01 Hoeg Danish vax schedule 508

Tracy Beth Høeg, M.D., Ph.D.
FDA Ex Officio to ACIP
Senior Advisor for Clinical Sciences
Office of the Commissioner (OC) &Center for Biologics Evaluation and Research (CBER)US Food and Drug Administration
Core Childhood Vaccination
Schedules: An International
Perspective with focus on
the US & Denmark
3
Danish- US double
citizen
MD (WI, USA- MCW),
Residency UC DavisPhD -Epidemiology &
Public Health (U
Copenhagen)
4
45 peer reviewed
publications -last 5
years focus on infectious disease
epidemiology &
vaccines
Before FDA was at
MIT Sloan & practicing physician
5
Core Childhood
Vaccines – as of
January 2025(assumes DTaP ,
HiB, IPV given
separately)
XX, 202X 6Assumes individual rather than
combined DTaP -Hib -HepB -IPV
vaccines given in US
ACIP April 2025-  US international outlier in yearly
COVID -19 vaccines for children
7
Core
Vaccines by Country as of January, 2025
8

Image Credit: Jonatan Pallesen 9
Core
Childhood Vaccines -As
of January 2025
Ipsunember XX, 202X 10
Aluminum exposure
in childhood
Center for Xxxxxx Xxxxx Xxxxxxxxxxxxxxxxxx
•Assumes individual
rather than combined DTaP -
Hib-HepB -IPV
vaccines given in US
•What is the “safe” bolus dose of parenteral aluminum in infancy?
11
What do we owe to our children?
Science -based recommendations
•Understand potential for absolute benefit in low
risk populations
•Understand the limitations in our knowledge about adverse effects
•Perform proper randomized, placebo -controlled
studies
•Continually monitor safety and update our recommendations based on evolving knowledge
•Vaccines treated like all medical products; may not be right for all children
12
What do we owe to our children?
Avoid overmedicalizing childhood
•Time in pediatricians’ offices can be spent
differently
•Less focus on medical products; more focus on healthy living
•Decreases overdiagnosis and overtreatment
13
What do we owe to our children?
Recommendations based on
data and not politics
•Manipulating data for political
reasons can be deadly
•Neo-Lamarkism /acquired genetics
•Silencing of opposing views
•Resulted in the death of potentially millions in the Chinese famine
14
Deaths
due to
polio, measlesDeaths and injuries due
to vaccines
15
USA - Political Polarization
Denmark
•Multi -party system
•Culture of Debate
•Transparent decision making
•Research culture (RCTs)
•Extensive documentation of
decision making about
vaccines
•Acknowledge Unknowns
•Promptly reverse
recommendationsHigher level of trust in Public Health Authorities
Undeniably a healthier
population
16

Does the US
have a good
track record in
terms of child
health?
17
Health Conditions -mental health disorders
Source: IHME -GHDx  18

Because the US has a larger high- risk population,
should the core childhood vaccination schedule be
larger  ?
•Should healthy children in the US receive different
vaccines than healthy children in Denmark?
•Root cause of diseases
19
Core Childhood
Vaccines -As of
January 2025
20What can we learn from
other countries?
Why do the US and Denmark have
such different core vaccination schedules?
Misconception:
 Because of differences in disease
prevalences
21
How do incidences and prevalences of
diseases compare?
US vs Denmark
Hepatitis B:
incidence in mothers & prevalence
of chronic Hepatitis B
https://journals.lww.com/ajg/fulltext/2020/09000/prevalence_of_chronic_hepatitis_b_virus_infection.20.aspx
https://www.cdc.gov/hepatitis -b/hcp/perinatal -provider- overview/index.html#cdc_generic_section_7 -infection -rates -and -
trend
Clinical Overview of Perinatal Hepatitis B | Hepatitis B | CDC
Efficacy of Selective Antenatal Screening for Hepatitis B Among Pregnant Women in Denmark: Is Selective Screening Still an
Acceptable Strategy in a Low -endemicity Country?: Scandinavian Journal of Infectious Diseases: Vol 35, No 6 -7 XX, 202X 23
Incidence of
Meningococcal Disease in
2023
https://www.cidrap.umn.edu/meningitis/cdc- data -show -sharp -rise -rates -meningococcal -disease .
https://en.ssi.dk/surveillance -and -preparedness/surveillance -in-denmark/annual- reports -on-disease -
incidence/m/meningococcal -disease -202324•<5/million in both the US and
Denmark

USA and Denmark Meningococcal Incidence over time
https://www.cdc.gov/acip/downloads/slides -2024 -10-23-24/01 -mening -Loehr- 508.pdf
https://ugeskriftet.dk/videnskab/vaccination- til-forebyggelse -af-meningokoksygdom
25

There has been an increase in Measles Cases in
the US and Europe
https://statistik.ssi.dk/sygdomsdata#!/?sygdomskode=M
EAS&xaxis=Aar&show=Graph&datatype=Individual 26
Measles Cases by Vaccination Status in Europe
https://www.ecdc.europa.eu/sites/default/files/documents/
MEAS -AER -2024-Report.pdf27

Measles Cases in Denmark Over Time
Ipsunember XX, 202Xhttps://statistik.ssi.dk/sygdomsdata#!/?sygdomskode=MEA
S&xaxis=Aar&show=Graph&datatype=Individual28
Vaccination
Rates by Age  5 in 2024
CDC. Vaccination Coverage and Exemptions among Kindergartners.  2025.
https://www.ssi.dk/vaccinationer/tilslutning -til-bornevaccinationsprogrammet -2024 29
2024 MMR vaccination
rates by state
The estimated critical
minimum vaccination threshold to prevent measles outbreaks is around 90%
https://publichealth.jhu.edu/sites/default/files/2024 -
09/Measles -Risk -Assessment-
Methodology_9.19.24.pdf
Ipsunember XX, 202X Center for Xxxxxx Xxxxx Xxxxxxxxxxxxxxxxxx 30

November 2025
31
Which countries
have or are at risk
of loss of measles elimination
status?
32Current numbers - December 2025
When and why do
citizens not trust
core childhood
vaccination
recommendations?
33Current numbers
Rubella
•Rubella can cause congenital rubella syndrome
•Has a community immunity threshold of 83 -85%
•Some pockets of America and entire states, such as
Idaho and Wisconsin, with average vaccination rates
below this, at risk of rubella outbreaks.
Otani N, Shima M, Ueda T, Nakajima K, Takesue  Y , Yamamoto T, Okuno T. Changes in the Epidemiology of Rubella: The Influence of Vaccine -Introducing Methods and COVID -
19. Vaccines (Basel). 2023 Aug 12;11(8):1358. doi: 10.3390/vaccines11081358. PMID: 37631927; PMCID: PMC10458369.
https://www.kff.org/medicaid/kindergarten -routine -vaccination- rates -continue -to-
decline/#:~:text=While%20measles%20has%20been%20officially,of%20an%20outbreak%20is%20higher34
Trust in US
healthcare decreased from 72% to 40%
35

Trust
decreased from 72% to 40%
Ipsunember XX, 202X 36

School based
vaccine mandates?
37
Focus on Denmark
The Current Core Childhood Vaccination Schedule
38

Denmark Core Childhood Vaccines
39

Core Vaccines
by Country as of January, 2025
40

Evolution of the
Core Vaccine Schedule in USA
41
Image Credit: Jonatan Pallesen 42
Danish Decision
Making about
Childhood
Vaccines
Examples of Child vaccines that were never or are no longer on the schedule43
COVID -19 Vaccine
Denmark was the first high income
nation to remove the COVID -19 vaccine
from childhood schedule
Ahead of the international curve
44
Head of Danish Ministry of health stating in June of
2022 that vaccinating children for COVID- 19 was a
mistake
Director of the Danish Health Authority: https://nyheder.tv2.dk/samfund/2022 -06-22-set -i-bakspejlet -fik-vi-ikke -meget -ud-af-at -vaccinere -
boernene -erkender -brostroem 45
Influenza Vaccine:
introduction for all
children ages 2- 6
in 2021 was
reversed in 2023
46
Pandemrix Vaccine History
•2009 H1N1 Pandemic Influenza
vaccine
•Side effects and narcolepsy Coverup/delayed reporting
•Never recommended for children in Denmark
•Now essentially of all Europe does not recommend seasonal influenza vaccine as core childhood vaccine
•1300 people with narcolepsy, mostly children
47

Hepatitis B Vaccine
•Hvis man indfører en vaccine,
som nogle vil opfatte som
mindre væsentlig , vil dette
kunne  påvirke den generelle
holdning  til vaccination i
negative retning .
•Resultatet heraf  kunne  være , at
det allerede eksisterende
program opnår lavere
tilslutning  i fremtiden .
https://www.sst.dk/ -
/media/Udgivelser/2004/hepatitis_b_180204, -d-,pdf.ashx48

Hepatitis B Vaccine
•If one includes a vaccine which
some consider less important,
it could negatively affect the view of vaccines in general.
•The result of this could be that
the current [vaccination]
program would have lower uptake.
https://www.sst.dk/ -
/media/Udgivelser/2004/hepatitis_b_180204, -d-,pdf.ashx49

Hepatitis B Vaccine: Targeted Program
https://www.eurosurveillance.org/cont
ent/10.2807/esw.10.44.02827-enhttps://www.ssi.dk/vaccinationer/risikogrupper/personer -med -sarlig- risiko -
for-hepatitis -b-
smitte#:~:text=Nogle%20grupper%20har%20dog%20en,Dag%200%20(evt.50•Substantial costs of hep B
vaccine coverage & low opportunity for benefit
•Population -wide
vaccination could not be justified from a health economics perspective
•List of high risk groups which have vaccination coverage

Meningococcal Vaccine
https://ugeskriftet.dk/videnskab/vaccination-til -
forebyggelse -af-meningokoksygdom51“Weekly writings for physicians”

Meningococcal Vaccine
https://ugeskriftet.dk/videnskab/vaccination-til -
forebyggelse -af-meningokoksygdom52•Opportunity for benefit among
non high risk children is very low
•Uncertainty about effectiveness
•Adding additional vaccines to
the core vaccine list may cause
some parents to opt out of other vaccines
•If the vaccine causes fevers in infant when given with other vaccines, this could have
negative consequences for
physicians and parents

Meningococcal Vaccine
https://ugeskriftet.dk/videnskab/vaccination-til -
forebyggelse -af-meningokoksygdom53
•List of high risk situations
•Asplenia
•Compliment deficiency
•Receiving Eculizumab (causes
compliment deficiency)
•Travel to high prevalence regions
•Meningococcal outbreak
•Required for study in the US
•Can be considered for student dormitory conditions

Rotavirus: rationale for not including
in Child Vaccination Schedule
•232 page document in Danish
describing the decision
•Will be reviewed again in the near future
•It has until now been the message of the Danish Ministry of Health that Denmark not introduce vaccines into the child vaccination schedule just because it is an option
•The Danish child vaccination program has… a goal of protecting children from infections that can be either deadly or have long term health consequences•Infection with rotavirus essentially never results in death or chronic consequences in a country like Denmark
•Literature review has not shown that this vaccine has an effect on children’s mortality
https://www.sst.dk/ -/media/Udgivelser/2012/Vaccination -mod -
rotavirus ---en -medicinsk -teknologivurdering/Vaccination-mod -
rotavirus -%E2%80%93-en -medicinsk -teknologivurdering.ashx54
Varicella Vaccine
Cons
•Worry that natural immunity is
stronger (they cite data supporting)
•Only 4% of genera/family physicians would recommend the vaccine to healthy children
•Insufficient data about long term effects
•Pros
•Denmark has a very low rate of stay -
at-home parents and they would
miss less work
https://www.speam.dk/files/21/skoldkoppevaccine_i_danm
ark.pdf .55

Varicella Vaccine
Cons
•Worry that natural immunity is
stronger (cite data supporting)
•Only 4% of family physicians would recommend the vaccine to healthy children
•Insufficient data about long term effects
Pros
•Denmark has a very low rate of stay -at-home parents and they
would miss less work
https://www.speam.dk/files/21/skoldkoppevaccine_i_danm
ark.pdf .56•bekymring  om, at immuniteten  er
•svagere  efter  vaccine.
•4% af de praktiserende læger synes at raske børn skal vaccineres mod skoldkopper,
•Fortsat utilstrækkelige data på langtidseffekten
•Gevinsten i Danmark kan være større end for mange andre lande, da andelen af hjemmegående mødre/fædre er lavere.

RSV Long Acting Monoclonal Antibodies
•Unfavorable imbalance in all cause mortality in all
four phase 3 randomized trials of standard dose
57

Ipsunember XX, 202X 58
Danish Child Vaccination Benefits
•Increase Trust in and Focus on Core Childhood Vaccines
•Based on thorough, transparent decision making and continually
updated and debated
•Prevent outbreaks of most deadly vaccine preventable diseases
•Equipoise=Opportunity for research
•Re-evaluate the evidence base for vaccines not currently on core
childhood vaccine schedule in Denmark with randomized trials
•Monitor Diseases such as Rotavirus; may be larger opportunity for
absolute benefit in the US population
59
Danish Vaccination Schedule Benefits
•Make more time for addressing overall health at doctors'
appointments/spend less time in the healthcare system/decrease
the medicalization of childhood
•Opportunity to better define high risk groups to target
•Improve informed consent
•Minimize coercion
60
Questions about Adopting the
Danish Schedule in the US
•Would it be appropriate to stop Varicella vaccine given high
vaccination uptake and chance of increasing average age of
chickenpox
•Perform thorough, updated Risk -Benefit analysis of evidence for 2
doses of HPV in girls and boys?
61
Questions about Adopting the
Danish Schedule in the US
•Would it be appropriate to stop Varicella vaccine given high
vaccination uptake and chance of increasing average age of
chickenpox
•Perform thorough, updated Risk -Benefit analysis of evidence for 2
doses of HPV in girls and boys?
62

FIN

Summary: Tracy Beth Høeg, M.D., Ph.D. FDA Ex Officio to ACIP Senior Advisor for Clinical Sciences Office of the Commissioner (OC) &Center for Biologics Evaluation and Research (CBER)US Food and Drug Administration Core Childhood Vaccination  Schedules: An International  Perspective with focus on  the US & Denmark 3 Danish- US double  citizen MD (WI, USA- MCW),  Residency UC DavisPhD -Epidemiology &  Public Health (U  Copenhagen) 4 45 peer reviewed  publications -last 5  years focus on infectious…


01 Griffin aluminum adjuvants 508

Considerations and Query for the
 Advisory Committee for Immunization Practices
Presented by Dr. Evelyn Griffin, MD, FACOG, IFMCP
Child/Adolescent Immunization Schedule Work Group
Vaccinations during Pregnancy Work Group
HPV Work GroupVaccines
and Aluminum Adjuvants
Background
Child/Adolescent Immunization Schedule Work Group Discussion
Objectives
ACIP Charter: provide “advice and guidance to the
Director of the CDC regarding the use of vaccines and
related agents”
•Consideration of an ACIP Adjuvant Work Group
•Educational forum
Some categories of vaccines:
•live attenuated (ie MMR), killed/subunit/recombinant, gene therapy -based
Many ingredients in vaccine products:
•Antigens
•Adjuvants
•Preservatives
•Stabilizers
•Surfactants
•Residuals
•Diluents
•(Adulterants in rare cases)Vaccine Overview
Some categories of vaccines:
•live attenuated (ie MMR), killed/subunit/recombinant, gene therapy -based
Many ingredients in vaccine products:
•Antigens
•Adjuvants
•Preservatives
•Stabilizers
•Surfactants
•Residuals
•Diluents
•(Adulterants in rare cases)
Each vaccine is unique, and each component may contribute to risk, safety, efficacy,
and effectiveness of a vaccine final drug product.Vaccine Overview
What is an Adjuvant?
•An adjuvant is any substance or compound added to a vaccine to enhance the
body’s immune response to the antigen (portion that mimics the pathogen).
•It stimulates the innate and adaptive immune responses to augment vaccine efficacy and longterm effectiveness.
Vaccine Overview:
Adjuvants
•Typically, only killed/subunit/recombinant – type vaccines include adjuvants.
•A large portion of the childhood and adolescent vaccine schedule and
vaccines given during pregnancy are formulated with adjuvants.
Does the FDA approve adjuvants?
•FDA approves final drug products, it does not approve adjuvants.
•There are no “FDA approved” adjuvants.Vaccine Overview:
Adjuvants
•Typically, only killed/subunit/recombinant – type vaccines include adjuvants.
•A large portion of the childhood and adolescent vaccine schedule and
vaccines given during pregnancy are formulated with adjuvants.
Are there Different Types of Adjuvants?
•Some adjuvants and adjuvant categories:
•Aluminum salts
•Oil-in-water emulsions
•Liposome-based
•Toll-Like Receptor (TLR) agonists
•Saponin (plant) -based
•Most killed/subunit/recombinant vaccines rely on aluminum salt -based
adjuvants (ABA).  Since the 1920s, these have been the most widely used
adjuvants in FDA-licensed human vaccines.
•Examples of ABA:  aluminum oxyhydroxide (Alhydrogel®) and aluminum hydroxyphosphate (Adju-Phos®)
Aluminum and Aluminum Salt Adjuvants

The only published/peer -reviewed study of aluminum blood levels observed in
infants after aluminum -adjuvant containing vaccine administration.
•Sample size (n= 15), serum aluminum levels measured before and 24 hours
after vaccination
•No significant detectable mean increase at 24h relative to pre-vax levels
•No long -term data, or organ distribution dataBiodistribution and Pharmacokinetics
Movsas et al. 2013
Current US Aluminum Exposure Limits
US Agency for Toxic Substances and Disease Registry (ATSDR) determined a
Minimum Risk Level (MRL) for orally ingested aluminum:
•Oral MRL ≈ 1 mg (1,000 mcg) Al/kg/day based on animal data
•Assumes  ~0.1% oral absorption
•Converted to an injected -equivalent threshold,
this approximates 1 mcg/kg/day
Current US Aluminum Exposure Limits
The U.S. Code of Federal Regulations (21 CFR 610.15(a))  limits aluminum in
vaccines to ≤0.85 mg (850mcg) per dose, regardless of age group.
•Flarend et al., 1997: Doses up to 850 mcg total IM aluminum (including aluminium hydroxide and aluminium phosphate adjuvants) in rabbits resulted in transient blood level increases that resolved quickly, with no acute or chronic adverse effects observed.
•This is still the current FDA -accepted benchmark for human vaccine adjuvant
dosing.
•Masson et al., 2018 examined the limitations of using the Flarend study as a basis for regulatory threshold setting.
Why Focus on Aluminum Dose in Vaccines?
•Infants receive multiple aluminum- containing vaccines in a single visit under the
current schedule.
•Dose per kilogram body weight is far higher in early infancy than in adults.
•Neonatal kidneys, blood –brain barrier, and detoxification systems are immature.
Why Focus on Aluminum Dose in Vaccines?
•Infants receive multiple aluminum- containing vaccines in a single visit under the
current schedule.
•Dose per kilogram body weight is far higher in early infancy than in adults.
•Neonatal kidneys, blood –brain barrier, and detoxification systems are immature.
*There are similar considerations for children
  and fetuses through pregnancy vaccination.
Multiple Aluminum Adjuvanted Vaccine Doses
Results in Cumulative Aluminum Exposure
The administration of one dose
each of Prevnar 20, PedvaxHIB,
Engerix -B, and Infanrix at one
visit delivers 1,225 mcg  of
aluminum.
PCV, Hib, HepB, and DTaP
vaccines are administered multiple times by 6mo of age.
The rate at which aluminum
from vaccines migrates from human muscle to the bloodstream is not known.
Vaccine Selection Can Double Aluminum
Exposure on the Same Schedule

"Term infants with normal renal function may also be at risk because of their
rapidly growing and immature brain and skeleton, and an immature blood -
brain barrier. Until they are 1 to 2 years old, infants have lower glomerular filtration rates than adults, which affects their kidney function. The agency is concerned that young children and children with immature renal function are at a higher risk resulting from any exposure to aluminum.”
Cited in the Federal RegisterUS FDA Child Health Concerns, June 2003
Aluminum Biodistribution
Experimental and clinical data suggest intramuscular injected aluminum
and aluminum salts can persist at the injection site, then migrate via immune cells to liver, spleen, and other organs including the brain.
"The distribution profile of aluminium
to tissues was the same for both adjuvants (AH and AP) kidney > spleen > liver > heart > lymph node > brain."
Gherardi RK et al
Macrophagic myofasciitis (MMF)
•Muscle biopsies show aluminum- containing macrophages in
granulomas at  prior IM vaccination injection sites (MMF lesions).
•Symptoms in many MMF patients: chronic myalgias, fatigue, and
cognitive difficulties.
•Causal link between injected aluminum or aluminum salts  (aluminum oxyhydroxide) to systemic symptoms is not universally accepted.
•Demonstrates long -term persistence of aluminum in human tissue.Persistence and Macrophagic Myofasciitis
•Exley and Mold, 2019: Aluminum in postmortem brain tissue of neurological
patients, reflecting cumulative environmental exposure
•Shoenfeld and Agmon- Levin, 2011: Auto Immune/Inflammatory Syndrome
Induced by Adjuvants
•Shaw and Tomljenovic, 2014: aluminum neurotoxicity
•Daley et al., 2023: Association between aluminum exposure from vaccines before age 24 months and persistent asthma at age 24 to 59 Months
•Emerging research in mechanisms of aluminum oxidative stress: mitochondrial dysfunction, and impaired energy metabolism, pro -inflammatory effects and
microglial activation, promotion of amyloidogenesis and disruption of metal homeostasis (i.e. iron)Aluminum Based Adjuvants:
Biocompatible and Always Well Tolerated?
Aluminum Adjuvant Toxicology:
Data Gaps and Ambiguity
•Currently available infant safety assessments rely on a small number of
toxicokinetic studies and modeled assumptions.
•No long -term human studies tracking vaccine- derived aluminum kinetics in infants
or children have been published.
•Critical reviews challenge absorption factors and clearance assumptions in influential models (e.g., Mitkus 2011)
•No large, prospective, well- controlled studies comparing neurodevelopmental or
autoimmune outcomes by cumulative aluminum dose have been performed or
published.
•No established safe dose of injected aluminum for fetuses, neonates and preterm
infants has been established.
•Existing toxicology and pharmacokinetic data are too sparse and model- dependent
to support definitive conclusions of safety at current cumulative doses.
Query for ACIP
How should ACIP continue to assess effectiveness and safety
of adjuvants in currently authorized vaccines on the schedule
(childhood/adolescent, adult, and vaccines during pregnancy),
and related implications of the entire schedule?
Additional discussion
•Should multiple aluminum- containing vaccines be administered on the same
day in early infancy?
•Should lower- aluminum formulations and spacing strategies be preferred
when possible?
•What research is needed to define a genuinely evidence- based safety
margin for injected aluminum?
•What prudent policy would reduce peak and cumulative aluminum exposure
in the most vulnerable while urgent research gaps are addressed?
Acknowledgement & Invitation
For Collaboration

Summary: Considerations and Query for the  Advisory Committee for Immunization Practices Presented by Dr. Evelyn Griffin, MD, FACOG, IFMCP   Child/Adolescent Immunization Schedule Work Group Vaccinations during Pregnancy Work Group  HPV Work GroupVaccines  and Aluminum Adjuvants Background Child/Adolescent Immunization Schedule Work Group Discussion Objectives ACIP Charter: provide “advice and guidance to the  Director of the CDC regarding the use of vaccines and  related agents”  •Consideration of an…


MMRV vaccine safety summary 508

Rapid Systematic Review of the Safety of MMRV Vaccine
A. Background
The measles -mumps -rubella -varicella (MMRV) vaccine (ProQuad, Merck) was licensed in the
United States in 2005 for use in children 12 months through 12 years of age. While not licensed
for use in the United States, Priorix -Tetra, a MMRV vaccine manufactured by GlaxoSmithKline ,
first received licensing in some European countries in 2006, and in Canada in 2007.  Both
ProQuad and Priorix -Tetra are tetravalent vaccines with similar measles, mumps, rubella and
varicella viral strain composition. [1]  Henceforth, any reference to MMRV in this report refers to
ProQuad, unless otherwise specified.
In 2006, the Advisory Committee on Immunization Practices (ACIP) noted that use of
combination vaccines, like MMRV, was preferred over separate injections of equivalent component vaccines (e.g., MMR vaccine and varicella vaccine  [MMR+V] ).[2]  Post- licensure
safety surveillance data indicated an increased risk for febrile seizures following the administration of the first dose of MMRV among children aged 12- 23 months compared to
those receiving separate MMR and varicella vaccines. [3]  Based on this data, ACIP and the
Centers for Disease Control and Prevention updated its guidance to note that the first dose of
MMR and varicella vaccines are preferred to be given separately in this age group, but MMRV
may be used as a first dose in chi ldren aged 12 -47 months based on parent or caregiver
preference. [4]  Given the importance of maintaining a thorough awareness and assessment of
MMRV vaccine safety publications, we propose a  review of the literature assessing  MMRV
vaccine safety to inform the public and healthcare providers, and aid in public health policy discussions.
B. Methods
B.1. Key Question Development
The below question is formulated according to the P I/ECO(ST)  strategy, and for this review,
those elements include and are not limited to  those identified in Table 1.
1. For children aged 12 months to 12 years, what is the safety of MMRV vaccine?
Table 1
PI/ECO(ST) Criteria for Key Question
PI/ECO(ST)
Element   Criteria
Population  Pediatric population that includes:
o Infants and toddlers aged 12 months – 23 months
o Young children and children aged 12 months – 12 years
Intervention or
Exposure  MMRV vaccination. Including ProQuad, Priorix -Tetra, and brand
unspecified.
Comparator (if
applicable)  Any or  none
Outcome(s)  Adverse events
PI/ECO(ST)
Element   Criteria
Adverse outcomes
Safety outcomes
Side effects
Setting  Any
Time Frame  Any publication years
B.2. Literature Search
A CDC informationist (J.T.) developed search strategies from the Key Question and PI/ECO
criteria, and performed the search in MEDLINE, EMBASE, CINAHL, and Cochrane Library from the start of each database to August 1, 2025. Search strategies and results ar e provided in
Table 3  in the Appendix .
B.3. Study Selection
Results of the literature searches were uploaded into EndNote 21 (Clarivate Analytics©, Thomson Reuters, New York, NY, USA), duplicate records were removed, and unique titles and abstracts were uploaded to Covidence (Veritas Health Innovation Ltd., Melbourne, VIC, Australia) where a second round of deduplication was conducted. Three reviewers (JR, EQ, JS)
independently screened all titles and abstracts and removed irrelevant references;
disagreements were resolved by consensus . Relevant full texts were scre ened independently
by three reviewers (JR, EQ, JS); disagreements were resolved by consensus. All studies were screened according to the pre -identified exclusion criteria below, and results of the study
selection process are provided in Figure 1 .
 Criteria for excluding studies from the literature review include:
1. No full text available;

2. Not available in English;
3. Pre-licensure clinical trials;
4. Not relevant to key question;
5. No primary data  or analysis,  or secondary data not systematically collected;
6. Insufficient methodologic reporting (i.e., meeting abstract or poster);
7. Study population includes participants <12 months or >12 years of age; or
8. Indeterminate age range of study population receiving vaccine.

   Figure 1. Results of the Study Selection Process

Identification
Studies screened (n = 326)
Studies sought for retrieval (n = 117 )
Studies assessed for eligibility (n = 117 )     References removed (n = 8)
Duplicates identified manually (n = 8 )
Duplicates identified by Covidence (n = 0 )
Marked as ineligible by automation tools (n =  0)
Other reasons (n = 0 )
Studies excluded (n = 191 )
Studies excluded (n = 107 )
Pre-licensure clinical trial  (n = 40)
No English translation available  (n = 1 )
No vaccine safety outcomes assessed  (n = 5)
Wrong study design, including
commentary/editorial , case report, case series
without primary analysis (n = 11 )
Coadministration of intervention with other
vaccines  (n = 4 )
Wrong intervention (intervention -specific data
not included in study)  (n = 20)
Study participants age not limited to 12 months
to 12 years  (n = 6 )
Studies included in review (n =  10)
Screening  Studies from databases/registers (n = 334 )
Embase  (n = 200)
MEDLINE  (n = 111)
Cochrane Library  (n = 20)
CINAHL  (n = 3 )
B.4. Data Extractio n and Outcome Summarization
Data from studies meeting inclusion criteria were independently extracted by four reviewers using
a standardized Microsoft Excel (2021) form, and differences were reconciled by discussion. Outcome data were extracted as presented in the studies. For the purposes of this review,
statistical significance was defined as p ≤ 0.05. The evidence was summarized and  synthesized for
each outcome domain.
C. Summary of Evidence
C.1. Summaries of Evidence
A review of literature was conducted addressing  safety of  MMRV vaccine (ProQuad  or Priorix -Tetra ).
This review focused on the v accine safety  for children aged 12 months to 12 years of age.  Priorix -
Tetra is not licensed for use in the United States, but was included in the review due to a similar
viral strain composition as the ProQuad formulation and a desire to report on comprehensive
MMRV safety data .  Additionally, this review focused on safety data related to post- licensure
studies, and did not include studies that did not present data on MMRV administration without
other vaccines coadministered on the same day. Refer to Secti on B3 for full exclusion criteria for
this review.   The 10 studies reviewed are listed in Table 2.   In the narrative text below , studies
performed in the United States are  presented first, and have a brief summary introduction for each
outcome discussed ; studies performed outside of the United States are briefly summarized under
the international heading s.

Table 2
Characteristics of  studies meeting inclusion criteria
Lead a uthor
last name ,
year of
publication  Study design  MMRV  trade
name
(ProQuad  or
Priorix -
Tetr a) Data
collection period Sample
size, N  Surveillance
system (if applicable)  Country
Cocchio,
2016[5]  Prospective
cohort  Priorix -Tetra  August 1,
2013 – July
31, 2014  10395  Not reported  Italy
Deichman,
2015[6]  Randomized
comparative
study  ProQuad  January 12,
2007 –
February 13,
2008 947  Not reported  Germany
and Italy
Haas, 2019 [7] Randomized
comparative
study  ProQuad  Pre-2019,
otherwise not defined  405  Not reported  France
Hambidge,
2014[8]  Self -controlled
case series  ProQuad  2004 – 2010  5667  Vaccine Safety
Datalink  United
States
Jacobsen,
2009[9]  Retrospective
cohort  ProQuad  February
2006 – June
2007 62596  Kaiser
Permanente
Southern
California
electronic data
system  United
States
Klein,
2010[10]  Self -controlled
case series  ProQuad  2000 – 2008  459461  Vaccine Safety
Datalink  United
States
Klein,
2012[11]  Retrospective
cohort  ProQuad  2006 -2008
for MMRV
2000 – 2008
for MMR + V  154188  Vaccine Safety
Datalink  United
States
MacDonald,
2014[12]  Retrospective
cohort  Priorix -Tetra  2006 – 2012  277774  Canadian
Institute for Health
Information
database  Canada
O’Leary,
2011[13]  Self -controlled
case series  ProQuad  2000 – 2009  1.8 million  Vaccine Safety
Datalink  United
States
Rowhani -
Rahbar,
2013[14]  Retrospective
cohort  ProQuad  2001 -2011  840348  Vaccine Safety
Datalink  United
States
Table 3
Selected outcomes reviewed in studies meeting inclusion criteria
Lead author last name,
year of publication  MMRV trade
name (ProQuad
or Priorix -Tetra)  Country  Outcome(s)  summarized
Cocchio, 2016 [5] Priorix -Tetra  Italy  Febrile seizure, afebrile seizure, fever,
irritability, parotid swelling, arthralgia,
local reaction s (pain, swelling,
redness )
Deichman, 2015 [6] ProQuad  Germany and Italy  Febrile seizure,  fever, irritability,  local
reactions (pain, swelling, redness)
Haas, 2019 [7] ProQuad  France  Fever, mumps -like illness
Hambidge, 2014 [8] ProQuad  United States  Seizure  (not otherwise specified)
Jacobsen, 2009 [9] ProQuad  United States  Febrile seizure
Klein, 2010 [10]  ProQuad  United States  Febr ile seizure
Klein, 2012 [11]  ProQuad  United States  Febrile seizure , fever
MacDonald, 2014 [12]  Priorix -Tetra  Canada  Seizure (not otherwise specified)
O’Leary, 2011 [13]  ProQuad  United States  Immune thrombocytopenic purpura
Rowhani -Rahbar, 2013 [14]  ProQuad  United States  Seizure  (not otherwise specified ),
fever

Neurologic al outcomes
Febrile seizure
 One retrospective cohort (Jacobsen, 2009) and one self- controlled case series within the
Vaccine Safety Datalink (VSD)  (Klein, 2010) suggested an increased risk for febrile seizures
following MMRV vaccination compared to separately administered MMR and varicella vaccines on
the same day  in children aged 12 -60 months and children aged 12 -23 months, respectively.
Another retrospective cohort within VSD  (Klein, 2012) suggested that MMRV and MMR + V were not
associated with increased risk of febrile seizures among children aged 4 -6 years old.
• Retrospective cohort (Jacobsen , 2009)  of 62596 children aged 12 -60 months who either
received MMRV vaccination (n=31298) or MMR+V vaccination given separately at the same visit
(n=31298).   The study identified 84 cases of confirmed febrile convulsion; there were 1.41/1000
(n=44) confirmed febrile convulsion diagnoses in the MMRV cohort, and 1.28/1000 (n=40) confirmed febrile convulsion diagnoses in the MMR+V cohort.  The analysis suggested  no
significant difference between MMRV and MMR+V in confirmed febril e convulsion in the 30
days following vaccination (RR=1.1 [95% CI, 0.72 -1.69]).  In days 5 -12 following vaccination, the
study identified 32 cases of confirmed febrile convulsion, with 0.7/1000 (n=22) confirmed
febrile convulsion diagnoses in the MMRV cohort, and 0.32/1000 (n=10 ) confirmed febrile
convulsion diagnoses in the MMR+V cohort; there was a suggested increased risk in the MMRV
cohort in the 5 -12-day post -vaccination window (RR=2.2 [95% CI, 1.04 -4.65]).
• Self-controlled case series (Klein , 2010)  analyzed 459461 healthy children aged 12 -23 months
within VSD , comparing MMRV vaccine recipients (n=83107) to recipients of MMR + V vaccines
given on the same day (n=376354).  The analysis suggested an increased risk for febrile seizures
after MMRV compared to separately administered same -day MMR and V vaccines (RR= 1.98
[95% CI, 1.43 -2.73]); the excess risk per 10,000 doses was 4.6 (95% CI, 2.8 -5.9).
• Retrospective cohort study  (Klein , 2012)  of 154188 children aged 4 -6 years  within VSD  analyzed
whether MMRV (n=86750) or same -day MMR+V (n=67438) affects risk for febrile seizure.  There
was one febrile seizure 7 -10 days after MMRV and 0 after MMR+V.  Febrile seizure risk was 1 per
86750 MMRV doses (95% CI, 1 per 3426441, 1 per 15570), and  0 per 67438 MMR+V doses (95%
CI, 0, 1 per 18282).

Seizure (not otherwise specified)
A self -controlled case series within VSD  (Hambidge, 2014)  suggested an association of more
postvaccination seizures in delayed MMRV vaccination (administered between age 12-15 months )
compared to on- time MMRV vaccination (administered between age 16-23 months) .
A retrospective cohort within VSD  (Rowhani -Rahbar , 2013) found that the incidence of seizures
during the 7 -10 days following immunization with MMRV was significantly greater than that
following immunization with MMR with or without varicella administered separately on the same
day.   The study suggested a 2 -fold increase in the risk of seizures in the 7 -10 days following MMRV
vaccination  compared with MMR administered with or without varicella vaccine in both younger (12
to 15 months of age) and older childr en (16 to 23 months of age).
• Self-controlled case series within VSD  (Hambidge , 2014) analyzed timely versus delayed early
childhood vaccination in a cohort of 5667 children with diagnosis of first seizure between 38 and 730 days of life.  For on -time MMRV vaccination (administered at age 361 – 488 days), the
IRR for seizure in the 7 -10 day s after vaccination was 4.95 (95% CI, 3.68 -6.66). For delayed
receipt of MMRV (administered at age 489 -730 days), the IRR was 9.8 (95% CI, 4.35 -22.06).  The
vaccine -seizure association was most pronou nced if MMRV vaccine was administered
between 16 and 18 months of age (IRR 11 [95% CI, 4.26 -28.38]).
• Retrospective cohort study  within VSD  (Rowhani -Rahbar , 2013)  examined the effect of age on
the risk of fever and seizures following immunization with measles- containing vaccines in
children aged 12 to 23 months of age (N =840348). A MMRV vs MMR +/ - V cohort analysis in
participants aged 12 -15 months indicated an in creased risk in seizures among MMRV
recipients (IRR 2.0 [95% CI, 1.4 -2.8]), with an excess risk of 4.2 cases per 10000 doses (95% CI,
1.8-16.3). A MMRV vs MMR +/-  V cohort analysis in participants aged 16 -23 months indicated an
increased risk in seizures among MMRV recipients (IRR 2.1 [95% CI, 1.3 -3.3]), with an excess
risk of 9 cases per 10000 doses (95% CI, 1.8 -16.3).  The relative risk of seizure during the 7 -10
days following MMRV immunization (MMR with or without varicella administered separately on
the same day as the reference) was not statistically different between children 16 to 23 months
of age and those 12 to 15 months of age.  The attributable risk of seizures during the 7 -10 days
following MMRV immunization (MMR with or without varicella admi nistered separately on the
same day as the reference) was greater among children 16 to 23 months of age than among
children 12 to 15 months of age; however, the difference did not gain statistical significance .

MMRV vaccine safety in international settings  – Neurological outcomes
• One prospective cohort from Italy  (Cocchio , 2016) of 10395 healthy fourteen -month old
children eligible for their first vaccination against measles, mumps, rubella, and varicella assessed adverse events relating to two different vaccination strategies: Priorix -Tetra
vaccination (n=5265) or separate MMR and varicella vaccination administered on the same day
(n=5130).  This study repor ted no difference in risk of febrile seizure following MMR + V
compared to Priorix -Tetra  [RR 0.80 (95% CI, 0.30 -2.15)] or afeb rile seizure following MMR +
V compared to Priorix -Tetra  [RR 2.05 (95% CI, 0.18 -22.6)].
• One randomized comparative study  (Deichmann, 2015) of 947 healthy German and Italian
children aged ≥12 to <24 months randomly assigned the children to one of three vaccination
arms in a 2:1:1. Group 1 received one MMRV dose and one hexavalent vaccine concomitantly
at separate injection sites, group 2 received MMRV only, and group 3 received the hexavalent
vaccine only.  In the MMRV -only group (n=234), no participants were reported to have febrile
convulsion within 0 -28 days following vaccination .
• One retrospective cohort study from Canada  (MacDonald , 2014)  compared the risk of
seizures after the first dose of Priorix -Tetra  with the risk after same -day administration of
separate MMR + V in 277774 children aged 12 to 23 months.  The risk of seizures 7 -10 days
after vaccination was twice as high with Priorix -Tetra  as with MMR + V (RR 1.99 [95% CI,
1.3-3.05]).  The excess absolute risk of seizures was 3.52 seizures per 10000 doses of
Priorix -Tetra  relative to MMR_V.  In high -risk children (those with a pe rsonal history of febrile
seizure; seizure disorder; central nervous system injury, infection or neoplasm;
encephalopathy; or a progressive, evolving or unstable neurologic condition), the risk was not
differentially higher fo r Priorix -Tetra  (RR 1.3 [95% CI, 0.6 -2.79]).

Systemic reaction  outcomes
Fever
A retrospective cohort within VSD  (Klein, 2012) reported that there was no  apparent  peak in
outpatient fever visits during days 7 to 10 after MMRV, MMR or varicella vaccines , and that
outpatient fever visits 7 to  10 days were not significantly higher after MMR + V than after MMR
alone, although there was a trend in that direction.
Another retrospective cohort study  within VSD  (Rowhani -Rahbar, 2013)  found that the
incidence of fever during the 7 -10 days following immunization with MMRV was significantly greater
than that following immunization with MMR with or without varicella administered separately on
the same day.  The study suggested a 1.4-fold increase in the risk of fevers  in the 7 -10 days
following MMRV vaccination compared with MMR administered with or without varicella vaccine in
both younger (12 to 15 months of age) and older children (16 to 23 months of age).
• The Klein (2012) r etrospective cohort within VSD reported o utpatient fever visits for MMRV
recipients occurred at an adjusted rate of 5.2 per 100 person- years (95% CI, 3.9 -6.8)) in the 7 -
10-day post -vaccination window, and 5 per 100 person- years (95% CI, 4.5 -5.4) in the 0 -42-day
post -vaccination window. Outpatient fever visits for MMR+V recipients occurred at an adjusted
rate of 8.8 per 100 person -years (95% CI, 6.2 -12) in the 7 -10-day post -vaccination window, and
6.4 per 100 person -years (95% CI, 5.7 -7.2) in the 0 -42-day post -vaccination window.
• The Rowhani -Rahbar (2013) r etrospective cohort within VSD  reported that a MMRV vs MMR +/ -
V cohort analysis in participants aged 12 -15 months indicated an increased risk in fever among
MMRV recipients (IRR 1.4 [95% CI, 1.3 -1.5]), with an excess risk of 8.9 cases per 10000 doses
(95% CI, 3.2 -15.2); in a cohort of participants age d 16 -23 months the IRR was 1.4 (95% CI, 1.1 -
1.7).

MMRV vaccine safety in international studies  – systemic reactions outcomes
• Randomized comparative study  (Deichmann , 2015) of 947 healthy German and Italian
children aged ≥12 to <24 months randomly assigned the children to one of three vaccination
arms in a 2:1:1. Group 1 received one MMRV dose and one hexavalent vaccine concomitantly
at separate injection sites, group 2 recei ved MMRV only, and group 3 received the hexavalent
vaccine only.  In the MMRV -only group (n=234), 61.1% (n=143) were reported to have a t least
one rectal (or equivalent) temperature ≥38 degrees Celsius  within 0 -28 days following vaccination
(48 of those study participants were reported to have at least one rectal (or equivalent )
temperature  ≥39.4 degrees Celsius) ; 1.3% (n=3) were reported to have irritability  within 0 -28
days following vaccination; no participants were reported to have mumps/mumps- like illn ess
within 0 -28 days following vaccination.
• One prospective cohort from Italy  (Cocchio , 2016) of 10395 healthy fourteen -month old
children eligible for their first vaccination against measles, mumps, rubella, and varicella
assessed adverse events relating to two different vaccination strategies: Priorix -Tetra
vaccination (n=5265) or separate MMR and varicella vaccination administered on the same day
(n=5130).   The findings suggested a decreased risk of fever ≤ 39.4 degrees Celsius following
MMR + V compared to Priorix -Tetra  [RR 0.58 (95% CI, 0.54 -0.63)]. This study reported no
difference in risk of fever ≥ 39.5 degrees Celsius  following MMR + V compared to Priorix -Tetra
[RR 0.80 (95% CI , 0.69 -1.00)] , an increased risk of irritability  following MMR + V compared to
MMRV*  [RR 1.35 (95% CI, 1.21 -1.51)] , increased risk of parotid swelling following MMR + V
compared to  Priorix -Tetra  [RR 1.73 (95% CI, 1.02 -2.92)] , and an increased risk of arthralgia
following MMR + V compared to Priorix -Tetra  [RR 1.82 (95% CI, 1.17 -2.82)] .
• Randomized comparative study  (Haas , 2019) of 405 healthy French children aged 12 -18
months compared intramuscular (IM) and subcutaneous (SC) administration of two doses of MMRV given one month apart.  In the 0 -28 days following the first MMRV dose administered by
IM route (n=202) or by SC route (n=203 ), vaccine -related pyrexia  was reported in 35.6% (n=72)
and 39.4% (n=80) of recipients, respectively ; and mumps/mumps -like illness  was reported in
the 0.5% (n=1) and 0% (n=0) of participants, respectively . In the 0 -28 days following the second
MMRV dose administered by IM route (n=201) or SC route (n=200), vaccine -related pyrexia
was reported in 16.9% (n=34) and 17% (n=34) of participants, respectively ; and
mumps/mumps -like illness  was reported in the 0.5% (n=1) and 0% (n=0) of participants,
respectively .
Local reactions outcomes
There were no studies from the United States in this review that assessed local reactions
outcomes.
MMRV vaccine safety in international studies – pain outcome
• One prospective cohort from Italy  (Cocchio , 2016) of 10395 healthy fourteen -month old
children eligible for their first vaccination against measles, mumps, rubella, and varicella
assessed adverse events relating to two different vaccination strategies: Priorix -Tetra
vaccination (n=5265) or separate MMR and varicella vaccination administered on the same day (n=5130).   The findings suggested an increased risk of pain following MMR+V compared to
Priorix -Tetra  [RR 3.33 (95% CI, 2.79 -3.98)].
• One randomized comparative study  (Deichmann, 2015) of 947 healthy German and Italian
children aged ≥12 to <24 months randomly assigned the children to one of three vaccination
arms in a 2:1:1. Group 1 received one MMRV dose and one hexavalent vaccine concomitantly
at separate injection sites, group 2 received MMRV only, and group 3 received the hexavalent
vaccine only.  In the MMRV -only group (n=234), 14.1% (n=33) were reported to have injection-
site pain within 0 -28 days following vaccination. owing vaccination  in groups 1 and 3,
respectively .
MMRV vaccine safety in international studies – swelling  outcome
• One prospective cohort from Italy  (Cocchio , 2016) of 10395 healthy fourteen -month old
children eligible for their first vaccination against measles, mumps, rubella, and varicella assessed adverse events relating to two different vaccination strategies: Priorix -Tetra
vaccination (n=5265) or separate MMR and varicella vaccination administered on the same day
(n=5130).  The findings suggested an increased risk of swelling following MMR + V compared
to Priorix -Tetra  [RR 3.38 (95% CI, 2.45 -4.68)].
• One randomized comparative study  (Deichmann, 2015) of 947 healthy German and Italian
children aged ≥12 to <24 months randomly assigned the children to one of three vaccination arms in a 2:1:1. Group 1 received one MMRV dose and one hexavalent vaccine concomitantly at separate injection sites, group 2 received MMRV only, and group 3 received the hexavalent
vaccine only. In the MMRV -only group (n=234), 2.6% (n=6) were reported to have injection -site
swelling  within 0 -28 days following vaccination.
MMRV vaccine safety in international studies – redness outcome
• One prospective cohort from Italy  (Cocchio , 2016) of 10395 healthy fourteen -month old
children eligible for their first vaccination against measles, mumps, rubella, and varicella
assessed adverse events relating to two different vaccination strategies: Priorix -Tetra
vaccination (n=5265) or separate MMR and varicella vaccination administered on the same day
(n=5130).  The findings suggested an increased risk of redness following MMR + V compared
to Priorix -Tetra  [RR 4.89 (95% CI, 3.73 -6.42)].
• One randomized comparative study  (Deichmann, 2015) of 947 healthy German and Italian
children aged ≥12 to <24 months randomly assigned the children to one of three vaccination
arms in a 2:1:1. Group 1 received one MMRV dose and one hexavalent vaccine concomitantly at separate injection sites, group 2 received MMRV only, and group 3 received the hexavalent
vaccine only.  In the MMRV -only group (n=234), 10.7% (n=25) were reported to have injection
site erythema  within 0 -28 days following vaccination.

Hematologic al outcome
Immune thrombocytopenic purpura  (ITP)
• A self -controlled case series  (O’Leary, 20 11) with a cohort of 1.8 million children aged 6
weeks to 17 years within VSD  identified a total of 197 chart- confirmed ITP cases.  The analysis
indicated no significant elevated risk of ITP in MMRV recipients aged 12 -19 months within
the 1 - to 42 -day post -vaccination window (IRR 2.87 [95% CI, 0.78 -10.56].
Appendix
Table 3
Primary search strategy of MEDLINE (OVID), Embase (OVID), Cochrane Library CINAHL
(EBSCOHost),
DATABASE  STRATEGY  RUN DATE  RECORD
COUNT
Medline
(OVID)
1946-  1. (Measles -Mumps -Rubella -Varicella OR chickenpox measles
mumps rubella vaccine OR MMRV OR ProQuad).mp
2. Exp Safety/ OR exp Treatment Outcome/ OR "Drug -Related
Side Effects and Adverse Reactions"/
3. (safety OR (vaccin* ADJ2 safe*) OR treatment outcome* OR
adverse* OR harm OR harmful OR harms OR side
effect*).ti,ab,kf. OR ae.fs
4. 2 OR 3
5. Exp Clinical Study/ OR exp Product Surveillance, Postmarketing/
6. (trial* OR observational stud* OR observation stud* OR
clinical stud* OR surveillance OR reporting system* OR VAERS OR postmarket* OR post -market*).ti,ab,kf,hw.
7. 5 OR 6
8. 1 AND 4 AND 7
9. Exp animals/ NOT exp humans/
10. 10 NOT 11
 08/1/2025  111
Embase
(OVID)
1947-  1. chickenpox measles mumps rubella vaccine/
2. (Measles -Mumps -Rubella -Varicella OR chickenpox measles
mumps rubella vaccine OR MMRV OR ProQuad).ti,ab,kf.
3. 1 OR 2
4. Exp Safety/ OR exp Treatment Outcome/ OR adverse drug reaction/
5. (safety OR (vaccin* ADJ2 safe*) OR treatment outcome* OR adverse* OR harm OR harmful OR harms OR side effect*).ti,ab,kf. OR ae.fs
6. 4 OR 5
7. Exp Clinical Study/ OR exp Postmarketing Surveillance/
8. (trial* OR observational stud* OR observation stud* OR clinical stud* OR surveillance OR reporting system* OR VAERS OR postmarket* OR post -market*).ti,ab,kf,hw.
9. 7 OR 8
10. 3 AND 6 AND 9
11. Exp animal/ NOT exp human/
12. 10 NOT 11
13. limit 12 to "pubmed/medline"   08/1/2025  297

-
DUPLICATES

=200
UNIQUE
RECORDS
DATABASE  STRATEGY  RUN DATE  RECORD
COUNT
14. 12 NOT 13
15. limit 14 to conference abstract status
16. 14 NOT 15
17.
Cochrane
Library
 #1 (Measles -Mumps -Rubella -Varicella:ti,ab,kw OR “chickenpox
measles mumps rubella vaccine”:ti,ab,kw OR MMRV:ti,ab,kw
OR ProQuad:ti,ab,kw)
#2 [mh Safety] OR [mh "Treatment Outcome"]
#3 (safety:ti,ab,kw OR (vaccin*:ti,ab,kw NEAR/2 safe*:ti,ab,kw)
OR ("treatment" NEXT outcome*):ti,ab,kw OR adverse*:ti,ab,kw OR harm:ti,ab,kw OR harmful:ti,ab,kw OR
harms:ti,ab,kw OR ("side" NEXT effect*):ti,ab,kw)
#4 #2 OR #3
#5 [mh ^"Clinical Study"] OR [mh ^"Product Surveillance,
Postmarketing"]
#6 (trial*:ti,ab,kw OR ("observational" NEXT stud*):ti,ab,kw OR
("observation" NEXT stud*):ti,ab,kw OR ("clinical" NEXT stud*):ti,ab,kw OR surveillance:ti,ab,kw OR ("reporting" NEXT system*):ti,ab,kw OR VAERS:ti,ab,kw OR postmarket*:ti,ab,kw OR post -market*:t i,ab,kw)
#7 #5 OR #6
#8 #1 AND #4 AND #7
 08/1/2025  54

-
DUPLICATES

=20
UNIQUE
RECORDS
CINAHL
(EBSCOHost)  S1 (Measles -Mumps -Rubella -Varicella OR “chickenpox measles
mumps rubella vaccine” OR MMRV OR ProQuad)
S2 (MH Safety+) OR (MH "Treatment Outcomes+") OR (MH
"Adverse Drug Event+")
S3 ((TI safety OR AB safety OR SU safety) OR ((TI vaccin* OR AB
vaccin* OR SU vaccin*) N2 (TI safe* OR AB safe* OR SU safe*)) OR (TI "treatment outcome*" OR AB "treatment outcome*" OR SU "treatment outcome*") OR (TI adverse* OR AB adverse* OR SU adverse*) OR (TI harm OR AB harm OR SU
harm) OR (TI harmful OR AB harmful OR SU harmful) OR (TI
harms OR AB harms OR SU harms) OR (TI "side effect*" OR AB
"side effect*" OR SU "side effect*"))
S4 S2 OR S3
S5 (MH "Clinical Study+") OR (MH "Product Surveillance,
Postmarketing+")   08/1/2025  5

-
DUPLICATES
 =3
UNIQUE RECORDS
DATABASE  STRATEGY  RUN DATE  RECORD
COUNT
S6 ((TI trial* OR AB trial* OR SU trial*) OR (TI "observational
stud*" OR AB "observational stud*" OR SU "observational
stud*") OR (TI "observation stud*" OR AB "observation stud*" OR SU "observation stud*") OR (TI "clinical stud*" OR AB "clinical stud*" OR S U "clinical stud*") OR (TI surveillance OR
AB surveillance OR SU surveillance) OR (TI "reporting system*" OR AB "reporting system*" OR SU "reporting system*") OR (TI VAERS OR AB VAERS OR SU VAERS) OR (TI postmarket* OR AB postmarket* OR SU postmarket*) OR (TI post -market* OR AB
post -market* OR SU post -market*))
S7 S5 OR S6
S8 S1 AND S4 AND S7
S9 Limiters - Exclude MEDLINE records

References
1. Tillieux, S.L., et al., Comparative analysis of the complete nucleotide sequences of
measles, mumps, and rubella strain genomes contained in Pr iorix -Tetra and ProQuad live
attenuated combined vaccines.  Vaccine, 2009. 27(16): p. 2265 -73.
2. CDC, Prevention of varicella: recommendations of the Advisory Committee on
Immunization Practices (ACIP).  MMWR, 2007. 56 : p. No. RR -4.
3. CDC, Update: recommendations from the Advisory Committee on Immunization Practices
(ACIP) regarding administration of comibination MMRV vaccine.  MMWR, 2008. 57 : p. 258 --
60.
4. Marin, M., et al., Use of combination measles, mumps, rubella, and varicella vaccine:
recommendations of the Advisory Committee on Immunization Practices (ACIP).  MMWR
Recomm Rep, 2010. 59(Rr-3): p. 1 -12.
5. Cocchio, S., et al., A postmarket safety comparison of 2 vaccination strategies for measles,
mumps, rubella and varicella in Italy.  Hum Vaccin Immunother, 2016. 12 (3): p. 651 -4.
6. Deichmann, K.A., et al., Immunogenicity and safety of a combined measles, mumps,
rubella and varicella live vaccine (ProQuad ®) administered concomitantly with a booster
dose of a hexavalent vaccine in 12 -23-month- old infants.  Vaccine, 2015. 33 (20): p. 2379 -86.
7. Haas, H., et al., Immunogenicity and safety of intramuscular versus subcutaneous administration of a combined measles, mumps, rubella, and varicella vaccine to children
12 to 18 months of age.  Hum Vaccin Immunother, 2019. 15(4): p. 778 -785.
8. Hambidge, S.J., et al., Timely versus delayed early childhood vaccination and seizures.
Pediatrics, 2014. 133 (6): p. e1492 -9.
9. Jacobsen, S.J., et al., Observational safety study of febrile convulsion following first dose
MMRV vaccination in a managed care setting.  Vaccine, 2009. 27 (34): p. 4656 -61.
10. Klein, N.P., et al., Measles -mumps- rubella -varicella combination vaccine and the risk of
febrile seizures.  Pediatrics, 2010. 126 (1): p. e1 -8.
11. Klein, N.P., et al., Measles -containing vaccines and febrile seizures in children age 4 to 6
years.  Pediatrics, 2012. 129 (5): p. 809 -14.
12. MacDonald, S.E., et al., Risk of febrile seizures after first dose of measles- mumps -rubella-
varicella vaccine: a population- based cohort study.  Cmaj, 2014. 186 (11): p. 824 -9.
13. O'Leary, S.T., et al., The risk of immune thrombocytopenic purpura after vaccination in
children and adolescents.  Pediatrics, 2012. 129 (2): p. 248 -55.
14. Rowhani -Rahbar, A., et al., Effect of age on the risk of Fever and seizures following
immunization with measles -containing vaccines in children.  JAMA Pediatr, 2013. 167 (12): p.
1111 -7.

Summary: Rapid Systematic Review of the Safety of MMRV Vaccine   A. Background   The measles -mumps -rubella -varicella (MMRV) vaccine (ProQuad, Merck) was licensed in the  United States in 2005 for use in children 12 months through 12 years of age. While not licensed  for use in the United States, Priorix -Tetra, a MMRV vaccine manufactured by GlaxoSmithKline ,  first received licensing in some European countries in 2006, and in Canada in 2007.  Both  ProQuad and Priorix -Tetra are tetravalent…


policy recs mmrv briefing 508

1
 Briefing Document : Policy Recommendations for  Use of
Measles , Mumps , Rubella, and Varicella (MMRV) Vaccine  in the
United States

Overall Summary:
• Current ACIP/CDC recommendations  for MMRV vaccine use in the U .S. summary
(MMWR, May 2010):
o The routinely recommended ages for measles, mumps, rubella and varicella
vaccination are 12 –15 months for the first dose and 4 –6 years for the second dose.
 Both the first and second dose can be administered at other ages provided
the minimum age and the interval between doses are respected .
 For children aged 12 months through 12 years, two vaccination options are available to implement the ACIP recommendation : 1) trivalent measles,
mumps, rubella (MMR)  vaccine and monovalent varicella vaccine
administered as two separate injections or 2) combination MMRV vaccine administered as one injection.  MMRV vaccine is licensed for use through 12
years of age.
o For the first dose of measles, mumps, rubella, and varicella vaccines at age 12 –
47 months , either MMR vaccine and varicella vaccine or MMRV vaccine may be
used. Providers who are considering administering MMRV vaccine should discuss the benefits and risks of both vaccination options with the parents or caregivers. Unless the parent or caregiver expresses a preference for MMRV vaccine,  CDC
recommends  that  MMR vaccine and varicella vaccine should be administered
for the first dose in this age group .
o For the second dose  of measles, mumps, rubella, and varicella vaccines at any age
through 12 years  (i.e., 15 months –12 years) and for the first dose at age ≥48 months,
use of MMRV vaccine generally is preferred over separate injections of its
equivalent component vaccines (i.e., MMR vaccine and varicella vaccine).
Considerations should include provider assessment, patient preference, and the
potential for adverse events.
• The two vaccination options (MMRV vaccine or separate injections of MMR vaccine and
varicella vaccine) are considered equivalent in terms of protection against measles,
mumps, rubella, and varicella .
• Febrile seizures are a rare event after MMRV vaccination (7 -8.5 per 10,000 vaccinations).
Compared with separate administration of MMR vaccine and varicella vaccine at the same
time , among children aged 12 -23 months, an estimated 1 additional febrile seizure occurs
per 2,300 –2,600 children vaccinated with the first dose MMRV vaccine.
• MMRV vaccine account s for 15.1%  (range by state 5.1% -31.8%, Q1 : 10.4%, Q3 : 18.3%) of
first dose  measles, mumps, rubella, and varicella vaccination among children 19 -35
months of age (National Immunization Survey -Child, 2023)  and ~75%  (range by jurisdiction
46% -96% ) of second dose  vaccination  (data  from 39 jurisdiction I mmunization Information
System s, children age  4-6 years  by Dec 31, 202 4 who received an MMR -containing vaccine ,
CDC, unpublished data ).
2
 Methods
This document was developed based on review of the  relevant  literature regarding the measles,
mumps, rubella, and varicella (MMRV) vaccine licensed in the U .S. (Proquad, Merck &Co., Inc.) for
general vaccine safety, association with febrile seizures, and immunogenicity; review of the
literature regarding the second MMRV vaccine, available internationally (Priorix -Tetra,
GlaxoSmithKline [GSK] Biologicals) for vac cine efficacy/effectiveness; participation in reviewing of
the evidence and discussions during the 2008 -2009 ACIP MMR V Vaccine Safety Work Group; and
CDC analyses  (unpublished)  on use of MMRV vaccine for the first and second dose vaccination.

MMRV Vaccine Recommendations and Safety Review :
• The currently available MMRV vaccine in the U .S. (Proquad) was licensed  by FDA  in
September 2005  based on  noninferior immunogenicity  of the antigenic components
compared with simultaneous administration of MMR vaccine and varicella vaccine.
Efficacy of the measles, mumps, rubella, and varicella components of MMRV  vaccine  was
previously established in clinical studies with the monovalent vaccines. As FDA licensure
was based on immunogenicity (antibody ) comparisons to the individual components (i. e.,
MMR vaccine and varicella vaccine) , studies to evaluate the efficacy of the MMRV
combination vaccine were not  performed pre -licensure .
o At the time of licensure, use of MMRV vaccine was preferred for both the first and second dose of measles, mumps, rubella, and varicella vaccination over separate
injections of equivalent component vaccines, consistent with the ACIP
recommendation on preferred use of combination vaccines.
• In MMRV vaccine pre -licensure clinical trials , two systemic adverse events were reported at
a significantly greater rate 0 -42 days after vaccination in children aged 12 -23 months  who
received a first dose of MMRV vaccine (n = 4,497) compare d with  children who received first
doses of MMR vaccine and varicella  vaccine at the same visit  (MMR+ varicella ) (n = 2,038):
fever ≥102
oF/≥38.9°C  (21.5% vs. 14.9%) and measles -like rash (3.0% vs. 2.1%). Both
adverse events were reported to occur more frequently 5 –12 days after vaccination and
typically resolved spontaneously without sequelae  (MMRV/Proquad Package Insert).
• Because of the known association between fever and febrile seizures, CDC (through the Vaccine Safety Datalink  [VSD], which routinely monitors vaccine safety by near real -time
surveillance ), and Merck sponsored separate  post -licensure studies  to understand the
risk for febrile seizures that might be associated with MMRV vaccination.
o Preliminary results
 from these two studies were presented to ACIP in February
2008 and  suggested a 2.3-times higher risk for febrile seizures  among children
aged 12 –23 months during the 5 –12 or 7– 10 days after administration of the first
dose of MMRV vaccine compared with administration of the first dose  of
MMR +varicella vaccines at the same visit .
o ACIP reviewed these preliminary data  on the elevated (but rare, see rates below )
risk for febrile seizure s after MMRV vaccine , as well as other considerations, such
as vaccine availability  (MMRV had not been distributed in the U .S. since July 2007
because of manufacturing constraints unrelated to vaccine safety or efficacy and it was not expected to be available again before 2009) . In February 2008 , ACIP issued
updated recommendations, changing from a preferential recommendation for MMRV  vaccine , to expressing no preference  for use of MMRV vaccine over separate
3
 injections of equivalent component vaccines (i.e., MMR vaccine and varicella
vaccine) for both the first and second dose.  ACIP also established a W ork Group to
evaluate post -licensure and other safety data regarding the risk for febrile seizures
after MMRV vaccine.

• The ACIP MMRV Vaccine Safety W ork Group , the first ever ACIP W ork Group
established specifically to examine the safety of a vaccine, was formed in spring 2008 and examined several lines of evidence during June 2008 -June 2009 .
o The Work Group  reviewed findings from two post -licensure studies on MMRV
vaccine and risk for febrile seizures  (unpublished at the time of the discussions);
pre-licensure MMRV vaccine data; literature regarding MMR vaccine and varicella
vaccine immunogenicity, efficacy, effectiveness, and safety; measles, mumps,
rubella, and varicella disease burden; the epidemiology of febrile seizures; the
medical and psychosoci al importance of febrile seizures; and program
implementation considerations. The W ork Group  also reviewed data from focus
groups with providers and parents regarding attitudes on multiple injections and
use  of MMRV vaccine in the context of an increased risk for febrile seizures after the
first dose  and had consultation s with ethics experts .
 Summary report from June 2009 ACIP meeting available  here
 (pages 137 -
165)
o Post- licensure MMRV vaccine studies reviewed:
 VSD study  included children aged 12 -23 months : 83,107 received the first
dose MMRV  vaccine , 376,35 4 received first dose MMR+ varicella vaccines,
and found that d uring 7 –10 days after vaccination, the unadjusted rate of
febrile seizures was 8.5 per 10,000  vaccinations among MMRV vaccine
recipients and 4.2  per 10,000  vaccinations among those who received
MMR +varicella vaccines at the same visit [ adjusted RR: 2.0 (1.4 –2.9);
p=0.0001 ].
• Published report: Klein NP, Fireman B, Yih WK, et al. Measles -mumps-
rubella -varicella combination vaccine and the risk of febrile
seizures.  Pediatrics . 2010;126(1):e1- e8. doi:10.1542/peds.2010- 0665
 Merck study  included children aged 12 -60 months (99% aged 12 -23
months) : 31,298 received first dose MMRV vaccine , 31,298  received first
dose MMR+ varicella vaccines , and found that 5 -12 days after vaccination,
the rate of febrile seizures was 7 per 10,000  vaccinations among MMRV
vaccine recipients and 3.2 per 10,000  vaccinations among those who
received MMR+ varicella vaccines at the same visit [RR: 2.2 (1.0–4.7); p
<0.05 ].
• Published repo rt: Jacobsen SJ, Ackerson BK, Sy LS, et al. Observational
safety study of febrile convulsion following first dose MMRV vaccination in
a managed care setting. Vaccine . 2009;27(34):4656- 4661.
doi:10.1016/j.vaccine.2009.05.056
 Consistent results in both studies: Febrile seizures are a rare event after
MMRV vaccination (7 -8.5 per 10,000 vaccinations) . The ~twofold
increased risk for febrile seizures after MMRV vaccine results in an
4
 estimated 1 additional febrile seizure per 2,300 –2,600 children
vaccinated with the first dose MMRV vaccine compared with those
receiving  first dose with MMR+ varicella  vaccines .
• Of note: the final published results did not differ meaningfully from the unpublished results reviewed by the WG.

o Pre-licensure data indicated that the rate of fever after the second dose of MMRV
vaccine administered to children aged 15 –26 months was lower  than after the first
dose administered to children the same age as either MMRV vaccine or MMR +varicella vaccines at the same visit.  Among children aged 4 –6 years who
received MMRV vaccine for their second dose, the rate of fever was similar to the rate following a second dose of MMR +varicella  vaccines at the same visit
[temperature reported as elevated (≥102°F, oral equivalent) or abnormal : MMR V:
2.5%, MMR+varicella vaccines: 4.1% ].
 VSD and Merck’s post- licensure studies also examined the risk for febrile
seizures after the second dose. Results from both studies  suggest ed that
children aged 4 –6 years who receive the second dose of MMRV vaccine  had
no increased risk for febrile seizures after vaccination compared with
children the same age who receive the second dose of MMR+ varicella
vaccines at the same visit.
• During 7 –10 days following vaccination, the VSD study identified one
febrile seizure among 84,653 children aged 4 –6 years who received
MMRV vaccine and no febrile seizures among 64,663 children the same age who received MMR +varicella vaccines.
• No febrile seizures occurred during the 5 –12 days postvaccination in
either group in the Merck ’s sponsored study , 25,212 children
received a second dose of MMRV vaccine, and 24,788 received a second dose of MMR +varicella  vaccine s.
o Febrile seizures
 can occur with any condition that causes a fever. Children who
have febrile seizures generally have an excellent prognosis. Typically, febrile
seizures are resolved spontaneously without sequelae . However, first febrile
seizures often require a medical visit to an emergency department and can be
distressing for parents and caregivers.
 Maximizing choice based on parent or caregiver and physician preference is
an important ethical principle. Given the balance of risks and benefits of a first dose of MMRV vaccine compared with a first dose of MMR vaccine and varicella vaccine, and the importance of individual values and preferences in weighing these risks and benefits, decisions should be made by providers and parents or caregivers on a case -by-case basis.
o In June 2009 , considering the safety and other evidence (e.g., use of MMRV vaccine
has the benefit of requiring one less injection than the alternative of MMR+ varicella
vaccines , epidemiology of febrile seizures, parent and provider input), ACIP
recommended:
 For the first dose of measles, mumps, rubella and varicella vaccination among children aged 12 -47 months, either MMRV vaccine or separate
injections of MMR vaccine and varicella vaccine can be used.  Providers who
5
 are considering administering MMRV vaccine as the first dose to young
children should discuss the benefits and risks of both vaccination options
with the parents or caregivers.
 For the first dose at age ≥48 months and the second dose at any age (15 months -12 years) MMRV vaccine is preferred over the component MMR
vaccine and varicella vaccine.
o At the time of the publication of the recommendations in the MMWR
, CDC provided
guidance regarding implementation of the recommendation for the first dose among young children that unless the parent or caregiver expresses a
preference for the MMRV vaccine, CDC recommends that MMR vaccine and varicella vaccine should be administered for the first dose among children
aged 12–47 months.
• Safety data post- licensure has continued to be closely and regularly monitored. A summary
of reports received to the Vaccine Adverse Event Reporting System (VAERS) after
administration of MMRV vaccine in the U .S. during 2006- 2020 was recently published .
o Approximately 35.5 million MMRV vaccine doses were distributed; 13 ,325 reports
were received (37.6  reports /100 ,000 doses distributed) with 3.3% classified as
serious (1.3  reports /100 ,000 doses distributed). The most common adverse health
events after MMRV vaccine were injection site reactions (27%), rash (20%), and
fever (14%). No new or unexpected adverse event  was disproportionally
reported, no new or unexpected safety findings were detected for MMRV vaccine
given as recommended, reinforcing the favorable safety profile of the vaccine.

Immunogenicity and Effectiveness of MMRV  Vaccine :
• Immunogenicity  after the first dose of MMRV  vaccine  vs. MMR+ varicella vaccines in
children aged 12 to 23 months was assessed in 4 randomized clinical trials  (5446 received
MMRV, 2038 received MMR +varicella  concomitantly at separate injection sites). Children
enrolled  in these trials had no history  of disease , no known recent exposure, and no
vaccination history for varicella, measles, mumps, and rubella.  The end points assessed
were response rates and geometric mean titers (GMTs).
o Response rates and GMTs were similar and met the pre -established criteria for non-
inferiority (lower bound of the 95% CI for the difference in measles, mumps, and
rubella seroconversion rates > -5.0%, lower bound of the 95% CI for the difference in
varicella seroprotection rates was either > -15% [one study] or > -10.0% [three
studies])  (Table).
o Work Group assessment during the 2008 -2009 deliberations: given the non -
inferior immunogenicity, effectiveness was assumed to be equal.

6
 Table . Summary of c ombined immunogenicity results 6 weeks after  administration of a s ingle
dose of ProQuad ( varicella virus potency ≥3.97 log10 PFU) or M -M-R II and VARIVAX

          *Combined numbers from 4 trials  with ProQuad with the varicella zoster potency similar to that in the
             licensed product ; children aged 12 to 23 months
           † The mumps antibody response was assessed by a vaccine -strain ELISA in  2 studies (serostatus was based
             on the OD cutoff)  and by a wild- type ELISA in 2 studies .
           n = Number of per- protocol subjects with evaluable serology.
           CI = Confidence interval.
           GMT = Geometric mean titer.
           ELISA = Enzyme -linked immunosorbent assay.
           PFU = Plaque -forming units.
           OD = Optical density .

• No specific post- licensure vaccine effectiveness (VE) estimates are available for the MMRV
vaccine used in the U .S.
o MMRV vaccine was licensed in the US in September 2005 and in July 2007 became
temporarily unavailable due to manufacturing constraints unrelated to efficacy or
safety. MMRV vaccine became available again in the U .S. in 201 2; however,  with
measles and rubella being eliminated in the U .S., mumps at low levels (and
outbreaks occurring  primarily  in young adults), and the number of cases of varicella
declining 90% by 2010, there were not enough cases of disease or outbreaks in
children to assess vaccine effectiveness in the U .S.
o Vaccinated persons continue to have very low rates of disease for measles,
mumps, rubella and varicella in the U.S , including in ages where MMRV is used
(data provided in references) . There have been  no reports to CDC indicating
concern for lower MMRV vaccine effectiveness compared to use of the separate
component vaccines, consistent with the  immunogenicity results seen in the
clinical trials .

7
 MMRV vaccine in international settings
• The second MMRV vaccine available globally (Priorix -Tetra ) was also licensed based on
non- inferior immunogenicity . Note there are important differences in the varicella- zoster
virus (VZV) antigen content between Priorix -Tetra and Proquad  (less VZV antigen in Pr iorix-
Tetra) .
o Post- licensure, a randomized, controlled trial  was conducted in 10 European
countries that reported on efficacy  against varicella
 2,279 c hildren aged 12 -22 months  received 2 doses of MMRV  vaccine, 42
days apart ; mean follow -up 36 months .
 Two  dose MMRV vaccine efficacy against all varicella: 94.9% (92 .4–96.6);
against moderate to severe varicella : 99.5% (97 .5–99.9).
• Prymula R, Bergsaker MR, Esposito S, et al. Protection against varicella
with two doses of combined measles -mumps -rubella -varicella vaccine
versus one dose of monovalent varicella vaccine: a multicentre, observer-
blind, randomised, controlled trial - PubMed . Lancet.
2014;383(9925):1313 -1324.
 A continuation of th e study above  a median follow -up of 9 .8 years  reported
• Two dose MMRV vaccine efficacy against all varicella: 95. 4% (94 .0–
96.4); against moderate or severe varicella : 99.1% (97 .9–99.6).
o Povey M, Henry O, Bergsaker MR et al. Protection against
varicella with two doses of combined measles -mumps -rubella -
varicella vaccine or one dose of monovalent varicella vaccine: 10 -
year follow -up of a phase 3 multicentre, observer- blind,
randomised, controlled trial . L ancet Infect Dis  2019;19: 287– 97.

References :
• CDC/ACIP Recommendations for MMRV use:
o Current Recommendations: Use of Combination Measles, Mumps, Rubella, and
Varicella Vaccine Recommendations of the Advisory Committee on Immunization
Practices; Published May 7, 2010. https://www.cdc.gov/mmwr/pdf/rr/rr5903.pdf
o Webpage with all MMRV recommendations: https://www.cdc.gov/acip -
recs/hcp/vaccine -specific/mmrv.html
o Summary from June 2009 ACIP meeting where Evidence to Recommendation framework from the MMRV Vaccine Work Group were presented and discussed:
Advisory Committee on Immunization Practices (ACIP) summary report : June 24 -
26, 2009, Atlanta, Georgia   (pages 137 -1 65)
• The published reports of the two post-licensure studies on MMRV vaccine and febri le
seizure among children 12 -23 months of age examined by ACIP in 2008 -2009
o Klein NP, Fireman B, Yih WK, et al. Measles -mumps -rubella -varicella combination
vaccine and the risk of febrile seizures.  Pediatrics . 2010;126(1):e1 -e8.
doi:10.1542/peds.2010- 0665
8
 o Jacobsen SJ, Ackerson BK, Sy LS, et al. Observational safety study of febrile
convulsion following first dose MMRV vaccination in a managed care
setting.  Vaccine. 2009;27(34):4656 -4661. doi:10.1016/j.vaccine.2009.05.056
• Study that examin ed MMRV vaccine and febrile seizures in children 4-6 years of age
o Klein NP,  Lewis E, Baxter R, et al .  Measles- containing vaccines and febrile seizures
in children age 4 to 6 years - PubMed . P ediatrics . 2012;129(5):809 -14.
• MMRV  (Proquad, Merck)  package insert ( Package Insert - Frozen Formulation - ProQuad )
o Merck added febrile seizures to the PI in Feb 2008 in the section of post- marketing
experience (under Nervous system disorders), Approved Products > February 27,
2008 Approval Letter - ProQuad
o Addition of “ additional safety data after a first or second dose of ProQuad® ”
approved in October 29, 2009, Approved Products > October 29, 2009 Approval
Letter - ProQuad
• MMRV (Priorix -Tetra, GSK) randomized clinical trials
o Prymula R, Bergsaker MR, Esposito S, et al. Protection against varicella with two
doses of combined measles -mumps -rubella -varicella vaccine versus one dose of
monovalent varicella vaccine: a multicentre, observer -blind, randomised,
controlled trial - PubMed . L ancet. 2014; 383(9925):1313 -1324.
o Povey M, Henry O, Bergsaker MR et al. Protection against varicella with two doses of
combined measles -mumps -rubella -varicella vaccine or one dose of monovalent
varicella vaccine: 10 -year follow -up of a phase 3 multicentre, observer- blind,
randomised, controlled trial . L ancet Infect Dis  2019;19: 287– 97.
• Current /recent epidemiology of measles, mumps, rubella, and varicella (including very low
rates among vaccinated individuals): Note for diseases eliminated in the US (measles and
rubella), recent U.S. studies to examine vaccine effectiveness are not possible .
o Measles : Measles Cases and Outbreaks : CDC Website:
https://www.cdc.gov/measles/data -research/index.html
o Mumps: Tappe J , et al. Characteristics of reported mumps cases in the United
Stats: 2018 -2023. Vaccine 2024;42(25):
o Rubella : Rubella in the United States: https://www.cdc.gov/rubella/vaccine -
impact/index.html
o Varicella : Shap iro E and Marin M. The effectiveness of varicella vaccine: 25 years of
post -licensure experience in the United States. The Journal of Infectious Diseases
2022: 226 (4): S425 –S430 ; Marin M, Leung J, Anderson TC, Lopez A. Monitoring
Varicella Vaccine Impact on Varicella Incidence in the United States: Surveillance
Challenges and Changing Epidemiology, 1995 –2019 . The Journal of Infectious
Diseases 2022: 226 (4): S 392 -399.

Summary: 1   Briefing Document : Policy Recommendations for  Use of            Measles , Mumps , Rubella, and Varicella (MMRV) Vaccine  in the  United States     Overall Summary:   • Current ACIP/CDC recommendations  for MMRV vaccine use in the U .S. summary   (MMWR, May 2010):  o The routinely recommended ages for measles, mumps, rubella and varicella  vaccination are 12 –15 months for the first dose and 4 –6 years for the second dose.    Both the first and second dose can be administered at other…


02 srinivasan mmrv 508

Background on Measles, Mumps, Rubella, and Varicella
(MMRV) Vaccine
Arjun Srinivasan, MD, MS, MBA
Acting Chief Medical Officer
National Center for Immunization and Respiratory Di seases
ACIP Meeting
September 18, 2025 National Center for Immunization & Respiratory Dise ases
During the last major rubella epidemic in the U.S. (1964-1965), in 1 year:
–11,000 pregnant women lost their babies
–2,100 newborns died
–20,000 born with congenital rubella syndrome, causing deaf ness, heart defects
and developmental delay Measles, mumps, rubella, and varicella caused signi ficant
disease burden pre-vaccine in the United States
2
Before the introduction of measles vaccine (1963), each year an estimated:
–48,000 hospitalizations
–400-500 deaths
Each year in the early 1990s (before varicella vaccine):
–10,500-13,500 hospitalizations
–100-150 deaths
Mumps was the leading cause of viral encephalitis and sud den onset deafness
The introduction of monovalent measles, mumps, rube lla vaccines (1963-1969), followed by
trivalent MMR (1971), then monovalent varicella (19 95) and the quadrivalent MMRV (2005)
vaccines, coupled with attaining and maintaining hi gh coverage rates (>90%) in the United States
(U.S.) led to: Dramatic reductions in measles, mumps, rubella, and
varicella in the United States after introduction o f vaccines
Manual for the Surveillance of Vaccine-Preventable Diseases for Public Health | Manual for the Surveil lance of Vaccine-Preventable Diseases | CDC 3–Elimination of endemic measles in 2000
–Elimination of endemic rubella in 2004
–99% decline in mumps cases by early 2000
–97% decline in varicella incidence by 2019

Two options for measles, mumps, rubella, and varice lla vaccination: MMRV vaccine or
MMR vaccine + varicella vaccine
–Recommended as two doses: routine ages - 1st dose: 12-15 months; 2 nd dose: 4-6 years
The MMRV vaccine available in the U.S. (ProQuad, Me rck & Co, Inc) was licensed by FDA
in September 2005 based on noninferior immunogenicity of the antigenic components
compared with simultaneous administration of MMR va ccine and varicella vaccine
–Efficacy of the measles, mumps, rubella, and varicella compo nents of MMRV vaccine was
previously established in clinical studies with the monovalent vaccines
–Burden of disease for these diseases too low to perform efficacy clinical trials in the U.S. MMRV vaccine in the United States
4
Immunogenicity after the first dose of MMRV vaccine vs. MMR + varicella vaccines in
children aged 12 to 23 months was assessed in 4 randomized clinical trials
–5446 received MMRV, 2038 received MMR + varicella v accines at separate injection sites
–End points assessed (seroconversion rates and geome tric mean titers) were similar and met the pre-
established criteria for noninferiority 1
Immunogenicity after the second dose of MMRV vaccine vs. MMR vaccine (+/- varicella
vaccine) in children aged 4-6 years was assessed in  1 randomized clinical trial
–399 received MMRV, 205 received MMR + placebo, 195 received MMR + varicella vaccine; also met
pre-established criteria for noninferiority
2008-2009 ACIP Work Group assessment: given the non inferior immunogenicity,
effectiveness was assumed to be equal Clinical trials for MMRV vaccine
1Lower bound of the 95% CI for the difference in mea sles, mumps, and rubella seroconversion rates >-5.0% , lower bound of the 95% CI for the
difference in varicella seroprotection rates was eit her >-15% [one study] or >-10.0% [three studies] 5
Timeline of recommendations for MMRV vaccine use in
the United States
6September 2005
MMRV vaccine licensed for children
aged 12 months–12 years
Use of MMRV vaccine preferred over separate administration of MMR and
varicella vaccines February 2008
Vaccine safety finding from post-
licensure monitoring: increased risk
of febrile seizures after first dose of
MMRV vaccine June 2009
Updated recommendations
(next slide)
ACIP issued interim recommendation: removed
preference for MMRV use vs. MMR and varicella
vaccines for both dose 1 and dose 2 1
1At the time, MMRV vaccine had not been distributed in the U.S. since July 2007 because of manufacturin g constraints unrelated to safety or efficacy: Notice to
Readers: Update on Supply of Vaccines Containing Va ricella-Zoster Virus .  MMRV vaccine became available again in the U.S. in 2012.
Use of Combination Measles, Mumps, Rubella, and Var icella Vaccine, MMWR 2010
Updated ACIP recommendations for MMRV vaccine use i n
the United States (current recommendations)
For the first dose of measles, mumps, rubella, and varicella
vaccination at age 12–47 months, either MMR vaccine and
varicella vaccine or MMRV vaccine may be used. Providers who
are considering administering the MMRV vaccine shou ld discuss
the benefits and risks of both vaccination options with the
parents or caregivers.
–CDC provided implementation guidance: unless the pa rent or caregiver
expresses a preference for the MMRV vaccine, CDC re commends that
MMR vaccine and varicella vaccine be administered f or the first dose in
this age group.
For the first dose at age ≥48 months and for the second dose at
any age (15 months–12 years), MMRV is generally preferred
over separate injections of MMR vaccine and varicel la vaccine
7
 Use of Combination Measles, Mumps, Rubella, and Var icella Vaccine, MMWR 2010
No post-licensure vaccine effectiveness estimates a re available for the MMRV vaccine
used in the U.S.
–With measles and rubella being eliminated in the U. S., mumps and varicella at very low levels,
there were not enough cases of disease or outbreaks in children to assess vaccine
effectiveness in the U.S.
–Those vaccinated with MMRV or MMR and varicella vacc ines continue to have very low
rates of disease for measles, mumps, rubella, and v aricella in the U.S.
–There have been no reports to CDC indicating concern for lower MMRV vaccine ef fectiveness
compared to use of the separate component vaccines,  consistent with the immunogenicity
results seen in the clinical trials Post-licensure effectiveness
8
MMRV vaccine accounts for 15% of first dose 1measles, mumps, rubella, and varicella
vaccination among children aged 19-35 months and 75% of second dose 2vaccination
among children aged 4-6 years
–First dose range by state: 5.1%-31.8%
–Second dose range by jurisdiction: 46%-96% MMRV vaccine utilization
1Data from National Immunization Survey-Child, 2023
2Data from 39 jurisdictions’ Immunization Informatio n Systems (IIS), children age 4-6 years by Dec 31, 2024 who received an MMR-
containing vaccine 9
MMRV vaccine is one of the two options for vaccination of U.S. children for protection
against measles, mumps, rubella, and varicella
The two vaccination options (MMRV vaccine or separa te injections of MMR vaccine and
varicella vaccine) are considered equivalent in terms of protection against disease
Due to the current recommendations, most MMRV vacci ne use in the U.S. is among children
age 4–6 years (for the second dose of MMR and varic ella vaccination)
Vaccination for measles, mumps, rubella, and varice lla has led to at least 97% reduction in
all four diseases compared with the pre-vaccine eraSummary
10
For more information, contact CDC 1-800-CDC-INFO (2 32-4636) TTY: 1-888-232-6348
www.cdc.gov The findings and conclusions in this report are tho se of the authors and do not
necessarily represent the official position of the Centers for Disease Control and
Prevention.
•Bloch AB, Orenstein WA, Stetler HC, et al. Pediatri cs 1985;76:524-32. Health impact of measles
vaccination in the United States
•CDC. MMWR 2005;54:279–82. Elimination of rubella and congenital rubella syndr ome—United States,
1969–2004
•Marin, et al., JID, 2022, Monitoring Varicella Vaccine Impact on Varicella In cidence in the United States:
Surveillance Challenges and Changing Epidemiology, 1995–2019
•Marin, et al., JID, 2022, Decline in Severe Varicella Disease During the Unit ed States Varicella Vaccination
Program: Hospitalizations and Deaths, 1990–2019
•National Communicable Disease Center. Rubella surveillance. Bethesda, MD: US Department of Health,
Education, and Welfare; 1969.
•Shapiro, et al., JID, 2022, The Effectiveness of Varicella Vaccine: 25 Years of  Postlicensure Experience in the
United States
•Witte JJ, Karchmer AW. Public Health Rep, 1968 Feb;8 3(2):5-100. Surveillance of mumps in the United
States as background for use of vaccine References: Pre-vaccine burden of measles, mumps, rubella, and varicella
•Measles : Measles Cases and Outbreaks: CDC Website: https://www.cdc.gov/measles/data-
research/index.html
•Mumps : Tappe J, et al. Vaccine 2024;42(25): Characteristics of reported mumps cases in the Unit ed Stats:
2018-2023.
•Rubella : Rubella in the United States: https://www.cdc.gov/rubella/vaccine-impact/index.ht ml
•Varicella : Shapiro E and Marin M. The effectiveness of varicella  vaccine: 25 years of post-licensure experience
in the United States. The Journal of Infectious Diseases 2022: 226 (4): S425–S430 ; Marin M, Leung J, Anderson
TC, Lopez A. Monitoring Varicella Vaccine Impact on Varicella Incidence in the United States: Surveilla nce
Challenges and Changing Epidemiology, 1995–2019. The Journal of Infectious Diseases 2022: 226 (4): S392-
399 .References: Current/recent epidemiology for measles ,
mumps, rubella, and varicella

Summary: Background on Measles, Mumps, Rubella, and Varicella  (MMRV) Vaccine  Arjun Srinivasan, MD, MS, MBA  Acting Chief Medical Officer  National Center for Immunization and Respiratory Di seases  ACIP Meeting  September 18, 2025 National Center for Immunization & Respiratory Dise ases  During the last major rubella epidemic in the U.S. (1964-1965), in 1 year:  –11,000 pregnant women lost their babies  –2,100 newborns died  –20,000 born with congenital rubella syndrome, causing deaf ness, heart…