Document text
Kenneth Schmader, MD
ACIP Meeting
October 25, 2023 Safety of Simultaneous Vaccination with Zoster
Vaccine Recombinant (RZV) and Quadrivalent
Adjuvanted Inactivated Influenza Vaccine (allV4)
(ClinicalTrials.gov ID: NCT05007041)
Disclaimer
•The findings and conclusions in this
presentation are those of the presenter and do not necessarily represent the official position of the Centers for Disease Control and Prevention
•Mention of a product or company name is for identification purposes only and does not constitute endorsement by CDC
•This study was supported by the CDC Clinical Immunization Safety Assessment (CISA) Project
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•Duke University
–Principal Investigator: Kenneth Schmader, MD
–Investigators: Emmanuel B. Walter, MD, MPH, Wes Rountree , MPH ,
Marek S. Poniewierski MD, MS
•CDC
–Principal Investigator: Karen Broder, MD
–Investigators: Michael McNeil, MD, MPH, Oidda Museru MSN, MPH
•John Hopkins University (JHU)
–Principal Investigator: Kawsar Talaat, MDStudy Team
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Rationale
•Novel (nonaluminum) adjuvants are powerful immune
stimulants employed in vaccine platforms to improve immunogenicity and efficacy. In recent years, the FDA licensed several vaccines with novel adjuvants
•Vaccines with novel adjuvants are more reactogenic than
vaccines without adjuvants.
•Clinicians may opt to administer these vaccines simultaneously.
•Data are needed on the safety of the simultaneous administration of vaccines with novel adjuvants
•For older adults seeking to prevent herpes zoster and influenza, data are needed on the safety of simultaneous administration of recombinant zoster vaccine (RZV; Shingrix) and quadrivalent adjuvanted inactivated influenza vaccine
(aIIV4; Fluad Quadrivalent)
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Study Design and Population
•Type:
–Prospective, randomized, observer blinded clinical trial
–Blinded except for vaccine administrator
•Population:
–Immunocompetent, cognitively intact, community -dwelling persons,
aged ≥65 years
–Not received the seasons flu vaccine or RZV
–Subjects enrolled at Duke University Medical Center (Lead Site) and
Johns Hopkins University (Contributing Site) during the 2021 -2022
and 2022- 2023 flu seasons
•Intervention:
–Randomized 1:1 to receive either <RZV and aIIV4> or <RZV and HD -
IIV4*>
•Study visit schedule (summary):
–Day 1: receive RZV dose 1 and influenza vaccine simultaneously
–Day 60:receive RZV dose 2
–Day 103:complete study
–Safety outcomes collected throughout study; blood collected for influenza immunogenicity assessment (lab analysis not completed)
5*quadrivalent high- dose inactivated influenza vaccine (Fluzone High -dose Quadrivalent)
Analysis Populations
6Intention -to-Treat (ITT) Population: defined as all
subjects who are randomized and vaccinated (received at
least one study vaccine).
Modified Intention- to-Treat ( mITT ) Population: defined
as all subjects who are randomized, vaccinated (received at
least one study vaccine), and provide at least one day of
complete data on the symptom diary.
Consort Diagram
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Demographic Summary
8Characteristic Fluzone -HD (n=137) FLUAD (n=130) Total (N= 267)
Gender
Male
Female 68 (49.6%)
69 (50.4%)69 (53.1%)61 (46.9%)137 (51.3%)130 (48.7%)
Race
White Only
Black Only
Other124 (90.5%)
12 (8.8%)
1 (0.7%)123 (94.6%)
7 (5.4%)0 (0.0%) 247 (92.5%)
19 (7.12%)
1 (0.37%)
Ethnicity
Hispanic or Latino
Non -Hispanic or Latino
Unknown1 (0.7%)
134 (97.8%)
2 (1.5%)2 (1.5%)
128 (98.5%)
0 (0.0%)3 (1.12%)
262 (98.1%)
2 (0.75%)
Age
65-69
70 or more48 (35%)89 (65%)44 (33.8%)86 (66.2%)92 (34.5%)
175 (65.5%)
PO1: To compare the proportion of participants
with at least one severe (Grade 3) solicited local or systemic reactogenicity event after RZV dose 1 in the RZV and aIIV4 group versus RZV and HD- IIV4
group.
Hypothesis: The proportion of participants with at
least one severe (Grade 3) solicited reactogenicity event will be noninferior (not higher) in the RZV and aIIV4 group compared with the RZV and HD -
IIV4 group. Primary Objective
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Outcome : Proportion of participants with at least one
severe (Grade 3) solicited local or systemic
reactogenicity event on days 1- 8 after RZV dose 1 in
each study group
*Met noninferiority objective with a 10% noninferiority margin, the upper bound is
less than 10%. The confidence interval contains 0, so there is no claim of superiority. Primary Outcome: mITT Population
101+ Grade 3 Event
No Yes Noninferiority Test 10% Margin
Group N % N % Diff Lower CI Upper CI p-value
FLUAD 115 88.46 15 11.54 . . . .
Fluzone -HD 119 87.50 17 12.50 -0.0096 -0.0894 0.0710 0.0037
Secondary Objectives
•SO1: To compare the proportion of participants with at
least one severe (Grade 3) solicited local reactogenicity
event after RZV dose 1 in the RZV and aIIV4 group vs. RZV
dose 1 and HD -IIV4 group (non -inferiority analysis)
•SO2: To compare the proportion of participants with at
least one severe (Grade 3) solicited systemic reactogenicity
event after RZV dose 1 in the RZV and aIIV4 group vs. RZV
dose 1 and HD -IIV4 group (non -inferiority analysis)
•SO3: To compare the proportion of participants with at
least one serious adverse event or adverse event of clinical
interest after RZV dose 1 in the RZV and aIIV4 group vs.
RZV dose 1 and HD -IIV4 group through Day 43 and
describe these events (95% confidence interval (CI)
comparison)
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SO1: Proportion of participants with at least one severe (grade 3)
solicited local reactogenicity event on days 1 -8 after RZV dose 1 in
each study groupSecondary Outcome SO1:mITT Population
121+ Grade 3 Event
No Yes Noninferiority Test 10% Margin
Group N % N % Diff Lower CI Upper CI p-value
FLUAD 122 93.85 8 6.15 . . . .
Fluzone -HD 130 95.59 6 4.41 0.0174 -0.0404 0.0777 0.0031
*Met noninferiority objective with a 10% noninferiority margin, the upper bound is
less than 10%. The confidence interval contains 0, so there is no claim of superiority.
SO2: Proportion of participants with at least one severe (grade 3)
solicited systemic reactogenicity event on days 1 -8 after RZV dose
1 in each study group
*Met noninferiority objective with a 10% noninferiority margin, the upper bound is
less than 10%. The confidence interval contains 0, so there is no claim of superiority Secondary Outcome SO2:mITT Population
131+ Grade 3 Event
No Yes Noninferiority Test 10% Margin
Group N % N % Diff Lower CI Upper CI p-value
FLUAD 123 94.62 7 5.38 . . . .
Fluzone -HD 123 90.44 13 9.56 -0.0417 -0.1090 0.0247 <.0001
020406080100
aIIV4 HD-IIV4 aIIV4 HD-IIV4 aIIV4 HD-IIV4 aIIV4 HD-IIV4 aIIV4 HD-IIV4 aIIV4 HD-IIV4
Pain Swelling Redness Pain Swelling RednessPercent
----------------- RZV Vaccine ----------------- ----------------- Flu Vaccine -------------- ---
Solicited Event and GroupLocal Reactions: RZV Dose 1 and Influenza Vaccines
Mild Moderate Severe
No significant differences in proportion of moderate/severe local reactogenicity events between aIIV4 and HD- IIV4 groups
020406080100
aIIV4 HD-IIV4 aIIV4 HD-IIV4 aIIV4 HD-IIV4 aIIV4 HD-IIV4 aIIV4 HD-IIV4 aIIV4 HD-IIV4 aIIV4 HD-IIV4 aIIV4 HD-IIV4 aIIV4 HD-IIV4 aIIV4 HD-IIV4
Fever Chills Fatigue Myalgia Headache Arthralgia Nausea Vomiting Diarrhea Abdominal PainPercent
Solicited Event and GroupSystemic Reactions: RZV Dose 1 and Influenza Vaccines
Mild Moderate Severe
No significant differences in proportion of moderate/severe systemic reactogenicity events between aIIV4 and HD- IIV4 groups
SO3: Proportion of participants with at least one serious
adverse event or adverse event of clinical interest after RZV
dose 1 within 43 days. Secondary Outcome SO3: ITT Population
Subjects with at Least One Serious Adverse
Event (SAE) Within 43 Days
16At Least One Serious Adverse Event Within
43 Days
No Yes Percent YesFLUAD -Fluzone -HD
95% CI of the Difference
Group N % N % 95% CI 95% CI
FLUAD 129 99.23 1 0.77 (0.02, 4.21)
Fluzone -HD 132 96.35 5 3.65 (1.20, 8.31) -2.88 ( -6.36, 0.60)•6 Subjects reported at least one SAE within 43 Days
•9 subjects reported at least one SAE during study period ITT Population
All Subjects with at Least One Serious
Adverse Event through Entire Study Period
17At Least One Serious Adverse Event
No Yes Percent YesFLUAD -Fluzone -HD
95% CI of the Difference
Group N % N % 95% CI 95% CI
FLUAD 126 96.92 4 3.08 (0.84, 7.69)
Fluzone -HD 132 96.35 5 3.65 (1.20, 8.31) -0.57 ( -4.89, 3.75)
Summary of SAEs within 43 days of RZV dose 1 and
influenza vaccination*
18Group Age group
yearsRelatedness Clinical description
aIIV4 ≥70 Not related Pacemaker due to arrhythmia
HD-IIV4 65-69 Not related Numbness, Cerebrovascular
accident (CVA)
HD-IIV4 ≥70 Not related Acute hyperkalemia
HD-IIV4 ≥70 Not related Shortness of breath
HD-IIV4 ≥70 Not related Acute pulmonary embolism and
acute deep vein thrombosis
HD-IIV4 65-69 Possibly related Left partial cranial
nerve III palsy
*All participants with SAE required hospitalization or had prolongation of hospitalization; no deaths
19*All participants with SAE required hospitalization or had prolongation of hospitalization; no deathsSummary of SAEs >43 days of RZV dose 1 and
influenza vaccination *
Group Age group
yearsRelatedness Clinical description
aIIV4 ≥70 Not related Heptocellular carcinoma
aIIV4 ≥70 Not related Revision of right shoulder rotator
cuff surgery
aIIV4 65-69 Not related Chronic obstructive pulmonary diseases (COPD) exacerbation
Safety Assessments: Adverse Events
•Pre-specified Adverse Events of Special
Interest (AESI)
–Syncope during the post -vaccination
monitoring period in clinic: none
–Anaphylaxis in the first 24 hours after
immunization: none
–New-onset immune -mediated disease during
42 days after vaccination: one case of partial cranial nerve III palsy (also considered an SAE): patient was in the HD- IIV4 group
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Exploratory Objective
•Objective : To describe and compare changes in health- related quality of life
after RZV dose 1 and aIIV4 with RZV dose 1 and HD -IIV4
21Average EQ-5D-5L Index by Treatment Group
0.00.10.20.30.40.50.60.70.80.91.0
Days After RZV Dose 1PreVax 1 2 3 4 5 6 7 8Plot of Average EQ-5D-5L Index by Treatment Group per Day
All Subjects and Any Grade 3 Reactogenicity Event After RZV Dose 1: N=32
FLUAD: All Subjects FLUAD: N=32 Subjects
Fluzone-HD: All Subjects Fluzone-HD: N=32 Subjects
Average Visual Analogue Scale (VAS) by Treatment Group0.0 10 20 30 40 50 60 70 80 90100
Days After RZV Dose 1PreVax 1 2 3 4 5 6 7 8Plot of Average Visual Analogue Scale (VAS) by Treatment Group per Day
All Subjects and Any Grade 3 Reactogenicity Event After RZV Dose 1: N=32
FLUAD: All Subjects FLUAD: N=32 Subjects
Fluzone-HD: All Subjects Fluzone-HD: N=32 Subjects
Limitations
•Enrollment limited by COVID -19
pandemic; enrolled ~70% of target
•Study population mostly white, non-
Hispanic
•Study too small to detect rare
adverse events
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Conclusion
•The proportion of participants with at least one severe
local or systemic reaction was not higher after RZV dose 1 and aIIV4 (11.5%) compared to RZV dose 1 and HD -IIV4 (12.5%)
•The frequency of moderate-severe local and systemic reactogenicity events were similar when RZV dose 1 was administered with aIIV4 or HD -IIV4
•Few participants had serious adverse events during the study after RZV dose 1 was administered with aIIV4 (3.1%) or HD -IIV4 (3.7%); the clinical
conditions were those expected in a population of
older adults
•From a safety standpoint, this study supports
simultaneous administration of RZV and aIIV4 as an acceptable option for vaccine delivery in older adults
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Extra Slides
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Serious Adverse Event Definition
•An SAE is defined as an adverse event that results in
one of the following:
–Death
–Is life threatening
–Hospitalization or prolongation of existing
hospitalization
–Persistent or significant disability/incapacity
–Important medical events that may jeopardize the subject's health and may require medical or surgical intervention to prevent one of the other outcomes listed in this (SAE) definition
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Injection Site Reactions Grading
26Injection- site Reactogenicity
Symptom Mild (Grade 1) Moderate (Grade 2) Severe (Grade 3)
Pain Any pain neither interfering with
nor preventing normal every
day activities.Painful when limb is moved and
interferes with every day
activities.Significant pain at rest.
Prevents
normal every day activities.
Induration/
Swelling≥20 mm to ≤50 mm diameter > 50 mm to ≤ 100 mm diameter > 100 mm diameter
Erythema
(Redness)≥20 mm to ≤50 mm diameter > 50 mm to ≤ 100 mm diameter > 100 mm diameter
Systemic Reactions Grading
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EQ-5D-5L and VAS
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Subject Inclusion Criteria
•Male or female age ≥ 65 years
•Intention of receiving IIV and RZV based on ACIP-
CDC guidelines
•Able to speak English
•Willing to provide written informed consent
•Living in the community
•Intention of being available for entire study period and complete all relevant study procedures, including follow -up phone calls and clinic visits.
•If HIV positive, HIV should be clinically stable
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Subject Exclusion Criteria
•IIV or recombinant influenza vaccine (RIV) receipt during the respective 2021 -2022 or 2022 -2023 influenza
season prior to study enrollment
•Prior receipt of recombinant zoster vaccine ( Shingrix )
•For non -COVID -19 Vaccines:
–Receipt of any inactivated vaccine within 2 weeks prior to enrollment in this study
–Receipt of any live vaccine within 4 weeks prior to enrollment in this study
–Planning receipt of any non -COVID -19 vaccine during the entire period
•For COVID -19 Vaccines:
–Receipt of COVID -19 vaccine within 2 weeks prior to enrollment in this study. For those who have initiated a
COVID -19 vaccine series, enrollment is not allowed until 2 weeks after the final dose of a COVID -19 vaccine is
completed.
–Planning receipt of a COVID -19 vaccine within 2 weeks after administration of study influenza and first dose
recombinant zoster study vaccines.
•Have acute illness or exacerbation of chronic illness within 72 hours of study vaccination
•Hospitalization within the last 30 days for any reason
•History of febrile illness (> 100.0 °F or 37.8 °C) within the past 24 hours prior to IIV administration
•Has immunosuppression as a result of an underlying illness or treatment, or use of chemotherapy or radiation
therapy within the preceding 12 months
•Has an active neoplastic disease (excluding non- melanoma skin cancer or prostate cancer that is stable in the
absence of therapy) *Participants with a history of malignancy may be included if, after previous treatment by surgical excision, chemotherapy or radiation therapy, the participant has been observed for a period that in the investigator’s estimation provides a reasonable assurance of sustained cure
•A history of autoimmune disease, that requires immunosuppressive agents or any other chronic medical condition considered clinically significant by the investigator
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Subject Exclusion Criteria
•Use of chronic oral or intravenous administration (≥14 days) of immunosuppressive doses of
steroids, i.e., prednisone >10 mg per day, immunosuppressants or other immune-modifying
drugs within 30 days of starting this study. (Use of topical, nasal, or inhaled steroids is permitted)
•Thrombocytopenia, bleeding disorder, or anticoagulant use contraindicating intramuscular injection (a daily aspirin may be acceptable)
•Contraindication to IIV receipt including history of severe allergic reaction after a previous dose of any influenza vaccine; or to a vaccine component, including egg protein
•Contraindication to RZV including history of a severe allergic reaction to any component of the RZV vaccine (including saponin or polysorbate 80) or to dose 2 of RZV
•History of Guillain -Barré syndrome
•History of Hepatitis C or active Hepatitis B
•Receipt of blood or blood -derived products (including immunoglobulin) within 6 months prior
to study vaccination
•Dementia, any cognitive condition, or substance abuse that could interfere with study compliance
•Anyone who is already enrolled or plans to enroll in another clinical trial with an investigational product within 28 days of vaccine receipt. Co -enrollment in observational or
behavioral intervention studies are allowed at any time while enrollment in a clinical trial involving an investigational product (other than vaccine) may occur after 28 days following vaccine receipt
•Any condition which, in the opinion of the investigators, may pose a health risk to the subject or interfere with the evaluation of the study objectives
•Anyone who is a relative of any research study personnel
•Anyone who is an employee of any research study personnel
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