FLUBLOK^® (INFLUENZA VACCINE): OVERVIEW OF EFFICACY AND SAFETY

FLUBLOK HAS BEEN SHOWN TO HELP PROTECT PATIENTS AGED 18+ AGAINST FLU AND ITS COMPLICATIONS^1,2

RECOMBINANT TECHNOLOGY

FLUBLOK COMBINES THE ADVANTAGES OF RECOMBINANT TECHNOLOGY WITH A HIGHER DOSE^2,3

^*Flublok contains 45 micrograms (mcg) of HA per strain vs 15 mcg of HA per strain in a standard-dose influenza vaccine.^1,2,4
†Flublok is produced using a novel production platform in which recombinant HA is expressed in insect cells using a baculovirus expression vector system (BEVS). Recombinant HA antigens produced using BEVS have been shown to induce significantly higher levels of broadly cross-reactive antibodies against highly conserved regions of HA compared with egg-derived vaccines, which may potentially protect against drift-variant influenza viruses.^3
‡According to the CDC, getting a flu vaccine will not give you the flu.⁸ 

CDC=Centers for Disease Control and Prevention; FDA=US Food and Drug Administration.

CROSS-PROTECTION MAY BE A RESULT OF SIMPLER GLYCOSYLATION BECAUSE RECOMBINANT DNA TECHNOLOGY ALLOWS FOR BROADER ACCESS TO CONSERVED ANTIGENIC SITES³

Glycosylation occurs during viral replication and in the vaccine manufacturing process, blocking access to antigenic sites on HA proteins, which are necessary for developing an immune response. Complex glycosylation interferes with antigenic site access.^3,9

HOW IT’S MADE

RECOMBINANT DNA TECHNOLOGY ELIMINATES THE NEED TO GROW INFLUENZA VIRUS AND AVOIDS THE POSSIBILITY OF MUTATION OR ADAPTATION²

PIVOTAL TRIAL IN ADULTS AGED 50+:

IN A RANDOMIZED, CONTROLLED TRIAL VS FLUARIX: 30% RELATIVE REDUCTION IN PCR-CONFIRMED FLU IN ADULTS AGED 50+^1,2

Study Design


• Phase 3-4 randomized, controlled trial in adults aged 50+ (N≈9,000) during the 2014-2015 influenza season in which A (H3N2) was predominant and antigenically mismatched^1,2
• Patients were randomized 1:1 to receive Flublok (quadrivalent) or Fluarix (quadrivalent)^1,2
• Patients with comorbidities who received Flublok: insulin-dependent diabetes: 3.9% (170); non-insulin-dependent diabetes: 10.8% (469); atherosclerotic cardiovascular disease: 30.5% (1320); condition requiring statin lipid-lowering therapy: 27.6% (1194); condition requiring thiazide diuretic: 7.7% (332); chronic obstructive pulmonary disease: 3.3% (144); acid reflux or peptic ulcer disease: 14.5% (629); depression: 18.2% (788)²

The efficacy of Flublok (quadrivalent) is relevant to Flublok (trivalent) because both vaccines are manufactured using the same process and have overlapping compositions.¹

Flublok prevented more cases of influenza than a standard-dose vaccine and satisfied the primary criterion for noninferiority and the prespecified exploratory superiority criterion.²

SAFETY IN ADULTS AGED 50+

• Comparable safety profile to a standard-dose quadrivalent inactivated influenza vaccine in adults aged 50+²
• Most common adverse events (≥10%) in the Flublok group in adults aged 50-64²:
  • Injection-site reactions: tenderness (37%), pain (32%)
  • Systemic adverse reactions: headache (17%), fatigue (13%), muscle pain (11%)

PIVOTAL TRIAL IN PATIENTS AGED 18-49:

EFFECTIVE FLU PROTECTION, EVEN IN A SEASON WITH SIGNIFICANT ANTIGENIC MISMATCH, IN PATIENTS AGED 18-49 YEARS^1,10

Study Design

• Randomized, observer-blind, placebo-controlled trial to evaluate the protective efficacy and safety of Flublok (trivalent) against influenza in 4648 adults aged 18-49 years^1,10
• The study was undertaken during the 2007-2008 influenza season when there was significant mismatch between vaccine antigens and circulating viruses¹⁰
• Primary endpoint: CDC-defined influenza-like illness (ILI) defined by presence of documented fever ≥100 °F plus either sore throat or cough with positive culture for an influenza virus strain antigenically resembling a strain represented in Flublok. Vaccine efficacy against antigenically matched culture-confirmed CDC-ILI could not be determined reliably because 96% of the influenza isolates obtained were not antigenically matched to the strains represented in the vaccine¹

IMMUNOGENICITY IN PATIENTS AGED 9-17

FLUBLOK DEMONSTRATED NON-INFERIOR IMMUNE RESPONSE IN PATIENTS AGED 9-17 COMPARED TO ADULTS AGED 18-49^1,11

Study Design

• A phase 3 non-randomized, open-label, uncontrolled, multicenter study of 1308 participants aged 9 to 49 years¹
• Primary objective was to demonstrate that vaccination with Flublok induced an immune response in children and adolescents aged 9 to 17 that was non-inferior to responses induced by Flublok in adults aged 18 to 49 for 4 viral strains at Day 29 post-vaccination¹
• Immune response was assessed by hemagglutination inhibition (HI), geometric mean titers (GMTs), and seroconversion (SCR) rates¹

• The non-inferiority of HI immune responses induced by Flublok (quadrivalent) in patients aged 9 to 17 relative to patients aged 18 to 49 was demonstrated for all 4 strains (A/H1N1, A/H3N2, B/Victoria, and B/Yamagata)^1*
• Non-inferiority was based on prespecified criteria (lower limit of the 2-sided 95% CIs of the ratios of GMTs between age groups [9-17 years/18-49 years] >0.667; lower limit of the 2-sided 95% CI of the difference in SCR rates > −10 at Day 29 post-vaccination)¹

^*Effectiveness of Flublok (quadrivalent) in children aged 9 to 17 is based on comparison to adults aged 18 to 49. The data for Flublok (quadrivalent) is relevant to Flublok (trivalent) because both vaccines are manufactured using the same process and have overlapping compositions.¹

REAL-WORLD EVIDENCE

FLUBLOK WAS STUDIED AGAINST STANDARD-DOSE VACCINES IN THE LARGEST RANDOMIZED REAL-WORLD FLU EFFECTIVENESS STUDY TO DATE^12,13

Study Design

• Modified cluster randomized observational study to evaluate Flublok (quadrivalent) vs quadrivalent standard-dose influenza vaccines¹²
• Study population: 1,630,328 members of the Kaiser Permanente Northern California (KPNC) healthcare system aged 18-64 years¹²
• Evaluated over 2 flu seasons: 2018-2019 influenza season, when A (H1N1) was predominant until March 2019, when A (H3N2) viruses became predominant; and the 2019-2020 influenza season, when A (H1N1) was predominant with B cocirculation^14-16
• Patients aged 50-64 with comorbid conditions: asthma: 14% (96,307); diabetes: 18% (119,430); chronic obstructive pulmonary disease: 2% (13,357); coronary heart disease: 4% (25,496)¹²

The efficacy of Flublok (quadrivalent) is relevant to Flublok (trivalent) because both vaccines are manufactured using the same process and have overlapping compositions.¹

Study Limitations¹²

• Data were limited to two influenza seasons; relative vaccine effectiveness may vary across seasons depending on the vaccine match with circulating strains
• Primary outcome did not include infections in persons who did not undergo PCR testing, which limits generalizability
• Although KPNC has a diverse population, it may not be representative of other populations in the US
• Compliance with the weekly assigned vaccine schedule varied from time to time due to logistical constraints
• The study had limited power to detect a clinically meaningful benefit of Flublok vs standard-dose vaccines with less frequent outcomes, such as hospitalized, PCR-confirmed influenza

FLUBLOK WAS ASSOCIATED WITH FEWER FLU HOSPITALIZATIONS VS CELL- AND EGG-BASED STANDARD-DOSE VACCINE COMPARATORS¹⁷

Study Design

• Retrospective test-negative case-control study in approximately 15,000 patients aged 18+ during the 2018-2019 and 2019-2020 flu seasons to investigate the rVE of Flublok vs standard-dose vaccines against influenza hospitalization^17* 
• In the primary analysis, Flublok was evaluated against standard-dose flu vaccines, including^17,18:
  •  Cell-based: Flucelvax 
  •  Egg-based: Fluarix, Afluria, FluLaval, and Fluzone^® (Influenza Vaccine)

^*Flublok (quadrivalent vaccine) was evaluated against quadrivalent standard-dose vaccines. The efficacy of Flublok (quadrivalent formulation) is relevant to Flublok (trivalent formation) because both vaccines are manufactured using the same process and have overlapping compositions.^1,17

Secondary Endpoints

When adjusted for propensity scores with IPWs¹⁷:


• Flublok was associated with providing greater protection against influenza hospitalization vs standard-dose vaccines for the following populations¹⁷:
  • Female sex: 37% rVE (95% CI: 13, 54)
  • Age 18-64 years: 28% rVE (95% CI: 3, 46)
  • No high-risk condition: 60% rVE (95% CI: 29, 78)

     
• Flublok was associated with providing greater (non–statistically significant) protection against influenza hospitalization vs standard-dose vaccines for the following populations¹⁷:

  • Male sex: 23% rVE (95% CI: -14, 48)
  • Age ≥65 years: 17% rVE (95% CI: -36, 48)
  • High-risk condition: 20% rVE (95% CI: -7, 40)

Study Strengths and Limitations¹⁷

• The demographics of the study population were representative of the adult population of Allegheny County, with 79% being white and 51% being female, which contributes to generalizability
• The University of Pittsburgh Medical Center hospitals in central and southwestern Pennsylvania are part of an integrated health system, with regular uploads of vaccination data from the state immunization registry; vaccination status was verified through the state registry with a specific data request
• Although the electronic medical records (EMR) system of University of Pittsburgh Medical Center hospitals in central and southwestern Pennsylvania is robust, if vaccinations were not captured in the EMRs or state registry, they were classified as unvaccinated
• Because data focused on hospitalizations, there may have been milder cases of influenza that were not captured in the EMRs because they didn’t require medical care
• There is a possibility of selection bias among those who received influenza testing; for instance, clinicians might preferentially test unvaccinated subjects, which would increase the proportion of unvaccinated cases
• While a relatively large cohort of adults is included in this study, the sample size of standard-dose flu vaccine recipients may have been inadequate to detect meaningful rVE estimates for specific subgroups

2019-2020 RETROSPECTIVE OBSERVATIONAL COHORT STUDY:

FLUBLOK WAS ASSOCIATED WITH SIGNIFICANTLY FEWER INFLUENZA HOSPITAL ENCOUNTERS COMPARED WITH STANDARD-DOSE INFLUENZA VACCINES¹⁹

Study Design

• Retrospective observational cohort study using real-world data from Medicare claims to analyze the rVE of US-licensed influenza vaccines in preventing influenza hospital encounters among beneficiaries aged 65+; 12.7 million adults aged 65+ were eligible for analysis¹⁹
• The efficacy of Flublok (quadrivalent) is relevant to Flublok (trivalent) because both vaccines are manufactured using the same process and have overlapping compositions¹

Relative Vaccine Effectiveness (rVE) Against Influenza Hospital Encounters (95% CI)¹⁹

The data above represents 1 of 3 primary analyses. Two additional primary analyses were conducted¹⁹:

• Cell-cultured standard-dose quadrivalent flu vaccine vs egg-based standard-dose quadrivalent flu vaccine
• Flublok vs egg-based standard-dose quadrivalent flu vaccine

2019-2020 Season Characteristics¹⁹

• Influenza A (H1N1) and influenza B (Victoria) were predominating strains with no significant circulation of influenza A (H3N2)
• An H1N1 strain with an amino acid change emerged late in the season and likely did not substantially affect the vaccine efficacy
• Trivalent vaccines contained the influenza B (Victoria) lineage

Study Limitations¹⁹

• Lack of access to virological case confirmation may have led to underestimation of the magnitude of differences
• Residual confounding by unmeasured covariates could have affected results
• The observation period was cut off at the end of February to avoid potential bias from the overlap between influenza season and the escalation of the COVID-19 pandemic in the US

FLUBLOK SAFETY

REAL-WORLD SAFETY EVIDENCE

SAFETY PROFILE SUPPORTED IN ONE OF THE LARGEST SAFETY STUDIES OF A FLU VACCINE IN PREGNANT WOMEN, WITH ~15,000 PATIENTS^1,20,21

Study Design

• This was an observational, retrospective safety surveillance study of Flublok Quadrivalent in 14,981 pregnant individuals across Northern Hemisphere influenza seasons 2018-2019 and 2019-2020^1*†‡
• This study represents one of the largest populations of pregnant people to be included in the prescribing information for any FDA-approved flu vaccine^1,20,21

^*5842 patients, including those with chronic conditions, were exposed to Flublok Quadrivalent during the 28 days prior to conception or during the first trimester. Miscarriage was reported in 464 (3.1%) patients. Among individuals exposed to Flublok Quadrivalent at any time during pregnancy, 1113 pregnancies (7.7%) had infants with major birth defects (56, 360, 381, and 316 among individuals exposed during the 28 days prior to conception, the first trimester, the second trimester, and the third trimester, respectively).^1
†Prespecified outcomes included spontaneous abortion and congenital/fetal anomalies. Data were not collected on ectopic pregnancy or elective terminations.^1
‡The data for Flublok (quadrivalent) are relevant to Flublok (trivalent) because both vaccines were manufactured using the same process and have overlapping compositions.¹

 
SIMILAR SAFETY PROFILE COMPARED TO STANDARD-DOSE FLU VACCINES IN ADULTS 50-64¹

Safety In Adults Aged 50-64: Reactions, Any Grade

• Rates of local and systemic adverse reactions were similar within 7 days of Flublok (trivalent) or standard-dose influenza vaccine administration¹
• Pooled data from 2 studies; comparators were Fluzone (trivalent standard-dose formulation) and Afluria (trivalent standard-dose formulation)¹

SAFETY PROFILE IN ADULTS AGED 18-49 COMPARED TO PLACEBO¹⁰

Safety Trial in Adults Aged 18-49:

• Safety data from a study of 4648 adults randomized to receive Flublok (trivalent; n=2344) or placebo (n=2304)¹⁰
• Systemic symptoms following vaccination were similar between people receiving Flublok and placebo¹⁰
• The most frequently reported systemic symptoms following vaccination were headache (15% with Flublok vs 16% with placebo) and fatigue (15% with Flublok vs 14% with placebo)¹⁰
  • 76% of headache complaints were mild
• Flublok was associated with local injection-site pain (37% with Flublok vs 8% with placebo) that was significantly more frequent than after saline placebo^1,10
  • 94% of all pain complaints after Flublok were rated as mild¹⁰

SAFETY IN PATIENTS AGED 9-17¹

• There were no significant observed differences in safety profile between the 9 to 17-year-old and 18 to 49-year-old populations
• Most common adverse reactions in 9 to 17-year-olds (N=608-618):
  • Injection-site reaction: pain (34.4%)
  • Systemic reactions: myalgia (19.3%), headache (18.5%), malaise (16.1%)

Learn about Fluzone High-Dose for your patients 65+