Quadrivalent Inactivated Influenza Vaccine (Vaxigriptetra™) : Expert Review of Vaccines

Expert Review of Vaccines
ISSN: 1476-0584 (Print) 1744-8395 (Online) Journal homepage: http://www.tandfonline.com/loi/ierv20
Quadrivalent inactivated influenza vaccine

(VaxigripTetra™)
Viviane Gresset-Bourgeois, Phillip S. Leventhal, Stéphanie Pepin, Rosalind

Hollingsworth, Marie-Pierre Kazek-Duret, Iris De Bruijn & Sandrine I. Samson
To cite this article: Viviane Gresset-Bourgeois, Phillip S. Leventhal, Stéphanie Pepin,

Rosalind Hollingsworth, Marie-Pierre Kazek-Duret, Iris De Bruijn & Sandrine I. Samson (2017):
Quadrivalent inactivated influenza vaccine (VaxigripTetra™), Expert Review of Vaccines, DOI:
10.1080/14760584.2018.1407650
To link to this article: https://doi.org/10.1080/14760584.2018.1407650
Accepted author version posted online: 20

Nov 2017.
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Download by: [University of New England] Date: 26 November 2017, At: 21:45
Vaccine Profile
Quadrivalent inactivated influenza vaccine (VaxigripTetra™)
Viviane Gresset-Bourgeois*, Global Medical Affairs, Sanofi Pasteur, 2 Pont Pasteur, 69007
Lyon, France. Tel: +33 4 37 37 77 62. Email: Viviane.Gresset-Bourgeois@sanofi.com.
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Phillip S. Leventhal, 4Clinics, 18-26 Rue Goubet 75019 Paris, France. Tel: +33 4 72 75 05 35.
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Email: pleventhal@4clinics.com.
Downloaded by [University of New England] at 21:45 26 November 2017
Stéphanie Pepin, Clinical Development, Sanofi Pasteur, 1541 Avenue Marcel Merieux, 69380
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Marcy l'Étoile, France. Tel: +33 4 37 37 58 50. Email: Stephanie.Pepin@sanofipasteur.com.
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Rosalind Hollingsworth, Global Medical Affairs, Sanofi Pasteur, 1 Discovery Drive,
Swiftwater, PA 18370, USA. Tel: +1 570-957-3793. Email: ros.hollingsworth@sanofi.com.

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Marie-Pierre Kazek-Duret, R&D, Sanofi Pasteur, 1541 Avenue Marcel Merieux, 69380 Marcy
l'Étoile, France. Tel: +33 4 37 37 58 85. Email: Marie-Pierre.Kazek-Duret@sanofi.com.

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Iris De Brujin, Clinical Development, Sanofi Pasteur, Sanofi Pasteur, 1541 Avenue Marcel
Merieux, 69380 Marcy l'Étoile, France. Tel: +33 4 37 65 66 43. Email :

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iris.debruijn@sanofi.com.
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Sandrine I. Samson, Global Medical Affairs, Sanofi Pasteur, 2 Pont Pasteur, 69007 Lyon,
France. Tel: +33 4 37 37 97 43. Email : Sandrine.Samson@sanofi.com.

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*Corresponding author :
Viviane Gresset-Bourgeois
Global Medical Affairs, Sanofi Pasteur, 2 Pont Pasteur, 69007 Lyon, France. Tel: +33 4 37 37 77
62.
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Email: Viviane.Gresset-Bourgeois@sanofi.com.
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Abstract
Introduction: VaxigripTetra™ (IIV4; Sanofi Pasteur) is a quadrivalent split-virion influenza
vaccine approved in Europe in 2016 for individuals ≥ 3 years of age. IIV4 builds on the well-
established record of the trivalent split-virion influenza vaccine (Vaxigrip®).
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Areas covered: This literature review summarizes the rationale for developing quadrivalent
influenza vaccines and discusses the phase III clinical trial results supporting the
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immunogenicity, safety, and tolerability of IIV4.
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Expert Commentary: IIV4 is immunogenic and well tolerated. Adding a second B strain to the
trivalent split-virion influenza vaccine provides a superior immune response for the additional
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strain but does not reduce the immune response for the three other strains or negatively affect the
safety profile. By offering broader protection against co-circulating influenza B lineages, IIV4
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has the potential to further reduce influenza-related morbidity and mortality beyond that achieved
with trivalent vaccines.

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Keywords: clinical trial; immunogenicity; inactivated influenza vaccine; influenza B;

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quadrivalent influenza vaccine; safety
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1. Introduction
Influenza B represents nearly one-quarter of circulating influenza viruses and results in illness
indistinguishable from that caused by influenza A [1,2]. All age groups are susceptible to
infection by influenza B, although children and adolescents 5 to 19 years of age seem to be the
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most affected by it [1,3]. Several outbreaks of influenza B, with associated hospitalizations, have
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also occurred in older adults [4-10].
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In the 1980s, influenza B split into two immunologically distinct lineages, Victoria and
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Yamagata, which have co-circulated globally with varying prevalence since the 2000’s [1,2].
Because circulation of B-strain viruses can be highly variable and unpredictable and because the
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two B-strain lineages commonly co-circulate, selecting the B strain to include in trivalent
vaccines can be difficult [2,11]. For example, the B-lineage strain in trivalent influenza vaccines
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was not the dominant circulating B lineage in the US for half of the influenza seasons between
1999–2000 and 2012–2013 [12]. Similarly, in Australia, the dominant circulating and vaccine B
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lineages were different in one-third of the influenza seasons between 2001 and 2014 [13]. Also, a
late-season surge in B/Victoria-lineage influenza occurred in Australia in 2015, when the vaccine
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contained a B/Yamagata-lineage strain [14,15]. During the 2015–2016 season in Europe, the two
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B lineages co-circulated, with the non-vaccine (Victoria) lineage dominating in most countries
[16]. Global data collected between 2000 and 2013 indicate that differences in B lineages
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between the vaccine and the predominant circulating strain occur in about one-quarter of seasons
in which influenza B accounts for ≥ 10% of influenza cases [1]. Thus, despite twice-yearly
assessments by the World Health Organization (WHO), the vaccine and dominant circulating B
lineages frequently differ.
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To what extent B-lineage strains can induce cross-lineage protection is not clear. Two meta-
analyses of controlled trials found that the relative efficacy of trivalent vaccines against influenza
B is lower when the vaccine and dominant circulating B-lineage strains differ (71% vs. 49% for
non-elderly adults [17] and 77% vs. 52% overall [18]). In agreement with this, influenza vaccine
efficacy (VE) was not significant against influenza B during the 2015–2016 season in Denmark,
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when the dominant circulating lineage was Victoria but the vaccine lineage was Yamagata [19];
however, in the UK during the same season, VE against influenza B was significant [20].
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Contradictory results have also been reported for the 2011–2012 season: VE against the non-
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vaccine B-lineage strain was significant in the US, and even higher against the non-vaccine than
the vaccine B-lineage strain [21], whereas in Canada, VE was significant against the vaccine but
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not the non-vaccine B-lineage strain [22]. In 2012–2013, VE was similar and significant against
the vaccine and the non-vaccine B-lineage strains in both the US [23] and Canada [24]. Clearly,
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the extent of cross-protection can vary, but in general, differences between the vaccine and
dominant circulating lineages should be avoided because they create a risk for suboptimal
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protection.
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Accordingly, in 2007, the US Food and Drug Administration proposed adding a second B lineage
strain to influenza vaccines to reduce the problem of selecting the correct B lineage and to
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provide simultaneous protection against both B lineages [25]. Soon after, several manufacturers
began developing quadrivalent formulations of influenza vaccines, and many are beginning to
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replace their trivalent formulations with quadrivalent formulations worldwide. The US was the
first country to adopt quadrivalent influenza vaccines [26], and the WHO and advisory
committees of Australia [27], Europe [28], and Canada [29] now include quadrivalent vaccines in
their immunization programs.
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2. VaxigripTetra™ (IIV4)
Sanofi Pasteur’s IIV4 is a quadrivalent split-virion inactivated influenza vaccine approved in
Europe in 2016 for individuals ≥ 3 years of age [30]. The vaccine contains the split antigens of
influenza viruses from the WHO-recommended A/H1N1, A/H3N2, B Yamagata-lineage, and B
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Victoria-lineage strains [31].
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IIV4 builds on more than 50 years of experience with the trivalent split-virion influenza vaccine
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(Vaxigrip®, Sanofi Pasteur; IIV3), which contains two A strains (A/H1N1 and A/H3N2) and a
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single B strain. Both vaccines are produced from virus strains grown in embryonated chicken
eggs, split with the detergent octoxynol-9, and inactivated with formaldehyde, so they may
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contain traces of egg components, neomycin, formaldehyde, and octoxynol-9 [31].
IIV3 is approved in 124 countries worldwide and is included in the list of the WHO-prequalified
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vaccines [32]. Many prospective clinical trials and retrospective studies have confirmed the
immunogenicity, effectiveness, and safety of IIV3 in children, adults, elderly adults, pregnant
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women, healthcare workers, and various at-risk populations [33]. IIV3’s safety profile has also
been confirmed by data collected from spontaneous reporting and enhanced safety surveillance in
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Europe.
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More than 1.8 billion doses of IIV3 have been distributed since its first regulatory approval in
1968 [33]. These doses are estimated to have prevented more than 37 million laboratory-
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confirmed influenza cases, more than 476,000 influenza-related hospitalizations, and more than
67,000 influenza-related deaths [33].
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3. Clinical immunogenicity of IIV4 in individuals ≥ 3 years of
age
Six phase III clinical trials have evaluated the safety and immunogenicity of IIV4 for the licensed
indication (≥ 3 years of age) (Table 1). Three of these trials [34-36] were considered pivotal for
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characterizing the immunogenicity of IIV4 for regulatory approval in Europe. These three trials
and another in adults 18 to 60 years [37] tested the licensed version of IIV4, which was
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manufactured using an updated process. Two supportive phase III trials [38,39] tested IIV4
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batches manufactured using the same process as IIV3.
In most studies, the primary objective was to demonstrate non-inferior immunogenicity of IIV4
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vs. IIV3 for the three shared strains. Non-inferiority was defined as a lower limit of the 2-sided
95% confidence interval (CIs) around the post-vaccination ratio of hemagglutination inhibition
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(HAI) geometric mean titers (GMTs) for IIV4/IIV3 > 1/1.5. A secondary objective was to
demonstrate superior immunogenicity of IIV4 vs. IIV3 for the additional B strain as indicated by
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a lower limit of the 2-sided 95% CI of the HAI GMT ratio for IIV4/IIV3 > 1.
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3.1 Children 3 to 8 years of age

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The pivotal study in this age group was a randomized, controlled phase III trial conducted in
Poland, Finland, Mexico, and Taiwan [35]. The trial included 1242 participants randomized 5:1:1
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to IIV4 manufactured using the final updated process, the licensed IIV3 containing the
B/Yamagata lineage strain, or an experimental IIV3 containing a B/Victoria lineage strain.
Participants who had not received two doses of seasonal influenza vaccine during a previous
season (unprimed participants) received a second dose of vaccine on day 28, and HAI titers were
measured at baseline and 28 days after the last vaccination.
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The primary objective of non-inferiority of HAI responses to IIV4 vs. IIV3 was met for the two
A strains and the shared B strain (Figure 1A). Also, HAI responses to both B strains in IIV4
were superior to those induced by the IIV3 containing the alternate B strain lineage (Figure 1B).
When participants were stratified according to whether they had received the seasonal influenza
vaccine the previous year, immune responses to IIV4 remained non-inferior vs. IIV3 for the
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shared strains and superior for the alternate B-lineage strain. Furthermore, despite the high
baseline antibody levels in this study, geometric mean post-/pre-vaccination HAI titer ratios were
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≥ 6 for all vaccine strains for IIV4, and seroconversion rates were 65% to 88%.
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3.2 Children and adolescents 9 to 17 years of age
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In a pivotal phase III open-label, uncontrolled trial in Taiwan, 100 children and adolescents 9 to
17 years of age were vaccinated with a single dose of IIV4 manufactured using the final updated
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process [34]. The objective of this study was to describe the immunogenicity and safety of the
2013–2014 Northern Hemisphere formulation of IIV4. Despite relatively high baseline antibody
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titers in the participants, vaccination with IIV4 increased HAI GMTs for all four strains (Figure
2). Geometric mean ratios of post-vaccination to pre-vaccination titers were 2.05 to 4.59 for the
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four vaccine strains, and seroconversion rates were 25% to 54%.

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A supportive phase III trial in Australia and the Philippines examined an IIV4 batch
manufactured using the IIV3 process. The trial included 385 children and adolescents 9 to 17
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years of age and 1705 adults 18 to 60 years of age (results for the adult participants are described
in Section 3.3) [38]. The children and adolescents in this study were randomized 2:2:2:1 to one
dose of three lots of IIV4 or the licensed IIV3, which contained the B Victoria-lineage strain.
HAI titers were measured after 21 days. For the three strains common to both vaccines (A/H1N1,
A/H3N2, and B/Victoria), post-vaccination HAI antibody responses to IIV4 and IIV3 were
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similar. HAI GMTs increased 7.5- to 23.4-fold with IIV4 and 6.4- to 16.6-fold with IIV3.
Furthermore, for the B strain not included in IIV3 (B/Yamagata), the fold rise in GMTs was
greater with IIV4 (19.4) than with IIV3 (3.8). The study also confirmed equivalent
immunogenicity of three consecutive lots of IIV4.
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3.3 Adults
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In a pivotal phase III randomized clinical trial performed in Europe, 1114 adults 18 to 60 years of
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age and 1111 adults > 60 years of age were randomized 2:2:2:1:1 to receive a single dose of one
of three lots of IIV4 manufactured using the final updated process, the licensed IIV3 containing a
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B/Yamagata strain, or an investigational IIV3 containing a B/Victoria strain [36]. The study had
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two co-primary objectives: to demonstrate equivalence of the post-vaccination HAI antibody
response induced by the three different lots of IIV4 for each vaccine strain; and to demonstrate
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non-inferiority of the post-vaccination (day 21) HAI antibody response induced by the pooled
IIV4 lots compared with the IIV3s.

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In both age groups, post-vaccination HAI GMTs induced by IIV4 were non-inferior to those
induced by the IIV3 for the A strains and for the B strain included in the comparator IIV3
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(Figure 3A). For the additional B-lineage strain, HAI antibody titers induced by IIV4 were
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superior to those induced by the IIV3 lacking it (Figure 3B). The study also confirmed
equivalence of the three lots of IIV4. Furthermore, HAI antibody titers were increased by IIV4
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for all vaccine strains by 7- to 12-fold in adults 18 to 60 years of age and by 4- to 6-fold in adults
> 60 years of age, and seroconversion rates were 64% to 71% in adults 18 to 60 years of age and
43% to 48% in adults > 60 years of age.
In an observer-blind, randomized, controlled phase III trial performed in the Republic of Korea,
300 adults 18 to 60 years of age were randomized 2:1 to a single dose of IIV4 manufactured
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using the final updated process or the licensed IIV3 [37]. The objectives of the study were to
evaluate the immunogenicity and safety of the IIV4 and IIV3 Northern Hemisphere 2015–2016
formulations and the compliance of IIV4 with the requirements of the Committee for Human
Medicinal Products former Note for Guidance [40], which was replaced by new guidelines in
2016 [41].
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For the three shared strains, immune responses induced by IIV3 and IIV4 were comparable
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(Figure 4). For the additional B strain not included in the IIV3 (B/Victoria), post-vaccination
(day 21) HAI GMTs were higher for IIV4 than for IIV3. In addition, despite relatively high
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baseline immunogenicity against the vaccine strains, HAI titers increased after vaccination for
each of the four strains by geometric mean of at least 4-fold, exceeding the criterion (> 2.5) in the
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former Note for Guidance. Rates of seroprotection (HAI titer ≥ 1:40) for all four strains also
exceeded the criterion (> 70%), and the rate of seroconversion exceeded the criterion (> 40%) for
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the A/H3N2, B Yamagata-lineage, and B Victoria-lineage strains but was just under (39.7%) for
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the A/H1N1 strain. According to these results, IIV4 met the former Note for Guidance for all
strains, which required exceeding at least one criterion for each included strain.
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Two other double-blind randomized phase III trials investigated the immunogenicity of IIV4
using batches manufactured using the IIV3 process. In the first of these studies, 783 adults 18 to
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60 years of age and 785 adults > 60 years of age in France and Germany were randomized 5:1:1
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to a single injection of IIV4, the licensed IIV3 containing a B/Victoria strain, or an
investigational IIV3 containing a B/Yamagata strain [39]. As in the other studies, for all vaccine
strains in IIV4, antibody responses were non-inferior to the response to IIV3 for the shared
strains and superior to the response to the IIV3 lacking the shared B strain.
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The supportive phase III trial performed in Australia and the Philippines investigated the
immunogenicity of IIV4 not only in children and adolescents (see Section 3.2) but also in 1705
adults 18 to 60 years of age [38]. The adult participants were randomized 10:10:10:1 to one dose
of three lots of IIV4 manufactured using the IIV3 process or the licensed IIV3 (containing a
B/Victoria strain). Post-vaccination (day 21) HAI antibody responses to IIV4 and IIV3 were
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similar for the three strains common to both vaccines (A/H1N1, A/H3N2, and B Victoria). HAI
GMTs for these three strains increased 7.3- to 10.0-fold with IIV4 and 6.6- and 9.3-fold with
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IIV3. For the B strain not included in IIV3 (B Yamagata), the fold increase in GMTs following
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vaccination with IIV4 (8.4) was greater than with IIV3 (3.2). The study also confirmed equivalent
immunogenicity of the three lots of IIV4.

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3.4 Antibody response to IIV4 in individuals at risk for influenza-related complications
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Descriptive data from the pivotal phase III trial in European adults ≥18 years of age (see Section
3.3) [36] suggested that the immunogenicity of IIV4 was not affected by the presence of
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conditions that increase the risk of influenza-related complications, such as chronic respiratory,
heart, renal, metabolic, and hematological disorders (Supplemental Figure 1).

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3.5 Persistence of the immune response to IIV4

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The persistence of HAI antibody responses to IIV4 was also investigated in the pivotal phase III
trial in European adults ≥18 years of age (see Section 3.3) [36]. HAI GMTs remained above
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baseline for at least 1 year, although post-vaccination HAI antibody titers gradually decreased
after day 21 and were 2- to 3-fold lower at month 6 and 12 than at day 21 (Figure 5).
3.6 B strain cross-lineage immunogenicity
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B strain cross-lineage immunogenicity of IIV4 was examined in the phase III trials in Korean and
European adults [36,37]. Some cross-reactivity between the B-lineage strains was detected: in
participants vaccinated with IIV3, roughly 20% to 40% seroconverted for the missing B-lineage
strain and HAI titers increased from baseline by a geometric mean of approximately 2 to 3
(Table 2). By comparison, in participants vaccinated with IIV4, roughly 40% to 70%
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seroconverted for each B strain, and HAI titers increased from baseline by a geometric mean of
approximately 4 to 12. For all study groups and for both B-lineage strains, proportions
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seroconverting and geometric mean post-/pre-vaccination titer ratios were higher for IIV4 than
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for IIV3 containing the alternate B strain. Additional data on B-strain cross-reactivity are
available from the supportive phase III trial in which adults 18 to 60 and > 60 years of age were
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vaccinated with an IIV4 batch manufactured using the IIV3 process [39] (Table 2). In this trial,
approximately 20% to 45% of participants vaccinated with IIV3 seroconverted for the missing B-
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lineage strain, and HAI titers increased from baseline by a geometric mean of approximately 2 to
4. However, in participants vaccinated with IIV4, approximately 45% to 75% seroconverted for
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each B strain, and HAI titers increased from baseline by a geometric mean of approximately 5 to
13. These results indicate that the two B strains in IIV4 simultaneously induce HAI antibody
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titers to each B strain that are substantially higher than those induced by cross-reactivity by an
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alternate B strain in IIV3.

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3.7 Seroneutralization (SN) antibody responses to IIV4
SN antibody responses were examined in a randomly selected subset of participants in the pivotal
European phase III trial in adults ≥18 years of age (see Section 3.3) [36]. Vaccination with IIV4
increased SN antibody titers for all strains. SN antibody titers increased ≥ 4-fold against each
vaccine strain in 47% to 70% of younger adults and 33% to 55% of older adults (Supplemental
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Figure 2). SN antibody responses were also examined in the phase III trial in children and
adolescents 9 to 17 years of age using an IIV4 batch manufactured using the IIV3 process [38].
The study showed that post-vaccination SN titers were similar for the three strains common to
IIV4 and IIV3 but that for the B strain absent from IIV3, the fold increase in SN titers was greater
following vaccination with IIV4 (26.5) than following vaccination with IIV3 (3.7).
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4. Clinical safety of IIV4 in individuals ≥ 3 years of age
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Safety data for IIV4 are available from the six phase III trials in individuals ≥ 3 years of age.
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These trials included a total of 5945 participants vaccinated with IIV4 (3240 adults 18 to 60 years
of age, 1392 adults > 60 years of age, 429 children and adolescents 9 to 17 years of age, and 884
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children 3 to 8 years of age).
Solicited reactions in these studies were recorded in diaries by participants or, for children, by
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their parents or legal guardians every day for 7 days after vaccination. Most of the solicited
reactions were grade 1, occurred within 3 days after vaccination, and resolved within 1 to 3 days.
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Pain at the injection site was the most common solicited reaction, followed by headache, malaise,
and myalgia, and most reactions became less frequent with increasing age (Table 3).
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Vaccine-related unsolicited adverse events were uncommon in the phase III trials. In all groups,
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the most common of these was pruritus occurring more than 1 week after vaccination and
therefore not recorded as a solicited reaction. Only one serious adverse event considered to be
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related to vaccination with IIV4 was reported: a 3-year-old participant experienced severe
thrombocytopenia 9 days after the first vaccination that resolved after 38 days without sequelae
but led to study discontinuation [35]. On long-term follow-up, the platelet level increased and
remained stable within normal ranges, indicating that it was a transient event.
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Overall, the safety profiles of IIV4 and IIV3 were comparable in the six phase III trials (Table 4),
and no safety signals were detected for IIV4. Importantly, no new safety signals were detected in
the study subjects with underlying chronic illnesses. Thus, including a second B strain does not
appear to affect vaccine safety or tolerability.
5. Clinical findings in children 6 to 35 months of age
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In addition to these trials supporting the licensed indication (≥ 3 years), a recently completed
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randomized, placebo-controlled phase III trial performed in Europe, Asia, Latin America, and
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South Africa examined the efficacy and safety of IIV4 in children 6 to 35 months of age who had
never been vaccinated. The children were followed for influenza-like illness until the end of the
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influenza season, and influenza was confirmed by viral culture and reverse transcription-
polymerase chain reaction. Preliminary results, which were presented at the 2017 European
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Society for Pediatric Infectious Diseases meeting in Madrid, Spain, demonstrated the efficacy of
IIV4 to protect against laboratory-confirmed influenza-like illness caused by any circulating

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strains as well as by vaccine-similar strains [42].
6. Conclusion
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Sanofi Pasteur’s IIV4 is a quadrivalent split-virion inactivated influenza vaccine approved in
Europe in 2016 for individuals ≥ 3 years of age. IIV4 builds on more than 50 years of experience
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with IIV3.
Six phase III clinical trials have been conducted to demonstrate the safety and immunogenicity of
IIV4 in individuals ≥ 3 years of age. In these trials, IIV4 was highly immunogenic and induced
non-inferior immunogenicity vs. IIV3 for the shared strains and superior immunogenicity for the
alternate B-lineage strain. Results from SN assays, where available, agree with these findings. In
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adults, HAI antibody titers persist for at least 1 year and the immunogenicity of IIV4 was not
affected by conditions increasing the risk of influenza-related complications. Although some
cross-reactivity between the B-lineage strains has been detected, the two B strains in IIV4
simultaneously induced HAI antibody titers to each B strain that were substantially higher than
those induced by cross-reactivity by an alternate B strain in IIV3.
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Safety profiles of IIV4 and IIV3 have been comparable in these trials, with no safety signals
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detected for IIV4. Also, no new safety signals were detected in the study subjects with underlying
chronic illnesses.
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Finally, a recently completed phase III trial examined the efficacy of IIV4 in children 6 to 35
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months of age. Initial analysis demonstrated the efficacy of IIV4 to protect against laboratory-
confirmed influenza-like illness caused by any circulating strains as well as by vaccine-similar

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strains.
7. Expert commentary
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Influenza B diverged into two immunologically distinct lineages in the 1980s, which have co-
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circulated since the 2000’s. The result has been frequent differences between the vaccine strains
and dominant circulating strains of influenza and therefore sub-optimal protection. Quadrivalent
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influenza vaccines, like IIV4, contain B strains from both lineages and therefore represent a
logical step in vaccine development to match viral evolution.

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The phase III clinical trials showed that, in individuals ≥ 3 years of age, IIV4 was as
immunogenic as IIV3 for each of the three shared influenza strains, meaning that adding the
second B strain does not affect the immune response to the other three strains. Also, although B
strains can induce some cross-lineage reactivity, adding the second B strain results in a superior
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immune response and therefore should provide broader protection against influenza B than IIV3.
In addition, the antibody response to IIV4 persisted for at least 12 months and, like IIV3, IIV4
induced satisfactory immune responses in all age groups irrespective of serological status at
baseline, prior influenza vaccination, or underlying chronic disease.
Data from the over 5900 subjects in these trials also showed that IIV4 has a similar safety profile
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as IIV3. No clinical concerns were identified, and IIV4 appeared safe and well tolerated,
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irrespective of age, sex, or underlying chronic diseases. Thus, including a second B strain did not
negatively affect vaccine safety or tolerability.
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IIV4 received regulatory approval in Europe in 2016 for individuals ≥ 3 years of age. The vaccine
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builds on more than 50 years of experience and more than 1.8 billion doses sold of IIV3. By
including B strains from both lineages, IIV4 should offer protection against influenza B during
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any season and therefore help reduce cases of influenza and its associated morbidity and
mortality.
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8. Five-year view
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Despite comprehensive influenza vaccination programs in many countries, the global burden of
influenza remains significant. Quadrivalent influenza vaccines provide an opportunity to further

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reduce the morbidity and mortality associated with annual influenza epidemics. Over the next
five years, IIV4 is expected to gradually replace IIV3 globally. This may help reduce influenza-
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associated morbidity and mortality.
Differences between the B strain in trivalent vaccines and the predominant circulating B lineage
increase influenza-related direct and indirect costs. For example, in the US between 2000 and
2009, average per-patient influenza-related medical costs were estimated at US$301 during
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seasons when the vaccine and predominant B lineages differed and US$239 when they were the
same [43]. Likewise, average per-patient productivity losses were estimated at US$237 for
seasons when the B lineages differed and US$175 when they were the same [43]. Accordingly,
compared to trivalent influenza vaccines, quadrivalent vaccines, including IIV4, are predicted to
be cost-effective [44-53] or cost-saving [54-58]. This will be confirmed in further studies.
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Worldwide, uptake of seasonal influenza vaccines remains below targets. A recent systematic
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review found that is often due to a poor public perception of influenza vaccines [59]. Indeed,
public confidence in seasonal influenza vaccines has been eroded by recent news stories of low
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efficacy due to differences between vaccine and circulating strains (e.g. [60-62]). By including a
second B-lineage strain, IIV4 offers an opportunity to restore public and healthcare provider
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confidence in influenza vaccination and therefore may help improve influenza vaccine uptake.
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9. Key issues:
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• Influenza B represents nearly one-quarter of circulating influenza viruses and results in

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illness indistinguishable from that caused by influenza A

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• Co-circulation of two B-strain lineages, which began two decades ago, has resulted in
frequent differences between the B strain in trivalent vaccines and the predominant
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circulating B strain, leading to suboptimal protection
• Quadrivalent influenza vaccines with both B strain lineages have been developed to
address this and are expected to gradually replace trivalent vaccines
• Sanofi Pasteur’s IIV4 is a quadrivalent split-virion influenza vaccine that builds on more
than 50 years of experience with their trivalent split-virion influenza vaccine
17
• Clinical trials show that IIV4 is immunogenic in all age groups ≥ 3 years of age
• Adding a second B strain provides a superior immune response to the additional B strain
without diminishing the response to the other three strains
• Adding a fourth strain does not negatively affect tolerability or safety of the vaccine
• IIV4 has the potential to further reduce influenza-related morbidity and mortality and
t
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should be cost-effective and perhaps cost-saving compared to trivalent influenza vaccines
cr
us
Funding
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The manuscript was funded by Sanofi Pasteur.
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Declaration of interest
ed
All authors except P. Leventhal are employees of Sanofi Pasteur. P. Leventhal is an employee of
4Clinics, which provided medical writing paid for by Sanofi Pasteur. The authors have no other
pt
relevant affiliations or financial involvement with any organization or entity with a financial
ce
interest in or financial conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other
Ac
relationships to disclose.
18
References
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Table 1. Phase III clinical trials on IIV4
Primary/main Total Vaccinated Clinical trial

Age group Study design objective Secondary objectives participants with IIV4 Countries Season Ref registry no.
Pivotal
studies
t
3–8 y Randomized, Non-inferiority of IIV4 Superiority of IIV4 vs. 1242 884 Poland, Finland, NH [35] EudraCT 2011-
rip
controlled vs. IIV3 for shared IIV3 for the alternate B- Mexico, Taiwan 2013−2014 005374-33
strains strain lineage
Safety
9–17 y Open label, Immunogenicity and - 100 100 Taiwan NH [34] WHO Universal
c
uncontrolled safety of IIV4 2013−2014 Trial U1111-
1127-7693
us
≥ 18 y Randomized, Equivalence of Superiority of IIV4 vs. 2225 1668 Belgium, France, NH [36] EudraCT 2014-
controlled immunogenicity of 3 IIV3 for the alternate B- Germany, Poland 2014−2015 000785-21
IIV4 lots strain lineage in each
an
Non-inferiority of IIV4 age group
vs. IIV3 for shared Safety
strains
18–60 y Observer-blind, Immunogenicity and - 300 200 Republic of Korea (5 NH [37] WHO Universal
M
randomized, safety of IIV4 and sites) 2015−2016 Trial U1111-
controlled IIV3 1143-9015
Supportive
studiesa
d
9–60 y Randomized, Safety of IIV4 Compliance of IIV4 with 2090 1977 Australia, Philippines SH [38] ClinicalTrials.gov
controlled immunogenicity criteria 2012/NH NCT01481454
te
in adults
Equivalence of
immunogenicity of 3
2011−2012
ep
IIV4 lots
Describe immunogenicity
in children/adolescents
≥ 18 y Randomized, Non-inferiority of IIV4 Superiority of IIV4 vs. 1568 1116 France, Germany NH [39] EudraCT 2011-
c
controlled vs. IIV3 for shared IIV3 for the alternate B- 2011−2012 001976-21
Ac
strains strain lineage in each

age group
Abbreviations: IIV3, trivalent split-virion inactivated influenza vaccine; IIV4, quadrivalent split-virion inactivated influenza vaccine; NH, Northern Hemisphere; SH,
Southern Hemisphere; Ref, reference.
a
Supportive data for immunogenicity was obtained using batches of IIV4 manufactured using the IIV3 process.
30
Table 2. B strain cross-lineage immunogenicity of split-virion inactivated influenza vaccines
Immunogenicity vs. B Yamagata-

lineage Immunogenicity vs. B Victoria-lineage
Age IIV3 without B- IIV3 without B-
Countries Ref Measure group IIV4 Yamagata lineage IIV4 Victoria lineage
t
Republic of [37] Geometric mean post-/pre- 18–60 y 4.17 (3.49, 4.98) - 3.97 (3.30, 4.78) 2.08 (1.75, 2.48)
rip
Korea vaccination HAI titer ratio (95%
CI)
Seroconversion/significant 18–60 y 48.7 (41.6, 55.9) - 46.2 (39.2, 53.4) 23.0 (15.2, 32.5)
c
increase, % (95% CI)b
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Belgium, [36] Geometric mean post-/pre- 18–60 y 7.35 (6.66, 8.12) 3.22 (2.67, 3.90) 11.6 (10.4, 12.9) 3.03 (2.49, 3.70)
France, vaccination HAI titer ratio (95%
Germany, CI)
an
Poland
> 60 y 4.61 (4.18, 5.09) 2.04 (1.71, 2.43) 1.99 (1.70, 2.34) -
Seroconversion/significant 18–60 y 63.7 (60.3, 67.0) 42.1 (33.9, 50.8) 70.9 (67.7, 74.0) 38.4 (30.3, 47.1)
M
> 60 y 42.7 (39.3, 46.2) 28.3 (20.9, 36.5) 45.2 (41.8, 48.7) 21.2 (14.7, 29.0)
d
France, [39]a Geometric mean post-/pre- 18–60 y 13.2 (11.5, 15.1) 3.94 (3.09, 5.03) 12.2 (10.6, 14.1) 3.63 (2.87, 4.58)
Germany vaccination HAI titer ratio (95%
CI) te> 60 y 7.20 (6.36, 8.15) 2.18 (1.79, 2.65) 4.81 (4.25, 5.43) 2.22 (1.83, 2.69)
ep
Seroconversion/significant 18–60 y 69.2 (65.2, 73.1) 42.7 (33.3, 52.5) 73.9 (70.1, 77.5) 46.0 (36.6, 55.6)
> 60 y 46.1 (41.9, 50.4) 25.9 (18.1, 35.0) 61.2 (57.0, 65.3) 23.9 (16.4, 32.8)
c
Abbreviations: CI, confidence interval; HAI, hemagglutination inhibition; IIV3, trivalent split-virion inactivated influenza vaccine; IIV4, quadrivalent split-virion inactivated
Ac
influenza vaccine; Ref, reference; -, not determined.

a
Used a batch of IIV4 manufactured using an alternate process not included in the licensed vaccine.
b
Seroconversion was defined as a pre-vaccination (day 0) HAI titer < 10 and a post-vaccination (day 21) HAI titer ≥ 1:40, and a significant increase was defined as a pre-
vaccination HAI titer ≥ 10 and a ≥ 4-fold increase in HAI titer
31
Table 3. Solicited reactions to IIV4 and IIV3 in the phase III clinical trials in individuals
≥ 3 years of age
% participants reporting the reaction between day 0 and 7

3–8 y 9–17 y 18–60 y > 60 y
IIV3 IIV4 IIV3 IIV4 IIV3 IIV4 IIV3 IIV4
Solicited reaction Grade N=354 N=884 N=55 N=429 N=657 N=3236 N=502 N=1392
Injection-site
Pain Any 55.4 56.5 54.5 54.5 54.5 53.9 22.3 25.8
Grade 3 2.0 1.1 0.0 0.0 0.5 0.4 0.2 0.1
t
Erythema Any 22.3 20.4 5.5 9.8 7.2 7.3 6.6 7.0
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Grade 3 2.3 2.9 0.0 0.7 0.3 0.0 0.4 0.0
Swelling Any 20.1 20.5 7.3 10.7 3.2 5.6 3.0 3.5
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Grade 3 0.8 2.4 0.0 0.2 0.2 0.0 0.0 0.0
Induration Any 14.1 16.4 7.3 6.8 4.7 5.4 2.6 3.0
Grade 3 0.8 1.2 1.8 0.5 0.0 0.0 0.0 0.0
us
Ecchymosis Any 6.2 5.8 1.8 1.6 0.6 0.0 0.2 0.4
Grade 3 0.0 0.3 0.0 0.0 0.0 0.0 0.0 0.0
Systemic
an
Fever Any 6.5 8.4 9.1 2.3 0.6 1.2 0.8 0.9
Grade 3 0.3 1.0 0.0 0.2 0.3 0.1 0.0 0.1
M
Headache Any 19.2 25.7 23.6 24.7 26.9 27.1 12.5 15.6
Grade 3 1.1 1.5 0.0 0.2 1.7 1.5 0.4 0.4
Malaise Any 28.2 30.7 16.4 20.3 21.8 20.1 9.6 9.3
Grade 3 1.7 2.0 0.0 0.7 0.8 1.2 0.6 0.4
ed
Myalgia Any 26.8 28.5 12.7 29.1 25.9 24.7 11.2 13.9
Grade 3 0.8 1.4 0.0 0.5 0.6 0.8 0.2 0.5
pt
Shivering Any 9.0 11.2 0.0 3.7 6.2 6.2 5.0 4.3
Grade 3 0.6 0.9 0.0 0.0 0.5 0.5 0.2 0.2
Abbreviations: IIV3, trivalent split-virion inactivated influenza vaccine; IIV4, quadrivalent split-virion
inactivated influenza vaccine.
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Table 4. Safety profile IIV4 and IIV3 in the phase III clinical trials in individuals ≥ 3
years of age
% participants reporting the reaction between day 0 and 7

3-8 y 9-17 y 18-60 y > 60 y
IIV3 IIV4 IIV3 IIV4 IIV3 IIV4 IIV3 IIV4
Event N=354 N=884 N=55 N=429 N=657 N=3236 N=502 N=1392
Injection-site reaction 62.4 62.4 56.4 57.1 57.1 56.3 27.1 30.3
Systemic reaction 45.5 48.9 41.8 44.5 35.8 39.7 23.7 25.7
Unsolicited AE 35.6 41.5 29.1 17.5 26.8 23.1 16.7 14.4
Vaccine-related 2 3.3 9.1 1.4 4.0 5.0 3.4 3.8
t
Immediate (< 30 min) 0 0.1 0 0 1.1 0.5 0.2 0
ip
SAE with 21/28 days 0.3 0.5 0 0.2 0.0 0.1 0 0.3
SAE within 6 months 1.1 1.6 0 0.2 0.9 0.6 1 1.5
Abbreviations: AE, adverse event; IIV3, trivalent split-virion inactivated influenza vaccine; IIV4, quadrivalent
cr
split-virion inactivated influenza vaccine; SAE, serious adverse event.figure
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Ac
33
Figure 1. Non-inferiority and superiority of HAI antibody response to IIV4 vs. IIV3s in
children 3 to 8 years of age
In a randomized, controlled phase III trial in Poland, Finland, Mexico, and Taiwan, 1242
children 3 to 8 years of age were randomized 5:1:1 to IIV4, IIV3 containing the B Victoria-
t
ip
lineage strain, or IIV3 containing the B Yamagata-lineage strain. Participants who had not
received two doses of seasonal influenza vaccine during a previous season (unprimed
cr
participants) received a second dose of vaccine on day 28, and HAI titers were measured at
us
baseline and 28 days after the last vaccination. (A) Non-inferior immunogenicity of IIV4 vs.
IIV3 containing the shared strains was indicated by a lower limit of the 2-sided 95% CIs
an
around the post-vaccination ratios of HAI GMTs for IIV4/IIV3 > 1/1.5 for all three shared
strains. (B) Superior immunogenicity of IIV4 to each IIV3 for the alternate B strain was
M
indicated by a lower limit of the 2-sided 95% CI of the GMT ratio for IIV4/IIV3 > 1. Results
are from [35].

ed
pt
ce
Ac
34
Figure 2. HAI antibody response to IIV4 in the pivotal phase III trial in children and
adolescents 9-17 years of age
In an open-label, uncontrolled phase III trial in the Republic of Korea, 100 children and
t
ip
adolescents 9–17 years of age were vaccinated with a single dose of IIV4. HAI titers
cr
measured on day 0 and day 21. Results are from [34].
us
an
M
ed
pt
ce
Ac
35
Figure 3. Non-inferiority and superiority of HAI antibody response to IIV4 vs. IIV3s in
adults ? 18 years of age
In the randomized, controlled phase III trial in Europe (Belgium, France, Germany, and
Poland), 2225 participants (1114 adults 18 to 60 y; 1111 adults > 60 y) were randomized
2:2:2:1:1 to receive a single dose of one of the three lots of IIV4, IIV3 containing the
t
ip
Victoria lineage strain, or IIV3 containing the Yamagata lineage strain. (A) Non-inferiority
of IIV4 vs. IIV3 in adults ? 18 years of age. Non-inferior immunogenicity of IIV4 vs. IIV3
cr
containing the shared strains was indicated by a lower limit of the 2-sided 95% CIs around
us
the post-vaccination ratios of HAI geometric mean titers (GMTs) for IIV4/IIV3 > 1/1.5 for
all three common strains (indicated by dashed line). (B) Superiority of IIV4 vs. IIV3 in
an
adults 18 to 60 and > 60 years of age. Superior immunogenicity of IIV4 to each IIV3 for the
alternate B strain was indicated by a lower limit of the 2-sided 95% CI of the GMT ratio for
M
IIV4/IIV3 > 1 (indicated by dashed line). Results are from [36].

ed
pt
ce
Ac
36
Figure 4. HAI antibody response to IIV4 and IIV3 in adults 18 to 60 years of age
In an observer-blind, randomized, controlled phase III trial in the Republic of Korea, 300 adults
18–60 years of age were randomized 2:1 to a single dose of IIV4 or the licensed IIV3 containing
the B Victoria-lineage strain. HAI titers were assessed 21 days after vaccination. Results are from
t
ip
[37].
cr
us
an
M
ed
pt
ce
Ac
37
Figure 5. Persistence of HAI antibody responses to IIV4 in adults ? 18 years of age
Persistence of HAI antibody responses to IIV4 was examined in the phase III trial in European
adults ? 18 years of age. HAI GMTs are shown for adults 18 to 60 years of age and > 60 years of
age at baseline (day 0), the end of the primary efficacy assessment period (day 21), the end of the
t
ip
safety follow-up period (month 6), and month 12. Results are from [36].
cr
us
an
M
ed
pt
ce
Ac
38
Supplemental Material for “VaxigripTetra™ quadrivalent influenza
vaccine”
t
ip
cr
us
an
M
ed
pt
Supplemental Figure 1. HAI antibody response to IIV4 in participants at

ce
risk and not at risk for influenza-related complications in adults ≥ 18 years
of age
Ac
In the pivotal phase III trial in European adults ≥ 18 years of age [1,2], participants could be
enrolled with medical conditions if they were stable. Participants were considered to be at risk for
influenza-related complications if they had at least one past or current high-risk condition as
defined by the US Centers for Disease Control and Prevention [3].
39
t
ip
cr
Suppllemental Figure 2.
2 Serone
eutraliza
ation (SN) antibod
dy
us
an
respo
onse to IIV4 and IIV3s in aadults ≥ 18
1 years of
o age
M
SN anttibody respoonses were assessed inn a random subset

s of paarticipants frrom the phaase
III trial in Europeean adults 18
8 to 60 yearrs of age (A
A) and adultss > 60 yearss of age (B)
[1,2].
ed
pt
ce
Refere
ences
Ac
1. Sesay S, Brzostek
B J, Meyer
M I et aal. Immunog genicity andd lot-to-lot cconsistency
study of a quadrivaleent influenzaa vaccine in n adult and elderly
e subjeects: A
phase III, randomized
r d, double-bblind clinicaal trial. Optioons IX for tthe Control
of Influenzza, Chicago
o (2017)
2. ClinicalTrrialsRegistry
y.eu. Immunnogenicity and a Lot-to-L Lot Consisteency
Study of a Quadrivallent Influenz nza Vaccine in Adult an nd Elderly SSubjects
(2014-0000785-21) [in nternet]. 20 16 [2017 Ju ul 3]. Availaable from:
https://ww
ww.clinicaltrrialsregisterr.eu/ctr- seaarch/trial/2014-000785--21/results
3. US Centerrs for Disease Control aand Preventtion. Peoplee at high riskk of
developingg flu- relateed complicaations. 2016 6 Available from:
http://wwww.cdc.gov/fl
flu/about/dissease/high_rrisk.htm
40

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ISSN: 1476-0584 (Print) 1744-8395 (Online) Journal homepage: http://www.tandfonline.com/loi/ierv20

Quadrivalent inactivated influenza vaccine

Viviane Gresset-Bourgeois, Phillip S. Leventhal, Stéphanie Pepin, Rosalind

To cite this article: Viviane Gresset-Bourgeois, Phillip S. Leventhal, Stéphanie Pepin,

To link to this article: https://doi.org/10.1080/14760584.2018.1407650

Accepted author version posted online: 20

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Quadrivalent inactivated influenza vaccine (VaxigripTetra™)

Lyon, France. Tel: +33 4 37 37 77 62. Email: Viviane.Gresset-Bourgeois@sanofi.com.

Swiftwater, PA 18370, USA. Tel: +1 570-957-3793. Email: ros.hollingsworth@sanofi.com.

l'Étoile, France. Tel: +33 4 37 37 58 85. Email: Marie-Pierre.Kazek-Duret@sanofi.com.

Merieux, 69380 Marcy l'Étoile, France. Tel: +33 4 37 65 66 43. Email :

France. Tel: +33 4 37 37 97 43. Email : Sandrine.Samson@sanofi.com.

Introduction: VaxigripTetra™ (IIV4; Sanofi Pasteur) is a quadrivalent split-virion influenza

established record of the trivalent split-virion influenza vaccine (Vaxigrip®).

immunogenicity, safety, and tolerability of IIV4.

with trivalent vaccines.

Keywords: clinical trial; immunogenicity; inactivated influenza vaccine; influenza B;

quadrivalent influenza vaccine; safety

lineages frequently differ.

their immunization programs.

Sanofi Pasteur’s IIV4 is a quadrivalent split-virion inactivated influenza vaccine approved in

influenza viruses from the WHO-recommended A/H1N1, A/H3N2, B Yamagata-lineage, and B

67,000 influenza-related deaths [33].

3.1 Children 3 to 8 years of age

B/Yamagata lineage strain, or an experimental IIV3 containing a B/Victoria lineage strain.

measured at baseline and 28 days after the last vaccination.

four vaccine strains, and seroconversion rates were 25% to 54%.

immunogenicity of three consecutive lots of IIV4.

IIV4 lots compared with the IIV3s.

43% to 48% in adults > 60 years of age.

to a single injection of IIV4, the licensed IIV3 containing a B/Victoria strain, or an

immunogenicity of the three lots of IIV4.

heart, renal, metabolic, and hematological disorders (Supplemental Figure 1).

3.5 Persistence of the immune response to IIV4

3.6 B strain cross-lineage immunogenicity

alternate B strain in IIV3.

3.7 Seroneutralization (SN) antibody responses to IIV4

appear to affect vaccine safety or tolerability.

5. Clinical findings in children 6 to 35 months of age

IIV4 to protect against laboratory-confirmed influenza-like illness caused by any circulating

strains as well as by vaccine-similar strains [42].

Sanofi Pasteur’s IIV4 is a quadrivalent split-virion inactivated influenza vaccine approved in

affected by conditions increasing the risk of influenza-related complications. Although some

those induced by cross-reactivity by an alternate B strain in IIV3.

confirmed influenza-like illness caused by any circulating strains as well as by vaccine-similar

logical step in vaccine development to match viral evolution.

baseline, prior influenza vaccination, or underlying chronic disease.

negatively affect vaccine safety or tolerability.

influenza remains significant. Quadrivalent influenza vaccines provide an opportunity to further

associated morbidity and mortality.

be cost-effective [44-53] or cost-saving [54-58]. This will be confirmed in further studies.

• Influenza B represents nearly one-quarter of circulating influenza viruses and results in

illness indistinguishable from that caused by influenza A