Manufacturing influenza virus vaccines using a mammalian cell line
rather than embryonated chicken eggs may carry certain advantages. A quadrivalent
inactivated influenza virus vaccine produced using the Madin Darby canine kidney
cell line has been approved in the EU (Flucelvax® Tetra)
and USA (Flucelvax Quadrivalent®; QIVc hereafter) for the
prevention of influenza in adults and children. The clinical development of QIVc has
built upon that of a cell-based trivalent influenza virus vaccine (TIVc)
manufactured using the same processes; the additional influenza B strain contained
in QIVc reduces the risk of the strain in the vaccine not matching that in
circulation. Pivotal phase III clinical trials in adult and paediatric participants
have demonstrated the immunogenicity of QIVc to be noninferior to that of TIVc
formulations against shared strains and superior against the influenza B strain
absent from each TIVc formulation. Protective efficacy data for TIVc is considered
foundational for QIVc and, in a phase III clinical trial, TIVc was effective in
protecting adults against antigenically matched influenza strains. Large real-world
studies from the 2017/2018 US influenza season further support the prophylactic
effectiveness of QIVc, with possible benefits over egg-based vaccines. QIVc was
generally well tolerated in clinical trials. In adult and paediatric QIVc
recipients, the most common solicited adverse reactions were injection site pain and
headache. Reactogenicity was comparable to that of TIVc; no safety signals unique to
QIVc emerged. Through circumventing concerns around egg adaptation, QIVc has the
potential to be more effective than currently available egg-based quadrivalent
vaccines.
The original version of this article was revised due to a retrospective Open
Access request.
The manuscript was reviewed by:G. Icardi, Department of Health Sciences,
University of Genoa, Genoa, Italy; F.
Krammer, Department of Microbiology, Icahn School of Medicine at Mount
Sinai, New York, NY, USA; M. Petras,
Preventive Medicine, Third Faculty of Medicine, Charles University, Prague, Czech
Republic.
QIVc: clinical considerations in the prevention of influenza virus
infections
First quadrivalent influenza virus vaccine produced
in mammalian cell cultures
Improves upon TIVc; protects against an additional
influenza B strain and now entirely
cell-derived
Immunogenicity not detrimentally impacted by
additional strain
Effectively protects against influenza, as indicated
by a phase III TIVc trial and real-world QIVc
data
Generally well tolerated; comparable reactogenicity
to TIVc
1 Introduction
Influenza is associated with considerable morbidity and mortality
worldwide, with 3–5 million cases of severe illness and an estimated 290,000–650,000
respiratory deaths resulting from seasonal influenza virus infections each year
[1, 2]. While not providing complete protection, vaccination does
substantially reduce the burden of influenza and thus represents a major public
health initiative [3, 4]. As influenza viruses rapidly mutate and the
prophylactic effects of vaccination wane over time, vaccine formulations are updated
each year to antigenically match circulating strains and annual vaccination is
recommended for optimal protection (and is of particular import in groups at high
risk of influenza complications) [1,
4‐6].
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Trivalent vaccines comprising two influenza A strains and one influenza
B strain have been used to protect against influenza since the late 1970s
[4]. However, there are two distinct
lineages of influenza B virus that now frequently co-circulate [the
B/Yamagata/16/88-like (Yamagata) and B/Victoria/2/87-like (Victoria) lineages]
[4, 7]. Effectiveness of trivalent vaccines is dependent on the
extent to which the influenza B strain in the vaccine matches the strains in
circulation, and it can be difficult to predict which lineage will predominate in a
given season [4, 7]. Within the last decade, a number of
quadrivalent vaccines containing a second influenza B strain have become available
to mitigate the issue of mismatch [4].
Most contemporary influenza virus vaccines are produced from viruses
grown in embryonated chicken eggs and chemically inactivated [3, 6]. While this production strategy is inexpensive and supported by
vast infrastructure, it does have a number of limitations associated with it
[6]. An adequate supply of eggs is
necessary and production must start long before the influenza season commences,
limiting the capacity for sudden changes in circulating strains to be reflected in
egg-based vaccines [3, 6]. Importantly, mutations accumulate in the
haemagglutinin proteins of influenza viruses in response to selective pressures in
the eggs [3, 6, 8]. These mutations can alter antigenicity and may detrimentally
impact the prophylactic effectiveness of the vaccine [3, 6, 8]; emerging evidence suggests that such
mutations have affected antigenicity against H3N2 viruses over a number of influenza
seasons [9].
Utilising mammalian cells instead of chicken eggs to grow influenza
viruses may reduce the chance of haemagglutinin mutations arising during the
production process, potentially improving vaccine effectiveness [3, 6,
8]. Cell-based vaccine manufacturing
also provides a more flexible production timeline once the necessary infrastructure
is established [6], and the cells that
are used are stored frozen in cell banks to ensure adequate supply [3]. Containing no egg protein, cell-based
vaccines eliminate the risk of allergic reactions to this in individuals with egg
allergies [3, 6].
A cell-based quadrivalent inactivated influenza virus vaccine (referred
to as QIVc hereafter) has been approved in the EU
(Flucelvax® Tetra) [10] and USA (Flucelvax Quadrivalent®)
[11] as an intramuscular injection
for the prophylaxis of influenza in adults and children. Rather than being produced
in chicken eggs, QIVc is manufactured from virus propagated in Madin Darby Canine
Kidney (MDCK) cells [10‐12]. Candidate
vaccine viruses (CVVs) are isolated and amplified in the MDCK cell line, then pass
through a number of steps validated for MDCK cell removal and are inactivated with
β-propiolactone for use in the vaccine [11‐13]. These processes reduce levels of viruses or bacteria and
other adventitious agents to effectively zero [12, 14]. The active
substance in QIVc is a suspension consisting predominantly of purified
haemagglutinin and neuraminidase surface antigens; one 0.5 mL dose of QIVc
contains ≈ 15 μg of haemagglutinin from each of four influenza strains (A/H1N1,
A/H3N2 and B strains from the Yamagata and Victoria lineages [13]; 60 μg in total), against which it provides
active immunisation [10, 11]. As with other influenza virus vaccines,
administration of QIVc results in the production of humoral antibodies against
haemagglutinins, which can neutralise influenza viruses [10, 11].
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QIVc is standardised annually in compliance with World Health
Organisation (WHO) and Committee for Medicinal Products for Human Use (CHMP)
recommendations (in the EU) [10,
13], or United States Public Health
Service requirements (in the USA) [11],
in order to provide protection against the strains expected to circulate in the
upcoming influenza season. While QIVc was initially produced using egg-derived CVVs
(with mutations associated with egg adaptation still likely to be present in the
vaccine antigens) [6, 8], a cell culture-derived CVV was used for the
A/H3N2 strain in the formulation for the 2017/2018 Northern Hemisphere influenza
season [8] and for both B strains (in
addition to the A/H3N2 strain) in the formulation for the 2018/2019 season
[5]. In the formulation for the
imminent 2019/2020 season, the use of a cell culture-derived CVV for the A/H1N1
strain will complete the transition to a purely cell-based product [15].
This article focuses on the immunogenicity, protective efficacy and
reactogenicity of QIVc. Where relevant, discussion of an established cell-based
trivalent inactivated influenza virus vaccine [TIVc;
Flucelvax® (USA)/Optaflu®
(EU; registration expired)] is also included. TIVc provides immunisation against two
influenza A strains (A/H1N1 and A/H3N2) and one influenza B strain (either of the
Yamagata or Victoria lineage), with ≈ 15 μg of haemagglutinin from each strain in
one 0.5 mL dose [13]. Developed as an
upgrade of TIVc, QIVc is manufactured using processes consistent with those used for
TIVc and the active drug substance and excipients are the same; the additional
antigen is not expected to modify the pharmacology of the vaccine [13].
2 Immunogenicity
The immunogenicity of QIVc was compared with that of TIVc in two
pivotal, double-blind, randomized, multicenter phase III noninferiority trials that
enrolled adults aged ≥ 18 years (V130_01) [16] and children and adolescents aged 4 to < 18 years
(V130_03) [17] in the USA. Key
exclusion criteria included a body temperature ≥ 38 °C within 3 days prior to the
vaccination, documented influenza or influenza virus vaccination within the prior
6 months, a history of known or suspected immunodeficiency (congenital or acquired)
or receipt of immunosuppressants (within the prior 6 months [16]), and being potentially pregnant, pregnant
or breast-feeding [16, 17].
Participants were assigned to either QIVc or one of two TIVc
formulations [16, 17]. The TIVc formulations differed only with
respect to influenza B strain lineage; TIV1c contained a strain of the Yamagata (B1)
lineage while TIV2c contained a strain of the Victoria (B2) lineage. QIVc and TIV1c
comprised the influenza strains recommended by the WHO for inclusion in quadrivalent
and trivalent vaccines, respectively, in the 2013/2014 Northern Hemisphere influenza
season, while the B/Victoria strain in TIV2c was recommended for inclusion in
quadrivalent (but not trivalent) vaccines. Randomization was stratified by age (18
to < 65 years vs. ≥ 65 years in V130_01, and 4 to < 9 years vs. 9
to < 18 years in VI30_03) and, in the youngest cohort only, whether or not they
had previously been vaccinated against seasonal influenza. Participants received a
single 0.5 mL dose of their assigned study vaccine, with the exception of not
previously vaccinated children aged 4 to < 9 years who received a second 0.5 mL
dose (with the vaccine being administered on days 1 and 29). Vaccines were
intramuscularly administered in the deltoid muscle, preferentially that of the
non-dominant arm [16, 17].
The co-primary objectives in both trials were to demonstrate the
noninferiority of QIVc to a TIVc comparator with respect to haemagglutinin
inhibition (HI) geometric mean antibody titre (GMT) ratios (TIVc to QIVc) and
differences in seroconversion rate (SCR) [TIVc minus QIVc] for each of the four
influenza strains [13, 16, 17]. HI GMT and SCR were assessed at day 22 (in participants
receiving one dose) or day 50 (in those receiving two doses) post-vaccination
[13, 16, 17]. The
comparator TIVc was TIV1c for A/H1N1, A/H3N2 and B1 (the Yamagata strain), and TIV2c
for B2 (the Victoria strain) [10,
11, 13]. In V130_01, a key secondary objective was to evaluate
antibody responses to all four influenza virus vaccine strains, based on Centre for
Biologics Evaluation and Research (CBER) criteria, in adults aged 18
to < 65 years and ≥ 65 years [13].
Noninferiority was assessed in the per-protocol set (PPS), while the full analysis
set (FAS) was used for all secondary immunogenicity outcomes [16, 17].
At baseline, demographics and other characteristics were generally well
balanced across the vaccine groups in each trial [16, 17].
Participants enrolled in V130_01 and V130_03 had mean ages of ≈ 57 and 9.5 years,
respectively, and roughly half were female (57% and 48%). The majority of
participants were white (77% in V130_01 and 53% in V130_03) or black (13% and 22%)
[16, 17]. In the trial in adults (V130_01), ≈ 25% of each vaccine
group had received an influenza virus vaccination within 6–12 months prior to
participation; across the four vaccine strains, 84–96% of participants had HI
titres ≥ 1:10 [16]. Of the 2680
participants randomized in V130_01, 98% were included in the FAS and 94% were
included in the PPS [16]; of the 2333
participants randomized in V130_03, the respective rates were 96% and 87%
[17].
In both trials, QIVc was noninferior to the TIVc comparator in terms of
HI GMT ratios and SCR differences (Table 1).
Where stated (V130_01), analyses of these outcomes in the FAS yielded results that
were consistent with those of the primary analyses [13]. Overall, QIVc performed well against the immunogenicity
criteria specified by the CBER and CHMP [13, 16, 17].
Table 1
Immunogenicity of cell-based quadrivalent inactivated
influenza virus vaccine in adult and paediatric
participants
Paediatric participants aged 4
to < 18years
(V130_03) [13]
QIVc (n = 1009–1014)
1090
(1027–1157)
72
(69–75)
738
(703–774)
47
(44–50)
155
(146–165)
66
(63–69)
185
(171–200)
73
(70–76)
TIV1c/TIV2c (n = 501–510)
1125
(1034–1224)
75
(70–78)
776
(725–831)
51
(46–55)
154
(141–168)
66
(62–70)
185
(166–207)
71
(67–75)
Group ratio (95%
CI)c
1.03
(0.93–1.14)
1.05
(0.97–1.14)
0.99
(0.89–1.1)
1
(0.87–1.14)
Group difference (95%
CI)c
2
(− 2.5 to 6.9)
4
(− 1.4 to 9.2)
0
(− 5.5 to 4.5)
− 2
(− 6.5 to 3.2)
Paediatric participants aged 9
to < 18years
(V130_03) [10, 17]
QIVc (n = 545–547)
1139
(1045–1242)
70
(66–74)
719
(673–767)
42
(38–47)
200
(185–218)
63
(58–67)
212
(192–235)
72
(68–75)
TIV1c/TIV2c (n = 265–272)
1138
(1007–1286)
72
(67–78)
762
(694–836)
53
(46–59)
200
(178–224)
63
(57–69)
203
(175–234)
68
(62–74)
GMT geometric mean titre,QIVc cell-based quadrivalent
inactivated influenza virus vaccine, SCR seroconversion rate, TIV1 cell-based trivalent inactivated influenza virus
vaccine (influenza B strain from the Yamagata lineage), TIV2c cell-based trivalent inactivated
influenza virus vaccine (influenza B strain from the Victoria
lineage)
aPer protocol set (defined as all
participants who correctly received the assigned vaccine and were not
excluded due to reasons defined prior to unblinding/analysis);
noninferiority analyses were conducted in this population
bPercentage of participants with
either a pre-vaccination H1 titre < 1:10 and post-vaccination H1
titre ≥ 1:40 or a pre-vaccination H1 titre ≥ 1:10 and ≥ 4-fold increase
in post-vaccination H1 antibody titre
cCo-primary endpoints; noninferiority
established if upper limit of the two-sided 95% CI for ratio of GMTs for
HI antibody response (TIV1c or TIV2c divided by QIVc) was < 1.5 and
if the upper limit of the two-sided 95% CI for SCR difference (TIV1c or
TIV2c minus QIVc) was < 10%
CBER criteria require that, for each vaccine strain, the lower limit of
the two-sided 95% CI for the percentage of participants achieving seroconversion for
HI antibody is ≥ 40% (≥ 30% in patients aged ≥ 65 years) and that for an HI antibody
titre ≥ 1:40 is ≥ 70% (≥ 60% in patients aged ≥ 65 years) [16, 17]. In adults aged 18 to < 65 years (at day 22) and
paediatric participants aged 4 to < 18 years (at day 22 or 50), QIVc met both of
these immunogenicity criteria for all four vaccine strains, as did TIV1c/TIV2c
[16, 17]. In adults aged ≥ 65 years at day 22, QIVc and TIV1c/TIV2c
met both CBER criteria for A/H1N1 and the HI antibody titre ≥ 1:40 criterion (but
not the seroconversion criterion) for A/H3N2, B1 and B2 [16].
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CHMP immunogenicity criteria for adults aged 18 to ≤ 60 years
and ≥ 61 years are met if, for each vaccine strain, the point estimate for the
geometric mean ratio (GMR; day 22 or 50/day 1) is > 2.5 and > 2.0,
respectively; SCR is > 40% and > 30%; and the percentage of patients achieving
an HI titre ≥ 1:40 is > 70% and > 60% [16, 17]. The
criteria for adults aged 18 to ≤ 60 years was also used in the paediatric study,
given the absence of specific CHMP criteria for this age group [17]. QIVc and TIV1c/TIV2c met all CHMP
immunogenicity criteria for all four strains in paediatric participants aged 4
to < 18 years and adult participants aged 18 to ≤ 60 years [16, 17]. In older adults (≥ 61 years of age), QIVc and TIV1c/TIV2c
met all CHMP criteria for the A/H1N1 strain and two criteria (GMR and HI
titre ≥ 1:40, but not seroconversion) for the A/H3N2 and B2 strains [16]. QIVc met two criteria (GMR and HI
titre ≥ 1:40, but not seroconversion) for the B1 strain, while TIV1c/TIV2c only met
the HI titre ≥ 1:40 criterion [16].
QIVc demonstrated superior immunogenicity to TIV1c and TIV2c with
respect to the influenza B strains not included in each trivalent formulation (i.e.
B2 for TIV1c and B1 for TIV2c) [16,
17]. In both trials, GMTs and SCRs
for the unmatched B strains were higher in QIVc recipients than in TIV1c and TIV2c
recipients at 3 weeks post-vaccination, with upper limits of the two-sided 95% CIs
for the ratio of GMTs for HI antibody response (GMT TIV1c or TIV2c divided by GMT
QIVc) not exceeding the superiority margin of 1 and upper limits of the two-sided
95% CIs for difference in SCR (SCR TIV1c or TIV2c minus SCR QIVc) not exceeding the
margin of 0 points [16, 17].
Post-hoc analyses of data from V130_01 and V130_03 generally showed no
substantial differences between QIVc and TIV1c/TIV2c within subgroups based on
variables such as age, sex, race/ethnicity and baseline immune status [13, 16]. In V130_01, noninferiority criteria were met in subgroups
based on age (18 to < 65 years of age vs. ≥ 65 years of age) for all four strains
[10, 13]. When stratified by baseline HI serostatus, SCRs were
significantly (based on non-overlapping 95% CIs) higher for each strain in
participants with baseline HI < 1:10 than in those with baseline HI ≥ 1:10 in
both QIVc (71–87% vs. 35–43%) and TIVc (80–88% vs. 32–42%) groups [16]. In both paediatric participants who were
seronegative at baseline and those with baseline titres ≥ 1:10, immune responses
were comparable between age groups (4 to < 9 years and 9 to < 18 years) for
all four strains following vaccination with either QIVc or TIV1c/TIV2c [13].
Results from V130_01 and V130_03 were consistent with the robust
immunogenicity of TIVc demonstrated in other large clinical trials in adults
aged ≥ 18 years [18‐20] and children
aged 4 to < 18 years [21]. These
include studies that have demonstrated the noninferiority of TIVc to egg-based
comparators for all strains in adult participants (based on CHMP immunogenicity
criteria) [V58P4] [20] and for the
A/H1NI and B strains in paediatric participants (based on ratios of GMTs and
differences in SCR, as determined using a cell-derived antigen assay; for A/H3N2,
noninferiority was shown for difference in SCR but not GMT ratio) [V58P12]
[21]. Persistence of antibodies has
also been demonstrated with TIVc; GMTs remained ≥ 3-fold higher than baseline
6 months after vaccination with TIVc in participants aged 18–60 years in V58P9
[18] and GMTs were ≈ 1.4–3-fold
higher than baseline 1 year after vaccination with TIVc in adults aged 18
to < 61 years and ≥ 61 years in V58P4E1 [13]. In V58P4EI and V58P4E2, immunogenicity of TIVc in adult and
elderly participants was not affected by concomitant vaccination with a pneumococcal
vaccine nor by type of influenza virus vaccine received in the previous season
[22].
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3 Protective Efficacy
While the protective efficacy of QIVc has not been evaluated in
clinical trials, the protective efficacy of TIVc is considered relevant due to the
trivalent and quadrivalent vaccines being manufactured in the same manner and having
overlapping compositions (Sect. 1)
[10, 11]. This section will thus focus on the protective efficacy of
TIVc in adults during the 2007–2008 influenza season, as evaluated in a
multinational, randomised, observer-blind, placebo-controlled phase III trial
(V58P13) [19]. Supportive evidence
comes from real-world studies of the effectiveness of QIVc in adults and children
during the 2017–2018 influenza season [23‐27].
3.1 In a Phase III Trial
V58P13 enrolled healthy adults aged 18 to < 50 years in the USA,
Finland and Poland [19]. Key
exclusion criteria included a body temperature ≥ 37.8 °C and/or acute illness
within 3 days of enrolment, laboratory-confirmed influenza or influenza virus
vaccination within the 6 months prior to enrolment, a health condition for which
an inactivated vaccine is recommended, and being pregnant or breast-feeding.
Participants were randomized to receive either a 0.5 mL dose of TIVc (n = 3828), an egg-based trivalent inactivated
influenza virus vaccine (TIVe; n = 3676) or
placebo (n = 3900), administered in the
deltoid muscle of their non-dominant arm. Each dose of TIVc or TIVe contained
15 μg haemagglutinin from each of the recommended virus strains for the
2007–2008 Northern Hemisphere influenza season [19].
The primary objective was to demonstrate the protective efficacy of
each vaccine against laboratory-confirmed influenza illness caused by virus
strains antigenically similar to those of the vaccines, compared with that of
placebo [19]. Influenza
surveillance commenced 21 days after vaccine administration, with participants
reporting influenza-like illness (ILI) symptoms [defined as fever
(temperature ≥ 37.8 °C) plus sore throat or cough], and body aches, chills,
headache and runny or stuffy nose; there was also active ILI surveillance via
weekly telephone calls. Participants who reported ILI symptoms were clinically
evaluated, with nasal and throat specimens collected within 120 h of ILI onset
for laboratory confirmation of the influenza virus. Each participant was
observed for either the 6-month study surveillance period or 6 months after
vaccination (whichever of these was longer) [19].
Demographic and baseline characteristics were similar across the
three vaccine groups [19]. In the
overall enrolled study population, the mean age was 33 years and 55% of
participants were female [11]. The
majority of participants were white (84%) [11]. Relatively few participants had previously received
influenza virus vaccinations (13–15%) [19]. Of all randomized participants, 11,257 (99%) were
evaluable during their 6-month surveillance period and thus included in the
efficacy PPS [19].
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During the surveillance period, ILI symptoms were reported in 189
TIVc recipients (5%), 243 TIVe recipients (7%) and 353 placebo recipients (9%)
in the PPS [19]. Specimen samples
were collected from 92% of these participants, with a mean interval of ≈ 39 h
from symptom onset to specimen collection. For the cases in which the specimen
was collected within the specified 120-h window (97% of cases), influenza virus
was confirmed in 25% (42/168), 22% (49/218) and 44% (140/318) of TIVc, TIVe and
placebo recipients, respectively [19]. While protective efficacy data pertaining to TIVe is
presented in Table 2 for completeness,
discussion focusses on TIVc.
Table 2
Protective efficacy of cell- and egg-based trivalent
inactivated influenza virus vaccines in adults
Results of V58P13 (NCT00630331) [19]. Efficacies of TIVc and TIVe
exceeded the CBER efficacy criteria
CBER Center for Biologics
Evaluation and Research, TIVc
cell-based trivalent inactivated influenza virus vaccine, TIVe egg-based trivalent inactivated
influenza virus vaccine
*p < 0.01, **p < 0.001 (adjusted p-values; p < 0.025 indicates a vaccine efficacy
significantly larger than 40%)
aEfficacy per protocol population
(participants who were evaluable during their individual 6-month
surveillance period)
b(1 − relative
risk) × 100
cSimultaneous one-sided 97.5% CIs
for vaccine efficacy of TIVc or TIVe relative to placebo; efficacy
success criterion was a lower limit > 40% (prespecified for
overall analyses but not for individual strains [11])
dIsolates were considered matched
if there was a ≤ 4-fold difference in titre of the isolate and the
vaccine strain against a reference antiserum
ePrimary endpoint (overall
vaccine efficacy of each vaccine relative to placebo) achieved for
each vaccine [13,
19]; see success
criterion above
fToo few cases to adequately
assess vaccine efficacy [10, 11]
gIsolates were considered
non-vaccine-like if the haemagglutination inhibition antibody titre
was ≥ 1:8 against specific reference strain antisera
TIVc provided effective prophylaxis against antigenically matched
strains overall (primary endpoint) and against antigenically matched A/H1N1
virus, with vaccine efficacy relative to placebo being significantly higher than
the prespecified criterion of 40% (Table 2) [19].
Overall, the attack rate for antigenically matched strains in participants who
received TIVc was about one-sixth of that seen in placebo recipients (0.19 vs.
1.14; Table 2). There were too few cases
of influenza caused by antigenically matched A/H3N2 and B strains to adequately
assess vaccine efficacy (Table 2).
When looking at all circulating strains (matched and non-matched)
responsible for cases of influenza, the vaccine efficacy of TIVc relative to
placebo was also significantly higher than 40% (Table 2). The attack rate with TIVc was less than one-third of that
seen with placebo (1.11 vs. 3.64; Table 2). With respect to individual virus strains, the vaccine
efficacy of TIVc relative to placebo was significantly higher than 40% for
A/H1N1 but not A/H3N2 or B (Table 2).
When considering only non-matched strains, the vaccine efficacy did not exceed
the 40% threshold for any individual strain nor overall (Table 2). Most cases of non-matched influenza were
caused by influenza B strain viruses; across the groups, non-matched strains
were responsible for 115/116 cases of culture-confirmed influenza B
[19].
3.2 In Real-World Studies (2017/2018 Season)
The real-world protective effectiveness of QIVc during the
2017/2018 influenza season in the USA has been investigated in retrospective
cohort studies [23, 25‐27] and test negative case–control studies
[24, 25, 28], the results of which indicate that, like egg-based
vaccines, cell-based influenza virus vaccines are effective in preventing
influenza. This section focuses on the three largest of these studies
(retrospective cohort studies each in n > 90,000 QIVc recipients) [23, 25,
26]. Relative vaccine
effectiveness [RVE; calculated as 100 × (1 − odds ratio) [23] or 100 × (1 − rate ratio) [26], with models adjusted for covariates
[23, 25, 26]] is reported.
In a study using data from electronic medical records of patients
aged ≥ 4 years of age presenting to primary care in the USA between 1 August
2017 and 31 March 2018, QIVc (n = 92,192
recipients) was significantly more effective than an egg-based quadrivalent
vaccine (QIVe; n = 1,255,983) in preventing
ILI after adjusting for demographic confounds (RVE of QIVc vs. QIVe 36.2%; 95%
CI 26.1–44.9; p < 0.001) [abstract]
[23]. When specific age groups
were examined, this effect was significant in adults aged 18 to < 65 years
(RVE 26.8; 95% CI 14.1–37.6; p < 0.001)
but not paediatric patients aged 4 to < 18 years (RVE 18.8%; 95% CI −53.9 to
57.2) or older adults aged ≥ 65 years (RVE −7.3; 95% CI −51.6 to 24.0)
[propensity-score matched models; no other covariates adjusted for]
[23].
Data from the Defense Medical Surveillance System (DMSS) was used
to examine the effectiveness of QIVc (n = 392,116) versus that of QIVe (n = 371,394) in active component US service members, the
majority of whom were aged 18 to < 40 years (91% and 90% in the respective
vaccine groups) and male (84% and 82%) [abstract] [25]. QIVc was significantly more effective
than QIVe in preventing influenza diagnosed during any medical encounter (2732
vs. 3360 cases; RVE 16%; 95% CI 11–20), but not influenza diagnosed during
hospitalization only (11 vs. 20 cases; RVE 46%; 95% CI −18 to 76), after
adjusting for age group, sex, month of vaccination and receipt of influenza
virus vaccination during the prior season (statistical significance based on 95%
CIs). With respect to ILI, there were no significant differences between QIVc
and QIVe for rates of ILI diagnosed during any medical encounter (40,736 vs.
40,991 cases; adjusted RVE 2%; 95% CI 0–4) or hospitalization only (120 vs 139
cases; adjusted RVE 16%; 95% CI −9 to 35) [25].
QIVc conferred significant benefits over QIVe in a large
retrospective cohort study of Medicare beneficiaries aged ≥ 65 years who
received an influenza virus vaccination from 6 August 2017 through 31 January
2018 [26]. QIVc was administered in
5% (n = 659,249) of eligible vaccinees, while
QIVe was administered in 14% (n = 1,863,654).
After adjusting for baseline differences in covariates between the vaccine
groups, QIVc was significantly more effective than QIVe in preventing
influenza-related hospital encounters (defined as an inpatient hospitalization
or emergency department visit; primary outcome) [RVE 10.0%; 95% CI 7.0–13.0].
Results from sensitivity analyses were consistent with this estimate. QIVc was
also significantly more effective than QIVe in preventing influenza-related
office visits (defined as community-based physician office visits or hospital
outpatient visits in which a rapid influenza diagnostic test was performed and a
therapeutic course of oseltamivir was prescribed within 2 days) [RVE 10.5%; 95%
CI 6.8–14.0 (2-way comparison adjusted for covariates)]. In five-way comparisons
that included data from eligible vaccinees who received egg-based standard-dose
(n = 1,018,494), high-dose (n = 8,489,159) or MF59-adjuvanted (n = 1,473,536) trivalent vaccinations, QIVc was
significantly more effective than QIVe and egg-based standard-dose (but not
high-dose) and adjuvanted trivalent vaccines in preventing influenza-related
hospital encounters and influenza-related inpatient stays, and significantly
more effective than QIVe and egg-based high-dose (but not standard-dose) and
adjuvanted trivalent vaccines in preventing influenza-related office visits
(adjusted for covariates; p ≤ 0.05 for all
comparisons) [26].
4 Reactogenicity and Safety
QIVc was generally well tolerated in the pivotal phase III trials in
adult (V130_01) [16] and paediatric
participants (V130_03) [17] (which will
be the focus of this section). Within 7 days of QIVc administration in the pivotal
trials, solicited adverse reactions occurred in 62% of adult participants aged 18
to < 65 years (vs. 57% and 60% with TIV1c and TIV2c) [16] and in 71% of paediatric participants aged 9
to < 18 years (vs. 68% and 61%) [17]. The most common solicited adverse reactions (incidence ≥ 10%
with any vaccine) reported in these age groups were injection site pain and headache
(Fig. 1) [11]. In older adults (aged ≥ 65 years; n = 1332 with 7 days of solicited adverse reaction data
[11]), solicited adverse reactions
were reported by 41% of QIVc recipients (vs. 39% and 43% of TIV1c and TIV2c
recipients) [16] and the most common
were injection site pain (21.6% vs. 18.8% and 18.5%), injection site erythema (11.9%
vs. 10.6% and 10.4%) and headache (9.3% vs. 8.5% and 8.3%) [11]. The overall paediatric population (aged 4
to < 18; n = 2264) reported similar rates of
local and systemic adverse reactions to those reported by participants aged 9
to < 18 years [10]. In both adult
and paediatric participants, the majority of solicited adverse reactions were mild
to moderate in severity [13,
16, 17]. Fever (body temperature ≥ 38.0 °C) occurred at low rates
across the QIVc, TIV1c and TIV2c arms (0.5%, 0.7% and 0.5% of adults aged ≥ 18 years
and 3%, 4% and 2% of children aged 4 to < 18 years [13]); no cases of body temperature ≥ 40.0 °C
were reported in adults and one case was reported in a paediatric participant (a
QIVc recipient aged 9 to < 18 years) [13, 16].
×
Severe solicited adverse reactions were infrequent (≥ 1%) of adults
aged ≥ 18 years administered QIVc [13];
severe pain occurred in 0.2% and 0.1% of QIVc and TIV1c recipients [16]. In the overall paediatric population, there
were low rates of severe injection site pain (1% of participants in each vaccine
group), tenderness (2%, 1% and 2% of participants administered QIVc, TIV1c and
TIV2c, respectively), erythema and induration (each < 1% of patients in each
group); in participants aged 9 to < 18 years, no severe solicited local adverse
reaction occurred at a rate of ≥ 1% in any vaccine group [13]. The only severe solicited systemic adverse
reaction experienced by > 1% of paediatric QIVc recipients was irritability (2%
with QIVc and TIV1c) [13].
Rates of unsolicited adverse events were comparable across vaccine
groups in both adult (16%, 15% and 17% with QIVc, TIV1c and TIV2c, respectively)
[13, 16] and paediatric participants (24%, 24% and 27%) [17]. Those considered to be at least possibly
related to the study vaccine were infrequent (in 3–5% of adults aged 18
to < 64 years, 4–5% of adults aged ≥ 65 years [16] and 5–6% of paediatric participants [17]). In QIVc recipients aged ≥ 18 years, the
most common possibly or probably vaccine-related unsolicited adverse event was
injection site haemorrhage (0.8% vs. 0.4% and 0.6% with TIV1c and TIV2c)
[16]. Medically attended adverse
events also occurred at similar rates across vaccine groups (26%, 26% and 25% of
adult participants receiving QIVc, TIV1c and TIV2c, respectively [16], and 27% of paediatric participants in each
vaccine group [17]).
Serious adverse events (SAEs; collected ≤ 6 months after vaccination)
were reported in 1.7%, 1.8% and 1.5% of QIVc, TIV1c and TIV2c recipients aged 18
to < 65 years, while the respective rates in adults aged ≥ 65 years were 6.2%,
4.7% and 4.7% [16]. New onset of
chronic disease (NOCD) was reported in 3.6% of QIVc recipients aged 18
to < 65 years (vs. 3.0% and 3.7% of TIV1c and TIV2c recipients) and 5.8% of QIVc
recipients aged ≥ 65 years (vs. 4.4% and 5.0%); these were most commonly metabolism
and nutritional disorders (0.8% vs. 0.7% and 0.5%), cardiac disorders (0.8% vs. 0.6%
and 0.3%), and musculoskeletal and connective tissue disorders (0.8% vs. 0.4% and
0.3%) [16]. In the paediatric trial,
SAEs occurred at low rates (0.5%, 1.2% and 0.4% of QIVc, TIV1c and TIV2c recipients,
respectively [13]), as did NOCD (2% of
patients in each vaccine group) [17].
No SAE or case of NOCD was considered to be related to the study vaccine in either
trial [13]. There were 12 deaths during
the adult trial, none of which were considered to be related to the study vaccine
and most of which occurred in adults ≥ 65 years of age (rates were 0.8%, 1.5% and
0.3% with QIVc, TIV1c and TIV2c, respectively, in this age group vs. 0%, 0% and 0.3%
in adults aged 18 to < 65 years) [16]. No deaths were reported during the paediatric trial
[17].
Safety data (pertaining to both QIVc and the TIVc comparators) from
these trials were generally consistent with those from numerous clinical studies of
TIVc in adults and children [13,
18‐22, 29‐33], with the
additional strain not altering the safety profile of the QIVc vaccine; no new safety
signals were identified [13]. The
clinical development program for TIVc found it to have a safety profile comparable
to that of an egg-based trivalent influenza virus vaccine [13, 18‐22, 31, 32, 34]. Post-marketing safety data are available
for TIVc, representing millions of adults and children vaccinated in Europe and the
USA in the 2016/2017 influenza season, and have confirmed its established safety
profile [13]; similarly, an earlier
surveillance study in the USA (2013–2015) found no concerning patterns in the
adverse events reported in TIVc recipients [35].
5 Dosage and Administration
QIVc is indicated for the prophylaxis of influenza in adults and
children [10]. A single dose is 0.5 mL
(which includes ≈ 15 μg of haemagglutinin from each influenza strain), administered
as an intramuscular injection to the deltoid muscle of the upper arm [10, 11]. The minimum age of eligibility for the vaccine and the
available presentations of the vaccine differ between the EU and USA (see
Supplementary Table 1); local prescribing information should be consulted for
specific details. Local prescribing information should also be consulted for details
concerning administration, storage and handling, contraindications, warnings and
precautions, and use in specific patient populations.
6 Place of Flucelvax® Tetra/Flucelvax
Quadrivalent® in the Prevention of
Influenza
Vaccination is currently the best strategy for reducing morbidity and
mortality associated with influenza infection [1, 8], and the WHO
recommends annual vaccination in individuals at high risk of influenza complications
and those who live with or care for them [1]. While influenza virus vaccines have historically been
produced in embryonated chicken eggs and the majority of contemporary quadrivalent
and trivalent vaccines are egg-based, some manufacturers are now moving towards
cell-based technology. Approved in the EU and USA (Sect. 5), QIVc is the most widely available cell-based quadrivalent
vaccine. The most recent recommendations from the US Centers for Disease Control and
Prevention (CDC) Advisory Committee on Immunization Practices (ACIP), developed for
the 2018/2019 influenza season, state that vaccination providers may choose to
administer any licensed, age-appropriate influenza virus vaccine; if more than one
is appropriate, no preferential recommendation is made for use of any particular
vaccine over another [5]. In individuals
with a history of egg allergy of any severity, providers may also select any of a
number of licensed, recommended and age-appropriate vaccines [5]. Benefits of quadrivalent versus trivalent
formulations in any one season are dependent on the extent to which the influenza B
strain in the trivalent vaccine matches those in circulation [4, 7]
and, while acknowledging that quadrivalent vaccines are designed to provide broader
influenza B protection, ACIP recommendations do not express a preference for either
quadrivalent or trivalent inactivated influenza virus vaccines [5]. For the 2019/2020 influenza season in the UK,
the Joint Committee on Vaccination and Immunisation has recommended the use of QIVc
or QIVe over a trivalent vaccine in individuals < 65 years in at risk groups
[36]. In adults ≥ 65 years of age,
the use of QIVc, an adjuvanted trivalent vaccine or a high-dose trivalent vaccine is
considered preferable to the use of QIVe [36].
The clinical development program of QIVc builds upon that of TIVc,
which has demonstrated TIVc to have comparable immunogenicity (Sect. 2) and reactogenicity (Sect. 4) to licensed egg-based comparator vaccines
[13]. Given that QIVc and TIVc are
manufactured in the same manner aside from the additional influenza B strain in QIVc
(Sect. 1), data from clinical trials of
TIVc are considered relevant to QIVc [13].
In well-designed, phase III clinical trials in adult and paediatric
participants, QIVc had noninferior immunogenicity to TIVc comparators based on
ratios of GMTs and differences in SCRs for each matched influenza strain; the
additional influenza B strain contained in QIVc did not interfere with immune
responses to the other three strains (Sect. 2). Furthermore, QIVc was superior to the TIVc comparators with
respect to the influenza B strain that each trivalent formulation did not contain
(of Yamagata or Victoria lineage), indicating the potential for broader protection
with the quadrivalent product. QIVc fulfilled all CBER and CHMP immunogenicity
criteria, except in older adults (in whom the majority of the criteria were met)
[Sect. 2]. These trials, whilst limited
to the USA and excluding pregnant or breastfeeding women and individuals with
impaired immunity, enrolled participants who were largely representative of the
general population (including those with different underlying medical conditions)
[13, 16].
While clinical trial data on the protective efficacy of QIVc are not
available, TIVc provided effective prophylaxis in the phase III V58P13 trial with a
vaccine efficacy of 84% (significantly > 40%) relative to placebo for
antigenically matched, culture-confirmed influenza (Sect. 3). Based on immunogenicity results from V130_01 considered
alongside immunogenicity and efficacy data from V58P13, QIVc is expected to induce
comparable clinical protection in adults [13]. While there are no protective efficacy data pertaining to
the use of TIVc in the paediatric age group, TIVc has demonstrated noninferior
immunogenicity to an egg-based trivalent comparator with respect to certain
influenza strains in a paediatric trial (Sect. 2) and the protective efficacy of this comparator has been
established in children and adolescents [13]. Furthermore, the immunogenicity of TIVc in paediatric
participants aged 9 to < 18 in the V58P12 study suggests that the protective
efficacy shown in adults in V58P13 (which was conducted during the same influenza
season) may be expected to apply to this younger age group [13]. Importantly, in addition to this indirect
immunobridging, there is a phase III/IV trial (V130_12) currently evaluating the
efficacy of QIVc in paediatric participants [37]. This trial was a post-approval requirement in the USA
[13], and results are awaited with
interest. Given the particular burden of influenza B infection in children and
adolescents [4, 38], protection against both influenza B
lineages is likely to be especially desirable in the paediatric population.
Manufacturing influenza virus vaccines using mammalian cell lines as
opposed to embryonated chicken eggs appears to improve protective effectiveness.
Replication of influenza viruses in MDCK cells rather than chicken eggs has been
theorised to reduce the risk of haemagglutinin mutations arising [3, 6,
8]. Consequently, compared with the
influenza strains contained in egg-based vaccines, the strains contained in
cell-based influenza virus vaccines may be more closely matched to circulating
strains [3, 6, 8]. Indeed, data from the 2011/2012 to 2017/2018 influenza seasons in
the Northern Hemisphere has shown that, consistently, substantially higher
proportions of circulating H3N2 viruses have matched MDCK-propagated reference
viruses than have matched egg-propagated reference viruses [9]. The tendency for mismatch between circulating
isolates and egg-propagated reference viruses may have contributed to historically
low vaccine effectiveness against H3N2 strains [9]. QIVc has been gradually shifting from the use of egg-derived
CVVs to cell culture-derived CVVs to ensure the insulation of the vaccine from
concerns around egg adaptation (Sect. 1),
and the upcoming 2019/2020 influenza season heralds the first purely cell-based
formulation of QIVc [15]. As of yet, it
is uncertain whether this shift to exclusively cell culture-derived CVVs will bestow
improved vaccine effectiveness.
Large real-world studies (n > 90,000 QIVc recipients) using data from the 2017/2018 US
influenza season suggest that, like egg-based alternatives, QIVc is effective in
preventing influenza and may offer benefits over these products for
influenza-related outcomes in some cohorts (Sect. 3.2). Medicare beneficiaries aged ≥ 65 years who received QIVc
were 10% less likely than those who received QIVe to have an influenza-related
hospital encounter, although this modest difference in vaccine effectiveness
suggests that egg adaptation was not the sole cause for the low vaccine
effectiveness reported during the A/H3N2-dominated 2017/2018 influenza season
[26]. In the QIVc formulation
produced for 2017/2018 influenza season, A/H3N2 was the only influenza strain for
which a cell culture-derived CVV (as opposed to an egg-derived CVV) was used
[8, 26]. Given the limitations of observational studies (e.g. the
potential presence of residual confounds), a definitive comparative trial would be
of use in determining the extent to which QIVc fully derived from and manufactured
in a mammalian cell line improves vaccine effectiveness relative to egg-based
quadrivalent products.
QIVc was generally well tolerated in both adult and paediatric
participants in the pivotal phase III trials, with a safety profile consistent with
that of TIVc; the additional strain did not markedly alter the reactogenicity of the
vaccine and no safety signals unique to QIVc emerged (Sect. 4). In both adult and paediatric participants
administered QIVc, the most common solicited local adverse reaction was injection
site pain and the most common solicited systemic adverse reaction was headache.
Solicited adverse reactions occurred at somewhat lower rates in older adults
(aged ≥ 65 years of age) compared with younger participants. The majority of
solicited adverse reactions were mild to moderate in severity. No SAE was considered
to be related to the study vaccine. As there are currently limited safety data for
QIVc in certain patient groups (e.g., those who are immunocompromised, have certain
underlying diseases or are pregnant or breastfeeding), these populations are being
followed post-authorization [13] and
there is a pregnancy registry for QIVc and TIVc recipients [39]. In general, inactivated influenza virus
vaccines such as QIVc are suitable for use in a wider population than live
attenuated vaccines, which are not recommended in a number of patient groups
[5].
As well as circumventing the issue of egg adaptation, cell-based
manufacturing has other benefits over the traditional egg-based approach. Containing
no egg protein, QIVc eliminates the risk of allergic reactions to this in
individuals with egg allergies [3,
6]. Unlike egg-based vaccines, QIVc
can be produced without need for antibiotics or preservatives [13]. Cell-based manufacturing is not dependent
on egg supply and provides a more flexible production timeline where production can
be promptly scaled up in the face of a pandemic and the vaccine can be altered at
short notice to reflect late-emerging strains [6, 8]. However, the
global-scale infrastructure necessary to produce QIVc in quantities comparable to
egg-based vaccines has not yet been established [6]. QIVc is also more expensive than egg-based quadrivalent
products (based on the CDC 2019/2020) price list [40], which may affect uptake of the product. Cost-effectiveness
analyses comparing QIVc with various other available vaccines would be of
interest.
In conclusion, QIVc is an immunogenic and generally well tolerated
quadrivalent inactivated influenza virus vaccine for the prevention of influenza in
adults and children. Immunogenicity and safety were not detrimentally impacted
relative to that of TIVc by the inclusion of the additional influenza B strain, and
QIVc has the capacity to offer broader influenza B protection than the trivalent
formulation. Unlike the majority of quadrivalent vaccines, QIVc is cell-based and
exemplifies a shift away from the use of egg-based technology in the manufacturing
of influenza virus vaccines. Through circumventing concerns around egg adaptation,
QIVc has the potential to be more effective than currently available egg-based
quadrivalent vaccines.
Data Selection Flucelvax Tetra: 226 records identified
Duplicates removed
73
Excluded during initial screening (e.g. press
releases; news reports; not relevant drug/indication;
preclinical study; reviews; case reports; not randomized
trial)
79
Excluded during writing (e.g. reviews; duplicate
data; small patient number; nonrandomized/phase I/II
trials)
34
Cited
efficacy/tolerability
articles
19
Cited articles not
efficacy/tolerability
21
Search Strategy: EMBASE, MEDLINE and PubMed from
1946 to present. Clinical trial registries/databases and
websites were also searched for relevant data. Key words
were Flucelvax TETRA, Flucelvax Quadrivalent, Optaflu,
influenza vaccine. Records were limited to those in
English language. Searches last updated 9 July
2019
Acknowledgements
During the peer review process, the manufacturer of QIVc was also offered an
opportunity to review this article. Changes resulting from comments received were
made on the basis of scientific and editorial merit.
Compliance with Ethical Standards
Funding
The preparation of this review was not supported by any external
funding.
Conflicts of interest
Yvette Lamb is a salaried employee of Adis International
Ltd/Springer Nature, is responsible for the article content and declares no
relevant conflicts of interest.
Open AccessThis article is distributed
under the terms of the Creative Commons Attribution-NonCommercial 4.0
International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, duplication, adaptation,
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appropriate credit original author(s) and the source, provide a link to the
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