Comparative Effectiveness of Influenza Vaccines Among U.S. Medicare Beneficiaries Ages 65 Years and Older During 2019-20 Season

Design

Retrospective, database analysis

N= ~12,700,000

Objective

To use real-world data from Medicare claims to analyze the relative vaccine effectiveness (RVE) of U.S. licensed influenza vaccines in preventing hospital encounters among beneficiaries ages ≥65 years during the 2019-20 season

Study Groups

HD-IIV3 (n= 7,177,250)

aIIV3 (n= 2,564,628)

IIV4 (n= 1,573,548)

cIIV4 (n= 813,838)

RIV4 (n= 638,905)

Inclusion Criteria

Medicare beneficiaries ages ≥65 years old continuously enrolled in Medicare part A/B without enrollment in Part C in the 6 months prior to vaccination; received an influenza vaccine from August 4 2019 to January 31 2020; beneficiaries who had aged into Medicare and had not received any other influenza between the start of the season and their cohort vaccination date

Exclusion Criteria

Beneficiaries not residing in a region defined in the Department of Health and Human Services(HHS) regions; residing in a nursing home and/or hospice

Methods

This was a retrospective analysis of Medicare fee for service (FFS) data for the 2019-20 flu season to analyze vaccine effectiveness of all influenza vaccines used by beneficiaries ≥65 years between August 4, 2019 to February 29, 2020. Cohorts were adjusted via propensity scores and inverse probability of treatment weighting (IPTW). Relative vaccine effectiveness was defined as (1- hospital encounter rate ratio[RR]) x 100.

Duration

Outcome Measures

Primary: RVE, defined as (1- rate ratio[RR]) x 100; influenza hospital encounters (which included inpatient hospitalizations and emergency department visits)

Secondary: influenza inpatient hospitalizations only

HD-IIV3

aIIV3

Age 65-74 years

Female

White

Results

HD-IIV3

Relative vaccine effectiveness

RIV4 was significantly more effective than all other vaccines except for aIIV3.

Adverse Events

Not reported

Study Author Conclusions

In this influenza B-Victoria and A(H1N1)-dominated season, RIV4 was moderately more effective than other vaccines, while the HD-IIV3 and aIIV3 were more effective than the IIV4 vaccines, highlighting the contributions of antigen amount and adjuvant use to vaccine effectiveness. Egg adaptation likely did not substantially affect our RVE evaluation.

InpharmD Researcher Critique

While this was a real-world analysis of Medicare data, this study is limited by access to necessary data (e.g., viral case confirmation). Some cases may have been misclassified or diagnosed incorrectly, which also may alter the results. While the cohorts were relatively balanced, there is still a possibility of confounding. Health-seeking behavior was not accounted for, which also may have confounded the primary endpoint of hospitalization. This study also only measured hospitalizations that occurred during high influenza circulation periods with an influenza-specific ICD code; however, the data was cut off on February 29, 2020 to avoid confounding by the COVID-19 pandemic.

Comparison of the Immunogenicity of Cell Culture-Based and Recombinant Quadrivalent Influenza Vaccines to Conventional Egg-Based Quadrivalent Influenza Vaccines Among Healthcare Personnel Aged 18–64 Years: A Randomized Open-Label Trial

Design

Randomized, open-label trial

N= 727

Objective

To assess humoral immune responses to cell-culture-based inactivated influenza vaccine (ccIIV4; Flucelvax Quadrivalent) and a recombinant influenza vaccine (RIV4; FluBlok Quadrivalent) compared to egg-based standard dose inactivated influenza vaccines (IIVs; Fluarix Quadrivalent and Fluzone Quadrivalent) among United States (US) healthcare personnel (HCP) aged 18–64 years

Study Groups

ccIIV4 (n= 283)

RIV4 (n= 202)

IIV4 (n= 242)

Inclusion Criteria

Healthcare personnel (HCP), 18-64 years old, in direct contact with patients, enrolled in their site's health system/insurance plan for at least 1 month, agreed to participate in study follow-up for at least 18 months

Exclusion Criteria

Already received flu vaccination for 2018-2019, allergic reaction to any influenza vaccine, received any vaccines four weeks before the first study visit, planning to receive any vaccines four weeks after the first study visit

Methods

Initial randomization was 2:2:1:1 but was changed to 4:1:1 due to combining Fluzone IIV4 and Fluarix IIV4 groups. Eligible HCPs were randomized to receive their yearly influenza vaccine (2018-2019 season) with either an IIV4, ccIV4, or RIV4 vaccine. Each participant received the assigned vaccine dose of 0.5 mL in the deltoid muscle of the upper arm via intramuscular (IM) injection.

Participants were required to come back at 1 month and 6 months after receiving the vaccine for serum sample collection. During flu season each site performed nasal swabs and tested for influenza to identify vaccine failures.

Duration

Follow-up: 6 months

Outcome Measures

Primary: Seroconversion 1 month after vaccination

Secondary: titers ≥1:40, 1:80, and 1:160 against cell-grown vaccine reference viruses by hemagglutination inhibition (HI) or microneutralization (MN) assay at approximately 1 month after being vaccinated

Baseline Characteristics

Fluzone IIV4 (n= 122)

Fluarix IIV4 (n=120)

ccIIV4 (n=283)

RIV4 (n=202)

Age, years

44 ± 11

Age group, years

18-44

45-64

57 (47%)

65 (53%)

55 (46%)

65 (54%)

135 (48%)

148 (52%)

102 (51%)

100 (49%)

Female

White

Diagnosed or treated for chronic medical condition during the past 12 months

Received the 2017–2018 influenza vaccine

Results

IIV4 (n= 242)

ccIIV4 (n=283)

RIV4 (n=202)

Seroconversion, % (95% CI)

Influenza A/H1N1

Influenza B/Victoria

Influenza B/Yamagata

Influenza A/H3N2

16 (11-21)

10 (6-13)

10 (6-13)

12 (8-16)

18 (13-22)

8 (5-11)

9 (6-13)

17 (13-21)

0.64

0.58

0.90

0.11

29 (23-35)

14 (10-19)

20 (15-26)

55 (49-62)

<0.01

0.11

<0.01

<0.01

Influenza A/H1N1

Titer ≥1:40

Titer ≥1:80

Titer ≥1:160

74%

59%

36%

80%

62%

37%

0.13

0.47

0.80

85%

72%

55%

<0.01

<0.01

<0.01

Influenza A/H3N2

Titer ≥1:40

Titer ≥1:80

Titer ≥1:160

86%

70%

52%

86%

72%

55%

0.99

0.64

0.60

95%

93%

85%

<0.01

<0.01

<0.01

Influenza B/Victoria

Titer ≥1:40

Titer ≥1:80

Titer ≥1:160

86%

57%

27%

89%

65%

33%

0.23

0.06

0.16

86%

67%

35%

0.93

0.04

0.06

Influenza B/Yamagata

Titer ≥1:40

Titer ≥1:80

Titer ≥1:160

80%

63%

34%

83%

68%

36%

0.34

0.23

0.68

88%

68%

39%

0.03

0.31

0.35

Titer ratios were based on the mean fold rise in geometric titer. 

Adverse Events

Not assessed

Study Author Conclusions

RIV4 resulted in improved antibody responses by HI and MN compared to egg-based vaccines against 3 of 4 cell-grown vaccine strains 1 month postvaccination, supporting a possible additional benefit from influenza vaccination with RIV4 or other vaccines with higher antigen content.

InpharmD Researcher Critique

The researchers did not assess other components of influenza vaccines such as neuraminidase, which have been shown to decrease illness severity due to the hormonal response to neuraminidase. The RIV does not contain neuraminidase, but various amounts of neuraminidase are in the egg-based vaccine and the cell-based vaccine.

Given that HCPs were the main participants and are likely to be regularly vaccinated, the study was not able to assess the role those previous vaccinations played on the humoral immune response. Additionally, clinical effectiveness was not assessed (i.e., influenza illness incidence).

Clinical trial to assess immunogenicity of high-dose, adjuvanted, and recombinant influenza vaccines against cell-grown A(H3N2) viruses in adults 65 to 74 years, 2017-2018

Design

Open-label, randomized, immunogenicity trial

N= 89

Objective

To compare the immunogenicity of trivalent high-dose inactivated influenza vaccine (HD-IIV3), adjuvanted inactivated influenza vaccine (aIIV3), and quadrivalent recombinant vaccine (RIV4) against cell-grown vaccine and circulating A(H3N2) viruses in 2017-2018

Study Groups

HD-IIV3 (n=29)

aIIV3 (n=30)

RIV4 (n=30)

Inclusion Criteria

Aged 65-74 years old, had not received high-dose or adjuvanted vaccines in the 2015-2016 season, followed up from the first year of the study

Exclusion Criteria

Participants who received a non-study vaccine before the study visit

Methods

Patients were randomized 1:1:1 to receive HD-IIV3 (Fluzone HD), aIIV3 (Fluad), or IIV3 (Fluzone) during the 2016-2017 flu season. During the second year of the study (2017-2018), patients randomized to IIV3 the prior year received RIV4 (FluBlok Quadrivalent) instead. Each vaccination was administered as a single 0.5 mL intramuscular injection in the deltoid via a 25 gauge one-inch needle. Six serum samples were drawn for every patient on day 0 and day 28 for microneutralization assays against the circulating strain.

Duration

2017-2018

Outcome Measures

Primary: post-vaccination geometric mean titer and geometric mean fold rise (GMFR) in neutralizing antibody titer from baseline to post vaccination 

Secondary: seroconversion

Baseline Characteristics

aIIV3 (n=30)

Mean age, years

Male

High-risk conditions*

Influenza vaccination in the past 5 years

1-3 doses

4-5 doses

4 (13%)

26 (87%)

6 (21%)

23 (79%)

5 (17%)

25 (83%)

Results

p-value

HD-IIV3 (n=29)

aIIV3 (n=30)

HD-IIV3 vs. RIV4

aIIV3 vs. RIV4

HK4801

GMFR (95% CI)

Seroconversion, % (95% CI)

1.6 (1.3-1.8)

3.5 (0.09-17.8)

1.6 (1.3-2.0)

6.7 (0.8-22.1)

2.0 (1.7-2.5)

13.3 (3.8-30.7)

0.04

0.10

SI16

GMFR (95% CI)

Seroconversion, % (95% CI)

1.4 (1.1-1.8)

6.9 (0.9-22.8)

1.7 (1.4-2.2)

10.0 (2.1-26.5)

3.3 (2.4-4.5)

26.7 (10.8-42.5)

0.0001

0.002

KY29

GMFR (95% CI)

Seroconversion, % (95% CI)

1.6 (1.2-2.0)

6.9 (0.9-22.8)

1.6 (1.2-2.0)

13.3 (3.8-30.7)

3.5 (2.7-4.7)

40.0 (22.7-57.5)

<0.0001

<0.0001

KS14

GMFR (95% CI)

Seroconversion, % (95% CI)

1.3 (1.1-1.6)

3.5 (0.1-17.8)

1.7 (1.3-2.1)

6.7 (0.8-22.1)

2.9 (2.0-4.3)

33.3 (16.5-50.2)

0.0004

0.01

GMFR= geometric mean fold rise; CI= confidence interval; HK4801= A/Hong Kong/4801/2014 (2017-2018 vaccine strain); SI16= A/Singapore/INFIMH-16-0019/2016 (2018-19 vaccine strain); KY29= A/Kentucky/29/2017; KS14= A/Kansas/14/2017 (2019-20 vaccine strain)

Adverse Events

Not studied

Study Author Conclusions

InpharmD Researcher Critique

Although all the vaccines worked, this study demonstrated that RIV4 provided a better response against certain flu strains. Some limitations of the study are that it was a small sample size of only 89 participants and they were all non-Hispanic white. This was also an exploratory study of surrogate endpoints instead of a clinical study.

Safety of recombinant quadrivalent influenza vaccine compared to inactivated influenza vaccine in Chinese adults: An observational study

Design

Retrospective, observational, safety study

N= 42,684

Objective

To evaluate the safety of quadrivalent recombinant influenza vaccine (RIV4; Flublok Quadrivalent) compared to standard dose quadrivalent inactivated influenza vaccine (SD-IIV4) in Chinese adults

Study Groups

RIV4 (n= 15,574)

SD-IIV4 (n= 27,110)

Inclusion Criteria

Kaiser Permanente Northern California (KPNC) Chinese members 18-64 years who were vaccinated with either RIV4 or SD-IIV4 influenza vaccines between 09/01/18 and 05/06/19

Exclusion Criteria

Individuals who self-identified as mixed race/ethnicity, persons who did not select English as their preferred language

Methods

Kaiser Permanente Northern California (KPNC) clinics within the region were randomized to administer RIV4 or SD-IIV4 in an alternating-weekly manner to minimize geographic and socioeconomic differences across the region. 

Duration

September 1, 2018 to May 6, 2019

Outcome Measures

Incident pre-specified diagnoses of interest (PSDI) found in the emergency department and inpatient settings up to 41 days following vaccination; deaths due to any cause within 6 months after vaccination

Baseline Characteristics

RIV4 (n= 15,574)

SD-IIV4 (n= 27,110)

Female

9846 (63.2%)

17404 (64.2%)

Male 

5728 (36.8%)

9706 (35.8%)

Pregnant Women

545 (5.5%)

1152 (6.6%)

Comorbidities

2462 (15.8%)

4161 (15.3%)

No inpatient stays in the past year

13243 (85%)

35893 (84.1%)

Results

RIV4 (n= 15,574)

SD-IIV4 (n= 27,110)

p-Value

Serious adverse events within days 0-2

Acute hypersensitivity

Fever

0

0

1

1

0.61

0.64

Serious adverse events within days 0-41

Convulsion

Acute non-infectious pericarditis

Non-infectious pleural effusion

Idiopathic thrombocytopenic purpura

1

0

1

4

2

1

1

14

0.97

0.61

0.73

0.24

Death from any cause (proportion per 10,000)

8 (5.14/10,000 vaccines)

27 (9.96/10,000 vaccines)

0.07

Adverse Events

Study Author Conclusions

Comparing RIV4 with SD-IIV4, this study did not identify any safety findings among KPNC vaccinees aged 18–64 years who self-identified as Chinese. The study supports the safety of RIV4 vaccine in this population.

InpharmD Researcher Critique

The study proved the safety of RIV4 (Flublok recombinant quadrivalent vaccine) as compared to SD-IIV4 (inactivated influenza vaccine) in Chinese adults in California. Since this study specifically examined the vaccine safety in a minority population, may not be extrapolatable to other populations. Since the study is retrospective, some data could be missing or underreported.