Immunogenicity and Safety of an AS03-Adjuvanted H7N9 Pandemic Influenza Vaccine in a Randomized Trial in Healthy Adults
Correspondence: A. Madan, Bldg
Immunogenicity and Safety of an AS03-Adjuvanted H7N9 Pandemic Influenza Vaccine in a Randomized Trial in Healthy Adults
Nathan Segall 0
Murdo Ferguson 4
Louise Frenette 3
Robin Kroll 5
Damien Friel 2
Jyoti Soni 6
Ping Li 1
Bruce L. Innis 1
Anne Schuind 1
0 Clinical Research Atlanta , Stockbridge , Georgia
1 GSK Vaccines, King of Prussia , Pennsylvania
2 GSK Vaccines , Wavre , Belgium
3 QT Research , Sherbrooke, Quebec , Canada
4 Colchester Research Group , Truro, Nova Scotia
5 Seattle Women's: Health, Research , Gynecology , University of Washington , Seattle
6 GSK Pharmaceuticals , Bangalore , India
Background. Almost 700 cases of human infection with avian influenza A/H7N9 have been reported since 2013. Pandemic preparedness strategies include H7N9 vaccine development. Methods. We evaluated an inactivated H7N9 vaccine in an observer-blind study in healthy adults aged 18-64 years. Participants (420) were randomized to receive 1 of 4 AS03-adjuvanted vaccines (low or medium dose of hemagglutinin with AS03A or AS03B), one nonadjuvanted vaccine, or placebo. The coprimary immunogenicity objective determined whether adjuvanted vaccines elicited an immune response against the vaccine-homologous virus, 21 days after the second vaccine dose per US and European licensure criteria in the per-protocol cohort (n = 389). Results. All adjuvanted vaccines met regulatory acceptance criteria. In groups receiving adjuvanted formulations, seroconversion rates were ≥85.7%, seroprotection rates ≥91.1%, and geometric mean titers ≥92.9% versus 23.2%, 28.6%, and 17.2 for the nonadjuvanted vaccine. The AS03 adjuvant enhanced immune response at antigen-sparing doses. Injection site pain occurred more frequently with adjuvanted vaccines (in ≤98.3% of vaccinees) than with the nonadjuvanted vaccine (40.7%) or placebo (20.0%). None of the 20 serious adverse events reported were related to vaccination. Conclusions. Two doses of AS03-adjuvanted H7N9 vaccine were well tolerated and induced a robust antibody response at antigen-sparing doses in healthy adults. Clinical Trials Registration. NCT01999842.
Periodic outbreaks of H7 avian influenza A virus infections occur
in poultry worldwide, with sporadic transmission to humans. In
2003, an outbreak of H7N7 disease in The Netherlands resulted
in 89 human infections and 1 death, with evidence of limited
human-to-human transmission . Human infections with
H7N9 viruses were first reported in China in February 2013; to
the present time, there have been 3 waves of infection . As
of December 2015, a total of 683 laboratory-confirmed cases,
including 275 deaths, had been reported to the World Health
Organization [2, 3]. The case fatality rate of H7N9 influenza is
approximately 40% [2, 3]. The virus can cause rapidly progressive
pneumonia, often complicated by extrapulmonary disease
associated with hypercytokinemia .
Genetic changes observed in the H7N9 virus suggest
adaptation to mammals, carrying the risk of human-to-human
transmission . It has been shown that H7N9 and H7N1 influenza
viruses are capable of airborne transmission in a mammalian
host (ferret), without losing virulence [6, 7]. These observations
suggest the potential for an H7 pandemic in humans, and
support pandemic H7 vaccine development. Several H7 inactivated
influenza vaccines and live-attenuated influenza vaccines are in
clinical development, but have not been highly immunogenic
in humans [8–10]. Adjuvanted vaccines have shown improved
immunogenicity [11–14]. A recent mix-and-match study
demonstrated that a monovalent H7N9 vaccine adjuvanted with
AS03 induced a better immune response than the
nonadjuvanted or MF59-adjuvanted formulations, when administered
to adults according to a 2-dose schedule . Here, we present
the findings of a study that evaluated H7N9 vaccine
formulations with hemagglutinin (HA) antigen doses of 2.78 and
5.09 µg, given with AS03 adjuvants of different potency and a
nonadjuvanted formulation. The doses of AS03-adjuvanted
HA antigen were chosen for testing based on a clinical
development program by GSK Biologicals with an AS03-adjuvanted
split virus H5N1 marketed vaccine.
Participants, Vaccines, and Study Design
This was a phase I/II, randomized, placebo-controlled,
multicenter trial evaluating an H7N9 influenza vaccine (NCT01999842).
The trial was approved by independent ethics committees or
institutional review boards and was conducted in accordance with
the Declaration of Helsinki, the International Conference on
Harmonisation Good Clinical Practice guidelines, and regulatory
requirements of participating countries. Participants provided
written informed consent.
The trial was observer blind and enrolled healthy participants
18–64 years of age in the United States and Canada (inclusion
criteria are detailed in Supplementary Text 1). The inactivated,
split-virion vaccine, manufactured with a reverse genetic–
derived reassortant seed virus developed by World Health
Organization Collaborating Centres and References
Laboratories from A/Shanghai/2/2013 (H7N9) (GSK Vaccines, Quebec,
Canada), was adjuvanted with AS03, an oil-in-water emulsion
containing 5.93 mg (AS03B) or 11.86 mg (AS03A) of
DL-αtocopherol. Participants were randomized 1:1:1:1:1:2 to 1 of
6 groups receiving different HA antigen doses (mixed with
adjuvant in groups 1–4) or placebo: (1) 2.78 µg of HA
adjuvanted with AS03B (low-dose [LD] HA/AS03B), (2) 2.78 µg of
HA adjuvanted with AS03A (LD HA/AS03A), (3) 5.08 µg of HA
adjuvanted with AS03B (medium-dose [MD] HA/AS03B), (4)
5.08 µg of HA adjuvanted with AS03A (MD HA/AS03A), (5)
10.15 µg HA without AS03 (high-dose [HD] HA
nonadjuvanted); or (6) phosphate-buffered saline ( placebo).
The antigen doses were less than the initially targeted
concentrations of 3.75 and 7.5 µg, because the single radial
immunodiffusion assay used to determine the antigen concentration
during formulation overestimated the concentration in relation
to subsequently available reagents provided by the Center for
Biologics Evaluation and Research (CBER) to evaluate vaccine
potency. Vaccines were administered twice, 21 days apart, by
intramuscular injection in the deltoid muscle.
The coprimary immunogenicity objective was to evaluate
whether the adjuvanted A/Shanghai/2/2013 (H7N9) vaccines
elicited an immune response against the vaccine-homologous
virus that met US CBER and European Committee for
Medicinal Products for Human Use (CHMP) immunogenicity targets
at day 42 (21 days after the second vaccine dose). The primary
immunogenicity objective of the study was met if the following
criteria were fulfilled for any adjuvanted vaccine formulation:
the lower limit of the 98.75% confidence interval was ≥40%
for the seroconversion rate (SCR) and ≥70% for seroprotection
rate (SPR), and CHMP criteria were met if point estimates were
>40% for SCR, >70% for SPR, and >2.5 for the mean geometric
increase (MGI). The coprimary safety objective was to describe
the safety and reactogenicity of the vaccines up to day 42.
Secondary objectives were: (1) to demonstrate the adjuvant
effect for adjuvanted groups that met the primary
immunogenicity objective by comparing the immune response of
adjuvanted versus nonadjuvanted vaccines measured by
hemagglutination inhibition (HI) antibody at day 42 (lower
limit of the 98.75% confidence interval for geometric mean
titer [GMT] ratio [adjuvanted over nonadjuvanted] >1.5 and
SCR difference [adjuvanted minus nonadjuvanted] >10%);
(2) to evaluate whether the nonadjuvanted vaccine elicited an
immune response against the vaccine-homologous virus that
meets CBER and CHMP guidance targets at day 42; (3) to
describe the vaccine-homologous and vaccine-heterologous
(H7N1 with HA derived from A/mallard/Netherlands/12/
2000) HI antibody profiles overall and by age group; (4) to
describe the vaccine-homologous (A/Anhui/1/2013 [H7N9]
strain) and vaccine-heterologous (H7N1 reverse genetic strain
with HA gene derived from A/mallard/Netherlands/12/2000
[H7N3]) microneutralization (MN) antibody profiles in a
subset of participants; (5) to describe the safety of the vaccines
up to day 385.
Study End Points and Procedures
Immunogenicity assessments were done with HI and MN
assays at baseline (day 0), at 21 days after each dose (days 21
and 42), and at 6 months after the first vaccine dose (day
182), and with HI assay only at 12 months after the first vaccine
dose (day 385). HI and MN antibody titers were assessed using
horse red blood cells (RBCs). To remove nonspecific agglutinin
to horse RBCs and nonspecific virus inhibitors introduced by
the hemadsorption step, a receptor-destroying enzyme
treatment step was added after horse RBC hemadsorption. Humoral
immune response assays were performed by a GSK Biologicals
laboratory (HI) and by Viroclinic Biosciences (MN).
The following derived parameters related to the tested
vaccine virus were estimated for HI titer: SPR, GMT, SCR, and
MGI. SPR was defined as the proportion of participants with
reciprocal HI titers ≥40. GMTs were defined as the antilog of
the mean of the log10-transformed inverse titers. SCR was
defined as the proportion of participants with either a
prevaccination reciprocal HI titer <10 and a postvaccination reciprocal
titer ≥40 or a prevaccination reciprocal HI titer ≥10 and a
≥4-fold increase in postvaccination reciprocal titer. MGI was
defined as the geometric mean of the within-participant ratios
of the postvaccination to the prevaccination reciprocal HI titer.
For MN titer, seropositivity rate and GMT were derived in a
similar way as for HI.
Participants recorded solicited injection site and general
symptoms between days 0 and 6 after each vaccination in
diary cards, collected at the next visit. Symptoms were graded
by severity from 1 (mild) to 3 (severe). Grade 3 was defined
as “significant pain at rest, preventing everyday activities” for
pain, “surface diameter >100 mm” for redness and swelling,
temperatures of “≥39.0°C (≥ 102.2°F)” for fever, and
“preventing normal activities” for all other solicited symptoms.
Blood samples for safety evaluations were collected on days 0,
7, 21, 28, and 42. Participants recorded unsolicited symptoms
(graded by severity) until 21 days after each vaccination.
Medically attended adverse events (AEs), potentially
immunemediated disorders ( pIMDs), and serious AEs (SAEs) were
followed up until the study end. Participants were asked to report
immediately any events perceived as serious.
Immunogenicity analyses were performed on the per-protocol
cohorts ( participants who complied with the protocol, received
vaccine, and had assay results available for antibodies against
the vaccine-homologous HA antigen at the specified intervals).
The safety analysis was descriptive and was performed on the
total vaccinated cohort ( participants who received ≥1 dose of
study vaccine or placebo). Statistical methods are described in
detail in Supplementary Text 2.
A total of 420 participants were included in the total vaccinated
cohort and 389 in the per-protocol cohort (Figure 1).
Demographics were similar in all study groups (Supplementary
Table 1). The mean participant age was 40 years, 65% of
participants were women, and most (85.5%) were of white
European/Caucasian ethnic origin.
CBER and CHMP criteria against the vaccine-homologous
virus were met for all adjuvanted vaccines at day 42, 21 days
after the second vaccine dose. The SCRs and SPRs were similar
in all adjuvanted vaccine groups; SCRs were 85.7%–96.3% and
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LD HA/AS03B (n = 56)
LD HA/AS03A (n = 56)
MD HA/AS03B (n = 54)
MD HA/AS03A (n = 54)
Abbreviations: CI, confidence interval; GMT, geometric mean titer; HA, hemagglutinin; HD,
high-dose; HI, hemagglutination inhibition; LD, low-dose; MD, medium-dose; SCR,
a Sample sizes represent number of participants with available data.
b GMT for adjuvanted vaccine (LD or MD HA plus AS03A or AS03B)/GMT for nonadjuvanted
vaccine (HD HA nonadjuvanted); GMTs were adjusted for baseline value and age.
c SCR for adjuvanted vaccine (LD or MD HA plus AS03A or AS03B) minus SCR for
nonadjuvanted vaccine (HD HA nonadjuvanted).
SPRs 91.1%–96.4% (Table 1). The MGI 21 days after the second
vaccine dose was highest for the MD HA/AS03A group (25.6),
followed by the LD HA/AS03A group (22.8) (Table 1). There
was a trend for a higher GMT ratio for the vaccine-homologous
virus with the AS03A adjuvant than with the AS03B adjuvant,
with a minimal effect of antigen content (Table 2). The
GMTs followed the same pattern: 151.1 in the MD HA/
AS03A group, 128.0 in the LD HA/AS03A group, 106.2 in the
MD HA/AS03B group, and 92.9 in the LD HA/AS03B group
(Supplementary Figure S1). Between 12.5% and 19.6% of
participants were seropositive before vaccination, although
all baseline GMT values were low (only 5 samples had a
titer ≥40). After the peak observed on day 42, seropositivity
rates and antibody titers declined at day 182 and further
at day 385, but GMTs remained above baseline levels in the
adjuvanted groups, ranging from 10.8 to 14.3 (Table 1;
Supplementary Figure S1). The SPRs at days 182 and 385 were 12.3%–
31.5% and 7.8%–19.6%, respectively.
An immune response against an H7N1 virus was also
observed at day 42, albeit at lower levels than against the
vaccine-homologous virus. In the adjuvanted groups, 21 days
after the second vaccine dose, SCRs were 57.7%–76.9%, MGIs
were 9.0–13.8 and GMTs were 46.9–72.8, with the highest
response observed in the AS03A adjuvanted groups (Table 1;
Figure 2). Immune responses assessed by the MN assay showed
a similar kinetic; however, titers remained 1.5–4.3 times higher
at day 182 compared with baseline (Figure 2). The vaccine
response rate is presented in Supplementary Table S2.
The non-adjuvanted HD HA vaccine elicited a considerably
lower immune response against both vaccine-homologous and
vaccine-heterologous viruses (Table 1; Figure 2). Adjuvant effect
was demonstrated in all adjuvanted groups, as the lower limit
of the 98.75% confidence interval for GMT ratio (adjuvanted
over nonadjuvanted) exceeded 1.5, and the SCR difference
(adjuvanted minus nonadjuvanted) exceeded 10% in all groups
at 21 days after the second vaccine dose (Table 2). At days 182
and 385, no study participant had reciprocal HI titers ≥40.
The immune response was low in all vaccine groups after
administration of only 1 vaccine dose (Table 1; Figure 2). In a
sub-analysis of the homologous immune response by age, the
adjuvanted vaccine was immunogenic in both age groups,
with SPRs ≥80.0% in participants 41–64 years of age, despite
lower GMTs (Table 3). The SPR was 11.5% in participants
41–64 years of age who received the nonadjuvanted HD HA
vaccine. The immune response was generally lower in
participants who had previously received seasonal influenza vaccine
than in nonrecipients. At day 42, GMT values in the adjuvanted
vaccine groups were 134.5–220.2 in prior recipients and 70.3–
129.0 in nonrecipients. SPR values were 83.9%–96.6% in prior
recipients and 95.8%–100% in nonrecipients.
Safety and Reactogenicity
Pain was the most common injection site solicited symptom,
occurring more frequently in the adjuvanted vaccine groups
than in the HD HA nonadjuvanted group (Table 4). Redness
and swelling at the injection site occurred in 3.3%–6.7% of
participants receiving vaccines adjuvanted with AS03B and in
13.3%–18.3% of those receiving vaccines adjuvanted with
AS03A (Table 4). Grade 3 injection site solicited symptoms
were reported by up to 6.7% of the participants in the
adjuvanted groups and by none of the participants in the
nonadjuvanted and placebo groups. Fatigue, headache, and muscle ache
were the most frequently reported solicited general symptoms
(Table 4). Fatigue and muscle ache occurred in 45.0%–55.0%
of participants in all adjuvanted groups, compared with
25.4%–28.8% in the HD HA nonadjuvanted and 25.0%–
20.8% in the placebo group. Fever occurred infrequently and
at a similar rate across all study groups.
Most solicited AEs resolved spontaneously. Grade 3
solicited and unsolicited events occurred at a low rate and few
unsolicited AEs were considered related to vaccination
(Table 4). Twenty SAEs were reported in 13 participants up
to the study end, and none of them were assessed as
vaccination related. Nine pregnancies occurred during the study. One
participant (exposed to the vaccine during the first trimester)
underwent elective abortion, not related to the vaccination.
For the other 8 pregnancies, the exposure to study vaccine
occurred before the pregnancy; 6 gave birth to live neonates, and
for 2 the outcome was unknown. One potentially
immunemediated disorder assessed by the investigator as not related
to vaccination—autoimmune thyroiditis—was reported 303
days after administration of the second dose of placebo. No
deaths were reported during the study. For hematological
and biochemical parameters, results outside of the normal
laboratory range were evenly distributed across all time points
(including baseline) and vaccine groups, and no clear clinical
trends were observed (Supplementary Tables S3 and S4).
The results of this phase I/II randomized, placebo-controlled
trial showed that 2 doses of the H7N9 AS03-adjuvanted
vaccine elicited a robust immune response in healthy adults
up to 64 years of age, with an acceptable safety profile.
Adjuvantation with AS03 enabled an immune response that
satisfied regulatory acceptance criteria at antigen-sparing
concentrations of HA, a prerequisite for a pandemic influenza
vaccine. A dose as low as 2.8 µg HA elicited a robust HI
Table 3. Vaccine-Homologous HI Antibody Response 21 Days After the Second Vaccine Dose by Age (Per-Protocol Cohort)
SPR, % (95% CI) SCR, % (95% CI)
GMT, (95% CI)
Abbreviations: CI, confidence interval; GMT, geometric mean titer; HA, hemagglutinin; HD,
high-dose; HI, hemagglutination inhibition; LD, low-dose; MD, medium-dose; SCR,
seroconversion rate; SPR, seroprotection rate.
a Sample sizes represent number of participants with available data (for SCR calculation,
number with available data both before and after vaccination).
b For SCR, n = 30.
HI responses were low after the first vaccine dose in all
vaccine groups, indicating that 2 doses are required to induce
an adequate immune response. Three weeks after the second
vaccine dose, SPRs and SCRs against the vaccine-homologous
virus were ≥85.7% in the adjuvanted vaccine groups. The
non-adjuvanted vaccine elicited a poor immune response, and
an adjuvant effect was demonstrated in all adjuvanted groups in
terms of GMT ratio and SCR difference. The GMT and MGI for
the AS03-adjuvanted vaccines against the vaccine-homologous
virus were highest in the MD HA/AS03A group, followed by the
LD HA/AS03A group, the HD HA/AS03B group, and finally the
LD HA/AS03B group. Thus, the potency of the AS03 adjuvant
(11.86 or 5.93 mg tocopherol in AS03A or AS03B, respectively)
seems to have more influence than antigen content on
immunogenicity. This was also observed in a study of a H7N9 HA
antigen produced by a different manufacturer mixed with GSK’s
AS03A at the point of use  and in a study of with the
AS03-adjuvanted H5N1 pandemic vaccine . Immune
responses in older participants (aged 41–64 years) were generally
lower than in younger participants (aged 18–40 years) and
lower in participants who had previously received seasonal
influenza vaccine than in nonrecipients, consistent with findings
in other studies of pandemic influenza vaccines [13, 14, 16, 17].
Up to 19.6% of study participants were seropositive before
vaccination. Detectable levels of HI antibody in the general
population before vaccination with pandemic influenza
vaccines have been reported in several studies [18–20], suggesting
either natural immune response to previous exposure or
crossreactivity between virus strains. Previous exposure is unlikely,
because the H7N9 virus circulated in China and no infections
in humans were reported in the North American population
. In addition, human antibody response to this strain has
been shown to be very poor . The same study suggests
cross-reactivity of H1 and H3 seasonal influenza subtypes to
the H7N9 virus, and this is the most likely explanation of our
finding. The CD8+ T cells to seasonal influenza are reported
to recognize H7N9 epitopes and to exhibit cross-reactivity
with the H7N9 virus . In our study, cross-reactivity could
originate either from previous infection or seasonal vaccination.
Of note, a total of 218 study participants had received
vaccination against influenza within the previous 3 seasons, although
the virus strain to which the participants were previously
exposed was not documented.
The study shows that the AS03 adjuvant enhances the
immune response against H7 antigens at antigen-sparing doses.
Previous studies of H7 vaccines that were nonadjuvanted or
adjuvanted with aluminum hydroxide have shown poor
immunogenicity in humans [8, 9]. Clinical studies of adjuvanted H7N9
vaccines from different manufacturers have found higher
immunogenicity compared to nonadjuvanted formulations [11–
14]. A phase II study of an H7N9 vaccine mixed at the point
of use with MF59 adjuvant resulted in seroconversion in 59%
of participants with the LD HA dose; higher antigen doses
did not elicit an increase in immunogenicity . A recent
phase II study compared different doses of an H7N9 vaccine
mixed at the point of use with AS03A or MF59 or administered
without an adjuvant . As in the present study, the immune
response with all formulations was low after 1 vaccine dose.
After 2 doses, the immune response was superior with the
AS03-adjuvanted formulations compared with the
MF59-adjuvanted or standard or high-dose nonadjuvanted formulations
. For AS03-adjuvanted vaccines, similar immunogenicity
was attained with antigen content varying between 3.75, 7,
and 15 µg of HA .
The present study also demonstrated cross-reactivity of the
vaccine against a vaccine-heterologous strain. Phylogenetic
analysis has shown a high degree of homology in the HA
gene sequence of various H7 viruses . An AS03-adjuvanted
H7N1 vaccine, engineered by reverse genetics from an H7N3
virus, has been developed by GSK Vaccines, and therefore
the present study evaluated cross-reactivity against an H7N1
vaccine-heterologous virus. Robust cross-reactivity was seen,
with SPRs ranging from 57.7% to 76.9%. In preclinical studies in
mice, an H7N1/AS03 vaccine elicited antibodies cross-reacting
with H7N9, H7N7, and H7N3 viruses , and an H7N9
viruslike particle vaccine produced in insect cells using a baculovirus
vector elicited antibodies cross-reacting with an H7N3 virus .
Table 4. Safety Outcomes Reported (Total Vaccinated Cohort)
Participants With Outcome, %a
To our knowledge, this is the first report on the immune
response against H7N9 in humans beyond day 42 after
vaccination. Based on the blood sampling schedule, HI antibody titers
against the vaccine-homologous virus peaked at 21 days after
the second dose. At day 182, a notable decrease in GMTs was
observed, although of different magnitude across groups.
However, seropositive rates remained above 90% at day 182 and
above 70% at day 385 in all adjuvanted groups, compared
with 50.0% and 22.6% in the nonadjuvanted group and 4.5%
and 1.9% in the placebo group. In addition, recent studies
seem to suggest that a robust immune response to the HA
head and stalk domains, as measured with enzyme-linked
immunosorbent assay, may be induced even in the absence of HI
and MN response , so the clinical relevance of the decline in
antibody titers is not clear. The observed kinetics of the
immune response in adjuvanted groups in our study is similar
to that elicited by other influenza vaccines, in particular the
adjuvanted H5N1 vaccines , for which a strong anamnestic
response was elicited by a heterologous booster dose, up to 3 years
after priming [29, 30].
The H7N9 AS03-adjuvanted vaccine was generally well
tolerated. Pain was the most common solicited injection site
symptom, as observed in other studies of adjuvanted influenza
vaccines [12–17, 19, 31, 32]. Tolerability seemed to be
acceptable, as most participants returned for the second vaccine
dose. Most AEs were low grade and resolved spontaneously.
None of the SAEs was assessed as related to vaccination.
In this study, a trend was observed for higher reactogenicity with
AS03A-adjuvanted vaccines than with AS03B formulations.
However, all formulations were well tolerated and no safety signal was
identified during the study. The use of the AS03A adjuvant led to
an improved immune response compared with that induced by
AS03B-adjuvanted formulations, so the risk-benefit ratio in using
a high potency adjuvant seems clinically acceptable.
Pandemic preparedness strategies include development of
vaccines that are antigen sparing, because the time available to
produce sufficient antigen to provide effective vaccine coverage is
likely to be limited. In addition, vaccines that elicit a broad
cross-reactive immune response are needed to allow pre-pandemic
priming and use of prime-boost vaccination schedules.
Formulation of pandemic vaccines with an effective adjuvant is an accepted
strategy to accomplish both goals  and to ensure adequate
immunogenicity for the elderly and those with reduced immune
responsiveness due to concurrent illness.
The assessment of immunogenicity for this study is based
on HI and MN assays; no additional evaluation such as
cellmediated immunity was performed which could bring
additional information but for which no regulatory acceptance
criteria have been established. No formal comparisons between
adjuvanted vaccine groups were performed, and analyses were
descriptive. These could constitute potential limitations to the
study. Nevertheless, the type I error was adjusted for the
evaluation of the primary immunogenicity objective, as well as the
secondary objective related to adjuvant effect.
In conclusion, 2 doses of an AS03-adjuvanted H7N9 vaccine
induce a robust anti-H7 immune response with an acceptable
safety profile. When balancing antigen sparing with effective
immunization, a 2.78-µg antigen dose (or 3.75 µg to align with the
already licensed H5N1 vaccines made by the same process) with
AS03A adjuvantation seems the most desirable formulation. This
vaccine candidate could be beneficially deployed should the
H7N9 virus acquire the ability for sustained human-to-human
transmission or to protect persons at risk.
Supplementary materials are available at http://jid.oxfordjournals.org.
Consisting of data provided by the author to benefit the reader, the posted
materials are not copyedited and are the sole responsibility of the author, so
questions or comments should be addressed to the author.
Acknowledgments. We are indebted to the participating study
volunteers, clinicians, nurses, and laboratory technicians at the study sites. We
are grateful to the principal investigators, Alan Kravitz and Jack Yakish. We
also thank Janine Linden for writing the study protocol; Stephanie Sharp
(Veristat on behalf of GSK Vaccines) for writing the study report; Thierry
Ollinger for contributing to immunological data generation; André Manon
and Benoît Le Pioufle for statistical analyses (Keyrus Biopharma on behalf
of GSK Vaccines); Judy Napolitano, Amy Blyskal, Amie Blanchfield, and
Eleanor Espejo for clinical operations; Mary Greenacre (freelance) for drafting
the manuscript; and Julie Todoroff and Shirin Khalili for manuscript
coordination (XPE Pharma & Science on behalf of GSK Vaccines).
Financial support. The trial was funded by the Biomedical
Advanced Research and Development Authority of the United States
Department of Health and Human Services (grant HHSO100201200013I)
and GlaxoSmithKline Biologicals, which paid for all costs associated
with the development of this manuscript.
Potential conflicts of interest. A. M., D. F., J. S., P. L., B. L. I., and
A. S. are employees of the GSK group of companies. A. M., P. L., B. L. I.,
and A. S. own stock/stock options/restricted shares in GSK. N. S. declares
receiving funding from GSK for multiple influenza clinical trials. R. K.
received funding from GSK for this trial. M. F. declares payment from
Colchester Research Group (CRG) for work as an investigator outside the submitted
work. M. F. is married to the CEO/owner of CRG, and they have conducted
numerous clinical trials with multiple sponsors over the last 10 years. The
CEO/owner of CRG received payment as per guidelines to present papers
at conferences. L. F. declares support for travel/accommodation/meeting
expenses from GSK. All authors have submitted the ICMJE Form for Disclosure
of Potential Conflicts of Interest. Conflicts that the editors consider relevant to
the content of the manuscript have been disclosed.
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