04 Influenza Walter 508

Safety of Simultaneous versus Sequential
Administration of mRNA COVID -19 and
Quadrivalent Inactivated Influenza (IIV4)
Vaccines: A Randomized Placebo Controlled Trial
(ClinicalTrials.gov ID: NCT05028361)
Emmanuel “Chip” Walter MD, MPH
ACIP October 25, 2023
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
2
Study Rationale
•Influenza and COVID -19 vaccines are recommended
for persons 6 months of age and older to prevent
illness and complications resulting from these infections.
*
•Available data support the simultaneous administration of these vaccines as currently ACIP recommended.
•However, there are limited data from placebo-controlled studies (none from the US) evaluating the safety of simultaneous administration of influenza and mRNA COVID -19 vaccines.
3*Clinical Guidance for COVID- 19 Vaccination | CDC and Prevention and Control of Seasonal Influenza with Vaccines: Recommendations
of the Advisory Committee on Immunization Practices —United States, 2023– 24 Influenza Season | MMWR (cdc.gov)
Design, Population, Recruitment
•Design : prospective, randomized,
placebo -controlled, observer -blind
study
•Population : non- pregnant persons aged
≥5 years if receiving primary two -dose
mRNA COVID -19 vaccine series or
persons aged ≥12 years if receiving a
booster mRNA COVID -19 vaccine dose
and intending to receive a quadrivalent
inactivated influenza vaccine (IIV4)*
•Recruitment : 3 CISA sites –Duke
University, Cincinnati Children’s Hospital Medical Center (CCHMC), and John Hopkins University (JHU) during
the 2021- 2022 and 2022- 2023
influenza seasons
4
SimultaneousSequentiala
*Persons ≥65 years received High -Dose IIV4 (Fluzone High -Dose Quadrivalent); those <65 years received standard dose IIV4 (FluLaval or Fluzone Quadrivalent)
Study Aims and Objectives:
Primary objective : To compare the proportion of participants with
moderate or more severe fever, chills, myalgia, or arthralgia (RE)*
in the group receiving IIV4 simultaneously with mRNA COVID -19
vaccine at Vaccination Visit  1 (Simultaneous group) with the group receiving IIV4 alone one to two weeks later at Vaccination Visit 2
(Sequential group) following both Vaccination Visit 1 and 2
–Primary outcome: considered present if participant has at least one of
the RE symptoms on at least one day during days 1 to 7 following Visit 1 and/or Visit 2
Hypothesis :  The proportion of participants with moderate or more
severe fever, chills, myalgia or arthralgia will be non -inferior (not
higher) in the Simultaneous group versus the Sequential group
5*RE: reactogenicity event
Secondary Objectives
•To compare the proportion of participants with RE in the
Simultaneous group versus the Sequential group following Vaccination Visit 1 and 2 separately
•To describe the proportions of participants in each group with solicited local and systemic reactogenicity events according to
severity grade after vaccination visits
•To describe the proportions of participants in each group experiencing at least one serious adverse event and a description of these events
6
Study Aims and Objectives:
Exploratory Objectives
•To further characterize and describe the proportion of participants
in each group with local or systemic reactogenicity events of
greater severity
•To describe the proportion of participants each group experiencing at least one unsolicited adverse event and one adverse event of special interest and to characterize these events
•To compare the change of health -related quality of life (HRQOL)
from baseline in both groups following the Vaccination Visit 1
7
Study Procedures Summary
•After randomization (1:1) to either the simultaneous or
sequential group and a baseline blood draw, participants
received study influenza vaccine or placebo according to
assignment
•Solicited Reactogenicity: Days 1 -7* after V1, V2, V3a
•Unsolicited Adverse Events: Days 1 -7 after V1, V2, V3a
•Health -Related Quality of Life (HRQOL): Days 1 -7 after V1
only
•Adverse Events of Special Interest (AESIs): Days 1 -121
•Serious Adverse Events (SAEs): Days 1 -121
•Blood draws for immunogenicity: baseline and post -
vaccination (data not yet available)
8 *Day 1 is the vaccination day
Statistical Methods
•Full Analysis Population 2
–All randomized and vaccinated participants
–Participant characteristics and adverse event outcomes
•Full Analysis Population 1
–All participants who are randomized, vaccinated, and provide at least one day of complete data on the
symptom diary
–Reactogenicity outcomes
•Statistical Testing
–Primary outcome was conducted at the one -sided alpha 0.025 level using the upper bound of a stratified by site
Newcombe binomial confidence interval with Cochran -Mantel -Haenszel (CMH) weighting of the difference with
a noninferiority margin of 10%.
–Comparisons of proportions between the simultaneous and sequential groups used an exact Mantel -Haenszel
statistic in a stratified analysis by site to control for the randomization blocks at the two- sided alpha 0.05 level.
Study site adjusted odds ratios and corresponding 95% confidence intervals for proportions were also calculated.
–The changes in HRQOL after Visit 1 were evaluated using Mann -Whitney U tests. For the HRQOL comparisons
we used a two- sided alpha at the 0.05 level.
–Summary statistics were used to describe REs, AEs, SAEs and AESIs.  95% confidence intervals of the difference between vaccination groups were calculated.
9
Study Consort Diagram
10

Demographics / Enrollment Site
Characteristic Simultaneous (n=169) Sequential (n=166) Total (N=335)
Sex:             Female 96 (56.8%) 115 (69.3%) 211 (63.0%)
Male 73 (43.2%) 51 (30.7%) 124 (37.0%)
Race:          White Only 123 (72.8%) 113 (68.1%) 236  (70.4%)
Black Only 31 (18.3%) 33(19.9%) 64 (19.1%)
Other 15 (8.9%) 20 (12.0%) 35 (10.4%)
Ethnicity: Hispanic 12 (7.1%) 9 (5.4%) 21 (6.3%)
Age (yrs):   5 to <12 4 (2.4%) 2 (1.2%) 6 (1.8%)
12 to <18 11 (6.5%) 13 (7.8%) 24 (7.2%)
18to <65 146 (86.4%) 143 (86.1%) 289 (86.3%)
>=65 8 (4.7%) 8 (4.8%) 16 (4.8%)
Site:           CCHMC 67 (39.6%) 63 (38.0%) 130 (38.8%)
Duke 79 (46.7%) 81 (48.8%) 160 (47.8%)
JHU 23 (13.6%) 22 (13.3%) 45 (13.4%)
11
Season, COVID -19 Vaccine Received,
Vaccination and COVID -19 History
Characteristic Simultaneous (n=169) Sequential (n=166) Total (N=335)
Season:     2021- 2022 37 (21.9%) 36 (21.7%) 73 (21.8%)
2022- 2023 132 (78.1%) 130 (78.3%) 262 (78.2%)
COVID -19 Vaccine Brand:
Pfizer -BioNTech Monovalent 34 (20.1%) 35(21.1%) 69(20.6%)
Pfizer -BioNTech Bivalent 130 (76.9%) 125 (75.3%) 255 (76.1%)
Moderna  Monovalent 4   (2.4%) 4 (2.4%) 8 (2.4%)
Moderna Bivalent 1   (0.6%) 2 (1.2%) 3 (0.9%)
Prior COVID -19 Vaccine
Yes 165 (97.6%) 166 (100.0%) 331 (98.8%)
Prior COVID -19 and/or
+ nucleocapsid ab
Yes 96 (56.8%) 95 (57.2%) 191 (57.0%)
12
Primary Outcome
Proportions with moderate or more severe fever, chills, myalgia, or arthralgia
(RE) in participants in sequential versus simultaneous group
13Moderate or more severe fever, chills, myalgia,  or arthralgia following Visit 1 and/or Visit 2
No Yes Non -inferiority Test 10% Margin*
Group N % N % Diff Lower
95% CIUpper
95% CIp-value
Simultaneous 125 74.40 43 25.60
Sequential 114 68.67 52 31.33 -0.0563 -0.1517 0.0404 0.0007
Ho: Sim-Seq≥ 0.10 (10%)
Conclusion: The rate of moderate or more server fever, chills, myalgia, or
arthralgia in simultaneous group is considered not worse/not higher than
the rate in sequential group and the noninferiority criteria was met. The
upper limit of the 95% confidence interval (CI) of the difference for Sim
minus Seq was 4.0% and the noninferiority margin was 10%; therefore, the
null hypothesis of inferiority was rejected . *Site -stratified Newcombe binomial confidence interval with Cochran -Mantel -Haenszel (CMH) weighting of the difference
Objective :  To compare the proportion of participants with
moderate or more severe fever, chills, myalgia, or arthralgia in the
Simultaneous versus the Sequential Group following the first
vaccination visitSecondary Objective
14Moderate or more severe fever, chills, myalgia,  or arthralgia following Visit 1
No Yes
Group N % N % Odds Ratio (95%CI) p-value*
Simultaneous 128 76.19 40 23.81
Sequential 119 71.69 47 28.31 0.80 (0.49, 1.30) 0.3851
*Exact Mantel -Haenszel statistic in a stratified analysis by site
Objective :  To compare the proportion of participants with
moderate or more severe fever, chills, myalgia, or arthralgia in the
Simultaneous versus the Sequential Group following the second
vaccination visitSecondary Objective
15Moderate or more severe fever, chills, myalgia,  or arthralgia following Visit 2
No Yes
Group N % N % Odds Ratio (95%CI) p-value*
Simultaneous 163 97.02 5 2.98
Sequential 157 94.58 9 5.42 0.54 (0.18, 1.63) 0.2886
*Exact Mantel -Haenszel statistic in a stratified analysis by site
Percent With Injection Site Reaction
Visit 1
16More ≥ moderate pain in simultaneous group* More ≥ moderate pain and swelling in sequential group*
*95% CI of difference in proportions between  does not contain zero020406080100
 Sim Seq Sim Seq Sim Seq Sim Seq
Pain Swelling Erythema Axillary Swelling
and TendernessPercent
Solicited Event and GroupInjection Site Reactions Visit 1
COVID -19 Vaccine
Mild Moderate Severe Life Threatening020406080100
Sim Seq Sim Seq Sim Seq Sim Seq
Pain* Swelling Erythema Axillary Swelling
and Tenderness*Percent
Solicited Event and GroupInjection Site Reactions Visit 1
Influenza Vaccine or Placebo
Mild Moderate Severe Life Threatening*95% CI of difference does not contain zero
*95% CI of difference in proportions between  does not contain zero
17Percent With Injection Site Reaction
Visit 2
More ≥ moderate pain and axillary swelling/ tenderness in sequential group*
*95% CI of difference in proportions between  does not contain zero020406080100
Sim Seq Sim Seq Sim Seq Sim Seq
Pain* Swelling* Erythema Axillary Swelling and
Tenderness*Percent
Solicited Event and GroupInjection Site Reactions Visit 2
Influenza Vaccine or Placebo
Mild Moderate Severe Life Threatening*95% CI of difference does not contain zero
18Percent With Systemic  Reaction
Visit 1
No differences in ≥ moderate systemic symptoms020406080100
Sim Seq Sim Seq Sim Seq Sim Seq Sim Seq Sim Seq Sim Seq Sim Seq
Fever Chills Fatigue Myalgia Headache Arthralgia Nausea &
VomitingDiarrheaPercent
Solicited Event and GroupSystemic Reactions Visit 1
Mild Moderate Severe Life Threatening
19Percent  With Systemic  Reaction
Visit 2
No differences in ≥ moderate systemic symptoms020406080100
Sim Seq Sim Seq Sim Seq Sim Seq Sim Seq Sim Seq Sim Seq Sim Seq
Fever Chills* Fatigue* Myalgia* Headache Arthralgia Nausea &
VomitingDiarrhea*Percent
Solicited Event and GroupSystemic Reactions Visit 2
Mild Moderate Severe Life Threatening*95% CI of difference does not contain zero
Objective : To describe the proportions of participants in the
Simultaneous and Sequential vaccination groups experiencing at
least one serious adverse event and a description of these
eventsSecondary Objective
20At  Least One Serious Adverse Event
No Yes
Group N % N % Difference (Sim -Seq)(95%CI)
Simultaneous 168 99.41 1 0.59
Sequential 165 99.40 1 0.60 -0.01 ( -1.66, 1.64)
SAE Descriptions
21Group Vaccine Onset
since Visit
1 Sex Age groupCategory Relatedness Description
Sequential Pfizer -BioNTech
Bivalent14 days Female 50-64 Hospitalization/
prolongation of
existing hospitalizationUnlikely related Small bowl obstruction with
incarcerated ventral herniaPast medical history (PMH): abdominal surgeries and cancer
Simultaneous Pfizer -BioNTech
Monovalent19  Weeks Female 18-49
years Other importantmedical eventNot related Spontaneous abortion occurring at
16 weeks gestation PMH: COVID -19 illness (mild) 9
weeks after visit 1; (Note: Participant did not report being pregnant or intention of becoming pregnant at enrollment)
•Objective : To describe the proportion of participants in Simultaneous and
Sequential groups experiencing at least one unsolicited adverse event
and one adverse event of special interest and to characterize these eventsExploratory Objective
22At  Least One Unsolicited Adverse Event within 7 Days of a Vaccination Visit (Preliminary)
No Yes Percent Yes
Group N % N % 95% CI Difference (Sim -Seq)
(95%CI)
Simultaneous 148 87.57 21 12.43 (7.86, 18.37)
Sequential 150 90.36 16 9.64 (5.61, 15.18) 2.79 ( -3.91, 9.49)
•AEs within 7 days of vaccine (n=45)
–29 simultaneous group in 21 participants (3 possibly related)
–16 sequential group in 16 participants (1 related, 2 possibly related)
•Objective : To describe the proportion of participants in Simultaneous and
Sequential groups experiencing at least one unsolicited adverse event and one
adverse event of special interest and to characterize these eventsExploratory Objective
23At  Least One Adverse Event of Special Interest
No Yes Percent Yes
Group N % N % 95% CI Difference (Sim -Seq)
(95%CI)
Simultaneous 150 88.76 19 11.24 (6.91, 17.00)
Sequential 157 94.58 9 5.42 (2.51, 10.04) 5.82 ( -0.06, 11.70)
•AESIs (n=28)
–29 COVID -19 illnesses (unrelated): Sim Group* (n=18) SeqGroup* (n=9)
–1 allergic type reaction (possibly related): Sim Group (n=1)
*One person in each group reported 2 COVID -19 illness events
Exploratory Objective
•Objective : To compare the change of health -related quality of life (HRQOL) from
baseline in the Simultaneous versus Sequential groups following the Vaccination
Visit 1
24

Limitations
•Most data come from use of bivalent Pfizer -BioNTech
mRNA COVID -19 vaccine during one season
–Very little use of Moderna mRNA vaccine
•Very few children ages 5- 11 years and older adults
≥65 years enrolled
•Enrollment limited by COVID -19 pandemic; enrolled
~70% of target
•Study too small to detect rare adverse events
•People known to be pregnant not included; a future
CISA study assessing safety of simultaneous influenza and COVID -19 vaccines during pregnancy is planned
25
Summary
•Simultaneous administration of influenza and mRNA COVID -19 vaccines is well tolerated
when compared to sequential administration
–Occurrence of moderate or more severe fever, chills, myalgia, or arthralgia was not
higher in the simultaneous (25.6%) vs. sequential (31.3%) group
–No significant differences in occurrence of adverse events within 7 days, adverse events of special interest, serious adverse events, and HRQOL
•As previously observed in other studies injection site and systemic reactions were associated with mRNA COVID -19 vaccine and influenza vaccine; most reactions were mild
or moderate
–Most frequent injection site reactions after either vaccine were pain and axillary swelling/tenderness
–Most frequent systemic reactions after COVID -19 vaccine, with or without influenza vaccine, were fatigue,
myalgia, headache, chills and arthralgia
–Receipt of influenza vaccine alone was associated chills, fatigue, myalgia and diarrhea
26
Acknowledgements
•Duke University (Duke)
–Principal Investigator: Emmanuel B. Walter, MD, MPH
–Investigators: Ken Schmader MD,  Wes Rountree , MPH , Marek S. Poniewierski MD, MS ,
Rachel L. Spreng PhD
•John Hopkins University (JHU)
–Principal Investigator: Kawsar Talaat, MD
•Cincinnati Children’s Hospital Medical Center (CCHMC)
–Principal Investigator: Elizabeth Schlaudecker, MD, MPH
–Investigator: Mary Staat, MD, MPH
•CDC
–Principal Investigator: Karen Broder, MD
–Investigators: Jonathan Duffy, MD, MPH, Oidda Museru MSN, MPH, Lisa A. Grohskopf
MD, MPH, Anju Goel MD, MPH (contractor)
27
Extra Slides
28
Serious Adverse Event (SAE) Definition
•An SAE is defined as an AE that meets one of the following conditions:
–Results in death during the period of protocol -defined surveillance
–Is life -threatening (defined as immediate risk of death at the time of the event)
–Requires inpatient hospitalization or prolonged hospitalization during the period of
protocol -defined surveillance
–Results in congenital anomaly or birth defect
–Results in a persistent or significant disability/incapacity
–Any other important medical event that may not result in death, be life threatening, or require hospitalization, may be considered an SAE when, based upon appropriate medical judgment, the event may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed above. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in
inpatient hospitalization, or the development of drug dependency or drug abuse.
29
Adverse Event of Special Interest (AESI)
Definition
•An AESI includes the following:
–COVID -19 illness
–Multisystem inflammatory syndrome
–Guillain -Barre syndrome
–Allergic type reactions (including anaphylaxis, hives, or facial
and limb swelling occurring within 7 days of a vaccination visit)
–Myocarditis or pericarditis
30
Injection Site Reactions Grading
31Table 8. Injection-site Reactogenicity Grading
Local Reaction to
Injectable Product Mild (Grade 1) Moderate (Grade 2) Severe (Grade 3) Potentially Life Threatening (Grade 4)
Pain
Noticeable but does
not interfere with
activityInterferes with activity
but did not need a
medical visit or
absenteeism [i.e.
missing work or
school]Significant; prevents
daily activity and/or
resulted in medical visit
and/or absenteeism [i.e.
missing work or school]Requires an emergency room (ER)
visit or hospitalization
Induration/Swelling
(≥ 12 years of age)2.5 –5 cm 5.1 –10 cm > 10 cmRequires an emergency room (ER)
visit or hospitalization
Induration/Swelling(< 12 years of age)0.5 –2 cm 2.0 -7.0 cm > 7 cmRequires an emergency room (ER)
visit or hospitalization
Erythema/Redness(≥ 12 years of age)2.5 –5 cm 5.1 –10 cm > 10 cmRequires an emergency room (ER)
visit or hospitalization
Erythema/Redness(< 12 years of age) 0.5 –2 cm 2.0 -7.0 cm > 7 cmRequires an emergency room (ER)
visit or hospitalization
Axillary (underarm)
swelling or tenderness ipsilateral to side of injection Noticeable but does
not interfere with
activityInterferes with activity
but did not need a
medical visit or
absenteeism [i.e.
missing work or
school]Significant; prevents
daily activity and/or
resulted in medical visit
and/or absenteeism [i.e.
missing work or school] Requires an emergency room (ER)
visit or hospitalization
Systemic Reactions Grading
32Table 9. Systemic Reactogenicity Grading (FDA modified)
Systemic Mild (Grade 1) Moderate (Grade 2) Severe (Grade 3)Potentially Life Threatening
(Grade 4)
Fever (°C)
(°F)38.0 -38.4
100.4 -101.1  38.5 -38.9
101.2 -102.0 39.0 –40.0
102.1- 104.0> 40.0
>104.0
Nausea/vomitingNoticeable but does not interfere
with activity or 1 –2 episodes/24
hoursSome interference with activity or
> 2 episodes/24 hoursSignificant; prevents daily activity and/or resulted in medical visit
and/or absenteeism [i.e. missing work or school]Requires an ER visit or
hospitalization
DiarrheaNoticeable but does not interfere
with activity or 2 –3 loose stools/24
hoursSome interference with activity or
4-5 loose stools/24 hoursSignificant; prevents daily activity
and/or resulted in medical visit
and/or absenteeism [i.e. missing work or school] or 6 or more watery stools or > 24 hoursRequires an ER visit or
hospitalization
HeadacheNoticeable but does not interfere
with activitySome interference with activity but did not need a medical visit or absenteeism [i.e. missing work or school]Significant; prevents daily routine
activity and/or resulted in medical
visit and/or absenteeism [i.e. missing work or school]Requires an ER visit or hospitalization
FatigueNoticeable but does not interfere
with activit ySome interference with activity but
did not need a medical visit or
absenteeism [i.e. missing work or
school]Significant; prevents daily routine
activity and/or resulted in medical
visit and/or absenteeism [i.e. missing work or school]Requires an ER visit or
hospitalization
Myalgia Noticeable but does not interfere
with activitySome interference with activity but
did not need a medical visit or
absenteeism [i.e. missing work or school]Significant; prevents daily routine
activity and/or resulted in medical
visit and/or absenteeism [i.e. missing work or school]Requires an ER visit or
hospitalization
ArthralgiaNoticeable but does not interfere
with activitySome interference with activity but
did not need a medical visit or
absenteeism [i.e. missing work or
school]Significant; prevents daily routine
activity and/or resulted in medical
visit and/or absenteeism [i.e. missing work or school]Requires an ER visit or
hospitalization
Chills Noticeable but does not interfere
with activitySome interference with activity but
did not need a medical visit or
absenteeism [i.e. missing work or
school] Significant; prevents daily routine
activity and/or resulted in medical
visit and/or absenteeism [i.e. missing work or school]Requires an ER visit or
hospitalization
EQ-5D-5L and VAS
33

Subject Inclusion Criteria
•Persons aged ≥5 years if receiving primary two -dose mRNA COVID -19
vaccine series or persons aged ≥12 years if receiving a booster mRNA
COVID -19 vaccine dose according to FDA authorization or approval and
ACIP recommendation. Note: receipt of an mRNA COVID -19 vaccine
within 8 hours of enrollment is permitted
* Individuals age 5 -11 receiving a booster may be enrolled in the event a
booster for individuals age 5 -11 is authorized or approved and recommended by
the ACIP.
•English or Spanish literate
•Intention of receiving influenza vaccine and mRNA COVID -19 vaccine
based on ACIP -CDC guidelines
•Willing to provide written informed consent
•Intention of being available for entire study period and complete all relevant study procedures, including follow -up phone calls and clinic visits
34
Subject Exclusion Criteria
•Currently pregnant, planning to become pregnant within the first three months of the study per
participant self -report or likely to be pregnant per screening criteria as defined in protocol at Visit 1
•Prior receipt of IIV4 during the respective influenza season in which they are being enrolled
•< 9 years of age and recommended to receive two doses of IIV4 during the respective influenza season in which they are being enrolled
•Prior receipt of non -mRNA COVID -19 vaccine
•Documented COVID -19 infection within 6 weeks prior to enrollment confirmed by either medical
history or lab testing
•History of severe allergic reaction after a previous dose of any influenza vaccine; or to an influenza vaccine component, including egg protein
•History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (e.g. anaphylaxis) to any component of an mRNA vaccine
•Receipt of any licensed inactivated vaccine within 2 weeks prior to enrollment in this study, receipt of any licensed live vaccine within 4 weeks prior to enrollment in this study, or receipt of Shingrix
(Zoster Vaccine Recombinant, Adjuvanted) or HEPLISAV -B (Hepatitis B Vaccine (Recombinant),
Adjuvanted) vaccine within 6 weeks prior to enrollment in this study or planning receipt of any vaccines following enrollment until 6 weeks after receipt of the second dose of mRNA COVID -19
vaccine
35
Subject Exclusion Criteria
•Has an active neoplastic disease (excluding non -melanoma skin cancer or prostate cancer that is
stable in the absence of therapy) or a history of any hematologic malignancy*
*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
•Thrombocytopenia, bleeding disorder, or anticoagulant use contraindicating intramuscular injection (a
daily aspirin may be acceptable).
•Has immunosuppression as a result of an underlying illness or medications, such as antirejection/transplant regimens or immunomodulatory agents. Stable HIV disease is permitted per
the following parameters:
–Confirmed stable HIV disease defined as document viral load <50 copies/mL and CD4 count
>200 within 6 months before enrollment, and on stable antiretroviral therapy for at least 6
months
•Has known hepatitis B (HBV) or hepatitis C (HBC). Stable HBV or HBC are permitted per the following
parameters:
–If known HBV: confirmed inactive chronic HBV infection:  HBsAg present for ≥6 months and
HBeAg negative, anti- HBepositive; serum HBV DNA <2000 IU/mL; persistently normal ALT or
AST levels; in those who had liver biopsy, findings that confirm absence of significant necroinflammation
–If known HCV: evidence of sustained virological response for ≥12 weeks after treatment or
without evidence of HCV RNA viremia (undetectable HCV RNA)
36
Subject Exclusion Criteria
•Use of oral, parenteral, or high -dose inhaled glucocorticoids*
*For definition of high -dose inhaled glucocorticoids, reference Appendix B.
•History of Guillain -Barré syndrome
•Prior enrollment in this study during the 2021 -22 flu season
•Anyone who is already enrolled or plans to enroll in another clinical trial with an
investigational product during the study period.*
*Per protocol, co- enrollment in observational or behavioral intervention studies are permitted at
any time. An investigational product may be permitted for therapy of an illness condition that
occurs during the study period e.g. COVID -19 illness.
•Hearing loss determined by the investigators to prevent successful communication over
the phone
•History of myocarditis or pericarditis
•History of multisystem inflammatory syndrome in children (MIS -C) or adults (MIS -A).
•Has injury or other reason why deltoid site on both arms cannot be used for vaccinations.
•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.
37

Summary: Safety of Simultaneous versus Sequential  Administration of mRNA COVID -19 and Quadrivalent Inactivated Influenza (IIV4)  Vaccines: A Randomized Placebo Controlled Trial (ClinicalTrials.gov ID: NCT05028361) Emmanuel “Chip” Walter MD, MPH ACIP October 25, 2023 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…


05 Influenza Schmader 508

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
2
•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
3
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)
4
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
7

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
9
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)
11
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
20
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
22
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
23
Extra Slides
24
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
25
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
27

EQ-5D-5L and VAS
28

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
29
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
30
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
31

Summary: 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…


01 VaxSafety Shimabukuro 508

National Center for Emerging and Zoonotic Infectious Diseases
Update on COVID -19 and influenza vaccine safety
Advisory Committee on Immunization Practices (ACIP) meeting
October 25, 2023
Tom T. Shimabukuro, MD, MPH, MBA
Director, Immunization Safety Office
Division of Healthcare Quality Promotion
Centers for Disease Control and Prevention (CDC)

Key points up front
2▪A statistical signal for ischemic stroke after Pfizer -BioNTech bivalent mRNA COVID -19 vaccine was
detected in CDC’s Vaccine Safety Datalink in persons aged ≥65 years during fall 2022; information
was presented at prior ACIP meetings and efforts have been underway to evaluate the signal*
▪Available data do not provide clear and consistent evidence of a safety problem for ischemic stroke
with bivalent mRNA COVID -19 vaccines when given alone or given simultaneously with influenza
vaccines, or when influenza vaccine is given alone
•Variable and inconsistent results were obtained in some analyses of the risk of ischemic stroke following
bivalent mRNA COVID -19 vaccination, simultaneous bivalent mRNA COVID -19 and influenza vaccination,
and influenza vaccination alone†
•Most study results have not shown an association between vaccination and ischemic stroke, and no clear
pattern demonstrating increased risk has emerged
▪Any real or theoretical risks of vaccine adverse events need to be placed in the context of the
known benefits of COVID -19 and influenza vaccination in preventing COVID -19 and influenza
disease and their potentially serious complications, including stroke
▪Our vaccine safety monitoring systems are designed to be sensitive, and the detection and
assessment of potential safety signals and communication of safety information to the public is an
example of the vaccine safety monitoring process working
* https://www.cdc.gov/vaccines/acip/meetings/downloads/slides -2023 -02/slides -02-24/COVID -02-Shimabukuro -508.pdf ;
https://www.cdc.gov/vaccines/acip/meetings/downloads/slides -2023 -04-19/03 -COVID -Shimabukuro -508.pdf
†For the purpose of this presentation, “influenza vaccination alone” is defined as not with simultaneous COVID -19 vaccination bu t may include other types of non -COVID -19 vaccines
Topics
▪Summary of analyses of ischemic stroke and bivalent mRNA COVID -19
and influenza vaccination
▪Additional data on ischemic stroke
▪Interpretation of data on ischemic stroke and bivalent mRNA COVID -
19 and influenza vaccination and next steps
3
Selected analyses of ischemic stroke and bivalent COVID -19 and
influenza vaccination
1.Vaccine Safety Datalink (VSD) Rapid Cycle Analysis (RCA) of ischemic stroke after bivalent
mRNA COVID -19 vaccination (Centers for Disease Control and Prevention)
2.Analysis of ischemic stroke after bivalent mRNA COVID -19 vaccination (Kaiser Permanente
Southern California)
3.Analysis of stroke risk following bivalent mRNA COVID -19 vaccination among U.S. adults aged
≥65 years in CMS data (U.S. Food and Drug Administration)
4.Analysis of ischemic stroke after bivalent mRNA COVID -19 vaccination in patients aged ≥65
years using nation -wide patient electronic health records (Case Western Reserve University
School of Medicine)
5.Analysis of stroke, myocardial infarction, and pulmonary embolism after bivalent Pfizer -
BioNTech COVID -19 vaccination (EPI -PHARE Scientific Interest Group, France)
6.Analysis of bivalent mRNA COVID -19 vaccination and stroke in England (UK Health Security
Agency and the London School of Hygiene and Tropical Medicine)
7.Analysis of the safety of monovalent and bivalent Pfizer -BioNTech COVID -19 vaccination in at -
risk populations (Israel)
4
1.) VSD COVID -19 Rapid Cycle Analysis: Analyses of Ischemic Stroke
after Pfizer -BioNTech Bivalent Booster Dose*
(April 2023 ACIP https://www.cdc.gov/vaccines/acip/meetings/downloads/slides -2023 -04-19/03 -COVID -Shimabukuro -508.pdf )
▪Data source: VSD data contributing sites
▪Methodology
•Primary : Vaccinated concurrent comparator (i.e., bivalent vaccinated vs. bivalent vaccinated) using a
1–21-day risk interval and a 22 –42-day comparison interval
•Supplemental : Bivalent vaccinated vs. bivalent unvaccinated but eligible for bivalent vaccine in a 1 –
21-day risk interval
•Age groups included 18 –64 and ≥65 years
▪Main findings
•Statistical signal for ischemic stroke detected in primary analysis after Pfizer -BioNTech in the age
group ≥65 years using a 1 –21-day risk interval; signal attenuated over time
•Post -signal assessment detected an elevated risk in the age group ≥65 years receiving same -day
Pfizer -BioNTech and high -dose inactivated influenza (HD -IIV4) or adjuvanted inactivated influenza
vaccine (aIIV4); finding attenuated over time
•No elevated risk for ischemic stroke detected in supplemental analysis using secondary comparators
•Additional supplemental analyses suggested that comparison interval (22 –42 days) rates of
ischemic stroke were lower than expected    5* Conducted through the CDC Vaccine Safety Datalink Indefinite Delivery, Indefinite Quantity (IDIQ) contract
2.) Ischemic Stroke after Bivalent COVID -19 Vaccination: A Self -
Controlled Case Series Study*
(Xu et al., 2023 https://www.medrxiv.org/content/10.1101/2023.10.12.23296968v1 )
6▪Data source: Kaiser Permanente Southern California electronic health record data
▪Methodology
•Modified self -controlled case series using age groups ≥12, 12 –64 and ≥65 years
▪Main findings
•No elevated risks detected for either Pfizer -BioNTech or Moderna in any age groups in automated data
with a 21 -day risk interval
•No elevated risks detected for either Pfizer -BioNTech or Moderna in the age group ≥65 years in automated
data with a 42 -day risk interval
•There were several analyses with statistically significant elevated risks in the age group 12 –64 years in
automated data with a 42 -day risk interval
‒Pfizer -BioNTech and simultaneous influenza vaccination, overall and in those with a history of SARS -
CoV-2 infection
‒Moderna in those with a history of SARS -CoV-2 infection
•After limiting signaling analyses to chart -verified cases, the findings were no longer statistically significant
* Funding provided through NIAID/NIH Award Number R01 AI168209
3.) Evaluation of Stroke Risk Following COVID -19 mRNA Bivalent
Vaccines Among U.S. Adults Aged ≥65 Years*
(Lu et al., 2023 https://www.medrxiv.org/content/10.1101/2023.10.10.23296624v1 )
7▪Data source: Medicare claims data
▪Populations: Community -dwelling Medicare beneficiaries aged ≥65 years
•Primary population: Recipients of bivalent mRNA COVID -19 vaccine
•Secondary population: Recipients of high -dose (HD -IIV4) or adjuvanted (aIIV4) influenza vaccine
▪Methodology: Modified self -controlled case series with Farrington adjustment
▪Main findings
•Primary population analyses showed no consistent stroke risk after mRNA COVID -19 vaccination
•An increased risk was observed with concomitant (same day administration) influenza vaccination
‒Non -hemorrhagic stroke after Pfizer -BioNTech + HD -IIV4/aIIV4 with a 22 –42-day risk interval
‒Transient ischemic attack after Moderna + HD -IIV4/aIIV4 with a 1 –21-day risk interval
•Secondary population analyses showed a small increased risk of non -hemorrhagic stroke after
HD-IIV4 or aIIV4 with a 22 –42-day risk interval, and the risk remained for people without
concomitant bivalent mRNA COVID -19 vaccination
* Funding provided by the FDA as part of the SafeRx Project, a joint initiative of the CMS and FDA
4.) Ischemic stroke after COVID -19 bivalent vaccine administration
in patients aged 65 years and older: analysis of nation -wide
patient electronic health records in the United States*
(Gorenflo et al., 2023 https://www.medrxiv.org/content/10.1101/2023.02.11.23285801v1 )
8▪Data source: TriNetX , a cloud -based analytics platform that includes electronic
health record data from >90 million unique patients in the United States
▪Methodology
•Retrospective cohort study among people aged ≥65 years
▪Main findings
•Patients who received bivalent Pfizer -BioNTech COVID -19 vaccination had a similar
hazard for ischemic stroke encounters compared to those who received bivalent
Moderna COVID -19 vaccination, but had a lower hazard than those who received the
monovalent Pfizer -BioNTech or Moderna COVID -19 booster vaccines in the 1 –21 or
22–42 days post -vaccination
* Support provided through NIA/NIH (grants nos. RF1AG076649), NIAAA/NIH (grant no. R01AA029831), CTSC of Cleveland (grant no. 1UL1TR002548)
5.) Stroke, Myocardial Infarction, and Pulmonary Embolism
after Bivalent Booster
(Jabagi et al., 2023 https://www.nejm.org/doi/full/10.1056/NEJMc2302134 )
9▪Data source: French National Health Data System linked to the national coronavirus
disease 2019 (Covid -19) vaccination database
▪Methodology
•Matched cohort study (1:5) in people aged ≥50 years
•Recipient of monovalent vaccine matched to recipients of bivalent mRNA COVID -19
vaccine*; followed for 21 days after vaccination
▪Main findings
•Compared to monovalent Pfizer -BioNTech COVID -19 vaccination, bivalent Pfizer -BioNTech
COVID -19 vaccination was not associated with an increased risk of ischemic stroke,
hemorrhagic stroke, myocardial infarction, or pulmonary embolism in people aged ≥50 years
•The authors previously found no increase in the incidence of stroke, acute myocardial
infarction, or pulmonary embolism after administration of the monovalent Pfizer -BioNTech
COVID -19 vaccine
*contains omicron BA.4 –BA.5 strains; used in the United States
6.) BA.1 Bivalent COVID -19 Vaccine Use and Stroke in England*
(Andrews et al., 2023 https://jamanetwork.com/journals/jama/fullarticle/2806456 )
10▪Data source: National Health Service hospital admissions in England linked to the
National Immunisation Management System
▪Methodology
•Self-controlled case -series design in people aged ≥50 and ≥65 years (1 –21-day risk
window) with further analysis in people aged ≥65 years given simultaneous bivalent mRNA
COVID -19†and influenza vaccination‡
▪Main findings
•No increased risk of stroke in the 21 days after vaccination with either the Pfizer -BioNTech
or the Moderna bivalent mRNA COVID -19 vaccines
•Similar results obtained for ischemic and hemorrhagic stroke for the subset of people aged
≥65 years given influenza vaccine on the same day as the bivalent mRNA COVID -19 vaccine
* Funded by the UK Health Security Agency; † Contains omicron BA.1 strain; not used in United States; ‡persons aged ≥ 65 years 95% received quadrivalent or
trivalent adjuvanted influenza vaccine (no high -dose influenza vaccine used)
7.) Safety of monovalent and bivalent BNT162b2 mRNA COVID -19
vaccine boosters in at -risk populations in Israel: a large -scale,
retrospective, self -controlled case series study*
(Yamin et al., 2023 https://www.sciencedirect.com/science/article/pii/S1473309923002074?via%3Dihub )
11▪Data source: Clalit Health Services medical records (largest healthcare
organization in Israel with over 3.5 million enrollees, 1.2 million aged ≥60 years)
▪Methodology
•Self-controlled case -series
▪Main findings
•No safety signals detected for ischemic stroke after either monovalent or bivalent
Pfizer -BioNTech COVID -19 vaccines used in Israel in the overall analysis or in people
aged ≥65 years
* Supported by Israel Science Foundation (grant 3409/19), within the Israel Precision Medicine Partnership
Additional data on ischemic stroke
12▪No unusual or unexpected reporting patterns observed, and no evidence of a safety concern
detected for ischemic stroke with either of the bivalent mRNA COVID -19 vaccines in Vaccine
Adverse Event Reporting System (VAERS) monitoring
▪FDA monitoring in the CMS data and Department of Veterans Affairs monitoring in the VA
system did not detect any safety signals for ischemic stroke following bivalent mRNA COVID -19
vaccination using historical comparator designs
▪A separate ad hoc CDC analysis during the bivalent Pfizer -BioNTech ischemic stroke signal
assessment did not detect an elevated risk for ischemic stroke after influenza vaccination alone
▪Surveillance conducted by international regulatory and public health partners did not detect a
safety concern for ischemic stroke following bivalent mRNA COVID -19 vaccination
▪No evidence of a safety signal for ischemic stroke detected in the manufacturers’ global
monitoring of bivalent mRNA COVID -19 vaccination
▪No safety signals were detected for ischemic stroke for primary series or monovalent boosters
for Pfizer -BioNTech or Moderna COVID -19 vaccines in U.S. and global monitoring)
▪Data suggest COVID -19 and influenza disease are associated with an increased risk of stroke
ACIP Ischemic Stroke, COVID -19 and Influenza in Adults Ages greater than or Equal to 65 years -Feb. 24, 2023 (cdc.gov)
Monthly incidence rates of non -hemorrhagic stroke (NHS)
in Medicare claims data suggesting seasonality*
13
* From eFigure 1. Monthly Incidence Rates of NHS, TIA, NHS/TIA, and HS per 100,000 Person -Years at Risk, in Lu et al., 2023 https://www.medrxiv.org/content/10.1101/2023.10.10.23296624v1
Outpatient visits for respiratory illness in the United States from ILINet
14

Interpretation of analyses of ischemic stroke and bivalent
COVID -19 and influenza vaccination
15▪Variable and inconsistent results were obtained in some analyses of risk of ischemic
stroke following bivalent COVID -19 vaccination, simultaneous bivalent COVID -19 and
influenza vaccination, and influenza vaccination alone
•There is a lack of consistency in findings from different data systems, when using different methods,
across age groups, and across sub -group analyses
•The most common findings across studies are findings of no association
•Multiple comparisons were conducted in studies without adjusting for multiplicity; few reached
statistical significance
•The studies were not designed to account for a potential protective effect of vaccination on stroke in
later post -vaccination periods
•Adjusting for seasonality and restricting analyses to chart -verified cases frequently resulted in
attenuated findings or findings that were no longer statistically significant
•Remaining statistically significant findings tended to be relatively small in magnitude (i.e., RRs<2)
•Ischemic stroke cases in the analyses are predominantly occurring in older people and in people in
the upper ranges of the age groups studied (e.g., upper range of a 12 –64-year -old age group);
relatively few cases are in younger people
Interpretation of analyses of ischemic stroke and bivalent
COVID -19 and influenza vaccination (cont.)
16▪Available data do not provide clear and consistent evidence of a safety problem for ischemic
stroke with bivalent mRNA COVID -19 vaccines when given alone or given simultaneously with
influenza vaccines, or when influenza vaccine is given alone
▪Most study results have not shown an association between vaccination and ischemic stroke, and
no clear pattern demonstrating increased risk has emerged
▪Seasonality of stroke risk and an unusual respiratory illness pattern in 2022 -2023 could be
impacting the results of some of these analyses; unrecognized SARS -CoV-2 infection could also
play a role in occurrence of stroke after vaccination
▪Any real or theoretical risk needs to be placed in the context of the known benefits of COVID -19
and influenza vaccination in preventing COVID -19 and influenza disease and their potentially
serious complications, including stroke
▪Simultaneous vaccination provides substantial benefits in keeping patients up -to-date with
recommended vaccines and protected from vaccine preventable diseases
▪Our vaccine safety monitoring systems are designed to be sensitive, and the detection and
assessment of the ischemic stroke signal and communication to the public is an example of the
vaccine safety monitoring process working
Next steps
17▪Conduct additional analyses on the possible relationship between
ischemic stroke and  bivalent mRNA COVID -19 vaccination,
simultaneous administration of bivalent mRNA COVID -19 and
influenza vaccines, and influenza vaccine alone
▪Continue vigilant safety monitoring of 2023 –2024 COVID -19 and
influenza vaccines, including for ischemic stroke
Acknowledgements
18▪CDC Immunization Safety Office
•VAERS Team
•Vaccine Safety Datalink (VSD) Team
•Clinical Immunization Safety Assessment
(CISA) Project
▪FDA Center for Biologics Evaluation and
Research, Office of Biostatistics and
Pharmacovigilance
▪Department of Veterans Affairs▪VSD sites
•Kaiser Permanente Northern California, Oakland, CA
•Kaiser Permanente Southern California, Los Angeles , CA
•Marshfield Clinic Research Institute, Marshfield, WI
•HealthPartners Institute, Minneapolis, MN
•Kaiser Permanente Colorado, Denver, CO
•Kaiser Permanente Northwest, Portland, OR
•Kaiser Permanente Washington, Seattle, WA
•Denver Health, Denver, CO
•Harvard Pilgrim Health Care Institute, Boston
Disclaimer
▪The findings and conclusions in this presentation are those of the presenter and
do not necessarily represent the official position of CDC or FDA
▪Mention of a product or company name is for identification purposes only and
does not constitute endorsement by CDC or FDA
19
For more information, contact CDC
1-800-CDC-INFO (232 -4636)
TTY:  1 -888-232-6348    www.cdc.gov
The findings and conclusions in this report are those of the authors and do not necessarily represent the
official position of the Centers for Disease Control and Prevention.
Photo credit: James Gathany
(https://wwwn.cdc.gov/phil/
Details.aspx?pid=8876 )

Summary: National Center for Emerging and Zoonotic Infectious Diseases Update on COVID -19 and influenza vaccine safety Advisory Committee on Immunization Practices (ACIP) meeting October 25, 2023 Tom T. Shimabukuro, MD, MPH, MBA Director, Immunization Safety Office Division of Healthcare Quality Promotion  Centers for Disease Control and Prevention (CDC)  Key points up front 2▪A statistical signal for ischemic stroke after Pfizer -BioNTech bivalent mRNA COVID -19 vaccine was  detected in CDC’s Vaccine…


01 IZ Schedules Cineas 508

Centers for Disease Control and Prevention
National Center for Immunization and Respiratory Diseases
Centers for Disease Control and Prevention
National Center for Immunization and Respiratory Diseases
Centers for Disease Control and Prevention
National Center for Immunization and Respiratory Diseases
Centers for Disease Control and Prevention
National Center for Immunization and Respiratory Diseases
Photographs and images included in this presentation are licensed solely for CDC/NCIRD online and presentation use. No rights are implied or extended for use in printing or any use by other CDC CIOs or any external audiences.Recommendations from the Combined Immunization
Schedule WG for the 2024 Immunization Schedules for Children/Adolescents and Adults
Sybil Cineas, MD, FAAP, FACP (ACIP Combined Immunization WG Chair)
A. Patricia Wodi, MD (CDC Co -Lead)
Neil Murthy, MD, MPH, MSJ (CDC Co -Lead)
ACIP Meeting
October 26, 2023
Combined Immunization Schedules Work Group
The Combined Immunization
Schedule WG updates the
immunization schedules annually.
–Child and adolescent schedule
(age birth through 18 years)
–Adult schedule (age 19 years or older)
The schedules are primarily
designed to be a tool for healthcare
providers to ensure individuals get
all the vaccines they need when they need them.
2Immunization Schedules | CDC
www.cdc.gov/vaccines/schedules/index.html

The goal of the Combined Immunization Schedule WG is to better harmonize
the child/adolescent and adult schedules.
New policies are not established in the  proposed schedules.
–Annual schedules reflect recommendations already approved by ACIPCombined Immunization Schedules Work Group
3
ACIP approval of the proposed schedules is necessary prior to publicationReason Topic is Being Presented to ACIP
Child/Adolescent Schedule Both Schedules Adult Schedule
•American Academy of Pediatrics
(AAP)
•National Association of Pediatric Nurse Practitioners (NAPNAP)•American Academy of Family
Physicians (AAFP)
•American Academy of Physician
Associates (AAPA)
•American College of Obstetricians and Gynecologists (ACOG)
•American College of Nurse -
Midwives (ACNM)•American College of Physicians (ACP)
•Society for Healthcare Epidemiology of America (SHEA)
•American Pharmacists Association
(APhA )
4
Traditional Publication Timeline
October November December January February
ACIP vote approves the
immunization schedulesProfessional organizations
approve schedules
Draft and clear MMWR reports (both
schedules) and Annals of Internal
Medicine report (adult schedule only)Publish Schedules (web, app, pdf),
MMWR Notice to Readers, &
Annals of Internal Medicine
report published
5
Insurance reimbursement
The ability of certain health care providers to administer
immunizations
–Some states link pharmacists’ immunization authority to the schedule
Health care provider knowledge and practices related to vaccine recommendationsImpacts of Timeliness of Schedule Publication
6
2024 immunization schedules: Publication Timeline
October November December January February
ACIP vote approves the
immunization schedulesProfessional
organizations
approve schedules
7Publish Schedules
(web, app, pdf )
Publish MMWR Notice to
Readers, &Annals of Internal
Medicine report published
ACIP Members
Sybil Cineas (ACIP WG Chair)
Veronica McNally
Matthew Daley
Liaison Representatives
John Epling (AAFP) Mary -Margaret Fill (CSTE)
Sarah Coles (AAFP) Chad Rittle (ANA)
Rhoda Sperling (ACOG) William Schafner (NFID)
Holly Fontenot (SAHM) Robert Hopkins (NFID)
Amy Middleman (SAHM) Ken Schmader (AGS)
Sandra Fryhofer (ACP/AMA)       Patsy Stinchfield (NAPNAP)Sarah McQueen (AAPA) Preeti Mehrotra (SHEA)
Marie -Michele Leger (AAPA) Pia Pannaraj (AAP)
Caitlin Newhouse (AIM)               Kelly Goode ( APhA)Ex Officios
David Kim (OASH)
Susan Farrall (OASH)
Jane Kim (DVA)
Uzo Chukwuma (IHS)
Consultants
Hank BernsteinKevin Ault
Peter Szilagyi
Diane Peterson
Carolyn Bridges
Karen Ketner
Kathleen HarrimanLitjen Tan
Robert HopkinsSusan LettCombined Immunization Schedule Work Group
8CDC Co -Leads
A. Patricia WodiNeil Murthy
ACIP Combined Immunization Work Group —CDC Contributors:
–Noele Nelson
–Paul Gastanaduy
–Samuel Crowe
–Sarah Kidd
–Sarah Schillie
–Susan Goldstein
–Susan Hariri
–Suzanne Johnson- DeLeon
–Tara Anderson
–Tami Skoff
–Tatiana LanzieriAcknowledgements
–Akiko Wilson
–Andrew Kroger
–Amadea Britton
–David Sugerman
–Donna Williams
–Erin Conners
–Hilda Razzaghi
–Holly Hill
–Jacqueline Tate
–Janell Routh
–Jefferson Jones
–Jennifer Collins–JoEllen Wolicki
–Katherine Fleming -Dutra
–Lakshmi Panagiotakopoulos
–Lauri Markowitz
–Lisa Grohskopf
–Lucy McNamara
–Mary Chamberland
–Megan Wallace
–Michael Melgar
–Michelle Hughes
–Miwako Kobayashi
–Mona Marin
9
The use of vaccine trade names is for identification purposes only and
does not imply endorsement by the Centers for Disease Control and
Prevention.
The 2024 schedules presented in the following slides are drafts and are
therefore subject to change based on ACIP’s discussion and vote.Disclaimer
10
Harmonization between the child/adolescent and adult schedules
Edits to all tables
Content changes of the notes
Content changes to the appendix listing contraindications and precautions
Discussion and VoteOutline
11

Summary: Centers for Disease Control and Prevention National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention National Center for Immunization and Respiratory Diseases Photographs and images included in this presentation are licensed solely for CDC/NCIRD online…


02 IZ Schedules Wodi 508

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01 Chikungunya Bell 508

CHIKUNGUNYA VACCINES
Beth Bell, MD, MPH
Chair, ACIP Chikungunya Vaccines Work GroupACIP Meeting
October 26, 2023
Background
Expected licensure date for Valneva’s chikungunya vaccine revised from
August 2023 to November 2023
No chikungunya vaccine ever licensed in United States or globally
No existing ACIP chikungunya vaccine recommendations
Chikungunya Vaccines Work Group is developing policy options for ACIP’s consideration for use of chikungunya vaccine among U.S. persons at risk of
chikungunya, including
–Travelers
–Laboratory workers
–Residents of U.S. territories and states with, or at risk of, transmission
Recap of previous Work Group presentations to ACIP
October 2022
–Overview of chikungunya virus disease and vaccines
–Immunogenicity and safety of Valneva’s chikungunya vaccine
February 2023
–Global epidemiology of chikungunya
–Chikungunya among U.S. travelers
–Persistent arthralgia following chikungunya
June 2023
–Value of a vaccine to U.S. travelers
–Chikungunya virus infection among laboratory workers
–Observations on a large chikungunya outbreak in Paraguay
Overview of today’s session
Evidence to Recommendations for chikungunya vaccine use among U.S.
travelers*
–Dr. Susan Hills (CDC/NCEZID)
Evidence to Recommendations for chikungunya vaccine use among
laboratory workers*
–Dr. Susan Hills (CDC/NCEZID)
*Anticipated vote at February 2024 ACIP meeting if vaccine is licensed
ACIP Ex Officio Invited Consultants
Beth Bell, Univ Washington (Chair) Robin Levis, FDA Alan Barrett, Univ Texas Galveston
Wilbur Chen, Univ Maryland Sixun Yang, FDA Carina Blackmore, Florida Dept Health
Lesley Dupuy, NIH Alan Lam, DoD
CDC Leads Margaret Ryan, DoD
Susan Hills, DVBD (Lead) ACIP Liaisons Steven Schofield, CATMAT
Nicole Lindsey, DVBD (Deputy Lead) Elizabeth Barnett, ISTM David Shlim, Jackson Hole Travel & Trop Med
James Campbell, AAP Nestor Sosa, Uni New Mexico Hospital
Mary Pat Friedlander, AAFP Sanet Torres, San Jorge Children & Women's Hospital
Saroj Rai, AIM Kirsten Vannice, Bill & Melinda Gates Foundation
Mary Wilson, Univ California San FranciscoChikungunya Vaccines Work Group members
DVBD DGMQ ISD
Erin Staples Sarah Guagliardo Elisabeth Velazque z
Ann Powers
Laura Adams DHQP GRADE/ETR consultants
Joshua Wong Michael McNeil Doug Campos -Outcalt
Rebecca Morgan
NCEZID GID
Rita Helfand Rebecca Casey ACIP Secretariat
Jessica MacNeil, NCIRD
Leslie Lee, NCIRDChikungunya Vaccines Work Group CDC participants

Summary: CHIKUNGUNYA VACCINES Beth Bell, MD, MPH Chair, ACIP Chikungunya Vaccines Work GroupACIP Meeting October 26, 2023 Background Expected licensure date for Valneva’s chikungunya vaccine revised from  August 2023 to November 2023 No chikungunya vaccine ever licensed in United States or globally No existing ACIP chikungunya vaccine recommendations Chikungunya Vaccines Work Group is developing policy options for ACIP’s consideration for use of chikungunya vaccine among U.S. persons at risk of …


02 Chikungunya Hills 508

National Center for Emerging and Zoonotic Infectious Diseases
EVIDENCE TO RECOMMENDATIONS FOR
CHIKUNGUNYA VACCINE USE AMONG
ADULT TRAVELERS
Susan Hills, MBBS, MTH
CDC Lead , Chikungunya Vaccines Work Group
Arboviral Diseases Branch
Division of Vector -Borne Diseases
Fort Collins, Colorado
ACIP meeting, October 26, 2023
Chikungunya virus and transmission
Alphavirus
Primarily transmitted by Aedes
aegypti and Aedes albopictus
Uncommon modes of
transmission
–Laboratory exposure
–Intrauterine and intrapartum
–Bloodborne transmission
through needlestick

Distribution
Tropical and subtropical
regions
Large outbreaks have occurred in most parts of
the world
–Often high attack ratesCountries and territories with current or past transmission
of chikungunya virus
https://www.cdc.gov/chikungunya/geo/index.html

Clinical features of acute chikungunya virus infection
Febrile illness with arthralgia which is often severe and debilitating
Rare serious complications (e.g., neurologic illness, myocarditis, hepatic or
renal disease)
No anti -viral treatment

Risk factors for severe disease
Age >65 years
Age <1 year
Underlying medical conditions
(e.g., diabetes, heart disease,
hypertension)
Intrapartum transmission

Chikungunya vaccine
Live attenuated vaccine manufactured by Valneva
Single dose primary schedule
Initial licensure for adults aged ≥18 years
Currently under consideration by US Food & Drug Administration
Not yet licensed anywhere in world
No existing vaccine recommendations from ACIP or other vaccine
advisory groups
Evidence to Recommendations for
chikungunya vaccination for travelers
Policy question
Should chikungunya vaccine be recommended for use in
persons aged ≥18 years traveling to areas with risk of
chikungunya virus transmission?
Domain 1. Public health problem
Is chikungunya of public health importance?
Hundreds of thousands of cases
reported annually
Risk highly variable for US travelers
100– 200 reported cases annually
Hundreds of thousands of cases
reported annually
Risk highly variable for US travelers
100– 200 reported cases annually
Hundreds of thousands of cases
reported annually

Risk highly variable for US travelers
100– 200 reported cases annually
Hundreds of thousands of cases
reported annually
Mortality <1%

Public health problem
Is chikungunya of public health importance?
oNo oProbably no oProbably yes oYes oVaries oDon’t know
Domain 2: Benefits and harms of chikungunya
vaccine
How substantial are the desirable anticipated effects?
Short -term and long -term protection from disease
No efficacy data so i mmunogenicity data reviewed
–No correlate of protection
Licensure through Accelerated Approval pathway
–Effectiveness demonstrated by clinical trials showing vaccine has effect on
surrogate endpoint reasonably likely to predict clinical benefit
–Vaccine effectiveness will need to be confirmed in post -licensure field studies
Marker of protection based on neutralizing antibody titer estimated from
validated non- human primate model
Seroresponse at 28 days after vaccination
Two studies
–One randomized controlled trial
–One lot -to-lot consistency study with no placebo group
Total of 622 subjects
Seroresponse at 28 days: ≥98%
None of 96 subjects in placebo arm of randomized controlled trial
had  seroresponse
Seroresponse at 12 months after vaccination
One study with 360 subjects
Seroresponse at 12 months: 99%
How substantial are the desirable anticipated effects?
oMinimal oSmall oModerate oLarge oVaries oDon’t know
How substantial are the undesirable anticipated effects?
Serious adverse events (SAE) within 6 months
SAE
–51 (1.5% ) of 3,490 vaccinated subjects in 2 trials reported SAE
–8 (0.8% ) of 1,033 placebo recipients in randomized controlled trial reported SAE*
Related SAEs
–2 events ( 0.1% ) considered vaccine -related by study investigators
•Hospitalization for severe myalgia
•Hospitalization for myalgia, high fever, syndrome of inappropriate antidiuretic
hormone excretion, and atrial fibrillation
*No significant difference from vaccine group; 46 (1.5%) of 3,082 vaccinated subjects in randomized, controlled trial
Arthralgia and arthritis in randomized controlled trial*
Vaccinated group
(N=3082)Placebo group
(N=1033)
n(%) n(%) Risk ratio (95% CI)
Any arthralgia within 10 days#520 (17%) 50 (5%) 3.5 (2.6, 4.6)¥
Severe arthralgia within 10 days#,€9(0.3%) 0(0%) 6.0 (0.4, 104.2)
Persistent arthralgia≠9(0.3%) 4(0.4%) 0.8 (0.2, 2.4)
Arthritis within 6 months£5(0.2%) 2(0.2%) 0.8 (0.2, 4.3)
New onset or worsening osteoarthritis
within 6 months£12 (0.4%) 2(0.2%) 2(0.5, 9.0)
#Solicited adverse event ; ¥Significant difference; €Severe arthralgia defined as an event that prevented daily activity;
≠Commencing within 10 days and with duration >15 days; £Unsolicited adverse event
*Similar percentage of events in vaccinated subjects in lot -to-lot consistency study (N=408) without placebo control group
Arthralgia and arthritis in randomized controlled trial
Vaccinated group
(N=3082)Placebo group
(N=1033)
n(%) n(%) Risk ratio (95% CI)
Any arthralgia within 10 days#520 (17%) 50 (5%) 3.5 (2.6, 4.6)¥
Severe arthralgia within 10 days#,€9(0.3%) 0(0%) 6.0 (0.4, 104.2)
Persistent arthralgia≠9(0.3%) 4(0.4%) 0.8 (0.2, 2.4)
Arthritis within 6 months£5(0.2%) 2(0.2%) 0.8 (0.2, 4.3)
New onset or worsening osteoarthritis
within 6 months£12 (0.4%) 2(0.2%) 2(0.5, 9.0)
#Solicited adverse event ; ¥Significant difference; €Severe arthralgia defined as an event that prevented daily activity;
≠Commencing within 10 days and with duration >15 days; £Unsolicited adverse event
Arthralgia and arthritis in randomized controlled trial
Vaccinated group
(N=3082)Placebo group
(N=1033)
n(%) n(%) Risk ratio (95% CI)
Any arthralgia within 10 days#520 (17%) 50 (5%) 3.5 (2.6, 4.6)¥
Severe arthralgia within 10 days#,€9(0.3%) 0(0%) 6.0 (0.4, 104.2)
Persistent arthralgia≠9(0.3%) 4(0.4%) 0.8 (0.2, 2.4)
Arthritis within 6 months£5(0.2%) 2(0.2%) 0.8 (0.2, 4.3)
New onset or worsening osteoarthritis
within 6 months£12 (0.4%) 2(0.2%) 2(0.5, 9.0)
#Solicited adverse event ; ¥Significant difference; €Severe arthralgia defined as an event that prevented daily activity;
≠Commencing within 10 days and with duration >15 days; £Unsolicited adverse event
Arthralgia and arthritis in randomized controlled trial
Vaccinated group
(N=3082)Placebo group
(N=1033)
n(%) n(%) Risk ratio (95% CI)
Any arthralgia within 10 days#520 (17%) 50 (5%) 3.5 (2.6, 4.6)¥
Severe arthralgia within 10 days#,€9(0.3%) 0(0%) 6.0 (0.4, 104.2)
Persistent arthralgia≠9(0.3%) 4(0.4%) 0.8 (0.2, 2.4)
Arthritis within 6 months£5(0.2%) 2(0.2%) 0.8 (0.2, 4.3)
New onset or worsening osteoarthritis
within 6 months£12 (0.4%) 2(0.2%) 2(0.5, 9.0)
#Solicited adverse event ; ¥Significant difference; €Severe arthralgia defined as an event that prevented daily activity;
≠Commencing within 10 days and with duration >15 days; £Unsolicited adverse event
Arthralgia and arthritis in randomized controlled trial
Vaccinated group
(N=3082)Placebo group
(N=1033)
n(%) n(%) Risk ratio (95% CI)
Any arthralgia within 10 days#520 (17%) 50 (5%) 3.5 (2.6, 4.6)¥
Severe arthralgia within 10 days#,€9(0.3%) 0(0%) 6.0 (0.4, 104.2)
Persistent arthralgia≠9(0.3%) 4(0.4%) 0.8 (0.2, 2.4)
Arthritis within 6 months£5(0.2%) 2(0.2%) 0.8 (0.2, 4.3)
New onset or worsening osteoarthritis
within 6 months£12 (0.4%) 2(0.2%) 2(0.5, 9.0)
#Solicited adverse event ; ¥Significant difference; €Severe arthralgia defined as an event that prevented daily activity;
≠Commencing within 10 days and with duration >15 days; £Unsolicited adverse event
Arthralgia and arthritis in randomized controlled trial
Vaccinated group
(N=3082)Placebo group
(N=1033)
n(%) n(%) Risk ratio (95% CI)
Any arthralgia within 10 days#520 (17%) 50 (5%) 3.5 (2.6, 4.6)¥
Severe arthralgia within 10 days#,€9(0.3%) 0(0%) 6.0 (0.4, 104.2)
Persistent arthralgia≠9(0.3%) 4(0.4%) 0.8 (0.2, 2.4)
Arthritis within 6 months£5(0.2%) 2(0.2%) 0.8 (0.2, 4.3)
New onset or worsening osteoarthritis
within 6 months£12 (0.4%) 2(0.2%) 2(0.5, 9.0)
#Solicited adverse event ; ¥Significant difference; €Severe arthralgia defined as an event that prevented daily activity;
≠Commencing within 10 days and with duration >15 days; £Unsolicited adverse event
How substantial are the undesirable anticipated effects?
oMinimal oSmall oModerate oLarge oVaries oDon’t know
Do the desirable effects outweigh the undesirable effects?
Balance of desirable and undesirable effects
High seroresponse rates through at least 1 year after vaccination
No serious safety concerns identified in trials performed to date
Prevents disease that can result in severe arthralgia during acute illness,
rare serious complications, and sometimes long -term arthralgia
Healthcare provider should discuss desirable and undesirable effects of vaccination and individual risk based on disease risk at destination,
activities, and personal factors
–For some travelers, even low probability of SAE might be higher than disease risk
–Target vaccine to travelers at higher risk for disease
Do the desirable effects outweigh the undesirable effects?
oFavors
intervention oFavors
comparisonoFavors
bothoFavors
neitheroVariesoDon’t
know
What is the overall certainty of the evidence for the
critical outcomes?
What is the overall certainty of the evidence for
protection from chikungunya ?
oNo studies found oVery low oLow oModerate oHigh
No vaccine efficacy data, no immunologic correlate of protection,
protection based on surrogate endpoint reasonably likely to predict
clinical benefit and requiring confirmation by post -licensure vaccine
effectiveness studies
What is the overall certainty of the evidence for
safety of chikungunya vaccination ?
oNo studies found oVery low oLow oModerate oHigh
Number of subjects in trials insufficient to detect rare adverse events,
confidence intervals indicated potential for benefit or harm, and/or
suboptimal method for collection of specific outcome information
Domain 3. Values
Does the target population feel that the desirable
effects are large relative to undesirable effects?
Is there important uncertainty about or variability
in how much people value the main outcomes?
Perceptions among US adults aged ≥18 years of the
value of a chikungunya vaccine (CDC study)
Online survey conducted in 2022
Participants provided information on
–Risk for disease with travel during outbreak or non -outbreak
periods
–Rates of chronic arthralgia after chikungunya
–Vaccine cost
Results
42%
26%32%
Likely* Unsure Unlikely**
*Includes very and somewhat likely responses
**Includes very and somewhat unlikely responsesOutbreak period (risk of 1 in 150) Non -outbreak period (risk of 1 in 15,000)
27%
24%49%
Likely* Unsure Unlikely**N=4,146N=4,138
Variability in responses
Lower likelihood of vaccination
–Persons aged 18 –29 years
–Lower education
–Lower household income
–Black race
Important factors in decision -making
Risk of disease
Vaccine side effects Avoid risk of long -term joint pain Vaccine cost
Perceptions among US adults aged ≥18 years of value of
chikungunya vaccine (Valneva study)
Online survey conducted in 2021
2,002 US residents who had traveled internationally during last 3
years or planned to do so within next 3 years
Limited information about participants provided but anyone who self-identified as ‘anti -vaccination’ excluded
Results
After being provided basic information on chikungunya
and its sequelae
–72% were very or somewhat likely to ask healthcare provider
about a vaccine
–81% were very or somewhat likely to be vaccinated if
recommended by healthcare provider
Values
Does the target population feel that the desirable
effects are large relative to undesirable effects?
oNo oProbably no oProbably yes oYes oVaries oDon’t know
Values
Is there important uncertainty about or variability
in how much people value the main outcomes?
oImportant
uncertainty
or variabilityoProbably important
uncertainty or variabilityoProbably not important uncertainty or variabilityoNo important
uncertainty or
variabilityoNo known undesirable outcomes
Domain 4. Acceptability
Is chikungunya vaccine acceptable to key stakeholders?
Acceptability to key stakeholders
Travel medicine and other healthcare providers
–Online survey in 2021 (Valneva) among 158 US healthcare
providers who routinely provide travel health services
indicated 87% were very or somewhat likely to
recommend vaccine if recommended by ACIP
Travelers
–Option for protection from a disease that can cause
severe arthralgia and potentially long -term joint pain
Acceptability
Is the intervention acceptable to key stakeholders?
oNo oProbably no oProbably yes oYes oVaries oDon’t know
Domain 5. Resource use
Is chikungunya vaccination a reasonable and efficient
allocation of resources?
Cost -effectiveness considerations
No cost- effectiveness analysis (CEA)
–Most travel vaccines are not cost -effective
–Chikungunya vaccine for travelers is not likely to be cost -effective
CEA less relevant for travel vaccine
–Decision is for individual traveler and not for population
–Vaccine paid for by traveler and generally not covered by insurance
Vaccine recommendations targeting higher risk travelers probably reasonable
allocation of resources
–Financial implications borne by travelers most at risk and who benefit most
Resource use
Is chikungunya vaccination a reasonable and
efficient allocation of resources?
oNo oProbably no oProbably yes oYes oVaries oDon’t know
Domain 6. Equity
What would be the impact on health equity?
Health equity considerations
Vaccine primarily paid for out of pocket
–Some travelers not have resources to pay for vaccine
Travel medicine providers likely have better awareness of disease and
vaccine availability than non- specialist providers
–People with fewer resources less likely to attend travel medicine provider
Chikungunya vaccine recommendations cannot address these issues
Equity
What would be the impact on health equity?
oReducedoProbably
reducedoProbably
no impactoProbably increasedoIncreased oVariesoDon’t know
Domain 7. Feasibility
Is the intervention feasible to implement?
Feasibility considerations
Single dose primary series allows administration in pre -travel
consultation
Disease risk highest, and vaccination most of benefit, during
outbreaks
–Challenge with delay in awareness of outbreaks
–CDC will post information on website once aware of outbreaks
Feasibility
Is the intervention feasible to implement?
oNo oProbably no oProbably yes oYes oVaries oDon’t know
Balance of consequences
o Undesirable
consequence clearly
outweighdesirable consequences in most settingso Undesirable consequences probably outweigh desirable consequences in most settingso The balance between desirable and undesirable consequences is
closely balanced or uncertaino Desirable
consequences
probably
outweigh
undesirable
consequences
in most settingso Desirable
consequences clearly outweigh undesirable consequences in most settingso There is insufficient evidence to determine the balance of consequences
Draft recommendations for
ACIP’s consideration
Draft recommendations
Chikungunya vaccine is recommended for persons aged ≥18 years
traveling to a country or territory where there is a chikungunya
outbreak
In addition, chikungunya vaccine may be considered forthe following
persons traveling to a country or territory without an outbreak but
with evidence of chikungunya virus transmission among humans within
the last 5 years
–Older persons (e.g., >65 years), particularly those with underlying
medical conditions, who are likely to have at least moderate exposure to mosquitoes
–Persons staying for a cumulative period of 6 months or more during a 2-year period
Example of data supporting recommendation: Substantially higher
risk for travelers during outbreak, Paraguay 2023
<1%
Percentage of all US persons
traveling to areas with
chikungunya risk visiting Paraguay 26%*
Percentage of all reported US traveler
chikungunya cases whose travel
destination was Paraguay
*18 of 69 travelers with destination data, preliminary ArboNET data, 2023
Providing clarity on chikungunya outbreaks
For the purposes of the recommendation, an outbreak
will be defined as occurring when CDC posts information on an outbreak on CDC website
Shared clinical decision- making recommendation
Chikungunya vaccine may be considered for the following persons
traveling to a country or territory without an outbreak but with
evidence of chikungunya virus transmission among humans within the last 5 years
–Older persons (e.g., >65 years), particularly those with underlying
medical conditions, who are likely to have at least moderate exposure to mosquitoes
–Persons staying for a cumulative period of 6 months or more during a 2-year period
Older persons, particularly those with underlying medical
conditions?
Key risk factors for severe disease
–Older age
–Underlying medical conditions
Key risk factors for chronic arthralgia
–Older age
–Presence of pre- existing joint problems
Risk for higher morbidity and mortality
in older persons supported by data
from recent outbreak in Paraguay1
1. Torales M, et al. Notes from the Field: Chikungunya Outbreak - Paraguay, 2022- 2023. MMWR Morb Mortal Wkly Rep 2023; 72:636- 638
Vaccine not
available for
children
Cumulative period of ≥6 months during 2 -year period*
Key risk factor for chikungunya virus infection is intensity of
transmission
–If equivalent transmission, cumulative duration of exposure important
Transmission patterns can be unpredictable over the longer term and likely to be some seasonal variation in mosquito activity that might
impact risk
*2-year period based on immunogenicity data showing high seroresponse rate (99%) at one year after vaccination
suggesting good protection at least through second year but no longer -term data
Evidence of chikungunya virus transmission among humans
within the last 5 years
Rationale: 5 -year time frame provides interval that allows reasonable
confidence there is transmission or insufficient transmission to be concern
for travelers
Tool: Map that shows countries
with chikungunya virus
transmission among humans
reported during last 5 years,
posted on CDC website
Mock map to demonstrate transmission of chikungunya virus among
humans during last 5 years
Moderate exposure
Moderate exposure could include travelers who might have at least 2
weeks (cumulative) of exposure to mosquitoes in indoor and/or
outdoor settings. It does not include travelers who might have limited exposure to mosquitoes (e.g., those traveling for business and likely to
be mainly in mosquito -protected indoor settings)
General considerations*
 All persons who travel to areas with possible chikungunya virus transmission should be advised to
take precautions to avoid mosquito bites
 The risk for chikungunya for most US travelers to countries or territories with evidence of
transmission is low. However, some travelers are at increased risk for infection or more severe
disease. In the discussion between the healthcare provider and traveler on the need for vaccination,
consideration should be given to
1) whether there is a recognized outbreak or ongoing disease activity
2) the duration of travel or residence, including likelihood of future travel to an area with
chikungunya virus transmission
3) the likelihood of exposure to Aedes mosquitoes
4) older age (e.g., >65 years)
5) underlying medical conditions that increase the risk for severe disease (e.g., diabetes, cardiac disease, hypertension)
6) underlying conditions that increase the risk for chronic arthralgia after infection (e.g., existing joint disease)
7) an individual’s personal perception and tolerance of risk
*Provided in background materials
Draft recommendations
Chikungunya vaccine is recommended for persons aged ≥18 years
traveling to a country or territory where there is a chikungunya
outbreak
In addition, chikungunya vaccine may be considered forthe following
persons traveling to a country or territory without an outbreak but
with evidence of chikungunya virus transmission among humans within
the last 5 years
–Older persons (e.g., >65 years), particularly those with underlying
medical conditions, who are likely to have at least moderate exposure* to mosquitoes
–Persons staying for a cumulative period of 6 months or more during a 2-year period
*Moderate exposure could include travelers who might have at least 2 weeks (cumulative) of exposure to mosquitoes in
indoor and/or outdoor settings

Summary: National Center for Emerging and Zoonotic Infectious Diseases EVIDENCE TO RECOMMENDATIONS FOR  CHIKUNGUNYA VACCINE USE AMONG  ADULT TRAVELERS Susan Hills, MBBS, MTH CDC Lead , Chikungunya Vaccines Work Group Arboviral Diseases Branch Division of Vector -Borne Diseases Fort Collins, Colorado ACIP meeting, October 26, 2023 Chikungunya virus and transmission Alphavirus  Primarily transmitted by Aedes  aegypti and Aedes albopictus Uncommon modes of  transmission –Laboratory exposure…