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Overview of mRNA -1647:
Investigational CMV Vaccine
ACIP
Robert Paris, MDApril 15, 2025
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Outline of Presentation
•Unmet medical need for a CMV vaccine
•Description of Moderna’s investigational CMV vaccine
•Overview of clinical program
•Phase 2 safety and immunogenicity study results
•Design of ongoing Phase 3 efficacy trial
•Summary
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Impact and Global Burden of Congenital CMV
Most common
congenital viral infection and non- genetic
cause of sensorineural hearing loss
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Major under -recognized
cause of miscarriage, stillbirth, preterm birth, and infant death
2-5
Significant Unmet Medical Need
High Priority for Vaccine Development by WHO & NAM
1. Boppana SB, et al. Vaccine. 2023;41:S53- S75. 2. Song X, et al. Front Pediatr . 2022;10:803568. 3. Iwasenko JM, et al. J Infect Dis. 2011; 203(11):1526- 1533. 4. Bryne J, et al. Am J Obstet Gynecol .
2015;213(6):905- 906. 5. Kimberlin DW, et al. 2021. Red Book: 2021– 2024 Report of the Committee on Infectious Diseases. American Academy of Pediatrics; doi:10.1542/9781610025782 -S3_037.
6. Ssentongo P, et al. JAMA Netw Open ; 2021;4(8):e2120736. 7. CDC | CMV in Newborns. Updated January 7, 2025. https://www.cdc.gov/cytomegalovirus/congenital -infectio n/index.html.
8. Grosse SD, et al. Perinatol . 2021;45(3):151393.
Congenital CMV: A Major
Public Health Burden
Annual Birth Prevalence
1 in 70 to
1 in 208
births6
~1 in 200
births7US Global $6-7 billion annual
healthcare costs in US (as of 2018)
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Management of congenital CMV challenging due to limited prevention, inconsistent screening, and lack of treatment options
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Economic & Clinical
Impact
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10%-15% Symptomatic at Birth
CMV -associated death occurs during in ~5%
of these infants
40%-58% develop long -term disability
Symptoms include hearing loss, cognitive
impairment, developmental delay, and
seizuresClinical Manifestations of Congenital CMV (cCMV)
May be present at birth & may develop or progress throughout childhood
Source: Dollard SC, et al. Rev Med Virol . 2007;17(5):355- 363. doi:10.1002/rmv.544
Infants with Congenital CMV ( cCMV )
85%-90% Asymptomatic at Birth
10%-15% develop long -term disability,
most commonly sensorineural hearing loss
~1 in 5 infants with cCMV (symptomatic or asymptomatic at birth)
develop long-term disability
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5CMV Vaccine Development Objective:
Prevent CMV Infection in CMV-seronegative Women
•Prevent CMV infection during pregnancy to reduce congenital CMV
•Vaccinate women of child -bearing potential prior to pregnancy
Current Focus
Women of
Childbearing Age
mRNA- 1647 vaccination
interrupts causal chain leading
to congenital infection
Fetus Infected
with CMVCMV infection in first
trimester presents highest risk of congenital disease
Pregnant
Women
•Prevention of CMV infection in females, 16 -40 years of age,
regardless of CMV serostatus
Indication
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Moderna’s Investigational CMV Vaccine (mRNA-1647) Composed of 6
mRNAs Designed to Elicit Humoral and Cellular immunity to CMV Infection
mRNA-1647 is an investigational vaccine, and the above diagram is for illustrative purposes only
CMV, cytomegalovirus; gB, glycoprotein B.
1. Diamond DJ, et al. Expert Rev Vaccines. 2018;17:889 -911. 2. John S, et al. Vaccine. 2018;36:1689- 1699. 3. Plotkin SA and Boppana SB. Vaccine. 2019;37:7437 -7442.
4. Kabanova A, et al. PNAS. 2014;111:17965- 17970. 5. Scarpani S, et al. Vaccines. 2021;9:1 -26. 6. Pass et al. N Engl J Med 2009;360: 1191- 9. 7. Bernstein, et al. Vaccine 2016; 34:313- 319.
•5 mRNAs encode the
pentamer subunits
•Required for CMV entry into most cell types, including epithelial and
endothelial cellsPentamer
•1 mRNA encodes
glycoprotein B
•Mediates fusion of virus and host membranes during cell entry
•Necessary for viral infectivity in all cell typesgB
•Antigen selection chosen to:
•Prevent CMV infection and subsequent fetal transmission
•Induce both humoral and cellular immune responses2-5
•43-50% efficacy for CMV infection in 2 previous trials of recombinant gB candidate vaccine1
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CMV Vaccine (mRNA -1647) Clinical Trials in Adults
Completed and ongoing trials
Population Study PhaseAge
(Years)mRNA -1647
Dose Levels
(µg)Objectives Study Start Status
Healthy
Adults101 1 18-49 30-300 Safety and immunogenicity Nov 2017 Completed
202 2 18-40 50-150Safety, immunogenicity, and
dose selectionJan 2020 Completed
202-
Extension2 18-40 50-150Safety and immune persistence May 2021 Ongoing
301 3 16-40 100Efficacy, safety, and
immunogenicity in femalesOct 2021 Ongoing
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Summary: mRNA-1647 Phase 1 Trial in Adults (18-40 Years)
•Data from Phase 1 allowed evaluation of an optimized dose range in Phase 2•Neutralizing antibody responses
•Exploratory analysis of cell mediated immunity Immunogenicity•Generally well tolerated; no new safety concerns identified Safety•Randomized, observer blind, placebo -controlled trial
•154 healthy participants, 18- 49 years of age (13- 19 per treatment group)
•80 CMV -seronegative and 74 CMV -seropositive
•Followed for 12 months after last doseDesign
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CMV mRNA -1647 Phase 2 Dose Selection Trial in 18 -40 Year Olds
•Primary: Safety and neutralizing antibody responses
•Secondary: Binding antibody responsesObjectivesDesign•Randomized (3:1), observer blind, placebo -controlled trial
•315 adult participants 18- 40 years of age (63- 109 per treatment group)
•218 CMV -seronegative and 97 CMV -seropositive participants
•Followed for 12 months after last dose
Dosing
3-Dose Series
(Month 0, 2 & 6)mRNA-1647 50 µg Placebo or
mRNA-1647 100 µg Placebo or
mRNA-1647 150 µg Placebo orPart 1: Dose Selection
mRNA-1647 100 µg Placebo orPart 2: Safety Expansion
•Focus of today’s presentation on 100 ug dose selected for further study
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10Solicited Local Reactions within 7 Days of injection
CMV mRNA -1647 Phase 2 Trial in Adults
0%20%40%60%80%100%
1 2 3 4 5 6 7 80%20%40%60%80%100%
Dose 1Injection Site Pain Injection Site Erythema Injection Site Swelling Axillary Swelling or
Tenderness
Dose 2
Dose 3
100 µg Placebo0%20%40%60%80%100%% Participants
Grade 3
Grade 2
Grade 1
100 µg Placebo 100 µg Placebo 100 µg Placebo
•Pain most frequent local reaction
•Local reactions mostly grade 1 or 2 and generally 1 -3 days duration
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11Solicited Systemic Reactions within 7 Days of Injection
CMV mRNA -1647 Phase 2 Trial in Adults
•Headache, fatigue, myalgia, and chills most common
•Some increase in systemic reactions with 2nd & 3rd dose
•Systemic reactions generally grade 1 or 2 of 1 -2 days duration0%20%40%60%80%100%
1 2 3 4 5 6 7 8 9 10 11 12 13 140%20%40%60%80%100%Fever Fatigue Myalgia Headache ArthralgiaNausea /
VomitingChills
Dose 1
Dose 2
Dose 30%20%40%60%80%100%% Participants
100 µg Placebo 100 µg Placebo 100 µg Placebo 100 µg Placebo 100 µg Placebo 100 µg Placebo 100 µg PlaceboGrade 3 -4*
Grade 2
Grade 1
*Only grade 4 reactions were fevers - 1 vaccine recipient & 1 placebo recipient after dose 1; 2 vaccine recipients after dose 2
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Incidence of Unsolicited Treatment Emergent Adverse Events
Within 28 Days After Vaccine/Placebo
CMV mRNA -1647 Phase 2 Trial in Adults (All Dose Levels)
mRNA -1647
N=235Placebo
N=80
All Related All Related
Participants reporting any adverse event (AE) 87 (37.0%) 42 (17.9% )29 (36.3%) 9 (11.3% )
Serious AEs 1 (0.4%) 0 0 0
Non-serious AEs 86 (36.6%) 42 (17.9% ) 29 (36.3%) 9 (11.3% )
Participants reporting clinically relevant events
Fatal 0 0 0 0
Medically -attended AEs 43 (18.3%) 17 (7.2% ) 17 (21.3%) 2 (2.5% )
Grade 3 or higher (all non- serious AEs) 26 (11.1%) 6 (2.6% ) 7 (8.8%) 0
AEs leading to discontinuation from study vaccine 7 (3.0%) 5 (2.1% ) 1 (1.3%) 0
AEs leading to discontinuation from study 0 0 0 0
•Related MAAEs higher in vaccine recipients; majority due to local reactions
•No significant safety concerns identified during study
Percentages based on number of events / total number of participants in either the mRNA -1647 group (n=235) or in the placebo gr oup (n=80), as applicable.
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Neutralizing Antibody Response to mRNA -1647 Based on Both
Epithelial and Fibroblast Cell Assays
Neutralizing
AntibodyVaccine Antigen Biological Relevance
Epithelial
cellPentamer•CMV infection of epithelial, endothelial,
myeloid cells requires pentameric complex
Fibroblast
cellgB•Essential for viral entry and cell fusion
•Used to assess antibody responses to gB and
other viral antigens
•Pentamer- specific antibodies not effectively
measured by this assay
•Today we will present neutralizing antibody data
•Analysis of T -cell data is ongoing
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110100100010000100000
0123456789101112131415161718Fibroblast Infection
Natural Infection
01 3 67 12 18 Month 2Neutralizing Antibody Response Demonstrated in
CMV Seronegative Adults
mRNA -1647 Phase 2 Trial
•Epithelial cell infecti on: GMTs Increased after each dose and remained above natural infection GMT through 18 months
•Fibroblast infecti on: GMTs reached natural infection GMT at months 3 & 7, then declined at months 12 & 18mRNA -1647 100 µg Placebo
1101001000100001000001000000
0123456789101112131415161718GMT
(95% CI)Epithelial Cell Infection
Natural Infection
01 3 67 12 18 Month 2
GMT – geometric mean titer; Natural infection defined as GMT at baseline in CMV seropositives
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1001000100001000001000000
0123456789101112131415161718Epithelial Cell Infection
Natural Infection
01 3 67 12 18 Month 2Neutralizing Antibody Response Demonstrated in
CMV Seropositive Adults
mRNA -1647 Phase 2 Trial
•GMTs for both assays remained above natural infection GMT through Month 18100100010000100000
0123456789101112131415161718Fibroblast Infection
01 3 67 12 18 Month 2mRNA -1647 100 µg Placebo
Natural Infection
GMT – geometric mean titer; Natural infection defined as GMT at baseline in CMV seropositives GMT
(95% CI)
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Phase 2 Extension Trial in Adults to Assess Persistence of Antibody
•Primary: Safety and neutralizing antibody -mediated immunogenicity
•Secondary: Binding antibody -mediated immunogenicityObjectivesDesign•3-year long -term follow -up of immunogenicity and safety in participants
who completed the phase 2 original study
•Provides ~4 years total follow -up after last vaccine dose
02 6 18 24 54 36Phase 2 Main Trial
18-Month Follow -upPhase 2 Extension Trial
Follow -up for Additional 3 Years
12 30 42 48Month
Vaccination
ESCMID, 2025
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Persistence of Neutralizing Antibodies Against Epithelial Cell
Infection Demonstrated Through 3 Years After Vaccination
Interim analysis of participants followed for 36 months
•Antibody GMTs remained stable
•nAb GMTs in CMV -seronegatives continued to exceed natural infection GMT through 3 yearsCMV-seronegative group
1101001000100001000001000000
0123456789101112131415161718192021222324252627282930313233343536GMT
(95% CI)
013 67 12 18 Month 2 24 30 36Natural InfectionmRNA -1647 100 µg (n=24)
Placebo (n=22)
ESCMID, 2025; GMT – geometric mean titer
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18Persistence of Neutralizing Antibodies Against Fibroblast Infection
Demonstrated Through 3 Years After Vaccination
Interim analysis of participants followed for 36 months
•Antibody GMTs remained stable through 3 yearsCMV-seronegative group
110100100010000100000
0123456789101112131415161718192021222324252627282930313233343536Natural Infection
GMT
(95% CI)
013 67 12 18 Month 2 24 30 36mRNA -1647 100 µg (n=24)
Placebo (n=22)
ESCMID, 2025; GMT – geometric mean titer
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Summary: mRNA-1647 Phase 2 Trial in Adults (18-40 Years)
NCT05085366•Persistence of neutralizing antibodies against epithelial cell infection
demonstrated through 3 years after vaccination in CMV -seronegative &
seropositive participantsPersistence of
Antibody•Generally well tolerated; no safety concerns identified
•3-dose 100 µg regimen regardless of serostatusSafety
•Highly immunogenic at 100 µg dose level
•Neutralizing antibody GMTs against epithelial cell infection remained above natural infection GMT through 12 months after the last
vaccination in CMV -seronegative participants
•Boosting effect observed in CMV -seropositive participantsImmunogenicity
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Design of mRNA-1647 Phase 3 Pivotal Efficacy Trial
Design •Randomized, observer -blind, placebo -controlled study
Study
Population•CMV -seronegative (80%) and CMV -seropositive females (20%), 16 - 40 years
of age
•Participants ≥ 20 years of age expected to have direct exposure in the
home, socially, or occupationally to at least one child ≤ 5 years of age
•Pregnancy was exclusionary
Treatment
Groups •Randomized 1:1 to receive 100 µg mRNA -1647 or placebo
•Doses at 0, 2, 6 months
Duration of
Follow -up•30 months
NCT05085366
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mRNA-1647 Phase 3 Trial: Key Objectives and Endpoints
ObjectiveCMV
SeronegativesCMV
Seropositives
Primary •Efficacy: Seroconversion from negative to
positive serum CMV IgG starting 28 days after
3rd injection
•Safety: Reactogenicity, adverse events
Secondary•Immunogenicity: Neutralizing and binding
antibody
Additional•CMV Viral Shedding: Kinetics of CMV shedding in
seronegatives who seroconverted
•CMV Viral Shedding: Longitudinal shedding in
urine of CMV seropositives
NCT05085366
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Phase 3 Pivotal Efficacy Trial in 16 –40-Year -Old Females
is Ongoing
•290 sites, 13 countries
•Enrollment completed Oct 2023
•7,484 participants enrolled
•5,987 (80%) CMV -seronegative
•1,497 (20%) CMV -seropositive
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mRNA-1647 Phase 3 Efficacy Trial: Two Planned Analyses
Interim Efficacy Analysis
•Independent Data Safety Monitoring Board (DSMB) conducted
comprehensive safety and efficacy evaluation, Dec 2024
•Notified Moderna that:
−No safety concerns identified
−Study should continue as planned in blinded manner
Final Efficacy Analysis
•Data anticipated late 2025
DSMB – Data Safety Monitoring Board
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Summary: Investigational CMV Vaccine mRNA -1647 in Adults
•Trial ongoing in seronegative and seropositive females, 16 -40 years of age Efficacy•Vaccine generally well tolerated in adults, 18 -40 years, regardless of CMV
serostatus, in Phase 1 & 2 trials
•No safety concerns identified from DSMB review of unblinded data in
Phase 3 efficacy trial.Safety
CMV Seronegatives:
•Vaccination elicited antibody- mediated immunogenicity that exceeded
levels observed in natural infection
•Immune persistence observed through 3 years after vaccination
CMV Seropositives:
•Vaccination boosted immune responses above baseline after first dose Immunogenicity
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THANK YOU•Investigators
•Study site personnel
•Laboratory personnel
•Most importantly, the individuals who
participated in these trials