Randomized comparison of the safety of Flublok® versus licensed inactivated influenza vaccine in healthy, medically stable adults ≥50 years of age

Vaccine 33 (2015) 6622–6628

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Randomized comparison of the safety of Flublok® versus licensed inactivated influenza vaccine in healthy, medically stable adults ≥50 years of age Ruvim Izikson a,∗ , David J. Leffell b , S. Allan Bock c , Peter A. Patriarca d , Penny Post a , Lisa M. Dunkle a,∗ , Manon M.J. Cox a a

Protein Sciences Corporation, Meriden, CT, United States Yale University School of Medicine, New Haven, CT, United States c University of Colorado Denver School of Medicine, Aurora, CO, United States d Biologics Consulting Group, Inc., Bethesda, MD, United States b

a r t i c l e

i n f o

Article history: Received 30 June 2015 Received in revised form 1 October 2015 Accepted 23 October 2015 Available online 1 November 2015 Keywords: Influenza vaccine Recombinant hemagglutinin vaccine Flublok Allergic reaction

a b s t r a c t Background: The safety and tolerability of Flublok® , a purified recombinant hemagglutinin seasonal influenza vaccine, was compared to AFLURIA® in a randomized, blinded clinical trial in adults ≥50 years of age with attention to hypersensitivity reactions. Methods: This blinded, randomized trial of healthy adults ≥50 years of age compared safety of Flublok vs. AFLURIA with respect to pre-specified possible hypersensitivity: “rash,” “urticaria,” “swelling” and “nondependent edema;” solicited reactogenicity and unsolicited adverse events. Subject-reported outcomes were collected for 30 days after vaccination. All adverse event terms were reviewed by physicians blinded to vaccine group, who added other terms possibly reflecting hypersensitivity. Case records of subjects with possible hypersensitivity were adjudicated by independent experts blinded to treatment assignment to identify likely hypersensitivity reactions. Non-inferiority of the incidence of hypersensitivity in the two vaccine groups was pre-defined as an absolute difference with an upper bound of 2-sided 95% confidence limits ≤0.015. Results: A total of 2640 subjects were enrolled, evenly split in age cohorts of 50–64 and ≥65 years. Fiftytwo subjects reported at least one term possibly representing hypersensitivity, with a slight imbalance of 31 on Flublok and 21 on AFLURIA. The adjudicators determined that six and four subjects on Flublok and AFLURIA, respectively, likely met clinical criteria for hypersensitivity, yielding a difference in incidence between the two vaccine groups of 0.15% (upper bound of 2-sided 95% CI = 0.9%). Reactogenicity and overall adverse event profiles were similar across both vaccines. Conclusions: Flublok was non-inferior to AFLURIA in adults ≥50 years of age with respect to expertadjudicated events of likely hypersensitivity during 30 days following vaccination (Sponsored by Protein Sciences Corporation; ClinicalTrials.gov number NCT01825200). © 2015 Elsevier Ltd. All rights reserved.

1. Introduction Immunization is recognized to be the best way to prevent influenza infection and, in older adults, to reduce the burden of disease related to influenza [1]. Universal vaccination for all individuals 6 months of age and older is recommended in the U.S [2].

∗ Corresponding authors. Tel.: +1 203 599 6064x153; fax: +1 203 5996069. E-mail addresses: [email protected] (R. Izikson), [email protected] (L.M. Dunkle). http://dx.doi.org/10.1016/j.vaccine.2015.10.097 0264-410X/© 2015 Elsevier Ltd. All rights reserved.

A new vaccine, Flublok® , uses recombinant DNA techniques to produce influenza hemagglutinin in cell culture. The production process does not require cultivation of live influenza viruses in embryonated hen’s eggs and generates a purified hemagglutinin protein that contains no egg protein, preservatives or antibiotics. The sequence of the hemagglutinin (HA) matches the HA sequence of wild-type virus and avoids mutations due to adaptation to growth in eggs [3]. The platform technology produces full-length rHA of the influenza strains of interest in the proprietary expresSF+® insect cells using a baculovirus expression vector [4]. The expresSF+ cell substrate is derived from Sf9 cells of the fall armyworm, Spodoptera frugiperda (which is related to moths, caterpillars and

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butterflies), Flublok was approved by FDA in 2013 for the prevention of season influenza for adults 18–49 years of age and was specifically recommended by ACIP for individuals in this age group with egg allergies of any kind [5]. Based on the additional safety data provided by this study, Flublok was approved for use in all adults ≥18 years of age in October, 2014. The safety and efficacy of HA antigens produced in expresSF+ cells by recombinant baculoviruses have been demonstrated in healthy adults and elderly adults aged 65 and above [6,7–11]. Flublok is well tolerated and raises higher antibody titers than inactivated influenza vaccine(IIV) for influenza A viruses, likely due to the 3-fold higher antigen content in Flublok [9,10,12,13]. This trial, intended to support approval in adults ≥50 years of age, assessed the safety of Flublok vs. another licensed inactivated influenza vaccine(IIV3). The study assessed the overall safety profile of Flublok vs. IIV3, and specifically evaluated the potential for prespecified hypersensitivity events, as requested by FDA reviewers. In addition to amplifying the overall safety database for adults ≥50 years of age, the assessment of hypersensitivity events was motivated by the likelihood of administration of Flublok to highly atopic individuals resulting from the CDC recommendation of Flublok for egg-allergic individuals. The IIV3 control (AFLURIA® , an inactivated split virus influenza vaccine) was chosen arbitrarily from among the several FDA-licensed brands based on availability. All IIV3s, whether split virion or subunit vaccines are treated equivalently by FDA and CDC, and are not generally considered to be clinically different in terms of safety or immunogenicity. 2. Methods 2.1. Trial design The study was a parallel design, observer-blind, randomized, active-controlled, multi-center clinical trial that enrolled ambulatory, medically stable adults aged 50 years and older, Subjects must not have received an influenza vaccine within 30 days prior to enrollment and must have no known contraindication to either study vaccine, which included hypersensitivity to eggs, neomycin, polymyxin, life-threatening reaction to previous influenza vaccination or known severe allergic reactions (e.g., anaphylaxis) to any component of Flublok. Subjects were stratified by age 50–64 and ≥65 years of age, and randomized 1:1 to receive either Flublok or IIV according to a randomization scheme produced by Biostatistics, ICON plc. Subjects and study staff (with the exception of designated vaccine administrators) were blinded to vaccine assignment. Unblinded vaccine administrators played no role in subsequent evaluation of study subjects. Subjects were monitored in the outpatient clinical setting and remotely by phone contact. Subjects recorded reactogenicity events on Memory Aids (Appendix A) during the 7 days following vaccine administration and any of the pre-specified hypersensitivity events, including “rash”, “urticaria”, “swelling” and “non-dependent edema,” experienced during Days 0–7 and 8–30. Spontaneously reported adverse events (AEs), serious adverse events (SAEs) and medically-attended adverse events (MAEs) during Days 0–30 were also collected, as this was considered an appropriate interval in which to assess hypersensitivity events. General safety of the product had been evaluated for up to 6 months in earlier studies. Subjects were queried regarding the hypersensitivity terms using a specific script at the Day 7 and 30 contacts. Subjects were instructed to return to the investigative site for medical evaluation of any potential hypersensitivity event. The study was approved and monitored by Western Institutional Review Board (Seattle, WA), registered at ClinicalTrials.gov (NCT01825200) and carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki).

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All subjects provided written informed consent prior to enrollment. 2.2. Vaccines The two study vaccines differ in their manufacturing and purification processes and in the quantity of hemagglutinin antigen present in each dose (Flublok (Lot 45-120046)) contains 45 ␮g rHA per antigen, whereas AFLURIA (Lot 07849221A) contains 15 ␮g HA per antigen. Both study vaccines contained HA recommended for the 2012–2013 season: A/H1N1: A/California/07/2009, A/H3N2: A/Victoria/361/2011 and Type B: B/Wisconsin/1/2010. Flublok antigens were provided in 0.5 mL single-dose vials containing sodium phosphate buffer with 0.005% Tween-20, pH 7.0 ± 0.4. AFLURIA is an inactivated influenza virus vaccine produced in embryonated chicken eggs, inactivated by detergent and purified. AFLURIA contains phosphate-buffered saline and traces of potassium phosphate, potassium chloride and calcium chloride and may contain residual quantities of taurodeoxycholate, ovalbumin, neomycin, polymyxin B and beta-propiolactone and was provided in 5 mL multi-dose vials [14]. Both study vaccines were stored at 2–8 ◦ C and administered by intramuscular injection in the deltoid on Day 0 of study participation using syringes and needles selected by the vaccine administrator at each investigative site. 2.3. Outcomes The primary objective of the study was to compare the incidence of a composite of pre-defined specific events including rash, urticaria, swelling and non-dependent edema. Additional AE terms suggestive of hypersensitivity reactions, e.g. anaphylaxis, were included in the primary endpoint as an “other” category. In addition, the patient-reported (pre-specified and “other”) AEs were adjudicated by two external expert reviewers blinded to treatment assignment to determine which qualified to be adjudicated endpoints. The secondary objectives included evaluation of common events of reactogenicity reported during the 7 days following vaccination and the frequency and severity of other spontaneously-reported adverse events during the 30 days following vaccination. The targeted sample size of 2500 subjects for the trial was selected to provide 80% statistical power to demonstrate noninferiority of Flublok to IIV3 with respect to the absolute difference in incidence of the composite primary endpoint [15]. Noninferiority based on a difference in incidence rather than a ratio of incidences was determined the appropriate statistical approach because a ratio of very low incidences could suggest a difference in incidence that would not be clinically meaningful. The noninferiority margin of no more than 1.5% was considered to represent an absolute difference that would not be clinically meaningful based on previous studies of Flublok in which the incidence of these events was very low [<1%]. The confidence intervals (CI) around this difference were expressed as either a one-sided 97.5% CI or a two-sided 95% CI, both of which yield the same results in the assessment of non-inferiority. A similarly low incidence with IIV3was presumed, despite the absence of published data regarding these specific events [12,13]. Reactogenicity events known to occur with injectable influenza vaccines were specifically solicited via the Memory Aid provided to study subjects (Appendix A). Subjects recorded the presence and severity of each event daily during Days 0–7 after study vaccine. Body temperature was recorded daily in the evening. The Memory Aid has yielded consistent and reliable data in previous Flublok studies. A standardized Toxicity Grading system was provided on the Memory Aid. The Memory Aid for hypersensitivity

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R. Izikson et al. / Vaccine 33 (2015) 6622–6628 Randomized N=2640

Flublok

IIV3

N=1319

N=1321

Age 50-64

Age ≥65

Age 50-64

Age ≥65

N=675

N=644

N=670

N=651

Completed Study

Completed Study

Completed Study

N=672

N=642

N=666

N=648

Reasons for Disconnuaon

Reasons for Disconnuaon

Reasons for Disconnuaon

Reasons for Disconnuaon

Lost to Follow-up

Lost to Follow-up

Lost to Follow-up

Lost to Follow-up

N=3

N=2

N=3

N=3

Completed Study

Subject Withdrawal N=1 Fig. 1. Disposition of randomized subjects.

events included a description in lay terms of each of the prespecified events. The primary endpoint hypersensitivity events were categorized as “rash”, “urticaria”, “swelling” or “non-dependent edema” using the MedDRA® coding dictionary (Version 15.1).

confirmatory visits was similar between the two vaccine groups, but potentially impacted the proper identification of the primary endpoint. Subject-reported events recorded during Days 0–30 on the hypersensitivity memory aid or identified as possible hypersensitivity by blinded medical review prior to database lock (“other”) were slightly more common among Flublok recipients than among IIV3 recipients (Table 2). Rash was the most common of these reported events, and was more frequently reported by Flublok recipients than by IIV recipients. Some of these rashes, based on their reported location, likely represented injection site reactions. There was no apparent difference in the incidence of any of the events between the two age strata. Subject-reported outcomes were largely mild (>75%) and transient. Adjudication of the 52 subjects was undertaken by independent external experts in the fields of allergy/immunology and dermatology who were blinded to treatment assignment. The adjudicators reviewed all case report forms, available subject medical records and source documents for subjects that reported these events. The adjudicators considered the location of the reported events, the timing with respect to receipt of study vaccine and underlying medical conditions in the assessment of whether an event met clinical criteria for a Type 1 (IgE-mediated) hypersensitivity reaction. The hypersensitivity endpoints clarified by this review were analyzed as adjudicated endpoints (Table 3). While the patientreported events were unbalanced between the vaccine groups, the adjudicated hypersensitivity events demonstrated similarity (non-inferiority by pre-specified criteria) between the two vaccine groups (Table 4).

3.3. Reactogenicity and overall safety 3. Results 3.1. Participant demographics and characteristics All 2640 enrolled subjects received one dose of study vaccine and had not received another influenza or other vaccine within 30 days of enrollment in this study. Study subjects were observed for 30 min following vaccination to assess immediate reactions. Safety data were available for 2627 subjects. Overall, the rate of retention of subjects was very high (>99%); of the 12 subjects who did not complete the 30 days follow-up, 11 were lost to follow-up and one withdrew consent (Fig. 1). No subject discontinued due to an adverse event. Enrollment to the study (March 11–April 15, 2013) and the 30-day follow-up period extended from study initiation to May 14, 2013. The trial enrolled largely white/Caucasian subjects with a slight majority of females (Table 1). There were no apparent differences among the two treatment groups or between the two age strata. The subjects’ history of influenza vaccination in the 2012–2013 season was not captured. 3.2. Hypersensitivity events Fifty-two subjects reported at least one possible hypersensitivity event, either on their Hypersensitivity Memory Aid or as an AE subsequently identified as possible hypersensitivity by medical review of all AEs reported during the 30 days following vaccination. Thirty-seven of the 45 (82%) subjects in both vaccine groups that recorded an event on the Hypersensitivity Memory Aid failed to return to the investigative site for a confirmatory visit within one day of the start date of the event. Absence of medical evaluations of these subject-reported events was largely attributed to the mild or transient nature of the complaint. The frequency of missed

Events of reactogenicity collected as subject-reported outcomes revealed infrequent systemic complaints (generally <5%), largely mild in severity (Table 6). There was no overall difference between the vaccine treatment groups, but a suggestion of slightly more frequent complaints in the younger 50–64 age stratum (data not shown). There were no reactogenicity events of Grade 4 severity reported from either vaccine group. Local injection site reactions were considerably more frequent than systemic reactions, the most common of which were injection site tenderness, generally of mild or moderate severity. All were numerically more frequent among IIV recipients than Flublok recipients, but these individual differences were not statistically significant. Total local reactogenicity appeared to be somewhat more frequent with the comparator IIV than with Flublok [p = 0.042] (Table 5). There were no deaths throughout the duration of the study. There were 37 SAEs reported overall from 15 subjects. Five subjects with SAEs were in the Flublok group and 10 were in the IIV group. No SAEs were considered related to study vaccine. The most common non-serious adverse events were diarrhea and headache that occurred in no more than1% of subjects in either vaccine group.

4. Discussion and conclusions This study was a relatively large randomized, controlled clinical trial to assess the safety and tolerability of a novel recombinant protein influenza vaccine product in adults 50 years of age and older. The composite primary endpoint was designed to assess the incidence of events of hypersensitivity following receipt of either Flublok (RIV3) or IIV3 (AFLURIA). The pre-specified criterion for non-inferiority (or similarity) between the two vaccine groups was

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Table 1 Demographics PSC11—subject demographics–safety population. Number (%) of subjects Parameter statistics

Flublok

Licensed IIV

Total

50–64 years (N = 672)

≥65 years (N = 642)

Total (N = 1314)

50–64 years (N = 665)

≥65 years (N = 648)

Total (N = 1313)

50–64 years (N = 1337)

≥65 years (N = 1290)

Total (N = 2627)

Age (years) n Mean Median Range

672 56.6 56.0 50–64

642 71.7 70.0 65–99

1314 64.0 64.0 50–99

665 56.5 56.0 50–64

648 71.2 70.0 65–93

1313 63.8 64.0 50–93

1337 56.6 56.0 50–64

1290 71.5 70.0 65–99

2627 63.9 64.0 50–99

Gender [n (%)] Female Male

383 (57) 289 (43)

347 (54) 295 (46)

730 (56) 584 (44)

377 (57) 288 (43)

348 (54) 300 (46)

725 55) 588 (45)

760 (57) 577 (43)

695 (54) 595 (46)

1455 (55) 1172 (45)

Ethnicity [n (%)] Hispanic/Latino Not Hispanic/Latino

66 (10) 606 (90)

39 (6) 603 (94)

105 (8) 1209 (92)

60 (9) 605 (91)

39 (6) 609 (94)

99 (8) 1214 (93)

126 (9) 1211 (91)

78 (6) 1212 (94)

204 (8) 2423 (92)

513 (76) 147 (22)

585 (91) 50 (8)

1098 (84) 197 (15)

496 (75) 161 (24)

587 (91) 51 (8)

1083 (83) 212 (16)

1009 (76) 308 (23)

1172 (91) 101 (.8)

2181 (83) 409 (16)

Race [n (%)]* White Black/African American Asian American Indian/Alaska Native Native Hawaiian/Other Pacific Islander Multiple *

4 (1) 6 (1)

3 (1) 2 (<1)

7 (1) 8 (1)

3 (1) 3 (1)

2 (<1) 3 (1)

5 (<1) 6 (1)

7 (1) 9 (1)

5 (<1) 5 (<1)

12 (2) 14 (1)

0

1 (<1)

1 (<1)

0

2 (<1)

2 (<1)

0

3 (<1)

3 (<1)

2 (<1)

1 (<1)

3 (<1)

2 (<1)

3 (1)

5 (<1)

4 (<1)

4 (<1)

8 (<1)

Subjects may have self-identified as multiracial.

Table 2 Subject-reported events on hypersensitivity memory aid PSC11—summary of all subject-reported events of possible hypersensitivity—days 0–30. Number (%) of subjects Flublok

1

Licensed IIV

Predefined hypersensitivity events

50–64 Years (N = 672)

≥65 Years (N = 642)

Total (N = 1314)

50–64 Years (N = 665)

≥65 Years (N = 648)

Total (N = 1313)

Subjects with ≥one event Rash Urticaria Swelling Non-dependent edema Other1

16 (2.4) 8 (1.2) 2 (0.3) 4 (0.6) 2 (0.3) 2 (0.3)

15 (2.3) 9 (1.4) 3 (0.5) 2 (0.3) 3 (0.5) 2 (0.3)

31 (2.4) 17 (1.3) 5 (0.4) 6 (0.5) 5 (0.4) 4 (0.3)

11 (1.7) 6 (0.9) 2 (0.3) 2 (0.3) 2 (0.3) 0 (0)

10 (1.5) 4 (0.6) 2 (0.3) 1 (0.2) 1 (0.2) 3 (0.5)

21 (1.6) 10 (0.8) 4 (0.3) 3 (0.2) 3 (0.2) 3 (0.2)

Other events were identified among unsolicited, subject-reported AEs after medical review of all AEs prior to database lock.

Table 3 Adjudicated hypersensitivity events incidence of adjudicated events possibly representing hypersensitivity—days 0–30. Number (%) of subjects Flublok

Licensed IIV

Predefined hypersensitivity events

50–64 Years (N = 672)

≥65 Years (N = 642)

Total (N = 1314)

50–64 Years (N = 665)

≥65 Years (N = 648)

Total (N = 1313)

Subjects with at least one event Rash Urticaria Swelling Non-dependent edema Other

4 (0.6) 2 (0.3) 1 (0.1) 1 (0.1) 1 (0.1) 0

2 (0.3) 2 (0.3) 1 (0.2) 0 0 0

6 (0.5) 4 (0.3) 2 (0.2) 1 (0.1) 1 (0.1) 0

1 (0.2) 0 1 (0.2) 0 0 0

3 (0.5) 2 (0.3) 1 (0.2) 0 0 1 (0.2)

4 (0.3) 2 (0.2) 2 (0.2) 0 0 1 (0.1)

Table 4 Comparison of hypersensitivity events by vaccine group PSC11—comparison of the incidence of composite possible hypersensitivity events. Source

Patient-reported Adjudicated 1 2

Flublok (N = 1314)

Licensed IIV (N = 1313)

n

n (N)

n

n (N)

31 6

0.024 0.005

21 4

0.016 0.003

Difference1

97.5% Confidence limit upper bound2

0.0076 0.0015

0.0191 0.0091

Proportion of Flublok subjects—proportion of IIV subjects with at least one of the pre-specified events of rash, urticaria, swelling, edema or other allergic reaction. Upper bound of one-sided 97.5% confidence interval calculated using the method of Farrington and Manning [15].

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Table 5 Comparison of incidence of local reactogenicity PSC11—comparison of frequency of local injection site reactions1 . Number (%) of subjects Flublok

1

Licensed IIV

Symptom

50–64 years (N = 669)

≥65 years (N = 642)

Total (N = 1311)

50–64 years (N = 665)

≥65 years (N = 648)

Total (N = 1313)

p-Value

Total local event Subjects with at least one local event

964 282 (42)

656 210 (33)

1620 492 (38)

1019 310 (47)

634 233 (36)

1653 543 (41)

0.042**

Subjects with at least one value on the Memory Aid during Days 0–7 following vaccine administration are included in the analysis. ** Cochran–Mantel–Haenszel test.

met for events adjudicated by independent allergy/immunology and dermatology experts. Patient-reported events possibly reflecting hypersensitivity (largely rashes) were far more frequent across both treatment groups than has been reported in previous clinical trials or the Package Inserts for either study vaccine and probably reflected the subjects’ lack of distinction between possible allergic reactions and other non-related rash or injection site reactions. That these

events were collected on a patient-reported outcome instrument that had not been utilized in previous trials may have contributed to reporting of events in unanticipated ways. Furthermore, while reported by phone to study personnel, the majority of patientreported events were not evaluated by medical personnel at the time of occurrence, making a large proportion of the patientreported events difficult to assess in terms of etiology. Adjudication of the medical records (all available source documents and the

Table 6 Solicited events of reactogenicity days 0–7 by severity. N (%) of subjects Flublok 135 ␮g (rHA) Symptom severity grade Fatigue Any Moderate Severe Shivering/chills Any Moderate Severe Joint pain Any Moderate Severe Muscle pain Any Moderate Severe Headache Any Moderate Severe Nausea Any Moderate Severe Temperature ≥100.4 F 101.2–102.0 ◦ F 102.1–104 ◦ F >104 ◦ F Injection site local pain Any Moderate Severe Injection site local tenderness Any Moderate Severe Injection site measurement of erythema Any Moderate Severe Injection site measurement of induration Any Moderate Severe

50–64 years (N = 670) number (%)

Licensed IIV ≥65 years (N = 643) number (%)

50–64 years (N = 664) number (%) 104 (15.6) 26 (3.9) 2 (0.3)

≥65 years (N = 647) number (%)

88 (13.1) 21 (3.1) 0 (0)

66 (10.2) 18 (2.8) 6 (0.9)

78 (12.0) 9 (1.4) 0 (0)

38 (5.7) 8 (1.2) 0 (0)

28 (4.4) 5 (0.8) 3 (0.5)

27 (4.1) 5 (0.8) 2 (0.3)

26 (4.0) 2 (0.3) 0 (0)

62 (9.3) 16 (2.4) 0 (0)

42 (6.5) 9 (1.4) 4 (0.6)

54 (8.1) 15 (2.3) 2 (0.3)

34 (5.3) 5 (0.8) 2 (0.3)

69 (10.3) 13 (1.9) 1 (0.1)

48 (7.5) 12 (1.9) 5 (0.8)

69 (10.4) 17 (2.6) 2 (0.3)

46 (7.1) 7 (1.1) 3 (0.5)

111 (16.6) 24 (3.6) 5 (0.7)

60 (9.3) 4 (0.6) 3 (0.5)

91 (13.7) 17 (2.6) 3 (0.5)

54 (8.3) 7 (1.1) 0 (0)

48 (7.2) 12 (1.8) 0 (0)

24 (3.7) 4 (0.6) 2 (0.3)

35 (5.3) 5 (0.8) 1 (0.2)

16 (2.5) 4 (0.6) 0 (0)

2 (0.3) 1 (0.1) 1 (0.1) 0 (0)

3 (0.5) 0 (0) 3 (0.5) 0 (0)

1 (0.2) 0 (0) 0 (0) 0 (0)

1 (0.2) 0 (0) 0 (0) 0 (0)

156 (23.2) 10 (1.5) 0 (0)

100 (15.6) 2 (0.3) 1 (0.2)

188 (28.3) 5 (0.8) 0 (0)

99 (15.3) 2 (0.3) 0 (0)

249 (37.2) 12 (1.8) 0 (0)

183 (28.5) 7 (1.1) 1 (0.2)

276 (41.6) 3 (0.5) 0 (0)

204 (31.5) 3 (0.5) 0 (0)

33 (4.9) 11 (1.6) 3 (0.4)

25 (3.9) 9 (1.4) 2 (0.3)

27 (4.1) 8 (1.2) 0 (0)

20 (3.1) 9 (1.4) 3 (0.5)

40 (6.0) 12 (1.8) 3 (0.4)

27 (4.2) 7 (1.1) 1 (0.2)

29 (4.4) 6 (0.9) 3 (0.5)

19 (2.9) 5 (0.8) 2 (0.3)

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subject-completed reports of rash, urticaria, edema and swelling) of these events by independent experts blinded to treatment assignment, yielded the judgment that a minority of the subject reports actually represented likely hypersensitivity events. The incidences of these adjudicated events (0.3–0.5%) were consistent with observations in earlier clinical trials [12,13]. Previously we showed that Flublok induced a higher antibody response against the influenza A viruses in older adults [12,13], likely due to the presence of 45 ␮g per antigen (total 135 ␮g rHA) per dose as compared with 15 ␮g per antigen (total 45 ␮g per dose) in conventional inactivated vaccine. The observed hypersensitivity reactions may be the result of the activation of complement in response to antigen-antibody (immune) complexes that are deposited in tissues as more immune cells are attracted to the site of the injection by higher concentrations of antigen. A licensed highdose (60 ␮g per antigen) inactivated influenza vaccine (Fluzone High-Dose® ) has been shown to induce higher levels of antibody responses in older adults that were associated with a superior level of protective efficacy [16,17]. The high-dose vaccine was also associated with a somewhat higher incidence of serious adverse events in the MedDRA categories of Immune System Disorders and Skin and Subcutaneous Tissue Disorders, which are the System Organ Classes (SOC) into which the adjudicated hypersensitivity events in this study fall (0.07% vs. 0.04% among Fluzone HighDose vs. Fluzone Standard Dose, respectively (RR 1.83 [95% CI 0.68, 4.95] p = 0.23) [18]. The incidence of non-serious adverse events in these or any other MedDRA SOC were not reported; however, the non-serious events of reactogenicity were consistently more frequent among recipients of High-Dose vaccine as compared with standard-dose vaccine [19]. These observations appear to support the concept that higher antigen concentrations may in some instances be associated with a greater likelihood of hypersensitivity reactions. Since marketing approval of Flublok, there has been an interest in allergic/hypersensitivity reactions occurring in Flublok recipients [20]. Due to the absence of egg protein in Flublok, safety of this recombinant protein vaccine can now be observed in the commercial setting among individuals who may represent a segment of the population that was not included in pre-registration clinical trials, including individuals who are egg-allergic and/or have experienced allergic reactions to previous influenza vaccines. The Advisory Committee on Immunization Practices made a specific recommendation to use Flublok in patients with known or suspected egg allergies of any severity [5]. Therefore, the “real-life” experience with Flublok, includes individuals excluded from the randomized controlled clinical trials that compared Flublok with conventional egg-based vaccines, including this trial. As a result of

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the ACIP recommendation, the population who received Flublok in its early seasons of commercialization very likely included a selected group of atopic individuals, for whom many (known and unknown) foreign antigens might induce an allergic reaction. A recent report from the CDC/FDA-sponsored Vaccine Adverse Event Reporting System (VAERS) reported that 17 individuals had submitted VAERS reports, largely of allergic reactions, during the 2013–2014 influenza season [20]. The author acknowledged that the nature of the VAERS database did not allow ascertainment of the total number of Flublok recipients or the incidence of these events. Given the likely self-selected atopic population to whom Flublok was administered, a bias toward reporting of apparent allergic reactions may also have contributed to the observations [21]. Despite these caveats, based on the number of Flublok doses distributed through commercial channels, the frequency of reported hypersensitivity was no greater among recipients of commercial Flublok during 2013–2014 than was observed in earlier randomized clinical trials or among recipients of the other new cell-grown influenza vaccine in the same year. The outcome of this randomized, controlled clinical trial in older, non-allergy-prone adults demonstrates that Type 1, IgE-mediated allergic reactions are no more frequent following Flublok than following inactivated influenza vaccines. Conflict of interest statement Drs. Izikson, Post, Dunkle and Cox are employees and shareholders of Protein Sciences Corporation; Drs. Bock, Leffell and Patriarca are consultants to Protein Sciences compensated for their professional time. All authors materially participated in the research and/or article preparation: Drs. Izikson, Patriarca, Dunkle and Cox designed the study, wrote the protocol and oversaw the conduct of the study; Drs. Bock and Laffell served as adjudicators for the primary hypersensitivity endpoints. All authors have approved the final article. Acknowledgements The authors thank the investigators, study personnel and volunteer participants who contributed to the study, and acknowledge the generous support of Biomedical Advanced Research and Development Authority (BARDA, HHS) under Contract HHSO100200900106C. Appendix A.

Memory aid.. Date Day of dose 1 Day after 2 Days after 3 Days after 4 Days after 5 Days after 6 Days after 7 Days after Day of immunization Record your temperature (taken by mouth) here Record Celsius (C) or Fahrenheit (F) Fill in today’s column by entering the worst grade for each symptom that you have had in the last day (24 h). Symptom grades are defined at the bottom of the page Symptoms Fatigue Shivering/chills Joint pain Muscle pain (not at injection site) Headache Nausea Injection site Local Pain Local Tenderness

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(Continued ) Now, as a reminder to you, tick the box in today’s column if your answer to the question below is YES Is there any other new problem you want to talk to a study doctor about? Have you experienced rash, urticaria, swelling or edema? (see below for description) Please use these qualitative definitions to grade your symptoms I didn’t have it at all Grade 0 I noticed it, but it didn’t interfere with my usual activities at all Grade 1 I had it, and it was bad enough to prevent a significant part of my usual activities Grade 2 I had it, and it prevented most or all of my normal activities, or I had to see a doctor for prescription medicine Grade 3 Fill in today’s column by entering the measurement of the longest dimension at your vaccine injection site Injection site Redness Firmness/swelling Please use these quantitative definitions to grade your injection site: Measures less than 10 mm Grade 0 Grade 1 Measures larger than or equal to 10 mm and smaller than 20 mm Measures larger than or equal to 20 mm and smaller than 50 mm Grade 2 Grade 3 Measures larger than 50 mm Guidance for characterization of possible hypersensitivity reactions1 Rash Pink-red spots that cannot be felt by running your fingers lightly over the rash Macular Pink-red spots that can be felt as raised lesions (bumps) by running your fingers lightly over the rash Maculopapular Papular Bumps that are not colored differently from the normal skin Rash that has blisters associated with it; vesicles may be combined with macular or papular rashes Vesicular Purpuric Spots or patches that appear like bruises or areas of bleeding into the skin Any rash that itches Pruritic Hives–raised, pinkish spots or patches that itch; may be localized (on a specific area of the body) or generalized (all over the body) Urticaria Swelling of body parts without prior trauma; may involve the lips, tongue or face; also includes swelling of airways that causes Swelling wheezing or other difficulty breathing Similar to the swelling described above. May also involve swelling of hands, feet or other extremities Edema 1 These terms refer only to events that occur someplace other than the site of vaccine injection. any such reaction must be reported immediately to the clinical site and you must return for medical evaluation of the event.

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