05 influenza redwood 508

ACIP 2025
BusinessThimerosal as a Vaccine Preservative
Prepared for the
Advisory Committee for
Immunization PracticesLyn Redwood RN, MSN, FP (Retired)

2The Food and Drug Administration
Modernization Act of 1997
•Compiled list of drugs and foods that contained intentionally introduced
mercury compounds
•Provided quantitative and qualitative analysis of mercury compounds
•Report included 219 products which included 11 biologics and immunoglobulin
therapies
Ref: U.S. Congress. (1997, November 21). Food and Drug Administration Modernization Act of 1997, Pub. L. No. 105 -115, 111 Stat. 2296.

31999 Joint Statement by US Public Health Service
(PHS) and American Academy of Pediatrics (AAP)
Thimerosal in Vaccines: A Joint Statement of the American Academy of Pediatrics and the Public Health
Service. MMWR Weekly. July 09, 1999 / 48(26);563 -565.•On July 9th , 1999, a joint statement issued by PHS and AAP called for the immediate
reduction and elimination of the mercury based preservative thimerosal from infant
vaccines based on the findings that infants and children who received vaccines
preserved with thimerosal could be exposed to mercury in excess of federal safety
guidelines.
•“because any potential risk is of concern, the Public Health Service (PHS), the
American Academy of Pediatrics (AAP), and vaccine manufacturers agree that
thimerosal -containing vaccines should be removed as soon as possible.”

4 Institute of Medicine
Immunization Safety Review of Thimerosal Containing Vaccines
and Neurodevelopmental Disorders (October 2001)
•The committee “supported prior decisions made by the ACIP and AAP to call for the removal of
thimerosal from vaccines that are part of the recommended childhood immunization schedule.”
But they noted that “vaccines that are not part of the recommended childhood immunization
schedule still contain thimerosal as a preservative and may be given to some children” and a
lingering concern that there remains “on the shelf” an unknown quantity of thimerosal -containing
Hib, hepatitis B, and DTaP vaccines.
•Recommended: “the use of thimerosal free DTaP , HiB and Hepatitis B vaccines despite the fact that
there might be remaining supplies available” and “full consideration be given by appropriate
professional societies and government agencies to removing thimerosal from vaccines
administered to infants, children or pregnant women in the united States. ”
Institute of Medicine (US) Immunization Safety Review Committee; Stratton K, Gable A, McCormick MC, editors. Immunization Saf ety Review: Thimerosal -
Containing Vaccines and Neurodevelopmental Disorders. Washington (DC): National Academies Press (US); 2001. Immunization Safe ty Review, Thimerosal -
Containing Vaccines and Neurodevelopmental Disorders. Available from: https://www.ncbi.nlm.nih.gov/books/NBK223724/

5Safety Studies
Prior to Marketing Thimerosal as Vaccine Preservative
(1) Ball LK, Ball R, Pratt RD. An assessment of thimerosal use in childhood vaccines  Pediatrics. 2001;(107)5:1147 -1153.
(2) Powell HM, Jamieson WA. Merthiolate as a germicide.  Am J. Hyg. 1931;(13):296 -310.
(3) Department of Health and Human Services. 21 Code of Federal Regulations: 601.25. 1985•In 1997, FDA Modernization Act prompted assessment of thimerosal use in vaccines.
•FDA was unable to find any clinical studies formally evaluating the use of thimerosal
before its initial marketing in 1930’s. (1)
•Single study published in 1931 where thimerosal administered to individuals suffering
from meningitis. (2)
-Not designed to specifically examine toxicity and no clinical assessments or laboratory
studies reported.
•FDA grandfathered in the use of thimerosal and did not require the typical animal safety
data for finished biological products, including active and inactive ingredients. (3)

6 Thimerosal use in vaccines
Ref:  1. Ball LK, Ball R, Pratt RD. An assessment of thimerosal use in childhood vaccines  Pediatrics. 2001;(107)5:1147 -1153.
         2. Powell HM, Jamieson WA. Merthiolate as a germicide.  Am J. Hyg. 1931;(13):296 -310.
         3. Department of Health and Human Services. 21 Code of Federal Regulations: 601.25. 1985 •Thimerosal was first introduced as a preservative in vaccines in the 1930’s after being
developed and patented in 1927 and subsequently marketed by Eli Lilly under the trade
name “Merthiolate” in 1928.
•After a deadly incident of bacterial contamination of vaccines in Australia where 12
children died from staphylococcal -contaminated diphtheria vaccine, the FDA began
enforcing safety standards which led to regulations requiring that all multidose vaccines
contain a preservative to prevent contamination.
•Thimerosal was used during the manufacturing process and in multi -dose vials to
prevent bacterial and fungal contamination. By the 1930’s thimerosal became widely
used as a preservative in vaccines and other medical products.

7 Thimerosal Not Generally Recognized
as Safe and Effective (GRASE) in OTC Drugs
Ref: Federal Register, Department of Health and Human Services, Food and Drug Administration. Mercury -Containing Drug Products for Topical
Antimicrobial Over -the-Counter Human Use; Establishment of a Monograph. (January 5, 1982);47(2):436 -442. 47 FR 436 [Docket No. 75N -0183(1)
Federal Register, Department of Health and Human Services, Food and Drug Administration. Status of Certain Additional Over -the-Counter Drug
Category II and III Active Ingredients. (April 22, 1998);63(77):19799 -19802. 21 CFR Part 310 [Docket No. 75N -183F, 75N -183D, and  80N-0280.    •In 1975, FDA convened panel of experts to evaluate the use of mercury -containing over -the-counter (OTC). The panel
found evidence that thimerosal was “35.3 times more toxic for embryonic chick heart tissue than for Staphylococcus
aureus” and “was no better than water in protecting mice from potential fatal streptococcal infections.”
•The FDA issued a report of the panel’s findings in the Federal Register in 1982 which concluded that “thimerosal was
not safe for OTC topical use because of its potential for cell damage if applied to broken skin and its allergy potential,
not effective “because bacteriostatic action could be reversed.”
• In response to the expert panels report, the FDA published final rules in the Federal Register in 1998  that concluded
the use of thimerosal in over -the-counter products is not “generally recognized as safe or effective.” (GRASE)

8
Evidence of Thimerosal
Ineffectiveness as a Preservative
Stetler HC, Garbe PL, Dwyer DM, Facklam RR, Orenstein WA, West GR, Dudley KJ, Bloch AB. Outbreaks of group A streptococcal ab scesses following diphtheria -
tetanus toxoid -pertussis vaccination. Pediatrics. 1985 Feb;75(2):299 -303. PMID: 3881728.
Smith S. Safety fears cut vaccine for flu. Priority urged for the aged, frail. Boston Globe . (October 6, 2004).
http://www.boston.com/news/globe/health_science/articles/2004/10/06/safety_fears_cut_vaccine_for_flu?mode=PF•In 1982, clusters of disease from Group A streptococcus infections were traced back to multi -dose vials of
diphtheria toxoid, pertussis, and tetanus toxoid (DPT) vaccine which were contaminated after being
opened. Thimerosal was present in acceptable limits in unopen vials of vaccine from the same lot. The
authors concluded that “Preservatives in multidose vials do not prevent short term bacterial
contamination ” and  the “only feasible and cost -effective preventative measure now available is careful
attention to sterile technique when administering vaccines from multidose vials.”
•In 2004, a Chiron plant that manufactured Fluvirin vaccine preserved with thimerosal was forced to close
because its vaccine was contaminated with Serratia marcescens.  The closure created shortages in the
vaccine supply and caused concern among providers and patients. In this case and others, thimerosal
failed to prevent bacterial growth.

9 Current Research
Thimerosal safety and effectiveness
•A more current in vitro investigation into the cytotoxic effects and
antimicrobial activity of thimerosal was published in 2023.  The authors
reported that thimerosal should be present in culture media at 100 μg/ml
concentration to achieve effective antimicrobial activity. But all tested cell
lines lost viability completely at 4.6 µg/ mL.
•“Overall, our study revealed Thimerosal was 333 -fold more cytotoxic to
human and animal cells as compared to bacterial and fungal cells . Our results
promote more study on Thimerosal toxicity and its antimicrobial effectiveness
to obtain more safe concentrations in biopharmaceuticals.”
Rahimian A, Lakzaei M, Askari H, Dostdari S, Khafri A, Aminian M. In vitro assessment of Thimerosal cytotoxicity and antimicr obial activity. J Trace Elem Med
Biol. 2023 May;77:127129. doi: 10.1016/j.jtemb.2023.127129. Epub 2023 Jan 4. PMID: 36630761.

10Evidence of Thimerosal
Developmental Neurotoxicity
Wallin, M. (1993). Effects of potential aneuploidy -inducing agents on microtubule assembly in vitro.
*Mutation Research. Fundamental and Molecular Mechanisms of Mutagenesis*, 287(1), 17 –22. https:// doi.org /10.1016/0027 -5107(93)90141 -2•In 1987 the Commission of the European Communities initiated a research project on 10
known or suspected spindle poisons. Thimerosal was found to cause significant
interference with microtubule polymerization destabilizing the spindle machinery that
ensures accurate chromosome separation during cell division.
•This mechanistic disruption suggests direct mutagenic potential via structural
chromosomal abnormalities, which is a known pathway to carcinogenesis or congenital
defects.
•By affecting fundamental cellular structures at the molecular level, thimerosal revealed
“strong mechanistic evidence for mutagenicity and developmental toxicity”.

11
Thimerosal has been recognized as a Prop 65 chemical since 1990.CALIFORNIA EPA Proposition - 65
•California’s Proposition 65, requires identification of chemicals known to cause cancer, birth
defects or other reproductive harm, and to ensure public warnings when people might be
exposed to them. Thimerosal has been on the Prop -65 list since 1990.
•In 2003 a petition was filed on behalf of the Bayer Corporation “for reconsideration of the
determination that mercury and mercury compounds (thimerosal) as reproductive toxicants.”
•The CA EPA responded that “The scientific evidence that thimerosal cause reproductive
toxicity is clear and voluminous.  Thimerosal dissociates in the body to ethyl mercury.  The
evidence for its reproductive toxicity includes severe mental retardation or malformations
in human offspring who were poisoned when their mothers were exposed to ethyl mercury
or thimerosal while pregnant, studies in animals demonstrating developmental toxicity after
exposure to either ethyl mercury or thimerosal, and data showing interconversion to other
forms of mercury that also clearly cause reproductive toxicity.”

12
Evidence From Human Research (1)
•A study published in Pediatrics in 2000 measured blood mercury levels in preterm and
term infants after administration of the Hepatitis B vaccine containing 12.5 µg ethyl
mercury.
•The investigation documented elevated post -immunization concentrations relative to
pre-immunization levels in all neonates studied. Levels of blood mercury after exposure
in low -birth -weight infants were 7.36 ( ± 4.99) µg/L.
•One infant was found to have developed a mercury level of 23.6 µg/L, thus meeting the
CDC criteria as a case of chemical poisoning from mercury 10µg /L.  The study subjects
had measurable blood Hg concentrations prior to immunization, indicating that risk
assessment must include background mercury levels from other sources.
Stajich GV, Lopez GP , Harry SW, Sexson WR. Iatrogenic exposure to mercury after Hepatitis B vaccination in preterm infants. J .Pediatrics. 2000;136 (5):679 -81.
Centers for Disease Control and Prevention. (2005, January 14). Case Definitions for Chemical Poisoning. MMWR Recommendations  and Reports, 54(RR -1), 1 –
24. Retrieved from https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5401a1.htm

13
Rice D, Barone S Jr. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal mod els. Environ Health Perspect .
2000;108 Suppl 3:511 -33.•Experts contend that there are “windows of vulnerability” which occur during neurological
development and that specific types of developmental outcomes may have separate
windows of vulnerability. These critical periods of development have not been established
and may be relatively short in duration.
•The fact that thimerosal from vaccines has been documented to raise blood mercury levels
over known thresholds where developmental effects have been documented to occur
during the first few months of life, means that particular "windows of vulnerability" may
have been breached.  Even minor neurological impairment can have profound societal
effects when amortized across the entire population and life span.Evidence From Human Research (2)

14 Exposure To Vaccine Level Thimerosal
Crosses the Blood Brain Barrier and Results in Significant
Deposition of Mercury in the Brain
•A 2005 study funded by NIH compared brain mercury levels in infant Macaca fascicularis
primates exposed to: 1) injected ethyl mercury (thimerosal) and 2) equal amounts of
ingested methylmercury.
•Ethyl mercury more rapidly converted to inorganic mercury in the brains of the primates
which resulted in increasing levels of inorganic mercury.
•Primates exposed to ethyl mercury retained much higher levels of inorganic mercury in
their brains, up to 71% vs. 10% compared to primates exposed to methyl mercury.
•Once organic mercury compounds reach the brain tissue and dealkylate, Hg2+ (toxic
inorganic mercury) the mercury cannot cross the blood brain barrier and becomes
trapped, resulting in neuroinflammation.
Burbacher TM, Shen DD, Liberato N, Grant KS, Cernichiari E, and Clarkson T. Comparison of blood and brain mercury levels I in fant monkeys exposed to
methylmercury or vaccines containing thimerosal. Environmental Health Perspectives. 2005;113(8):1015 -1021.

15 Inorganic Mercury and the Developing Brain
Thimerosal is ~49.6%
mercury by weight•A recent review outlined evidence from human and animal studies which estimated the
inorganic mercury half -life in human brains of at least five to 27 years. (1)
•The impact of mercury exposure to the developing brain interferes with neuronal
proliferation, migration, differentiation, synaptogenesis, tightly regulated apoptosis, and
other processes vital to the formation and functioning of the nervous system which can
result in lifelong neurodevelopmental impacts.
•Exposure during the first trimester of pregnancy may result in deficits or defects very
different from those developed by someone who is exposed during the third trimester of
pregnancy. “There may never be a safe level of mercury exposure, especially for an
unborn child.” (2)
1.Rooney JP . The retention time of inorganic mercury in the brain --a systematic review of the evidence. Toxicol Appl Pharmacol. 2014 Feb 1;274(3):425 -35.
2. Pletz J, Sánchez -Bayo F, Tennekes HA. Dose -response analysis indicating time -dependent neurotoxicity caused by organic and in organic mercury -Implications
for toxic effects in the developing brain. Toxicology. 2016 Mar 10;347 -349:1 -5. doi: 10.1016/j.tox.2016.02.006. Epub 2016 Mar 2.  PMID: 26945727.

16 Mercury Content In
Thimerosal -containing Flu Vaccines
•Thimerosal is ~49.6% mercury by weight with a concentration of 0.01% thimerosal in
vaccines. This equates to 100 µg/mL of thimerosal and 50 µg/mL of ethyl mercury per ml.
•The EPA’s Toxicity Characteristic Leaching Procedure (TCLP) determines whether a
substance is considered hazardous waste based on its potential to leach toxic chemicals
into groundwater.
•According to EPA TCLP Mercury Threshold (40 CFR § 261.24) the regulatory threshold for
mercury (D009) under TCLP is: 0.2 mg/L (200 parts per billion, or 200 µg/L).
•Flu vaccine mercury concentration (~50,000 µg/L) is 250 times greater than the TCLP limit.
Therefore, thimerosal -containing vaccines exceed the TCLP threshold by orders of
magnitude and are classified as D009 Hazardous Waste
17 Vaccine Mercury: Disposal Guidelines

18
Population Susceptibility Factors
Fetus / Developing InfantRapid neurodevelopment, immature blood -brain barrier, low glutathione,
high brain accumulation
Pregnant Women Placental transfer, fetal susceptibility, breast milk transfer
Young Children Higher exposure per kg, immature detoxification systems
Older Adults Reduced renal clearance, pre -existing neurodegenerative conditions
Genetically Susceptible Impaired detox (e.g., GST, MTHFR, APOE4), mitochondrial dysfunction
High Fish Consumers Bioaccumulation through predatory fish, dietary exposure
Occupationally Exposed Workers Inhalation exposure, chronic accumulation (e.g., dentists, miners)Susceptible Populations

19 Summary (1)
•Mercury is the third most toxic element on earth, behind polonium and plutonium,
and has no physiological role in the human body.
•Thimerosal was grandfathered for use without adequate safety testing by the FDA.
•Thimerosal is not “generally recognized as safe or effective” (GRASE) by the FDA OTC
Division since 1998.
•There is evidence that thimerosal is not an effective preservative at vaccine levels.
•Thimerosal can cross the placenta and blood brain barriers and converts to inorganic
mercury in the brain at higher levels that methyl mercury.
•Studies have identified infants with blood levels after exposure to thimerosal that
breach CDC guidelines for a case of mercury chemical poisoning.
20 Summary (2)
•Thimerosal is recognized as a developmental and reproductive toxicant and is listed as
a chemical on the California Proposition 65 list since 1990.
•Unused doses of  thimerosal preserved flu shots must be disposed of as hazardous
waste.
•Tremendous progress has been made in removing thimerosal, but more than 60,000
pregnant mothers receiving Medicaid in the 2019 -2020 flu season received TCVs.
•We currently have enough thimerosal free flu vaccines to recommend that all
pregnant women, infants and children receive only thimerosal free vaccines.
•After a critical appraisal of this issue almost 25 years ago, the prestigious Institute of
Medicine made this same recommendation.
•Removing a known neurotoxin from being injected into our most vulnerable
populations is a good place to start with Making America Healthy Again.

Summary: ACIP 2025 BusinessThimerosal as a Vaccine Preservative Prepared for the  Advisory Committee for  Immunization PracticesLyn Redwood RN, MSN, FP (Retired)  2The Food and Drug Administration  Modernization Act of 1997 •Compiled list of drugs and foods that contained intentionally introduced  mercury compounds •Provided quantitative and qualitative analysis of mercury compounds •Report included 219 products which included 11 biologics and immunoglobulin  therapies Ref: U.S. Congress. (1997,…


01 Petersen chikungunya 508

Partial Evidence to Recommendations for use of
chikungunya vaccines among persons in U.S.
territories at risk for chikungunya virus
transmissionNational Center for Emerging and Zoonotic Infectious Diseases
Dr. Lyle Petersen
Director, Division of Vector -Borne Diseases
Advisory Committee on Immunization Practices meeting
June 26, 2025
•Two licensed chikungunya vaccines
-Live attenuated vaccine licensed in November 2023 for use in persons aged ≥18
years  (manufactured by Valneva)
-Virus -like particle vaccine licensed in February 2025 for use in persons aged ≥12
years (manufactured by Bavarian Nordic)
•Chikungunya Vaccines Work Group formed in May 2022
-Approved recommendations exist for use of vaccines in travelers and laboratory
workers
-Recent topic under discussion has been use of chikungunya vaccines in persons in
U.S. territories and states at risk for chikungunya virus transmissionBackground
Evidence to Recommendations ( EtR) for use of
chikungunya vaccines among persons in U.S. territories
at risk for chikungunya virus transmission:
Public health problem and value of a vaccine
EtR framework
EtR Domain Question
Public health problem •Is the problem (chikungunya) of public health importance?
Benefits and harms•How substantial are the desirable anticipated  effects of CHIK -VLP?
•How substantial are the undesirable anticipated  effects?
•Do the desirable effects outweigh the undesirable  effects?
•What is the overall certainty of this evidence for the critical outcomes?
Values•Does the target population feel the desirable effects are large relative to
the undesirable effects?
•Is there important variability in how patients value theoutcomes?
Acceptability •Is the intervention acceptable to keystakeholders?
Resource use •Is the intervention a reasonable and efficient allocation ofresources?
Equity •What would be the impact of the intervention on health equity?
Feasibility •Is the intervention feasible to implement?
Public Health Problem
Question: Is the problem of public health importance?
Key related questions include:
•Are the consequences of the problem serious?
•Are a large number of people affected by the problem?
•Is the problem related to emerging diseases …. or epidemic potential?
Chikungunya virus transmission
Countries and territories with current or past transmission of chikungunya virus
Globally, ~620,000 cases
reported in 2024 but likely
underestimate
 Outbreaks can be
large and explosive
•One-third to three -
quarters of po pulation
affected
•Substantial morbidity
•Stresses healthcare
capacity
No highly effective alternatives to vaccination for
disease control
Acknowledgement: Claudia Colon -Burgos & Coral Rosado- Santiago, CDC Dengue Branch•Mosquito prevention and control
measures
-Use of insect repellent challenging as
requires daily use during outbreaks
-Source reduction important but difficult to remove enough water -
holding containers where mosquitoes
lay eggs
•Other prevention measures have
had variable impact
•Fever and joint pain
-Arthralgia often severe and can be
debilitating
-Multiple joints involved, most
commonly hands and feet
•Other symptoms include
headache, myalgia, fatigue, rash,
abdominal pain, and vomiting
•No anti -viral treatment
-Supportive managementImpact of acute illness
Image above from : https://www.paho.org/en/topics/chikungunya
•Rare serious complications (e.g., cardiac,
renal, ocular, neurologic illness)
•Hospitalization rate ~3%
•Case fatality rate: 0.01% –0.5%
•Serious outcomes mostly in older adults and young infantsImpact of disease: severe presentations
Images from : https://www.paho.org/en/topics/chikungunya
Impact of disease: Arthralgia that persists or recurs
•Most patients have arthralgia that resolves in
7–10 days
•Arthralgia sometimes persists or relapses with
other symptoms e.g., fatigue

Impact of disease: Arthralgia that persists or recurs
Based on recent meta -analysis (Lindsey N. Chronic arthralgia after chikungunya. US Advisory Committee on Immunization Practices meeting, June 2023)*
*Rates likely overestimated as background rate of arthralgia in the population could not be taken into account51% 3 months
post -infection12 months
post -infection
38%Acute
illness
100%
Chikungunya previously documented in five U.S. territories
and affiliated states
•Puerto Rico
•United States Virgin Islands (USVI)
•American Samoa
•Federated States of Micronesia
•Marshall Islands
Reported chikungunya cases by month of illness onset,
Puerto Rico, 2014 –2015*
050010001500200025003000
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
2015 2014*Cases reported to Puerto
Rico Department of Health
Reported chikungunya cases by year and case status,
Puerto Rico, 2014 –2020
0200040006000800010000
2014 2015 2016 2017 2018 2019 2020Probable
Confirmed
Last laboratory -confirmed
symptomatic clinical case
•Seroprevalence study indicated
~30% population infected during
outbreak1
•Based on 30% seroprevalence
rate, ~1 million persons infected,
and 65% –85% of chikungunya
virus infections being symptomatic
-~650,000 –850,000 clinical
cases Estimated number of clinical cases in Puerto Rico
chikungunya outbreak
1. 1,268 of 4,035 participants (Adams LE at al, PLoS  NTD 2022);
Estimated 650,000– 850,000
clinical cases during the outbreak
in Puerto Rico*
*Based on ~30% post -outbreak population seroprevalence (Adams LE at al, PLoS NTD 2022) and 65% –85% of infections being symptomatic
Estimated hospitalizations and deaths in
chikungunya outbreak in Puerto Rico, 2014 –2015
19,500– 25,500 hospitalizations* 65-85 deaths#
*Based on 3% hospitalization rate#Based on 0.01% case -fatality rate
•Federated States of Micronesia (Yap State): 2013– 2014
•USVI: 2014– 2015
•American Samoa : began June 2014
•Marshall Islands: began February 2015Chikungunya in other U.S. territories and affiliated states*
*ACIP presentation, June 2024 (https://www.cdc.gov/acip/downloads/slides -2024- 06-26-28/03- Chikungunya -Hills -508.pdf)
Summary: Is chikungunya of public health importance
in U.S territories with risk of transmission?
1. Acute illness can be severe, hospitalizations can occur (particularly in
vulnerable groups), and arthralgia can persist for months or years
2. Timing of next outbreak is unknown but is likely to evolve rapidly and might affect a substantial proportion of population
3. Outbreaks can impact health services through patient loads and staff absenteeism
4. No highly effective control measures exist apart from vaccination
Question: Is the problem of public health importance?
□No
□Probably no
□Probably yes
□Yes
□Varies
□Don’t know
Values and preferences
1. Target population perception of value
Do potential vaccine recipients feel that the desirable effects are large relative
to undesirable effects?
2. Uncertainty around target population perception of value
Is there important uncertainty about, or variability in, how much people value the main outcomes? Values and preferences
Value of a chikungunya vaccine for residents of Ponce,
Puerto Rico: Study methods
•Data collected as part of larger study mos quito -borne disease study*
•Chikungunya component conducted in 2024, ~10 years after chikungunya
outbreak  in Puerto Rico
•Included 2,437 individuals or caregivers aged 1– 56 years
•Asked basic question about interest in vaccination with hypothetical chikungunya vaccine if free of charge or at ≤$10, and reasons if not
interested or unsure
*Adams LE et al. PLoS  Negl  Trop Dis 2022
If there was an approved chikungunya vaccine available
in Puerto Rico, free of charge or at low cost ($ 10 or less), would you get vaccinated (N=2,437)?
No Unsure Yes71%23%
7%Participants who had
completed at least some
higher education or had no
history of chikungunya
more likely to respond
“no” or “don’t know”*
*Preliminary analyses
What are the reasons why you would not be interested
or are not sure if you would be interested in getting vaccinated against chikungunya?*
*Could select ≥1 reason0510152025303540Percentage
•Part of larger population -based household study
•Conducted soon after end of outbreak in June 2015
•Included 966 participants aged 1– 91 years
•Subjects or caregivers questioned about interest in
receiving a hypothetical chikungunya vaccine
•Estimates calibrated to age and sex of USVI population Value of chikungunya vaccine in United States Virgin Islands
Population of 106,405 in 2010
Curren EJ et al. Am J Trop Med Hyg 2022
010203040506070Adjusted proportions with 95% CI
Vaccine interest56% interested in vaccineVaccine interest among participants (adjusted proportion)
25%
19%
Interested (n=520)          Not interested (n=258)        Unsure (n=188)
010203040506070Adjusted proportions with 95% CI
Vaccine interest56% interested in vaccineVaccine interest among participants (adjusted proportion)
25%
19%
Interested (n=520)          Not interested (n=258)        Unsure (n=188)        Persons aged ≥40 years less
likely to be interested vs. persons aged 0 –19 years
Reasons for potential lack of interest in vaccine among
those not interested or uncertain about vaccination (N=446)
•Wanting more safety information: 47% (95% CI: 41– 52%)
•Lack of concern for getting disease: 16% (95% CI: 13– 20%)
•Already had chikungunya disease: 10% (95% CI: 7– 13%)
•Majority of participants indicated interested in a hypothetical vaccine at time
surveys implemented
-Higher interest in Puerto Rico (71%) v s. USVI (56%) possibly influenced by timing of
surveys in relation to outbreaks and general vaccine uptake differences in two
territories
•For respondents potentially not interested in vaccine, key concern was
needing a better understanding of vaccine safety
-Will be important to provide resources and education on vaccine safety if
chikungunya vaccine introducedSummary
Question: Does the target population feel that the
desirable effects of vaccination are large relative to undesirable effects?
□No
□Probably no
□Probably yes
□Yes
□Varies
□Don’t know
Question: Is there important uncertainty about or
variability in how much people value the main outcomes?
□Important uncertainty or variability
□Probably not important uncertainty
or variability
□No important uncertainty or variability
□No known undesirable outcomes
Update on safety of live attenuated chikungunya
vaccine in older personsNational Center for Emerging and Zoonotic Infectious Diseases

Serious adverse events in older persons
•Status as of April 2025 ACIP meeting
-6 serious adverse events (SAEs) occurred in US persons aged ≥65 years during 2024*
-Discussed at ACIP meeting on April 16 and CDC determined age ≥65 years is
precaution to vaccination with live attenuated chikungunya vaccine
•Updates since April 2025 ACIP meeting
-In the 3 weeks following ACIP meeting, 11 additional SAEs reported internationally in
persons aged 62 –89 years, most with underlying medical conditions#
-European Medicines Agency recommended temporary pause in vaccine use in ages ≥65 years (May 7)
-FDA and CDC recommended temporary pause in the live, attenuated vaccine use in ages ≥60 years to allow investigations of reports (May 9)
¥
-Awaiting outcome of FDA investigations
*Reported through Vaccine Adverse Events Reporting System (VAERS)     #Mainly from Reunion where large outbreak occurring
¥FDA and CDC Recommend Pause in Use of Ixchiq  (Chikungunya Vaccine, Live) in Individuals 60 Years of Age and Older While Postmarketing  Safety Reports are Investigated | FDA

ACIP Chikungunya Vaccines Work Group
Arboviral Diseases Branch, CDC
•Sarah Guagliardo
•Susan Hills
•Erin Staples
Dengue Branch, CDC
•Laura AdamsAcknowledgements
For more information, contact CDC
1-800- CDC- INFO (232 -4636)
TTY:  1 -888- 232- 6348    www.cdc.gov
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Summary: Partial Evidence to Recommendations for use of  chikungunya vaccines among persons in U.S.  territories at risk for chikungunya virus  transmissionNational Center for Emerging and Zoonotic Infectious Diseases Dr. Lyle Petersen Director, Division of Vector -Borne Diseases Advisory Committee on Immunization Practices meeting June 26, 2025 •Two licensed chikungunya vaccines  -Live attenuated vaccine licensed in November 2023 for use in persons aged ≥18  years  (manufactured by Valneva) -Virus…


01 Jackson Anthrax 508

Introduction to the Anthrax Vaccine Work Group
Brendan Jackson, MD, MPH
Captain, U.S. Public Health Service
Principal Deputy Director
Division of High -Consequence Pathogens and Pathology
June 26, 2025
Advisory Committee on Immunization PracticesNational Center for Emerging and Zoonotic Infectious Diseases

•Bacillus anthracis , the causative agent of anthrax, is an endospore -forming
bacterium found naturally in soil around the world
•Humans are most often infected by exposure to infected animals or animal
by-products via cutaneous, gastrointestinal, or inhalational routes
•Bacillus anthracis isa Tier 1 select agent
-Potential for use as a bioweapon
-High case fatality rate
-Ability to cause great harm to public health and safety, particularly when
aerosolizedPublic Health Problem
•Vaccine : Anthrax vaccine adsorbed, adjuvanted (AVA,A) ( Cyfendus )
-Second -generation anthrax vaccine
-Licensed in July of 2023 for post -exposure prophylaxis (PEP) following exposure
to Bacillus anthracis in adults aged 18 to 65
•Work Group Objective: Review existing safety and immunogenicity data to
develop recommendations for ACIP to consider for domestic use of AVA,A
for anthrax PEPAnthrax Vaccine Work Group
For more information, contact CDC
1-800-CDC-INFO (232 -4636)
TTY:  1 -888-232-6348    www.cdc.gov
The findings and conclusions in this report are those of the authors and do not necessarily represent the official
position of the Centers for Disease Control and Prevention.
Thank you.

Summary: Introduction to the Anthrax Vaccine Work Group Brendan Jackson, MD, MPH Captain, U.S. Public Health Service Principal Deputy Director Division of High -Consequence Pathogens and Pathology June 26, 2025 Advisory Committee on Immunization PracticesNational Center for Emerging and Zoonotic Infectious Diseases  •Bacillus anthracis , the causative agent of anthrax, is an endospore -forming  bacterium found naturally in soil around the world •Humans are most often infected by exposure to infected…


01 MMRV safety summary 508

1

MMRV Vaccine Safety

Contents
Summary  ................................ ................................ ................................ ................................ ......  1
Cochrane Review  ................................ ................................ ................................ ...........................  2
General safety  ................................ ................................ ................................ ...............................  3
Febrile convulsion/febrile seizure  ................................ ................................ ................................ .... 6
Studies performed outside of the United States  ................................ ................................ ................  8
Clinical Trial data  ................................ ................................ ................................ .........................  10

Summary
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. In 2006, the
Advisory Committee on Immunization Practices (ACIP) recommended MMRV as an option for
both the first and second doses of measles, mumps, rubella, and varicella vaccination. However,
post -licensure safety surveillance identified an increased risk of febrile seizures 5 –12 days aft er
the first dose in children aged 12 –23 months compared to those receiving separate MMR and
varicella (MMR + V) vaccines. Based on this finding, ACIP updated its guidance in 2009.
ACIP currently recommends that MMR  and varicella vaccines be given separately for the first
dose in children 12 –47 months ; however , MMRV may be  used if parents or caregivers request a
preference. Compared with use of MMR vaccine and varicella vaccine at the same visit, use of
MMRV vaccine results in one fewer injection but is associated with a higher risk for fever and
febrile seizures 5 -12 days after the first dose among children aged 12 -23 months . Use of MMR
vaccine and varicella vaccine avoids this increased risk for fever and febrile seizures following
MMRV vaccine.  Studies of febrile seizures after vaccination with first dose of MMRV vaccine
have not been done in older children, but experts agree that this increased risk of fever and
febrile seizures during the 5 -12 days after first dose vaccination likely also occur s in ch ildren
aged 24 -47 months because that is the biologic window of vulnerability for febrile seizures in
children (approximately 97% of febrile seizures occur in children aged <4 years). First febrile
seizures are uncommon after age 4 years  (MMRV Questions and Answers for Healthcare
Providers | CDC ). Either MMRV or MMR + V may be used for the second dose or for children
aged 4 years and older  (Use of Combination Measles, Mumps, Rubella, and Varicella Vaccine ).
Over the past 15+ years  and multiple studies , mild fever and rash are the most common ly
reported adverse events  following MMRV vaccination . The primary safety concern is an
increased risk of febrile seizures following the first dose in children aged 12 -23 months.  This risk
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is estimated at 1 additional seizure occurring 5 -12 days after vaccination per 2,300 -2,600
vaccinated children  compared to those receiving MMR + V separately  (Use of Combination
Measles, Mumps, Rubella, and Varicella Vaccine ).  These events resolve without long -term
consequences  (Measles, Mumps, Rubella, Varicella (MMRV) Vaccine Safety | Vaccine Safety |
CDC). No increased seizure risk has been observed with the second dose or in children aged 48
months or older.
Several clinical trials have also evaluated the safety of MMRV when administered concomitantly
with other routine childhood vaccines , including pneumococcal conjugate vaccine (PCV -7),
meningococcal conjugate vaccines (MenACWY , MenC), and DTaP -containing vaccines. These
studies found no increase in serious adverse events or clinically meaningful differences in
reactogenicity .  International surveillance and real-world  data from Canada and Europe have
confirm ed the most common adverse events as mild fever and rash , along with the increased
risk of febrile seizure as the only serious adverse event  following MMRV vaccination. Although
rare case s of encephalitis and death have been reported after MMRV vaccination, no direct link
between these events and the vaccine has been established in persons with healthy immune
systems .
Cochrane Review
• Di Pietrantonj C, Rivetti A, Marchione P , Debalini MG, Demicheli V. Vaccines for measles,
mumps, rubella, and varicella in children.  Cochrane Database Syst Rev .
2021;11(11):CD004407. Published 2021 Nov 22. doi:10.1002/14651858.CD004407.pub5
o Authors searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the
Cochrane Library 2019, Issue 5), which includes the Cochrane Acute Respiratory
Infections Group's Specialised Register, MEDLINE (1966 to 2 May 2019), Embase
(1974 to 2 May 2019), th e WHO International Clinical Trials Registry Platform (2 May
2019), and ClinicalTrials.gov (2 May 2019).
o Includes randomized  controlled trials (RCTs), controlled clinical trials (CCTs),
prospective and retrospective cohort studies (PCS/RCS), case-control studies (CCS),
interrupted time-series (ITS) studies, case cross-over (CCO) studies, case-only
ecological method (COEM) studi es, self-controlled case series (SCCS) studies, person-
time cohort (PTC) studies, and case-coverage design/screening methods (CCD/SM)
studies, assessing any combined MMR or MMRV / MMR+V vaccine given in any
dose, preparation or time sche dule compared with no intervention or placebo, on
healthy children up to 15 years of age.
o Seizure:  The analyses provide evidence supporting an association between
MMR/MMR+V/MMRV vaccines (Jeryl Lynn strain) and febrile seizures. Febrile
seizures normally occur in 2% to 4% of healthy children at least once before the
age of 5. The attributable risk febri le seizures vaccine‐induced is estimated to be
from 1 per 1700 to 1 per 1150 administered doses.
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o ITP: ITP can happen after natural measles infection.  The analyses provide evidence
supporting an association between MMR  vaccination and ITP .  However, the risk of
ITP after vaccination is smaller than after natural infection with these viruses. Natural
infection of ITP occur in 5 cases per 100,000 (1 case per 20,000) per year. The
attributable risk is estimated about 1 case of ITP per 40,000 adm inistered MMR
doses.
 The overall meta-analysis estimate of association between MMR
vaccination and ITP in children aged 9 to 23 months was RR 4.21 (95% CI 2.28 to
7.78). There was no statistical evidence in children aged 4 to 6 y ears ( RR 3.06, 95% CI
0.42 to 22.30), and no statistical evidence of association between MMRV
vaccination and ITP in children aged 9 to 23 months ( RR 2.87, 95% CI 0.78 to 10.56).
The latter two results came from one study ( db-O'Leary 2012 ).
General safety
• Klopfer SO, Stek JE, Petrecz M, et al. Analysis of safety data in children after receiving two
doses of ProQuad® (MMRV).  Vaccine . 2014;32(52):7154 -7160.
doi:10.1016/j.vaccine.2014.08.067
o Safety data from five clinical studies were combined for all children who were
scheduled to receive two doses of MMRV ∼3-6 months apart. All vaccinated children
were followed for safety following each dose of MMRV.
o Of 3112 children who received a first dose of MMRV, 2780 (89.3%) received a second
dose of MMRV. Overall, 70.5% and 57.7% of children reported ≥1 adverse
experiences following first and second doses of MMRV, respectively . Injection ‐site
redness  was statistically significantly higher postdose 2 than postdose 1, while
injection ‐site pain/tenderness  was statistically significantly higher postdose 1
compared to postdose 2. Rashes  were statistically significantly lower postdose 2
compared to postdose 1. Ten febr ile seizures  (8 postdose 1, 2 postdose 2) were
reported following MMRV vaccination. The incidence of febrile seizures postdose 1
of MMRV was 0.26% (8/3019) compared to 0.07% (2/2695) postdose 2 of MMRV.
o Author’s conclusions: a dministration of two doses of MMRV has an acceptable safety
profile in children 12 to 23 months of age. There is a small increase in the risk of
febrile seizures following the first dose of MMRV as compared to the component
vaccines, but the risk for any i ndividual child is relatively low.
• Klein NP , Lewis E, Fireman B, et al. Safety of measles -containing vaccines in 1 -year -old
children.  Pediatrics . 2015;135(2):e321 -e329. doi:10.1542/peds.2014 -1822
o Study children were aged 12 to 23 months in the Vaccine Safety Datalink from 2000
to 2012. Nine study outcomes were investigated : 7 main outcomes (anaphylaxis,
ITP, ataxia, arthritis, meningitis/encephalitis, acute disseminated
encephalomyelitis, and Kawasaki disease), seizure, and fever.  Comparing MMRV
with MMR + V, relative risk was estimated by using stratified exact binomial tests.
Secondary analyses examined post -MMRV or MMR + V risk versus comparison
4

intervals; risk and comparison intervals were then contrasted for MMRV versus
MMR+V.
o Authors  evaluated 123,200 MMRV and 584,987 MMR + V doses . Comparing MMRV
with MMR + V, risks for the 7 main outcomes were not significantly different.
Several outcomes had few or zero postvaccination events. Comparing risk versus
comparison intervals, ITP risk was higher after MMRV (odds ratio [OR]: 11.3 [95%
confidence interval (CI): 1.9 to 68.2]) and MMR + V (OR: 10 [95% CI: 4.5 to 22.5])
and ataxia risk was lower after both vaccines (MMRV OR: 0.8 [95% CI: 0 .5 to 1];
MMR + V OR: 0.8 [95% CI: 0.7 to 0.9]).  Compared with MMR + V, MMRV increased
risk of seizure and fever 7 to 10 days after vaccination.
o Author’s conclusions: This study did not identify any new safety concerns comparing
MMRV with MMR + V or after either the MMRV or the MMR + V vaccine. This study
provides reassurance that these outcomes are unlikely after either vaccine.
• Ma SJ, Li X, Xiong YQ, Yao AL, Chen Q. Combination Measles -Mumps -Rubella -Varicella
Vaccine in Healthy Children: A Systematic Review and Meta -analysis of Immunogenicity and
Safety.  Medicine (Baltimore) . 2015;94(44):e1721. doi:10.1097/MD.0000000000001721
o Authors  searched PubMed, Embase, BIOSIS Previews, Web of Science, Cochrane
Library, and other databases through September 9, 2014. Eligible randomized
controlled trials (RCTs) were selected and collected independently by 2 reviewers.
Meta -analysis was conducted u sing Stata 12.0 and RevMan 5.3.
o Incidences of any serious adverse events (SAEs) were around 1% in all the groups;
only about one -tenth of the events were considered to be related to vaccination
studied. About half of the related SAEs were febrile seizures. The incidence of related
febril e seizure was under 0.8 % in MMRV groups and under 0.5‰ in MMR + V/MMR
groups. No statistical difference was found between groups with no evidence of
heterogeneity . No related fatal SAE was reported in any studies included.
o Well tolerated safety profiles were demonstrated except higher incidence of fever
(relative risks 1.12 –1.60) and measles/rubella ‐like rash (relative risks 1.44 –1.45) in
MMRV groups.
o Author’s conclusions: MMRV had comparable immunogenicity and overall safety
profiles to MMR + V/MMR in healthy children based on current evidence.
• Woo EJ, Winiecki SK, Arya D, Beeler J. Adverse Events After MMR or MMRV Vaccine in
Infants Under Nine Months Old.  Pediatr Infect Dis J . 2016;35(8):e253 -e257.
doi:10.1097/INF.0000000000001201
o The Vaccine Adverse Event Reporting System  was searched  for reports of measles,
mumps and rubella vaccine (MMR) or measles, mumps, rubella and varicella vaccine
(MMRV) vaccination in children less than 9 months of age. A clinical assessment of
each report was conducted and the frequency, range, onset time and severity of
adverse events  was summarized .
5

o After excluding 346 reports because they were duplicates or because they contained
insufficient information about the child's age or vaccine(s), authors  retained 204
reports in the analysis, including 35 (17%) that were serious. Among the 169
nonserious reports, more than half (88; 52%) described a vaccination error without
any adverse event per se. Other nonserious reports described fever, injection
reactions and gastrointestinal symptoms . Serious adverse events included
developmental disorders, fever and fussiness. There were 44 reports of fever, but
only 4 cases began 5 ‐12 days after immunization, the peak risk window. The vast
majority of fever reports listed concomitant vaccines, such as diphtheria and
tetanus toxoids, acellular or whole ‐cell pertussis vaccine.
o Author’s conclusions:  This review did not identify any major safety concerns. These
findings may facilitate discussions about the risks and benefits of vaccinating infants
who are potentially exposed to this life -threatening disease.
• Safety Surveillance of Varicella Vaccines in the Vaccine Adverse Event Reporting System, United
States, 2006 –2020 - PMC
o US VAERS reports received after administration of VAR and MMRV during 2006 -2020
were identified. Reports were analyzed by vaccine type, age, seriousness, most
common adverse events (AEs), and concomitant vaccines. Medical records of
selected reports of AEs of special interest were reviewed and empirical Bayesian data
mining to identify disproportionally reported AEs  was conducted .
o During 2006 -2020, approximately 132.8 million VAR doses were distributed; 40 684
reports were received in VAERS (30.6/100 000 doses distributed), with 4.1%
classified as serious (1.3/100 000 doses distributed). Approximately 35.5 million
MMRV doses were di stributed; 13 325 reports were received (37.6/100 000 doses
distributed) with 3.3% classified as serious (1.3/100 000 doses distributed). The most
common adverse health events after both VAR and MMRV were injection site
reactions (31% and 27%), rash (28% a nd 20%), and fever (12% and 14%),
respectively. Vaccination errors accounted for 23% of reports after VAR
administration and 41% after MMRV administration, but ≥95% of them did not
describe an adverse health event. AEs associated with evidence of vaccine s train
varicella -zoster virus (vVZV) infection included meningitis, encephalitis, herpes
zoster, and 6 deaths (all in immunocompromised persons with contraindications for
vaccination). No new or unexpected AE was disproportionally reported .
o Author’s conclusions: No new or unexpected safety findings were detected for VAR
and MMRV given as recommended, reinforcing the favorable safety profiles of these
vaccines. Providers should obtain specimens for viral testing and strain -typing for
serious AEs if they consider vV ZV as the possible causative agent.
• Vittrup DM, Charabi S, Jensen A, Stensballe LG. A systematic review and meta -analysis of
adverse events following measles -containing vaccines in infants less than 12 months of
age. Vaccine . 2025;47:126687. doi:10.1016/j.vaccine.2024.126687
6

o EMBASE and PubMed were searched in February 2021 , and the search was  updated
in February 2024. With the exception of case reports, we included all English -written
original studies published >1985 that contained frequency measures on adverse
events (AEs) within 56  days following MCV1 in infants <12  months of age. We
identified all common AEs and their frequencies and combined these across studies
in a meta -analysis. The effect of measles strain and vaccine valency  was also
evaluated.
o 24 studies were included in the analysis: 18 randomized controlled trials (RCTs),
three interventional studies, and three observational studies. Only one RCT was
placebo -controlled. Commonly reported AEs were injection site reactions, fever,
rash, gastrointestinal symptoms, respiratory t ract symptoms, conjunctivitis, and
symptoms related to the general condition of the infant . The frequency of any AE
was generally <10  %; however, the placebo ‐controlled trial showed no difference
between MCV1 and placebo ‐injected infants. Edmonston B strains and measles ‐
mumps ‐rubella ‐varicella vaccine (MMRV) were associated with a higher rate of
high fever >39  °C.
o Most AEs occurred in <10  % of infants receiving MCV1  at < 12 months of age. The
placebo -controlled trial suggested no excess reactogenicity following early MCV.
Measles strain and vaccine valency may affect AE risks, but other factors such as
socioeconomic  status, race, and setting could also explain this finding, as these were
not equally distributed between studies. Caution is advised when interpreting
findings from studies without a placebo group.
Febrile convulsion/febrile seizure
• 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
o Children ages 12 –60 months who received a first dose of MMRV in February
2006 –June 2007 in a managed care organization were included in the study.
Subjects were optimally matched on age, sex, and calendar date of vaccination to
children who received MMR  + V concomitantly in November 2003 –January 2006,
before MMRV licensure. Potential cases of febrile convulsion were identified
through administrative data and adjudicated by expert panel, according to pre -
specified criteria.
o During the 30 days post -vaccination, there were 128 and 94 potential convulsion
cases among the 31,298 children in the MMRV and MMR+V cohorts,
respectively. After review of available medical charts and adjudication, there
were 84 cases of confirmed febrile  convulsion, 44 (1.41/1000) and 40
(1.28/1000) in the MMRV and MMR+V cohorts, respectively (RR=1.10, 95%
CI=0.72, 1.69). In days 5 -12 following vaccination, a pre -specified period of
7

interest, the respective numbers were 22 (0.70/1000) and 10 (0.32/1000)
(RR=2.20, 95% CI=1.04, 4.65).
o These data suggest that the risk of febrile convulsion is increased in days 5 ‐12
following vaccination with MMRV as compared to MMR+V given separately
during the same visit, when post ‐vaccination fever and rash are also increased
in clinical trials.
• 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
o Using 2000 –2008 Vaccine Safety Datalink data, authors assessed seizures and
fever visits among children aged 12 to 23 months after MMRV and separate
MMR + varicella vaccines. Authors  compared seizure risk after MMRV vaccine to
that after MMR + varicella vaccines by using Poisson regression as well as with
supplementary regressions that incorporated chart -review results and self -
controlled analyses.
o MMRV vaccine recipients (83 107) were compared with recipients of MMR +
varicella vaccines (376 354). Seizure and fever significantly clustered 7 to 10 days
after vaccination with all measles -containing vaccines but not after varicella
vaccination alone. S eizure risk during days 7 to 10 was higher after MMRV than
after MMR + varicella vaccination (relative risk: 1.98 [95% confidence interval:
1.43 –2.73]). Supplementary analyses yielded similar results. The excess risk for
febrile seizures 7 to 10 days after  MMRV compared with separate MMR +
varicella vaccination was 4.3 per 10 000 doses (95% confidence interval: 2.6 –5.6).
o Among 12 ‐ to 23 ‐month ‐olds who received their first dose of measles ‐
containing vaccine, fever and seizure were elevated 7 to 10 days after
vaccination. Vaccination with MMRV results in 1 additional febrile seizure for
every 2300 doses given instead of sepa rate MMR + varicella vaccines.
• Klein NP , Lewis E, Baxter R, et al. Measles -containing vaccines and febrile seizures in
children age 4 to 6 years.  Pediatrics . 2012;129(5):809 -814. doi:10.1542/peds.2011 -3198
o Among 4 - to 6-year -old Vaccine Safety Datalink members, authors  identified
seizures in the emergency department and hospital from 2000 to 2008 and
outpatient visits for fever from 2006 to 2008 during days 7 to 10 and 0 to 42 after
MMRV and MMR + V. Incorporating medical record reviews, we assessed seizure
risk after M MRV and MMR + V.
o From 2006 through 2008, 86 750 children received MMRV; from 2000 through
2008, 67 438 received same -day MMR + V. Seizures were rare throughout days 0
to 42 without peaking during days 7 to 10. There was 1 febrile seizure 7 to 10
days after MMRV and 0 after  MMR + V. Febrile seizure risk was 1 per 86 750
MMRV doses (95% confidence interval, 1 per 3 426 441, 1 per 15 570) and 0 per
67 438 MMR + V doses (1 per 18 282).
8

o This study provides reassurance that MMRV and MMR + V were not associated
with increased risk of febrile seizures among 4 ‐ to 6‐year ‐olds. We can rule out
with 95% confidence a risk greater than 1 febrile seizure per 15 500 MMRV
doses and 1 per 18 000 MMR + V doses.
• Ma SJ, Xiong YQ, Jiang LN, Chen Q. Risk of febrile seizure after measles -mumps -rubella -
varicella vaccine: A systematic review and meta -analysis.  Vaccine . 2015;33(31):3636 -
3649. doi:10.1016/j.vaccine.2015.06.009
o PubMed, Embase, BIOSIS Previews, Scopus, Web of Science, Cochrane Library
and other databases  were searched  through 12 December 2014.
o A total of thirty -nine studies were included. Thirty -one published or unpublished
clinical trials involving about 40,000 subjects did not show significant differences
in incidence of febrile seizure or vaccine related febrile seizure between MMRV
and MMR w ith or without varicella vaccine after any doses, in the risk windows
of 0-28, 0 -42 or 0 -56 days and 7 -10 days. In addition, these studies showed that
the receipt of concomitant use of MMRV and other pediatric vaccines was not a
significant predictor of fe brile seizure. Eight post -marketing observations
involving more than 3,200,000 subjects were included. No evidence suggested
elevated risk of febrile seizure associated with MMRV vaccine among children
aged 4 ‐6 years old during 7 ‐10 days or 0 ‐42 days after vaccination. However, an
approximately 2 ‐fold increase in risk of seizure or febrile seizure during 7 ‐10
days or 5 ‐12 days after MMRV vaccination was found among children aged 10 ‐
24 months, although the highest incidence of seizure was still lower than
2.95%.
o First MMRV vaccine dose in children aged 10 -24 months was associated with an
elevated risk of seizure or febrile seizure.
Studies performed outside of the United States
Canada
• Seo CY , Rashid M, Harris T, Stapleton J, Deeks SL. Assessing safety of Ontario's publicly
funded MMR and MMRV immunization programs, 2012 to 2016.  Paediatr Child Health .
2019;25(6):358 -364. Published 2019 Apr 8. doi:10.1093/pch/pxz037
o Reports of AEFIs were extracted from the provincial surveillance database on
May 9, 2017. Events were grouped by provincial surveillance definitions.
Reporting rates were calculated using provincial population estimates or net
doses distributed as the deno minator. A serious AEFI is defined as an AEFI that
resulted in an in -patient hospitalization or death.
o  Overall, 289 AEFIs were reported following administration of MMR (n=246) or
MMRV (n=43) vaccines, for annualized reporting rates of 16.6 and 8.8 reports per
100,000 distributed doses, respectively. The highest age -specific reporting rate
was in children ag ed 1 to 3 years for MMR (7.7 per 100,000 population) and
9

children aged 4 to 9 years for MMRV (0.8 per 100,000 population). Systemic
reactions were the most frequently reported event category, while rash was the
most frequently reported event for both vaccines. There were 22 serious AEFIs,
19 following MMR and 3 following MMRV (1.3 and 0.6 per 100,000 doses
distributed, respectively).
o Authors  found a low reporting rate of adverse events following MMR and MMRV
vaccines in Ontario. No safety concerns were identified.
Germany
• Schäfer W, Reinders T, Schink T. Second dose of measles -mumps -rubella -varicella vaccine
(MMRV) and the risk of febrile convulsions.  Vaccine . 2022;40(14):2168 -2172.
doi:10.1016/j.vaccine.2022.02.072
o A retrospective cohort study using claims data from the German
Pharmacoepidemiological Research database (GePaRD) was performed in
children born between January 1st, 2004 and October 31st, 2015 who received
two doses of MMRV, MMR  + V or MMR. Cases were defi ned as hospitalization
with a diagnosis of febrile convulsions ( FC) without neurological conditions coded
as main discharge diagnosis. Unadjusted and adjusted odds ratios (OR) with 95%
confidence inte rvals (CIs) were calculated to compare the risk of FC. Stratified
analyses were performed to examine potential effect modification by age, sex,
history of FC or type of first dose vaccine.
o In the first 30  days after second dose  vaccination , 464 FCs were observed in a
cohort of 528,639 children with a median age of 17  months. After adjustment for
potential confounders, the adjusted OR for FC in the 30  days after vaccination
was 1.25 (95% CI 0.67 –2.30) for MMRV compared to MMR  + V and 1.04 (0 .82–
1.32) for MMRV compared to MMR. History of FC was the most important risk
factor with an OR of 36.26 (29.30 –44.89). We found no effect modification by
age, sex, history of FC, or type of first dose vaccine.
o Author’s conclusions: Use of MMRV at second dose is not associated with an
increased risk of FC compared to MMR  + V or MMR, irrespective of age, sex,
history of FC, or type of first dose vaccine.
Italy
• Stefanizzi P , Stella P , Ancona D, et al. Adverse Events Following Measles -Mumps -Rubella -
Varicella Vaccination and the Case of Seizures: A Post Marketing Active Surveillance in
Puglia Italian Region, 2017 -2018.  Vaccines (Basel) . 2019;7(4):140. Published 2019 Oct 7.
doi:10.3390/vaccines7040140
o In the Puglia Region launched, from May 2017 to November 2018, a post -
marketing active surveillance program of adverse events following MMRV
immunization (AEFIs). Immunized children (second year of life) were enrolled on
10

a voluntary basis, AEFIs diaries were used, and their parents were interviewed 25
days after the immunization.
o There were 2540 children enrolled; 2149/2540 (84.6%) completed the post -
vaccination follow -up. Of these, 992 AEFIs were registered with a reporting rate
of 46.2 × 100 doses: 883/992 (89.0%) AEFIs were not serious, while 109/992
(11.0%) were serious. For se rious AEFIs, the evaluation of causality assessment
was performed using the algorithm proposed by the World Health Organisation
(WHO): 82/109 consistent causal associations to MMRV immunization were
detected (reporting rate of consistent AEFIs: 3.8 × 100 f ollow -up). All serious
AEFIs consistently associated with immunization resulted completely resolved at
the follow -up. The reporting rate of seizure consistently associated with
immunization was 0.05 × 100, lower than data previous published in the
literatu re that did not report the causality assessment.
o Author’s conclusion: Because  no emerging signals were detected, data from the
active surveillance program confirmed the safety profile of the MMRV vaccine.
Clinical Trial data
• Reisinger KS, Brown ML, Xu J, et al. A combination measles, mumps, rubella, and varicella
vaccine (ProQuad) given to 4 - to 6-year-old healthy children vaccinated previously with M -
M-RII and Varivax [published correction appears in Pediatrics. 2006
Jun;117(6):2338].  Pediatrics . 2006;117(2):265 -272. doi:10.1542/peds.2005 -0092
o Four- to 6-year-old children who had been immunized previously with M -M-RII and
Varivax were assigned randomly to receive either ProQuad and placebo ( N = 399), M -
M-RII and placebo ( N = 195), or M -M-RII and Varivax ( N = 205) and were then
monitored for safety and immunogenicity.  ProQuad was generally well tolerated.
Similarity (noninferiority) was demonstrated in postvaccination antibody responses
to measles, mumps, and rubella between recipients of ProQuad and all recipients
of M-M-RII and in responses to varicella between recipients of ProQuad and
recipients of Var ivax. Postvaccination seropositivity rates for antibodies against all 4
viruses were nearly 100% in all 3 groups. Small fold increases were observed for
measles, mumps, and rubella antibody titers. In contrast, substantial boosts in
varicella antibody titers were observed among recipients of a second dose of
varicella vaccine, administered as ProQuad or Varivax.
o ProQuad may be used in place of a second dose of M -M-RII or second doses of M -
M-RII and Varivax for 4 - to 6-year-old children.
• Shinefield H, Black S, Thear M, et al. Safety and immunogenicity of a measles, mumps,
rubella and varicella vaccine given with combined Haemophilus influenzae type b
conjugate/hepatitis B vaccines and combined diphtheria -tetanus -acellular pertussis
vaccine s. Pediatr Infect Dis J . 2006;25(4):287 -292.
doi:10.1097/01.inf.0000207857.10947.1f
o In this open, multicenter trial, 1915 healthy children ages 12 -15 months were
randomized into 3 groups: group 1, MMRV, combined Haemophilus influenzae
11

type b conjugate -hepatitis B vaccines (Hib/HepB) and combined diphtheria -
tetanus -acellular pertussis vaccines (DTaP) concomitantly; group 2, MMRV
followed by Hib/HepB and DTaP 42 days later; group 3, MMR and varicella
vaccine followed by Hib/HepB and DTaP 42 days later.
o Antibody responses to measles, mumps, rubella, varicella, Hib, HepB, diphtheria
and tetanus were similar between groups 1 and 2 (all >95%, except varicella,
89.7% in group 1 and 90.9% in group 2). Pertussis toxin and filamentous
hemagglutinin responses wer e significantly lower in group 1 than in group 2
(group 1, 74.1 and 67.1%; group 2, 90.4 and 86.8%, respectively). An exploratory
analysis suggested that the difference in pertussis toxin and filamentous
hemagglutinin responses was likely the result of stu dy design rather than
interference among vaccine components because the groups differed in age of
receipt of DTaP (group 1, approximately 12 months; group 2, approximately 13.5
months). When the groups were matched for age, sample size was sufficient for
comparison only in children > or =13.5 months old. Pertussis toxin and
filamentous hemagglutinin responses were similar in these children. The safety
profiles for each vaccination regimen were comparable.
o Concomitant administration of MMRV, Hib/HepB and DTaP is well -tolerated.
• Leonardi M, Bromberg K, Baxter R, et al. Immunogenicity and safety of MMRV and PCV -7
administered concomitantly in healthy children.  Pediatrics . 2011;128(6):e1387 -e1394.
doi:10.1542/peds.2010 -2132
o Healthy 12 - to 15 -month -old children who lacked vaccination and clinical
histories for measles, mumps, rubella, varicella, and zoster but had written
documentation of receipt of a 3 -dose primary series of PCV -7 were randomly
assigned in a 2:1:1 ratio to re ceive either the MMRV and PCV -7 (group 1), PCV -7
followed 6 weeks later by MMRV (group 2), or MMRV followed 6 weeks later by
PCV-7 (group 3). The primary safety analysis was 56 days (28 days after each
visit). Immunogenicity was evaluated 6 weeks after eac h vaccination.
o A total of 1027 children were enrolled (group 1: 510; group 2: 258; group 3: 259).
For all 3 groups, the antibody response rate was ≥96.8% for measles, mumps,
and rubella, ≥88.0% for varicella -zoster virus, and ≥98.3% for all of the 7
Streptococcus pneumon iae serotypes. The immune responses to all antigens
present in MMRV and PCV -7 were similar whether administered concomitantly
or sequentially. The incidence of local and systemic adverse experiences (AEs)
was comparable between group 1 and groups 2 and 3 c ombined. No vaccine ‐
related serious AEs were reported.
o Concomitant administration of the MMRV and PCV -7 is highly immunogenic and
generally well tolerated . Similar immune responses between the groups support
concomitant administration of the MMRV and PCV -7 to healthy children 12 to 15
months of age.
12

• Klein NP , Shepard J, Bedell L, Odrljin T, Dull P . Immunogenicity and safety of a
quadrivalent meningococcal conjugate vaccine administered concomitantly with
measles, mumps, rubella, varicella vaccine in healthy toddlers.  Vaccine .
2012;30(26):3929 -3936. doi:10.1016/j.vaccine.2012.03.080
o Should be noted that for this study, because of a shortage of Pro Quad during
part of the study, MMR+V was used.  When “MMRV” is used in this paper, it
includes subjects vaccinated with MMRV or MMR+V.
o Two age groups were concurrently enrolled: 7 - to 9-month -old infants who
received 2 doses of MenACWY -CRM at 7 -9 and 12 months and were randomized
1:1 to receive MenACWY -CRM with or without MMRV at 12 months, and 12 -
month -old infants who received MMRV only at 12 months. Using predefined
non-inferiority criteria, immune responses to the antigens in MMRV were
compared between those who did and did not receive MenACWY -CRM; immune
responses to MenACWY -CRM as measured by the percentage of subjects with
human seru m bactericidal activity (hSBA) titers ≥ 8, were compared between
those who did and did not receive concomitant MMRV. Adequacy of the immune
response to 2 doses of MenACWY -CRM administered at 7 -9 and 12 months was
also assessed. Local and systemic reactions , adverse events resulting in
withdrawal or requiring medical attention and serious adverse events were
monitored.
o Concomitant administration of MMRV with MenACWY -CRM did not affect the
immune response to either vaccine. The 2 -dose series of MenACWY -CRM
induced adequate immune response to all 4 serogroups. No increased
reactogenicity was observed with MenACWY ‐CRM+MMRV compared with
MMRV alone, and there were no study ‐related serious adverse events.
o Concomitant administration of MenACWY -CRM with MMRV vaccinations at 12
months was well -tolerated, without safety concerns. Robust immune responses
to all components of both vaccines were produced and all criteria for non -
inferiority were met, supporting th e use of a 2 -dose regimen of MenACWY -CRM
in this age group.

Summary: 1    MMRV Vaccine Safety     Contents   Summary  ................................ ................................ ................................ ................................ ......  1  Cochrane Review  ................................ ................................ ................................ ...........................  2  General safety  ................................ ................................ ................................ ...............................  3  Febrile…


01 kulldorff MMRV 508

MMRV
MMRV = One combined shot for Measles, Mumps,
Rubella and Varicella
alternative to
MMR+V = Two shots, one for Measles, Mumps and
Rubella and another for Varicella
No known difference in efficacy

MMRV Timeline
2005: FDA licensed the combined MMRV
vaccine for use in children 12 months to 12
years of age.
2006: The CDC Advisory Committee on
Immunization Practices recommended use of
MMRV, with preference over separate MMR
and Varicella vaccines.

Weekly Safety Surveillance
CDC’s Vaccine Safety Datalink Rapid Cycle
Analysis
Weekly Data from Electronic Health Records
First MMRV dose, at age 12 -23 months
2007: Signal for an excess number of febrile
seizures after ~26,000 doses

Seizure Signal
For 12 -23 month olds,
seizure signal on February
11, 2007.
Cumulative doses at that
time: 25,779
Observed Expected Relative
RiskLLR (critical
value)
Number
Seizures 59 38 1.57 5.17 (4.12)
Note: No seizure risk after second dose at age 4 -6 years old

Postvaccination seizures among 12 - to 23 -month -olds according
to vaccine received: VSD study population, 2000 –2008.

Risk for Febrile Seizures after
MMRV Compared to MMR+V

Also excess in post -vaccination fever

MMRV Working Group Vote
Four Options for the Vote, ages 12 -47 months:
1.Both recommended, Preference for MMRV
2.Both recommended, Equal preference
3.Both recommended, Preference for MMR+V
4.Only recommend MMR+V1. Zero votes
2. Minority
3. Majority
4. One vote
2009
ACIP Vote
Four Options for the Vote, ages 12 -47 months:
1.Both recommended, Preference for MMRV
2.Both recommended, Equal preference
3.Recommend both, Preference for MMR+V
4.Only recommend MMR+V1. Zero votes
2. Majority
3. Minority
4. Zero votesJune 2009

CDC 2009 Recommendation
ACIP is only advisory. CDC decided:
-Either MMRV or MMR+V may be
administered
-For dose 1 in children age 12 -47 months,
preference for MMR+V

Summary
-No known difference in efficacy between
MMRV and MMR+V
-After first dose for children at ages 12 -23
months, more febrile seizures after MMRV
than MMR+V, ~ 1 per 2,300 doses
-After second dose at ages 4 -6 years, no
excess risk for febrile seizures
Proposed Recommendation
As there exist a safer equally effective
alternative, the MMRV vaccine should
not be administered to children under
the age of 47 months.

Summary: MMRV MMRV = One combined shot for Measles, Mumps,  Rubella and Varicella  alternative to MMR+V = Two shots, one for Measles, Mumps and  Rubella and another for Varicella No known difference in efficacy   MMRV Timeline 2005: FDA licensed the combined MMRV  vaccine for use in children 12 months to 12  years of age. 2006: The CDC Advisory Committee on   Immunization Practices recommended use of  MMRV, with preference over separate MMR  and Varicella vaccines.    Weekly Safety Surveillance CDC’s…


01 minhaj Mpox 508

Agency for Toxic Substances and Disease Registry National Center for Environmental Health
Centers for Disease Control and Prevention
Mpox Vaccine Work Group
Faisal Syed Minhaj, PharmD, MPH Poxvirus and Rabies Branch Centers for Disease Control and Prevention
ACIP Meeting April 15, 2025
•Genus: Orthopoxvirus
•Family: Poxviridae
•Discovered in 1958 after two pox-like disease outbreaks in research monkey colonies
•Specific animal reservoir unknown, but likely African small mammals
•On November 28, 2022, WHO implemented the preferred term “mpox” for the disease
•Two clades of MPXV:
-Clade I: found in central Africa and historically associated with greater disease severity in a higher proportion of people
-Clade II: found in West Africa and caused the 2022 global outbreak Monkeypox virus (MPXV)

Mpox historical context
Mpox historical context
Mpox historical context
Mpox historical context
Mpox historical context
• First case in this outbreak identified in the Unite d Kingdom in May 2022
• Primarily affecting gay, bisexual, and other men wh o have sex with men (MSM)
• Associated with person-to-person spread via close s kin-to-skin contact including
sex
• Deaths have occurred, primarily among persons with severe immunocompromise
from advanced HIV
• U.S. case counts and deaths comprise 1/3 of cases a nd deaths globally
- >30,000 cases
- >60 deaths Global Mpox Outbreak, 2022
United States mpox case count and 7-day moving Average – May 2022 through March 2025
Peak Confirmed Daily Cases (7-day average): 467 cases
Date
United States mpox case count and 7-day moving Average – August 2024 through March 2025
Subject to reporting delays
The currentmedian 7-
daymovingaverage for confirmedcases for February is 3.3-1.2per day.
•ACIP recommends the 2-dose* JYNNEOS vaccine series fo r persons aged 18
years and older at risk of mpox during an mpox outbrea k §.
*Dose 2 administered one month after dose 1 §Public health authorities determine whether there i s an mpox outbreak; a
single case may be considered an mpox outbreak at t he discretion of public
health authorities. Other circumstances in which a public health response may
be indicated include ongoing risk of introduction o f mpox into a community
due to disease activity in another geographic area.Current Recommendation (voted February 2023)
ACIP recommends vaccination* with the 2-dose †JYNNEOS vaccine series for
persons aged 18 years and older at risk for mpox §?Current Recommendation (voted October 2023) –updated language
*Interim recommendation to be revisited in 2-3 year s
† Dose 2 administered 28 days after dose 1
§Persons at risk:
1. Gay, bisexual, and other men who have sex with m en (MSM), or a person who has sex with
MSM who in the past 6 months have had one of the follow ing:
•A new diagnosis of ≥ 1 sexually transmitted disease
•More than one sex partner
•Sex at a commercial sex venue
•Sex in association with a large public event in a g eographic area where mpox
transmission is occurring
2. Sexual partners of persons with the risks descri bed in above
3. Persons who anticipate experiencing any of the a bove
Mpox current situation
•Modeling data suggests any increase in coverage reduces the risk of
outbreaks, and low coverage (<50%) could promote la rger outbreaks Jynneos vaccine coverage in the United States among  people
at risk for mpox – June 2022 to September 2024
Overall vaccine coverage
1-dose: 42.2% and 2-dose: 26.2 %
U.S. mpox case trends in adolescents and pediatrics ,
May 2022 – March 2025
Case
Count Age
group
92 12-17
17 6-11
23 1-5
15 <1
147 Total
Subject to reporting delays
•Previously, there was no data evaluating Jynneos in childr en <18 years
•An NIH sponsored trial completed last year evaluating Jyn neos in 12–17-
year-old adolescents
-DMID 22-0020: A Phase 2 Randomized, Open-Label Mult isite Trial to Inform
Public Health Strategies Involving Use of MVA-BN Va ccine for Mpox (DoSES)
•Stage 2: non-inferiority trial of Jynneos in adoles cents compared to adults
•Proposed recommendations would extend current recommendations to
12–17-year-old adolescents New data on safety and immunogenicity in adolescents
•ACIP recommends the 2-dose* JYNNEOS vaccine series fo r persons 12–17
years of age at risk of mpox during an mpox outbreak §.
*Dose 2 administered one month after dose 1 §Public health authorities determine whether there i s an mpox outbreak; a
single case may be considered an mpox outbreak at t he discretion of public
health authorities. Other circumstances in which a public health response may
be indicated include ongoing risk of introduction o f mpox into a community
due to disease activity in another geographic area.Proposed Recommendation 1
ACIP recommends vaccination* with the 2-dose †JYNNEOS vaccine series for
persons aged 12–17 years at risk for mpox §?Proposed Recommendation 2
*Interim recommendation to be revisited in 2-3 year s
† Dose 2 administered 28 days after dose 1
§Persons at risk:
1. Gay, bisexual, and other men who have sex with m en (MSM), or a person who has sex with
MSM who in the past 6 months have had one of the fo llowing:
•A new diagnosis of ≥ 1 sexually transmitted disease
•More than one sex partner
•Sex at a commercial sex venue
•Sex in association with a large public event in a g eographic area where mpox
transmission is occurring
2. Sexual partners of persons with the risks descri bed in above
3. Persons who anticipate experiencing any of the a bove
•Presentation of the safety and immunogenicity of Jynneo s in 12–17-year-
olds: Dr. C. Buddy Creech
•Evidence to recommendations framework:
-Outbreak recommendations: Dr. Faisal Minhaj
-Routine recommendations: Dr. Faisal Minhaj Goals for today’s meeting
Tentative timeline for ACIP discussions and votes
ACIP Meeting:
Presentation
of two EtR
April 2025 ACIP Meeting:
Voting on two
EtR
June 2025 Continue monitoring
mpox epidemiology
and vaccine
recommendations
Ongoing
•WG Chair
-Yvonne (Bonnie) Maldonado
•WG Lead
-Faisal Syed Minhaj
•ACIP Members
-Edwin Asturias
-Lin Chen
•Ex Officio/Liaison members
-CSTE: Paul Cieslak
-ASTHO: Chris Taylor
-NACHO: Philip Huang
-FDA: Sixun Yang, Pete Weina
-ACOG: Howard Minkoff
-AAP: Jim Campbell WG Composition
•Ex Officio/Liaison members (cont.)
-HRSA: Vikram Krishnasamy
-AIM: Heather Roth
-NIH: Kimberly Taylor
-IHS: Uzo Chukwama
-NACI: Nicole Forbes, Joshua Montroy
-IDSA: Shireesha Dhanireddy, Katherine Hsu
•Invited Consultants
-Inger Damon
-Stuart Isaacs
-Mike Merchlinsky
-Amanda Zarrabian •Clinician experts
STIs, HIV, mpox, pediatrics
-Jason Zucker
-Kim Workowski
-Pablo Sánchez
-Beth Bell
Immunization
-Ruth Karron
-Flor Munoz-Rivas
CDC Contributors
•Mpox Epi/Lab/Vaccine experts
-Agam Rao
-Andrea McCollum
-Christina Hutson
-Sathesh Panayampalli
-Shama Cash-Goldwasser
•Vaccine Safety
-Michael McNeil
-Jonathan Duffy •Regulatory Affairs
-Yon Yu
•STIs and HIV
-Laura Bachman
-Jesse O’Shea
•Drug Services
-Julian Jolly
•Vaccine Implementation
-Liz Velazquez
For more information, contact CDC 1-800-CDC-INFO (232-4636) TTY:  1-888-232-6348    www.cdc.gov The findings and conclusions in this report are tho se of the authors and do not necessarily represent the official
position of the Centers for Disease Control and Pre vention.
Thank you

Summary: Agency for Toxic Substances and Disease Registry National Center for Environmental Health  Centers for Disease Control and Prevention  Mpox Vaccine Work Group  Faisal Syed Minhaj, PharmD, MPH Poxvirus and Rabies Branch Centers for Disease Control and Prevention  ACIP Meeting April 15, 2025  •Genus: Orthopoxvirus  •Family: Poxviridae  •Discovered in 1958 after two pox-like disease outbreaks in research monkey colonies  •Specific animal reservoir unknown, but likely African small mammals  •On…


02 Creech Mpox 508

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03 minhaj Mpox 508

Agency for Toxic Substances and Disease Registry National Center for Environmental Health
Centers for Disease Control and Prevention
Evidence to Recommendations Framework: Vaccination with Jynneos for Adolescents at Risk of
Mpox During Outbreaks
Faisal Syed Minhaj, PharmD, MPH Poxvirus and Rabies Branch Centers for Disease Control and Prevention Advisory Committee on Immunization Practices April 15, 2025
•Structure to describe information considering in moving fr om evidence to
ACIP vaccine recommendations
•Provides transparency around the impact of additional fa ctors on
deliberations when considering a recommendation Evidence to Recommendations (EtR) Framework
•Does ACIP recommend the 2-dose* JYNNEOS vaccine serie s for persons 12–
17 years of age at risk of mpox during an mpox outbre ak §?
*Dose 2 administered one month after dose 1 §Public health authorities determine whether there is an mpox outbreak; a single case may be
considered an mpox outbreak at the discretion of pu blic health authorities. Other circumstances
in which a public health response may be indicated include ongoing risk of introduction of mpox
into a community due to disease activity in another  geographic area. EtR question
Evidence to Recommendation Domains
Question(s) EtR Domain
•Is the problem of public health importance? Public Health Problem
•How substantial are the desirable anticipated effec ts?
•How substantial are the undesirable anticipated eff ects?
•Do the desirable effects outweigh the undesirable e ffects? Benefits and Harms
•Does the target population feel the desirable effec ts are large relative to the
undesirable effects?
•Is there important uncertainty or variability in ho w much people value the
main outcome? Values
•Is the intervention acceptable to key stakeholders? Acceptability
•What would be the impact on health equity? Equity
•Is the intervention feasible to implement? Feasibility
•Is the intervention a reasonable and efficient allo cation of resources? Resource Use
EtR Domain: Public Health Problem
Mpox current situation
Global distribution of confirmed mpox cases, January 1, 2024 – March 26, 2025

Global distribution of confirmed clade I mpox casesJanuary 1, 2024 – April 13, 2025

United States mpox case count and 7-day moving Average – May 2022 through March 2025
Peak Confirmed Daily Cases (7-day average): 467 cases
U.S. mpox case counts in pediatrics, May 2022
through March 2025
Case Count Age
group
92 12-17
17 6-11
23 1-5
15 <1
147 Total

Typical mpox manifestations

Severe manifestations of mpox
Keratitis and conjunctival ulcer
T-wave inversions in inferior and anterolateral lea ds of a patient
with mpox with elevated Tn, SOB, decreased exercise  tolerance Encephalomyelitis in a patient with mpox
Severe manifestations from uncontrolled viral replication in severely immunocompromised
Carrubba S. Lancet Infect Dis. 2023 May;23(5):e190-e 197.
Mitjà O. Lancet. 2023 Mar 18;401(10380):939-949.

Are outbreaks of mpox of public health importance?
No Probably no Uncertain Yes
Varies
Probably Yes
EtR Domain: Benefits and Harms
•Adolescent arm met pre-specified criteria for non-inferior ity
-GMT ratio of adolescents to adults was 1.60 (CI 1.3 2, 1.95)
•Vaccine was safe and well tolerated in adolescents
-Solicited systemic and local AEs were similar betwe en adolescents and adults
•Systemic: 74% (CI 69, 79) vs 73% (CI 66, 79)
•Local: 88% (CI 84, 91) vs 91% (CI 87,95)
-Unsolicited related AEs: mainly injection site rela ted
-Dizziness in adolescents is common with vaccine adm inistration in this age group
and is not likely to represent a safety concern Adolescent safety and immunogenicity study summary
•Vaccine Adverse Event Reporting System (VAERS)
-National passive reporting system
•Vaccine Safety Datalink (VSD)
-Large linked healthcare data
•V-safe
-Web-based survey of vaccinees
•Single-patient Emergency Investigational New Drug ( EIND) procedures
-EIND provided vaccine access for individuals <18 ye ars of age prior to EUA
-Collected adverse event information from the vaccin ation provider 28 days after
each dose CDC’s vaccine safety data sources for JYNNEOS
•Vaccine adverse event reporting system (VAERS) 1
-At least 1,245 vaccinees nationwide
-One report of syncope
-Three reports of unspecified mild local and systemi c reactions
•VSD 2
-88 vaccinees
-No adverse events of special interest observed
•V-safe 1
-No participants were <18 years of age
•EIND 3
-57 vaccinees
-21% reported local or systemic reactions. No seriou s adverse events were reported Adverse events among individuals <18 years of age 2022–2023
1) https://pubmed.ncbi.nlm.nih.gov/38647241/ 2) htt ps://pubmed.ncbi.nlm.nih.gov/39565485/ 3) https://p ubmed.ncbi.nlm.nih.gov/36480476/
How substantial are the desirable anticipated effects
Minimal Small Moderate Large
Don’t Know Varies

How substantial are the undesirable anticipated effects
Minimal Small Moderate Large
Don’t Know Varies

Do the desirable effects outweigh the undesirable ef fects?
Favors Intervention Favors Comparison Favors Both
Favors Neither Unclear

EtR Domain: Values
•NIH rapidly completed trial recruitment
•Participants were supportive in participating to help frien ds
•When an outbreak occurred (i.e., 2022 global outbreak) , pediatric close
contacts were vaccinated
•Adolescent Medicine Trials Network for HIV/AIDS Intervent ions (ATN)
youth advisors were surveyed and 12/13 respondents we re supportive of
vaccination
•We do not know what type of outbreak would occur in t he future, and how
adolescents would perceive their risk or acceptability of vaccine Values Considerations
JYNNEOS first doses administered to children 17 yea rs
and younger by sex May 2022 – September 2024
Persons with no age data available were removed fro m the analysis Total first doses Age group
798 12-17
391 6-11
293 1-5
150 <1
1,632 Total
Does the target population feel that the desirable effects are large relative to the undesirable effec ts?
No Probably no Uncertain Yes
Varies
Probably Yes
Is there important uncertainty about or variability  in
how much people value the main outcomes?
Important uncertainty or variability Possibly important uncertainty or variability
No known undesirable outcomes
Probably no important uncertainty or variability No important uncertainty or variability
EtR Domain: Acceptability
Data available for acceptability domain
Survey administered to
Adolescent Medicine Trials
Network (ATN) providers Survey of mothers of
adolescents and younger
children
Data available for acceptability domain
Survey administered to
Adolescent Medicine Trials
Network (ATN) providers Survey of mothers of
adolescents and younger
children

ATN V Sites
Eastern U.S.
New Orleans, Louisiana
Tulane University Adolescent Medicine
Atlanta, Georgia
Emory University
San Francisco, California
Bridge HIV, San Francisco Department of Public Health
Los Angeles, California
Children’s Hospital Los Angeles Southern U.S.
New York City, New York
Callen -Lorde Community
Health Center Washington, D.C.
Children’s National Hospital Boston, Massachusetts
The Fenway Institute Houston, Texas
Baylor College of Medicine/ Texas Children’s Hospital Tampa, Florida
University of South Florida
Memphis, Tennessee
St. Jude Children’s Research Hospital Western & Midwestern U.S.
Chicago, Illinois
Adolescent and Young Adult Research (AWAR) @ The CORE Center
•Distributed to clinicians for 1 week in January 2025
•23 providers responded
-21 (91%) treat 12–17-year-olds at risk for mpox
•Among those 21 providers:
-17 (81%) offer vaccines in clinic; 11 (52%) offer mpox vaccine.
-Type of practice:
o19 (90%) university-based;
o1 (5%) FQHC;
o3 (14%) community-based. Survey to Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) providers
N = 21
n (%) Provider Characteristics Provider type
16 (76) Physician
5 (24) NP/PA
Specialty
10 (48) Adolescent medicine
3 (14) Pediatrics
3 (14) Medicine and pediatrics
3 (14) Family medicine
1 (5) Internal medicine
1 (5) Pediatric ID
Survey to ATN providers (N = 21)
If CDC recommended the mpox vaccine for 12–17-year-o lds with risk
factors, would you recommend it for eligible patien ts?
20 1
Yes
No NP/PA, family medicine
What are your concerns about recommending mpox vacc ine for your
eligible 12–17-year-old patients? Survey to ATN providers (N = 21)
20 1
I have no concerns.
I have concerns. “I am not sure if it is effective in preventing mpox”
What are challenges associated with offering the mp ox vaccine in your practice?Survey to ATN providers (N = 21)
N = 21
n (%) Statement
5 (24) There are no challenges in my practice
16 (76) There are challenges
7 (33) It is costly for the clinic to stock
5 (24) Patients are unfamiliar with mpox vaccine
4 (19) I do not know if there are challenges
3 (14) It is costly for patients
2 (10) I do not know how to access mpox vaccine
1 (5) I do not have enough staff trained to administer th is vaccine
1 (5) I am unfamiliar with mpox
1 (5) I am unfamiliar with mpox vaccine
1 (5) Other
Data available for acceptability domain
Survey administered to
Adolescent Medicine Trials
Network (ATN) providers Survey of mothers of
adolescents and younger
children

•Total surveyed: 566
•Unclear the age of all children of the mothers
-Oldest child mean age 9.6 (SD 4.8)
-43% of the population had their oldest child age between 12-17 years
•Timeframe: July 2022
•Variety of household incomes were represented Online survey of Mothers with children ≤18 years
Liu S, Chu H. Patient Educ Couns. 2023 Sep;114:1078 42.
n (%) Variable
510 (90) Receipt of all or some CDC recommended immunizations Race/Ethnicity
59 (10) Black
40 (7.1) Hispanic
19 (3.4) Asian/NHOPI/Native American
439 (78) White
9 (1.6) Other
Number of children
238 (42) One
205 (36) Two
78 (14) Three
45 (8.0) More than three
$150,000 or more $100,000 -$149,999 $75,000 -$99,999 $50,000 -$74,999 $35,000 -$49,999 $25,000 -$34,999 $15,000 -$24,999 Below $15,000
62 81 105 119 66 70 39 24
Liu S, Chu H. Patient Educ Couns. 2023 Sep;114:1078 42. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% It is likely that my children will get mpox My children are at risk of getting mpox It is possible that my children will get mpox
Strongly disagree Disagree Neither agree nor disagree Agree Strongly Agree Low belief that children were at risk of getting mp ox
Some agreement that vaccination will impact disease
Liu S, Chu H. Patient Educ Couns. 2023 Sep;114:1078 42. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Mpox vaccine will work in preventing disease If my children get the vaccine, they will be less
likely to get mpox
Strongly disagree Disagree Neither agree nor disagree Agree Strongly Agree
•Asked “what is the likelihood that you will”: Likelihood to vaccinate is numerically low, but hig her
than expected
Liu S, Chu H. Patient Educ Couns. 2023 Sep;114:1078 42. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Consider getting an mpox vaccine for your children Try to get an mpox vaccine for your children Actually get your children an mpox vaccine
Very unlikely Unlikely Neutral Likely Very Likely
•Mothers from the survey do not view their children at r isk for mpox.
-However, the intent to vaccinate is higher than exp ected.
•Vaccines were primarily given to adolescents both through  public health
and STI clinics.
•Among 21 surveyed ATN providers who provide care for at-risk adolescents:
-Over half already offer the mpox vaccine.
-95% would recommend mpox vaccines for eligible pati ents and do not have
concerns about recommending the vaccine.
-Majority expressed challenges associated with offer ing the vaccine; most
common concern was financial cost to the clinic. Summary of Acceptability data
Is the intervention acceptable to key stakeholders?
No Probably no Uncertain Yes
Varies
Probably Yes
EtR Domain: Health Equity
Vaccine administrations* and cases in adolescents by
race and ethnicity, May 2022 – March 2025
n=92 n=798
*Vaccine administration through September 2024 Case dat a
through March 2025 +Includes 3 mpox cases indicating Multiple races. Mul tiple
races was not reported for vaccine administration da ta.
If Hispanic or Latino was indicated for ethnicity, Race/ethnicity is indicated as Hispanic or Latino; if Hispanic or
Latino ethnicity was not indicated, Race/ethnicity is indicated
as Race Vaccine Administrations Mpox Cases
+
•No groups or settings would be disadvantaged by recomm endation for
JYNNEOS use during mpox outbreaks.
•Immunogenicity is the same for immunocompetent persons 12-17 years.
•Implementation of vaccine should assure equitable access.
•Endorsement by ACIP could facilitate broad acceptance o f recommendation
(e.g., insurance, health departments, pharmacies). Health Equity
What would be the impact on health equity?
Reduced Probably Reduced Probably no impact Increased
Varies
Probably Increased
Don’t know

EtR Domain: Feasibility
•Wide range of vaccinators can administer vaccine (e.g., pediatricians,
pharmacists, public health nurses)
•Wide range of potential facilities: public health, STI clinic, a dolescent health
clinic, pediatrician offices
•Same Immunization Information Systems (IIS) requirement s and reporting
infrastructure as other vaccines
•Limitations to access
-Poor access in rural communities
-Cost of vaccine and 10 vial minimum ordering quanti ty could hinder practices
stocking vaccine
-Pediatricians may defer to STI/adolescent clinics Feasibility Considerations
•Two doses, 28 days apart requires follow up and reminde rs
•JYNNEOS, once thawed/refrigerated, is good for either 4 or 8 weeks,
allowing some time to schedule a second dose.
•Frozen storage is ~18 months Feasibility considerations (cont.)
Is the intervention feasible to implement?
No Probably no Uncertain Yes
Varies
Probably Yes
EtR Domain: Resource Use
•JYNNEOS is commercially available
-Similar mechanisms for billing/reimbursement
•Medicaid/Medicare/317 funding
-Requires similar resources to other vaccine outbrea k responses
•Generally, vaccines are a good use of resources during an outbreak
•Cost-effectiveness of vaccination during a future outbr eak in adolescents is
uncertain Resource Use
Is the intervention a reasonable and efficient allocation of resources?
No Probably no Uncertain Yes
Varies
Probably Yes
Balance of Consequences
Summary of Work Group Interpretation of EtR Domains
Work Group Interpretation EtR Domain
Yes Public Health Problem Benefits and Harms
Large Benefits
Small Harms
Favors intervention Benefit>Harm?
Values
Probably yes Desirable>Undesirable?
Possibly important OR probably no important
uncertainty or variability Uncertainty?
Probably yes Acceptability
Probably increased Equity
Probably yes Feasibility
Probably yes Resource Use
Balance of consequences
There is
insufficient evidence to determine the balance of consequences Desirable consequences clearly
outweigh
undesirable consequences in most settings Desirable consequences
probably
outweigh
undesirable consequences in most settings The balance
between the desirable and undesirable consequences is closely
balanced or
uncertain Undesirable consequences
probably
outweigh
desirable consequences in most settings Undesirable consequences clearly
outweigh
desirable consequences in most settings
•ACIP recommends the 2-dose* JYNNEOS vaccine series fo r persons 12 to 17
years of age at risk of mpox during an mpox outbreak §.
*Dose 2 administered one month after dose 1 §Public health authorities determine whether there i s an mpox outbreak; a
single case may be considered an mpox outbreak at t he discretion of public
health authorities. Other circumstances in which a public health response may
be indicated include ongoing risk of introduction o f mpox into a community
due to disease activity in another geographic area.Proposed Recommendation 1

Summary: Agency for Toxic Substances and Disease Registry National Center for Environmental Health  Centers for Disease Control and Prevention  Evidence to Recommendations Framework: Vaccination with Jynneos for Adolescents at Risk of   Mpox During Outbreaks  Faisal Syed Minhaj, PharmD, MPH Poxvirus and Rabies Branch Centers for Disease Control and Prevention Advisory Committee on Immunization Practices April 15, 2025  •Structure to describe information considering in moving fr om evidence to  ACIP…