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, MD

Study 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) 

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*quadrivalent high-dose inactivated influenza vaccine (Fluzone High-dose Quadrivalent)
Analysis Populations

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Intention-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 

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Characteristic 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 

Other

124 (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

Unknown

1 (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 more

48 (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 HDIIV4 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

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1+ 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 group

Secondary Outcome SO1:mITT Population

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1+ 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

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1+ 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
0

20

40

60

80

100

aIIV4 HD-IIV4 aIIV4 HD-IIV4 aIIV4 HD-IIV4 aIIV4 HD-IIV4 aIIV4 HD-IIV4 aIIV4 HD-IIV4

Pain Swelling Redness Pain Swelling Redness

Percent

----------------- RZV Vaccine ----------------- ----------------- Flu Vaccine -----------------

Solicited Event and Group

Local 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 
0

20

40

60

80

100

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 Pain

Percent

Solicited Event and Group

Systemic 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

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At Least One Serious Adverse Event Within 

43 Days 

No Yes Percent Yes

FLUAD-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 

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At Least One Serious Adverse Event

No Yes Percent Yes

FLUAD-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* 

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Group Age group 

years

Relatedness 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
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*All participants with SAE required hospitalization or had prolongation of hospitalization; no deaths

Summary of SAEs >43 days of RZV dose 1 and 

influenza vaccination * 

Group Age group 

years

Relatedness 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

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Average EQ-5D-5L Index by Treatment Group

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Days After RZV Dose 1

PreVax 1 2 3 4 5 6 7 8

Plot 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 Group

0.0

 10

 20

 30

 40

 50

 60

 70

 80

 90

100

Days After RZV Dose 1

PreVax 1 2 3 4 5 6 7 8

Plot 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, nonHispanic 

• 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

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Injection-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 ACIPCDC 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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