ,56 ]. The stalk-antibodies
continue to occur [30–33]. These viruses also pose a have the ability to neutralize virus within and across
pandemic threat, because they may adapt to replicate subtypes [57,58]. In addition, stalk-antibodies can pre-
in humans by acquiring necessary mutations [2,3,34–37] vent endosomal fusion and cytosolic release of viral
or by genetic reassortment with human IAVs. genome, as well as preventing particle egress [57,59].
Recent studies also suggest that their function may
Continuous antigenic drift of seasonal influenza viruses depend on Fc Receptor (FcR), as interactions between
due to accumulation of amino acid replacements near the the stalk-antibody Fc region and the FcR were essential
receptor binding site within the HA globular head domain for protection of mice from lethal challenge [60]; in that
that is recognized by VN antibodies complicates the study however, this was dose-dependent where higher
production of efficacious vaccines [38,39 ,40]. Alterna- antibody doses did not require FcR for their effect. While
tively, posttranslational changes (i.e. glycosylation) can natural infection induces anti-stalk antibodies, they
affect recognition by VN antibodies [41,42]. Furthermore, remain at significantly lower concentrations than those
in 2009 it proved to be difficult to produce sufficient targeting the immunodominant head domain (reviewed
pandemic vaccine doses in a timely fashion and in many in Refs. [61] and [62]). To tackle this problem, several
countries the vaccination campaign started after the peak headless and/or stalk chimeric HAs have been designed
of the pandemic. and utilized for the preferential induction of stalk-specific
antibodies [63–65,66 ,67].
Until recently, inactivated trivalent influenza vaccines
were used predominantly to target co-circulating IAV Compared to the influenza virus HA, the NA is more
H1N1 and H3N2 strains and a single IBV strain. How- conserved but less immunogenic [68]. However, a mono-
ever, difficulty in predicting whether IBV strains of the clonal antibody targeting an epitope conserved among all
B/Victoria/2/87 or B/Yamagata/16/88-lineage will be influenza A and B viruses provided heterosubtypic pro-
dominant in the next influenza season, has resulted in tection in mouse challenge experiments [69,70]. More-
production of a quadrivalent vaccine, which contain over, both human and animal studies have demonstrated
antigens of both IBV lineages which provided additional that NA-specific immunity blunts viral shedding and
protection compared to the trivalent vaccine [43 ,44]. symptom severity [71,72]. Although these studies suggest
The LAIV, that are available [45,46,47 ,48] have been that the NA of the N1 subtype can induce a potent intra-
shown to induce more broadly protective immunity and subtypic immunity, several other studies suggest that the
www.sciencedirect.com Current Opinion in Virology 2019, 34:1–9
4 Emergining virus: intraspecies transmission
response to N2 NAs is much more robust in humans ([73] on single VLPs and recent studies have explored
and reviewed in [74 ]). expression of chimeric proteins in chimeric VLPs
(reviewed in Ref. [92]). Moreover, the use of VLPs
Virus specific CD4+ and in particular CD8+ T cell containing H1, N1, M1 and NA afford cross-protection
responses are largely directed to epitopes located in against lethal challenge of mice with IAV of the H3N2
the internal viral proteins (M1 protein and nucleoprotein subtype [93]. The M2e protein has been coupled to
(NP) that are relatively conserved across subtypes of various fusion proteins or as tandem repeats and/or
influenza A viruses and are therefore highly cross-reac- adjuvants to elicit cross-protective humoral and cellular
tive [75–81]. CD4+ T cells have a variety of effector immunity [94–98].
functions and are important for establishing high affinity
class-switched memory B cells and memory CD8+ T Replication deficient or attenuated viral vectors have
cells. The main function of CD8+ cytotoxic T lympho- been investigated as candidate influenza vaccines includ-
cytes (CTL) is the recognition and elimination of virus- ing recombinant adenovirus, parainfluenza virus, modi-
infected cells, thus restricting viral replication and shed- fied vaccinia virus Ankara (MVA) and alphaviruses [99–
ding and contributing to controlling the infection. The 106,107 ,108–112]. For example, recombinant MVA
presence of pre-existing cross-reactive CTL induced by could be used for the expression of the influenza virus
infection with seasonal influenza A viruses correlated NP and induction of protective T cell responses and
with protection against infection with the pandemic heterosubtypic immunity [106,113,114]. With recombi-
H1N1 virus and zoonotic infection with avian virus of nant MVA that expressed influenza viral HA derived from
the H7N9 subtype [15,16 ,17,77]. The HLA alleles various influenza viruses, VN antibody responses were
make up of any given individual dictates which T cell induces in mice, ferrets, non-human primates and
epitopes are displayed and recognized. Differences in T humans [106,114,115].
cell repertoires due to HLA variability in and across
populations can influence the protective potential of the Vaccine production platforms based on nucleic acid pre-
virus specific CTL response and consequently suscepti- parations (DNA and RNA) have several potential advan-
bility to disease [9 ]. It is of interest that like epitopes tages over current technologies including being flexible,
recognized by antibodies, CTL epitopes are also under safe, cost effective, easy to produce and stable. In contrast
selective pressure and mutations in these epitopes at to the use of viral vectors, nucleic acid-based vaccines do
anchor residues and TCR contact residues have been not induce vector-specific immunity nor is their perfor-
identified. Additionally, amino acid residues outside mance influenced by pre-existing immunity to the vector,
epitopes have been found to affect T cell recognition which sometimes is a concern (e.g. adenoviruses).
and activation [82 ,83–90]. The latter observation should
be taken into consideration when developing vaccines DNA vaccines typically induce potent immune responses
that aim at the induction of virus specific CD8+ T cell in experimental animals, but seem less immunogenic in
responses. humans [116,117]. Boosting with a seasonal vaccine fol-
lowing vaccination with a H1 HA-recombinant DNA
Alternative vaccine production platforms vaccine resulted in the induction of stalk-specific neu-
Apart from identifying (conserved) viral targets for the tralizing antibodies [28]. Intramuscular inoculation with a
development of universal influenza vaccines, there is Vaxfectin-adjuvanted monovalent plasmid DNA vaccine
considerable interest in novel vaccine production tech- encoding H5 HA- or trivalent HA/NP/M DNA vaccines
nologies that would allow rapid production of vaccines tested in a Phase I study resulted in immune responses
able to induce protective antibodies and T cell responses. measured by HI titers and H5-specific T-cells to the
Several technologies to produce influenza vaccines have vaccine in over 60% of recipients; T cell and/or B cell
emerged in recent years that can induce either humoral or responses to at least one antigen were observed in 70%
cellular immunity or both (reviewed in Ref. [91]). of participants [118].
Virus-like particles (VLPs) are composed of viral struc- Candidate RNA vaccines developed against influenza are
tural proteins only to form non-replicative viral particles either non-replicating messenger RNA (mRNA) or self-
lacking genomes. VLPs can self-assemble in cell cul- amplifying (SAM) mRNA vaccines (reviewed in Ref.
ture systems and mimic conformational and antigenic [119 ]). Non-replicating mRNA vaccines encoding HA,
structures of native influenza viruses. Importantly, NP or NA induced protective immunity after intradermal
VLPs can activate innate immunity directly in epithe- immunization of ferrets and intravenous injection of
lial cells or by stimulation of professional antigen pre- mice; the latter study showed evidence of CD4+ T cell
senting cells (dendritic cells and macrophages), which activation after a single dose [120,121]. Interestingly,
facilitates efficient induction of virus specific B and T modified nucleoside mRNA-lipid nanoparticle vaccines
cell responses. Influenza VLP vaccines can contain HA, encoding the HA gene of H7N9 or H10N8 IAVs showed
NA, M1 or M2e proteins individually or in combination promising results in preclinical and phase I clinical trials
Current Opinion in Virology 2019, 34:1–9 www.sciencedirect.com
Development of universal influenza vaccines Elbahesh et al. 5
and induced stronger antibody responses than observed in Thus, recent developments in influenza vaccine design
response to inactivated H5 and H7 HAs split vaccines and production technology may help mitigate the impact
[122 ]. SAM-mRNA vaccines improve on non-replicating future outbreaks of influenza may have.
mRNA vaccines by enabling extended antigen expres-
sion at high levels using small immunization doses. This Conflict of interest statement
improvement is due to intracellular replication of the Nothing declared.
vaccine mRNA. Most SAM vaccines are based on antigen
expression by an alphavirus replicon lacking structural Acknowledgements
This work was funded by the Alexander von Humboldt Foundation in the
genes [123,124]. Several studies have demonstrated that
framework of the Alexander von Humboldt Professorship endowed by the
immunization with SAM-mRNA vaccines resulted in
German Federal Ministry of Education and Research.
strong HI antibody responses and afforded protection
against homologous and heterologous challenge infec-
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