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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 ).
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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
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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
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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
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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.
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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 .
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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
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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.