03 su mmrv 508

Febrile Seizures following Measles, Mumps, Rubella,
and Varicella (MMRV) vaccine
John Su
Acting Director
Immunization Safety Office
Centers for Disease Control and Prevention
September 18, 2025
September 2025:  Request to CDC from ACIP Chair
Presentation on febrile seizures post administration of MMRV vs.
simultaneous administration of separate MMR and Varicella vaccines, by
two different age groups, 1 –2 and 4– 6-year -olds. Please use data both from
randomized trials and from the Vaccine Safety Datalink (VSD), presented
from the VSD project.
2
Timeline of recommendations for MMRV vaccine use in
the United States
3September 2005 :
 MMRV vaccine licensed in
the U. S. in children 12
months –12 years of age
Use of MMRV vaccine
preferred over separate
administration of MMR and
varicella vaccinesFebruary 2008 :
Vaccine safety finding
from post -licensure
monitoring: increased risk
of febrile seizures after
first doseJune 2009
Updated
recommendations
ACIP issued interim recommendation: removed
preference for MMRV use vs. MMR and varicella
vaccines for both dose 1 and dose 2
Presentation of preliminary safety findings to ACIP
February 2008 to June 2009 that led to revised MMRV recommendations in June 2009
•Multiple presentations to ACIP from Vaccine Safety Datalink and Merck
•Evidence review and synthesis of data to ACIP: MMRV ACIP Working Group
assessed multiple sources of data
-Review of two post -licensure studies
•Merck -sponsored study
•Vaccine Safety Datalink study
-Review of literature and other data sources (e.g., parent/provider focus groups data)
-Consultation with experts
-MMRV Vaccine Safety Working Group (WG) discussions
-WG member surveys
•October 2008 and June 2009
Use of Combination Measles, Mumps, Rubella, and Varicella Vaccine 4
ACIP Updated Recommendations:  June 2009
•For the first dose of measles, mumps, rubella, and
varicella vaccination at age 12 –47 months, either MMR
vaccine and varicella vaccine or MMRV vaccine may be used. Providers who are considering administering the MMRV vaccine should discuss the benefits and risks of
both vaccination options with the parents or caregivers.
-CDC implementation guidance: unless the parent or caregiver
expresses a preference for the MMRV vaccine, CDC recommends that MMR vaccine and varicella vaccine be
administered for the first dose in this age group.
•For the first dose at age ≥48 months and for the second
dose at any age (15 months –12 years), MMRV is
generally preferred over separate injections of MMR
vaccine and varicella vaccine
5
Marin, M, et al. Use of Combination Measles, Mumps, Rubella, and Varicella Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR May 7, 2010/59(RR03);1 -12
Background:  MMRV vaccine
•Combination vaccine*
-Decreases the number of injections
-Increases vaccine compliance
-Increases vaccine coverage rates
•MMRV licensed for children 12 months through 12 years of age
-Routinely recommended ages:
•First dose: age 12 through 15 months
•Second dose: age 4 through 6 years
-In the United States, MMRV vaccine licensed is ProQuad  (Merck & Co, Inc)
* https://www.cdc.gov/vaccines/hcp/imz -best -practices/timing -spacing -immunobiologics.html
6
Background:  Febrile seizures
•By 5 years of age, 2 -4% of children have had ≥ 1 febrile seizure1
•Occurs primarily 6 months – 5 years of age, peak age is 14 -18 months
•Typically of short (<15 min) duration1,2; majority resolve without sequelae
•Observed during early childhood infections and diseases1, 2
-Middle ear infections, viral upper respiratory tract infections, roseola
-Can be associated with any condition that results in fever
•Observed following a fever associated with vaccination1,2
-DTaP , pneumococcal conjugate, MMR
•Family history of febrile seizures increases the risk of febrile seizures3
1 Marin, M, et al. Use of Combination Measles, Mumps, Rubella, and Varicella Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR May 7, 2010/59(RR03);1 -12
2https://www.cdc.gov/vaccine -safety/about/febrile -seizures.html
3 Sawires R, Buttery J, Fahey M. A Review of Febrile Seizures: Recent Advances in Understanding of Febrile Seizure Pathophysiology and Commonly Implicated Viral Triggers. Front Pediatr . 2022 Jan 13;9:801321. 7
Background: Pre -licensure MMRV studies
•MMRV prelicensure studies conducted among children aged 12 to 23 months
-Fever  and measles- like rash  were reported at significantly greater rate among children
receiving the first dose of MMRV vaccine than children receiving first doses of MMR
vaccine and varicella vaccine (at the same visit)
•Fever (reported as abnormal or elevated ≥102oF [≥39oC])
–21.5% of MMRV vaccine recipients compared with 14.9% of separate MMR vaccine and
varicella vaccine recipients (risk difference [RD]: 6.6%; 95% confidence interval [CI] = 4.6 -8.5)
•Measles -like rash:
–3.0% of MMRV vaccine recipients compared with 2.1% of separate MMR vaccine and
varicella vaccine recipients (RD: 1.0%; 95% CI = 0.1 -1.8)
•In light of these findings, CDC and Merck initiated separate post- licensure
studies to evaluate if an increased risk for febrile seizures might be associated
with the first dose of MMRV vaccine
8Marin, M, et al. Use of Combination Measles, Mumps, Rubella, and Varicella Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR May 7, 2010/59(RR03);1 -12
Merck ProQuad  package insert, 2024
Febrile seizures following first dose of MMRV
9
Summary results from VSD and Merck -sponsored studies for chart
confirmed febrile seizures after first dose of MMRV vs. MMR and varicella (MMR+V) vaccines
*Klein NP, et al. Vaccine Safety Datalink. Measles -mumps- rubella -varicella combination vaccine and the risk of febrile seizures.  Pediatrics. 2010 Jul;126(1):e1 -8
†Jacobsen SJ et al. Observational safety study of febrile convulsion following first dose MMRV vaccination in a managed care s etting. Vaccine. 2009 Jul 23;27(34):4656 -61.
§ Significant p <0.05
RR = relative risk; AR= attributable risk; CI: confidence interval10Post-
vaccination
IntervalVSD study*
All aged 12 -23 monthsMerck -sponsored study†
99% aged 12 -23 months
MMRV: N= 83,107
MMR+V: N= 376,354 MMRV: N=31,298
MMR+V: N=31,298
Weeks 1 -2 7–10 days
RR: 2.0 (95% CI: 1.4, 2.9)§
AR: 4.3 per 10,000
(95% CI: 2.6, 5.6)5–12 days
RR: 2.2 (95% CI: 1.0, 4.7)§
AR: 3.8 per 10,000 (95% CI: 0.3, 7.4)
Weeks 1 -4
0-30 days
RR: 1.4 (95% CI: 1.1, 2.0)§
AR: 4.7 per 10,000 (95% CI: 0.7, 7.6)0-30 days
RR: 1.1 (95% CI: 0.7, 1.7)
AR: 1.3 per 10,000
(95% CI: -4.5, 7.0)
Post -vaccination outpatient fever visits among 12 -23-
month -olds according to vaccine received by vaccine
type, VSD, 2000 –2008
11
Vaccine Days RR P-value
MMRV*
(N=83,107)7-10 6.1 0.001
MMR + V†
(N=376,354)7-10 4.4 0.001
MMR†
(N=145,302)7-10 4.3 0.001
Varicella†
(N=107,744)No temporal clustering of fever visits after varicella vaccination alone.Temporal Scan
* Vaccinated between January 2006 and October 2008; † Vaccinated between January 2000- October 2008
Klein NP, et al. Vaccine Safety Datalink. Measles -mumps -rubella -varicella combination vaccine and the risk of febrile seizures. Pediatrics. 2010 Jul;126(1):e1- 8
Post -vaccination febrile seizures among 12- 23-month -
olds by vaccine type, VSD, 2000 -2008
12
Temporal Scan
* Vaccinated between January 2006 and October 2008; † V accinated between January 2000 -October 2008
Klein NP, et al. Vaccine Safety Datalink. Measles -mumps- rubella -varicella combination vaccine and the risk of febrile seizures. Pediatrics. 2010 Jul;126(1):e1 -8Vaccine Days RR P-value
MMRV*
(N=83,107)8-10 7.6 0.001
MMR + V†
(N=376,354)7-10 4.0 0.001
MMR†
(N=145,302)7-11 3.7 0.001
V aricella†
(N=107,744)No seizure peak observable;  no significant temp oral clustering
U.S. post -licensure experience:  Febrile seizures after
MMR or varicella vaccination
•MMR vaccine: Study of ~137,000 children aged <7 years vaccinated with
MMR identified an increased risk for febrile seizures during 8 –14 days after
vaccination, compared with unvaccinated children1
-RR 2.83 (95% CI: 1.44, 5.55)
-~1 additional febrile seizure per 3,000 –4,000 children vaccinated
•Varicella vaccine: Study of ~35,000 children aged 12– 23 months vaccinated
with varicella vaccine identified no increased risk for febrile seizures during
0–30 days after vaccination, after controlling for co- administration of MMR
vaccine2
1. Barlow WE, Davis RL, et al. The risk of seizures after receipt of whole- cell pertussis or measles, mumps, and rubella vaccine. N  Engl J Med. 2001 Aug 30;345(9):656 -61.
2. Black S; Shinefield  H, et al. Postmarketing  evaluation of the safety and effectiveness of varicella vaccine. The Pediatric Infectious Disease Journal 18(12):p 1041 -1046, D ecember
1999.
13
Risk of febrile seizure after MMRV vaccines:
A systematic review and meta -analysis
•Included some studies that had subjects as young as 9 months of age
•Clinical trial review and analysis (31 published or unpublished studies involving
about 40,000 subjects)
-No evidence of significant differences in incidence of febrile seizure or vaccine -related
febrile seizure between MMRV and MMR +/ - V after any doses, in the risk windows of 0 -28,
0-42, 0- 56, and 7- 10 days
-Receipt of concomitant MMRV and other pediatric vaccines was not a significant predictor
of febrile seizure
•Post -marketing review and analysis
-Included data from 8 post -marketing studies, involving more than 3,200,000 children*
-Approximately 2 -fold increase in risk of seizure or febrile seizure during 7 -10 days or 5- 12
days after MMRV in children aged 10-24 months
* One study included children ages 4 -6 years who received second dose MMRV:  Study included both ProQuad  (available in US) and Priorix -Tetra study (available internationally)
Ma SJ, Xiong YQ, Jiang LN, Chen Q. Risk of febrile seizure after measles -mumps -rubella -varicella vaccine: A systematic review an d meta -analysis. Vaccine . 2015;33(31):3636 -3649.
doi:10.1016/j.vaccine.2015.06.009 14
Cochrane review: MMRV vs MMR + V in children
•Febrile seizure review
-Risk of febrile seizures after MMRV vaccination compared to MMR+V vaccination
•Includes evidence from five cohort studies*
•Overall estimates:
–Within 42 days after vaccination: RR 1.31 (95% CI: 1.19 to 1.45)
–Within 7 to 10 days after vaccination: RR 1.98 (95% CI: 1.69 to 2.33)
-Risk of febrile seizure after MMRV studies (grouped by brand) compared to MMR+V
vaccination
•Priorix -Tetra study:
–Within 0 to 42 days after vaccination: RR 1.95 (95% CI: 0.85 to 4.48)
–Within 7 to 10 days after vaccination: RR 1.69 (95% CI: 0.93 to 3.07)
•ProQuad studiesᵻ:
–Within 0 to 42 days after vaccination:  RR 1.30 (95% CI: 1.17 to 1.44)
–Within 7 to 10 days after vaccination:  RR 2.01 (95% CI: 1.70 to 2.38)
* Four studies are dose 1; One study includes children ages 4 -6 years who received dose 2; ᵻ Includes one study of children ages 4 -6 years who received dose 2.
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 15
Summary of evidence for febrile seizure risk after
first dose of MMRV vaccination
•Post -licensure studies assessed rates of febrile seizures in children aged 12 -
23 months who received dose 1 MMRV vaccine and compared these rates
with children who received separate dose 1 injections of MMR and varicella
vaccines at the same visit.
•The studies used different methods, populations of children, and different
formulations of MMRV.
•Despite these differences, studies show remarkable consistency in findings
16
Conclusion:  Evidence for febrile seizure risk after first
dose MMRV vaccination
•During the 6 weeks after vaccination, an increased risk for febrile seizures
after dose 1 MMRV compared with dose 1 MMR+V is only present during
the 1 -2 weeks after vaccination
•The risk of febrile seizures occurring during other periods after
vaccination is similar between dose 1 MMRV and MMR+V
Klein NP, Fireman B, Yih WK, et al. Measles -mumps- rubella -varicella combination vaccine and the risk of febrile seizures. Pediat rics. 2010 Jul;126(1):e1 -8.
17
18Febrile Seizures following second dose of MMRV
Risk of febrile seizures and fever following second
dose of MMRV vaccine
•Risk for febrile seizures is lower among children aged 4 -6 years than
among children aged 12- 15 months
•Prelicensure trials:
-Lower fever rates in children aged 15 -31 months receiving dose 2 MMRV
compared with dose 1 MMRV (N=1035)1
-Similar fever rates in children aged 4 -6 years receiving dose 2 MMRV (N=397)
compared with dose 2 MMR + varicella vaccines (N=193)2
1 Merck ProQuad  package insert, 2024
2 Reisinger KS, et al. 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
MM- RII and Varivax  . Pediatrics. 2006;117(2):265 -272.19
Merck -sponsored study findings of febrile seizures
following second dose of MMRV and MMR+V
•Among children aged 4- 6 years:
-No febrile seizures occurred during the 5- 12 days post -vaccination
•22,212 children receiving second dose MMRV vaccine
•24,778  children receiving second dose of MMR + V vaccine at same visit
Marin, M, et al. Use of Combination Measles, Mumps, Rubella, and Varicella Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR May 7, 2010/59(RR03);1 -1220
VSD findings for all seizures after second- dose of
measles -containing vaccine identified from electronic
medical records for children aged 4- 6 years
Klein NP, et al. Measles -containing vaccines and febrile seizures in children age 4 to 6 years. Pediatrics. 2012 May;129(5):809 -14.
21
-Very few seizures identified by ICD -9 codes in electronic data
VSD findings of chart -confirmed febrile seizures 7 to 10
days after second dose of measles -containing
vaccination for children aged 4–6 years, 2000 –2008
•Electronic medical record review of the 4 post- MMRV seizures:
-Febrile seizure: 1
-Afebrile seizures:  2
-Improbable seizure: 1
22
 Klein NP, et al. Measles -containing vaccines and febrile seizures in children age 4 to 6 years. Pediatrics. 2012 May;129(5):809 -14.
Risk of febrile seizure after second dose of MMRV:
Systematic review and meta -analysis
•Pre-licensure studies:
•Po
•Post -licensure study:
-Only included one study of children 4-6 years; no evidence to suggest elevated risk of febrile seizure
23Ma SJ, et al. . Risk of febrile seizure after measles -mumps -rubella -varicella vaccine: A systematic review and meta -analysis. Vaccine . 2015;33(31):3636 -3649.

Conclusion:  No evidence for febrile seizure risk after
dose 2 MMRV vaccination
•Among children aged 4- 6 years
-Data do not suggest that children who receive dose 2 MMRV have an increased
risk of febrile seizures after vaccination compared with those who receive dose 2
as MMR + varicella vaccination at the same visit
Marin, M, et al. Use of Combination Measles, Mumps, Rubella, and Varicella Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR May 7, 2010/59(RR03);1 -12
24
Conclusion
•There is a small increased risk for febrile seizures after  first dose of MMR
and MMRV vaccines
•The risk is slightly higher with MMRV combination vaccine after the first
dose
-Studies have shown a small increased risk for febrile seizures during the 5 - 12
days after a child has received their first vaccination with MMR vaccine
-Studies have not shown an increased risk for febrile seizures after the varicella
vaccine
•There is no increased risk of febrile seizures after vaccination
with MMRV vaccine in children aged 4 through 6 years
25
Questions?
For more information, contact CDC
1-800- CDC- INFO (232 -4636)
TTY:  1 -888- 232- 6348    cdc.gov atsdr.cdc.gov
Follow us on X (Twitter) @CDCgov & @CDCEnvironment
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position
of the U. S. Centers for Disease Control and Prevention and the Agency for Toxic Substances and Disease Registry.
26

Summary: Febrile Seizures following Measles, Mumps, Rubella,  and Varicella (MMRV) vaccine John Su Acting Director Immunization Safety Office Centers for Disease Control and Prevention September 18, 2025 September 2025:  Request to CDC from ACIP Chair Presentation on febrile seizures post administration of MMRV vs.  simultaneous administration of separate MMR and Varicella vaccines, by  two different age groups, 1 –2 and 4– 6-year -olds. Please use data both from  randomized trials and from the Vaccine…


hep b birth dose briefing 508

1
 ACIP Meeting Materials for Public Posting:  Hepatitis B Birth Dose Briefing Document

Contents
1. Background
2. Epidemiology
3. Systematic Review s for studies  on hepatitis B birth dose vaccine
4. Appendices
Appendix 1 ACIP Recommendations
Appendix 2 Global Recommendations

1. Background

Introduction
Hepatitis B virus (HBV) infection can be transmitted from mother -to-child during pregnancy and delivery.
Without any interventions, up to 85% of infants born to women with HBV infection acquire HBV
infection. Perinatal ly acquired  HBV infection has severe health and economic consequences : about 90%
of infants perinatally infected with HBV will develop chronic hepatitis B, and 25% of people infected with
HBV during childhood will die prematurely due to HBV-related complications  including liver cirrhosis and
liver cancer . (1, 2)

Up to 2.4 million people in the United States are estimated to have hepatitis B; about half of people with
hepatitis B in the U.S. are  unaware of their infection. About 75% of people with chronic hepatitis B in the
United States  were born in counties with intermediate and high prevalence of hepatitis B  and
predominantly were infected at birth  or during early childhood . In the United States, decades of evolving
hepatitis B vaccination recommendations  among infants and children have shifted the epidemiology of
acute hepatitis B cases from children to unvaccinated adults . In 2023, 14,400 acute hepatitis B cases
were estimated to occur in the U.S., with the highest rates among adults aged 40 -59 years; among
reported cases of acute hepatitis B, only 26% reported an associated risk behavior, with 28% reporting
no risk, and 4 6% missing data on risk factors. Unlike children, adults who acquire new HBV infection have
higher viral clearance rates  and lower risk for developing chronic infection. (3-9)

Hepatitis B vaccination is the cornerstone of hepatitis B prevention and control.  The hepatitis B vaccine is
the first anti -cancer vaccine and has been available in the United States for more than 40 years. Two
types of products are available for prophylaxis against  perinatal  HBV infection: hepatitis B vaccine, which
provides long -term protection against HBV infection and is recommended for both preexposure and
postexposure prophylaxis; and hepatitis B immune globulin (HBIG), which provides temporary protection
and is indicated only in certain postexposure settings.  Two single -antigen h epatitis B recombinant
vaccines are FDA -approved for the vaccination of persons starting at birth in the U.S.: Recombivax HB,
approved in  1986 and Engerix -B, approved in 1989 . Hepatitis B vaccination is a multi dose series , typically
consisting of 3 doses, with increasing s eroprotection after each dose. Three doses of hepatitis B are
needed to ensure full protection  where 95% of healthy infants develop  a protective antibody response
2
 (anti -HBs ≥ 10  mIU/ mL). When administered shortly after birth  to infants born to HBsAg -positive women ,
hepatitis B vaccination and HBIG reduce mother -to-child transmission by 94%. (1, 10 -13)

Prevention of perinatal or early life HBV infection underpins the recommendation  for hepatitis B
vaccination starting at birth.  Since 1988, u niversal hepatitis B screening (with HBsAg) has been
recommended for all pregnant women in the first trimester of pregnancy , as has testing later in
pregnancy for women with risk behaviors  and testing at delivery for women whose hepatitis B status is
unknown. Hepatitis B vaccination has been recommended  at birth for all infants born to women known
to have HBV infection since 198 4 (specified to within 12 hours of birth in 1988),  and among all infants
born to women with unknown hepatitis B status since 1991.  Hepatitis B immune globulin has been
recommended to be administered  within 12 hours of  birth for all infants born to women known to have
HBV infection since 198 4, and among infants born to women with unknown hepatitis B status since
2018.  In 1991, the US adopted a strategy for u niversal h epatitis B vaccination  of all  infants . Beginning in
2005, the first dose of hepatitis B vaccine among infants born to HBsAg -negative women was
recommended to be administered at the birth hospital ; this was updated in 2018 to specify within 24
hours of birth . (1, 14 -20)

In the context of these evolving hepatitis B vaccination recommendations among newborns and children,
the number of reported US cases of acute hepatitis B has dropped 88% from 1991 (18,003 cases) to 2023
(2,214 cases). The United States’ comprehensive strategy to prevent  hepatitis B is based on : 1) routine
testing of all pregnant women for HBsAg ; 2) post exposure  prophylaxis within 12 hours of birth with
hepatitis B vaccine and HBIG of all infants born to women who are HBsAg -positive or HBsAg -status
unknown ; 3) universal vaccination of all infants beginning at birth; 4) routine vaccination of previously
unvaccinated children, adolescents, and adults aged 19 -59 years ; and 5) vaccination of all adults at risk
for HBV infection or who request vaccination . (1, 9, 20, 21)

Transmission , Natural History of Disease , and Associated Healthcare Costs
HBV transmission occurs through percutaneous or mucosal exposure to infectious blood or body fluids .
The virus  can remain viable for over 7 days on environmental surfaces at room temperature. The two
primary sources of HBV infection among children are perinatal transmission from mothers with hepatitis
B and horizontal transmission from infected household contacts.  Prior to the widespread availability of
postexposure prophylaxis  (i.e., vaccine and HBIG  within 12 hours of birth ), the proportion of infants born
to HBsAg -positive women who acquir ed HBV infection was as high as 85%. Children living with a person
with chronic HBV infection in a household or community setting are also at risk and transmission rates
have ranged to up to 11% in US settings. (1, 22 -24)

Young children with acute hepatitis B rarely have symptoms, but 90% of infants who are infected with
HBV become chronically infected . In contrast, among persons 5 years of age and older , fewer t han 5%
develop chronic infection . Since the risk of chronic infection increases with decreasing age, people who
are infected in early childhood experience a disproportionately higher burden of disease attributable to
chronic HBV infection. About 25% of individuals chronically infected during childhood will develop end
3
 stage liver disease or liver cancer and die prematurely.  Fulminant hepatitis occurs in ≤1% of acute
infections, but the incidence of fulminant hepatitis B is higher in infancy than in other pediatric age
groups . (1, 8, 21, 25 -28)

Chronic HBV infection  can progress to cirrhosis, hepatocellular carcinoma (HCC), liver transplant, and
death. Based on US cancer data from the Surveillance, Epidemiology and End Results (SEER) Program,
over 38,000 HCC cases were forecasted for 2020 and over 56,000 HCC cases we re forecasted for 2030.
HBV is an important cause of HCC, with 10% to 15% of patients with HCC attributed to HBV  infection . The
burden of US hepatitis B related hospitalizations is significant; each year, more than $1 billion is spent on
hepatitis B -relate d hospitalizations, not including indirect costs such as poor quality of life, reduced
economic productivity, long -term disability, and premature death. The estimated annual costs of treating
one patient with hepatitis B in the United States, adjusted for inflation are up to $93,935 for those with
less severe disease and up to $324,849 for those requiring liver transplant.  (2, 29 -33)

Hepatitis B is Vaccine Preventable with Robust Seroprotection
Hepatitis B vaccination is the most effective measure to prevent HBV infection and its consequences . The
plasma -derived hepatitis B vaccine was licensed in 1981; recombinant hepatitis B vaccines replaced the
plasma -derived vaccines in the U.S. by the late 1980’s.  Hepatitis B  recombinant vaccines  are available as
a single -antigen formulation and in combination with other vaccines. Two single -antigen vaccines
recommended for use in the United States, Engerix -B and Recombivax HB, are used for the vaccination of
persons starting at birth. An extensive  body of literature resulting from over more than 40 years of use  in
the United States and other countr ies demonstrates that the hepatitis B vaccines are safe and effective in
protecting infants from hepatitis B.  (1)

The efficacy of the hepatitis B  vaccine alone in preventing perinatal transmission is ~75%. Hepatitis B
immunoglobulin provides passively acquired anti -HBs and temporary protection (i.e., 3 –6 months) and is
generally used as an adjunct to hepatitis B vaccine in infants born to HBsAg -positive mothers and in
certain other postexposure prophylaxis situations. The efficacy of HBIG alone is around 71%. When
combined with the hepatitis B  vaccine, the efficacy of HBIG and hepatitis B birth dose (HepB -BD) vaccine
is 94%. The sooner the HepB -BD vaccine is provided after birth, the greater its effectiveness in
preventing perinatal transmission. The optimal recommended timing is to provide the vaccine within 24
hours of birth , accelerated to  within 12 hours if the maternal HBsAg status is p ositive or unknown.
Unvaccinated infants remain at risk of non -perinatal HBV acquisition  through exposure to a  person with
HBV infection in a household or community  setting .  HepB -BD provides protection for infants at risk from
household exposure after the perinatal period. (1, 23, 24, 34, 35)

Among health y infants, 25% and 63% achieve protective hepatitis B surface antibody levels after the first
and second dose, respectively , however full protection is only achieved with the complete vaccine series .
The 3 -dose hepatitis B  vaccine series produces a protective antibody response in 98% of healthy term
infants, and 95% of healthy infants overall. Seroprotection from vaccination lasts for decades. In one
4
 Alaska -based study, over 90% of primary responders were estimated to have protective immunity for
more than 30 years after vaccination. (1, 11, 13, 28, 36 -40)

Hepatitis B Birth Dose Provides a Critical Safety Net in the Preve ntion of Perinatal and Early Childhood
Transmission
Universal  HepB -BD provides a critical safety net for infants who may have unrecognized exposure(s) to
HBV infection during pregnancy or early childhood  due to a multitude of reasons  resulting in gaps in
protection against perinatal infection.  Reasons for missed opportunities to prevent perinatal
transmission include lack of prenatal care,  where overall 15% of pregnancies receive inadequate or no
prenatal care  (where inadequate care is defined a s care after the 4th month of pregnancy and includes
less than 50% of visits) . Additionally , missed opportunities arise from  gaps in maternal screening
implementation, incorrect screening tests performed, errors in interpreting the screening test or the
transcription of the screening test , lapses in providing standard of care post exposure prophylaxis , and
acute /window period infection . Gaps in perinatal HBV testing during  pregnancy indicate 12 -16% of
pregnant women in the United States  had no record of being test ed for HBsAg, with lower testing rates
among Medi caid-enrolled women. Further, d espite a robust national perinatal hepatitis B prevention
program, the program identifies less than one -half of infants estimated to be born to HBsAg -positive
women each year, highlighting a critical gap in identifying perinatally  exposed infants . Case reports of  the
medical  outcomes  for perinatally exposed infants demonstrate the catastrophic impact when universal
HepB -BD is not fully implemented. (41-47)

Infants who receive HepB -BD are more likely to complete their vaccination series and had a positive
impact on rates of being up to date for other age -appropriate vaccines . Additionally, there is a risk for
horizontal transmission in the household from persons who are not aware of their infection status; 50%
of people in the US are unaware of their infection.  Universal HepB -BD is of critical importance and
provides a safety net for infants who may have unrecognized exposure(s) to HBV infection during
pregnancy or early childhood. (1, 3, 19, 25, 48, 49)

2. Epidemiology
Shifting Epidemiology of Acute Hepatitis B in the U.S.  Reflects Success of Hepatitis B Vaccination
among Newborns and Infants
Three decades  of evolving  hepatitis B vaccination recommendations among newborns and infants ha ve
paralleled marked  reductions in acute hepatitis B cases in the United States. Following the introduction
of recommendations for all infants born to HBsAg+ women to receive hepatitis B vaccination and HBIG
within 12 hours of birth, the reported number of acute hepatitis B cases in the U.S. fell by 22% from
23,177 in 1988 to 18,003 in 1991. Following the 1991 recommendations which included  provid ing
hepatitis B vaccination within 12 hours of birth for infants born to women with unknown HBsAg status as
well as introducing universal hepatitis B vaccination for all infants, reported number of acute hepatitis B
cases dropped another 69% from 1991 to 2005 ( 5,494 ). Finally, following the 2005 recommendation
specifying that  the first dose of infant hepatitis B vaccination occur prior to hospital discharge  and the
5
 further specification that the dose occur within the first 24 hours of life , the reported number  of acute
hepatitis B  cases  fell an additional 60% from 2005 to 20 23 (2,214 ).
Figure 1

From 1991 through 2023, rates of reported cases of acute hepatitis B have decreased among all age
groups, with the lowest rates among persons <19 years of age and those aged 20 -29 years, indicating a
generational impact of more than 3 decades of evolving h epatitis B vaccination recommendations
among newborns and infants. (9, 17, 19, 21, 25, 50)

6
 Figure 2  Viral Hepatitis Surveillance Reports | Viral Hepatitis | CDC

References: CDC NNDSS Viral Hepatitis Surveillance : (https://www.cdc.gov/hepatitis/php/statistics -
surveillance/index.html ); (4, 9, 21)

3. Updated Rapid Systematic Review for studies on hepatitis B birth dose vaccine within 24 hours of
birth
In response to the request from the ACIP Chair to provide “ results from randomized trials concerning the
administration of the HepB vaccine within 24 hours of birth, with all results stratified by the HepB
infection status of the mother. Include both efficacy data and adverse events, including all -cause
morbidity a nd mortality. For children whose mothers are HepB negative, present results for all children
combined as well as stratified by pre -mature birth and birth weight. If randomized data is lacking for any
of the requested populations, please mention that ”, an updated rapid systematic review (URSR) for
studies on hepatitis B birth dose (HepB -BD) vaccination within 24 hours of birth was conducted spanning
12/17/2011 – 8/14/2025,  building on an existing systematic review  (ESR)  (28) spanning 1/1/1987 –
12/16/2011.
The inclusion criteria  for the review included studies for  newborn infants receiving a  monovalent
hepatitis B vaccine within 24 hours of birth  for a list  of outcomes ( seroprotection , efficacy,  safety ,
morbidity and mortality). The definitions and timepoints for seroprotection, efficacy, and safety
outcomes are as follows: s eroprotection is defined as  anti -HBs ≥10 mIU/mL mL at least 1 -2 month s after
the final dose in the vaccine series or between 9 -12 months of age and is the first time point reported
immediately following the last dose in a vaccine series; efficacy is defined as HBsAg and/or HBV DNA
positivity at the latest available timepoint ; safety is reported by local and systemic adverse events and is
reported at birth or the closest time point immediately after the birth dose.  Morbidity is defined as
severe illness or hospitalization and mortality is defined as death.

7
 The ESR search (n=833) and the URSR (n=1380) were further assessed using the inclusion criteria
focused on the ACIP request. Seventeen studies met the inclusion criteria  (7 from the ESR and 10 from
the URSR). The 17 studies were grouped by efficacy trials,  timing of the vaccination, product or
formulation differences , dose and schedule , and HBIG co -intervention for the specified outcomes of
interest (seroprotection, efficacy and safety outcomes). The two HBIG co -intervention trials were
reviewed but not inc luded in the briefing document since these  studies did not address the question .
Other intervention characteristics included the vaccine type administered (Engerix, Recombivax or other
hep B vaccines), dose and schedule.
Across intervention study types (timing of vaccination (birth vs 18 months); efficacy trials; product and
formulation; dose of vaccine and schedule) meeting the rapid systematic review inclusion criteria  can be
summarized as:
• Hepatitis B vaccine series first administered at birth achieved high levels of seroprotection in
infants born to HBsAg -positive women  and HBsAg -negative women;
• Among infants born to HBsAg -positive mothers, hepatitis B birth dose vaccin ation demonstrated
efficacy in the prevention of perinatal transmission ;
• Hepatitis B birth dose  vaccine  is safe and resulted in few local and systemic adverse effects,
including infants born to HBsAg -negative mothers ; and
• Head -to-head comparisons of various hepatitis B recombinant vaccine products, doses, and
schedule show ed no meaningful differences in reported outcomes .
The URSR did not identify placebo -controlled trials assessing efficacy; given that the efficacy of the HepB
vaccine was established in the 1980s and 1990s , this is unsurprising as  it is unethical to withhold a
proven, safe and effective intervention simply to include a placebo group . There were  also limited
reporting outcomes for preterm, low birth weight and extremely low birthweight infants, as well as for
morbidity and mortality. Bias was assessed using the Cochrane Risk of Bias, version 2 (RoB 2) (51). This
tool assesses  risk of bias in RCTs related to  the following domains : randomization process, deviation from
intended intervention, missing outcome data, measurement of outcome and selection of reported
results . Of note, many of the studies were done before the wide application of the CONSORT statement
(52), which seeks to improve reporting of randomized controlled trials (RCTs)  Most of the RCTs (59%)
assessed had a high risk of overall bias primarily due to the  domains of randomization and measurement
of outcomes . In summary, the body of evidence from the ESR and the URSR support the findings that:
• Hepatitis B birth dose induces high seroprotection and efficacy ;
• Hepatitis B birth dose vaccine is safe ; and
• Head -to-head comparisons of various hepatitis B recombinant vaccine products, doses, and
schedule show no meaningful differences  in reported outcomes in efficacy and safety .

8
 Appendix 1
Hepatitis B screening recommendations for pregnant women and ACIP hepatitis B vaccination
recommendations for infants, United States, 198 4-2022.

Modified from Bixler PHR 2023, Suppl Table 2.
ACIP = Advisory Committee on Immunization Practices; HBIG = hepatitis B immune globulin; HepB, hepatitis B
vaccine.
*Only single -antigen HepB vaccine should be used for the birth dose.
Note: All hepatitis B birth dose vaccinations are considered to be the first dose of the infant series except among
pre-term infants weighing <2,000 grams who are born to mothers who are HBsAg positive.
1. CDC. MMWR Morb Mortal Wkly Rep 37, 341 -346, 351 (1988).
2. CDC. MMWR Morb Mortal Wkly Rep 33, 285 -290 (1984).
3. CDC. Update on hepatitis B prevention. MMWR Morb Mortal Wkly Rep 36, 353 -360, 366 (1987).
4. CDC. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Recomm Rep
40, 1 -25 (1991).
5. Schillie, S. et al. MMWR Recomm Rep 67, 1 -31 (2018).
6. Mast, E. E. et al. MMWR Recomm Rep 54, 1 -31 (2005).
7. Bixler D et al. Public Health Rep. 2023 Jun 9

9
 Appendix 2
Global hepatitis B v accination policies and prevalence in pregnant women
Global Hepatitis B Birth Dose Vaccination Policies
In 1987, the WHO Hepatitis and Immunization Technical Advisory group s emphasized the importance of
hepatitis B vaccination to control infections globally  and recommended hepatitis B vaccination in infancy
focusing on countries where HBsAg prevalence was higher than 2% . In 2004, the WHO recommended
hepatitis B birth dose vaccination as soon as possible after birth (within 24 hours) focusing on countries
with intermediate and high endemicity (HBsAg  prevalence >2%) while also recommending hepatitis B
vaccination  in low endemicity settings especially to infants born to HBsAg positive mothers. In 2009 and
then in 2017, the WHO Strategic Advisory Group of Experts reevaluated  the data and base d on evidence
to recommendations analysis, recommended universal hepatitis B birth dose vaccination as soon as
possible after birth, preferably within 24 hours of birth , followed by completion of 3 or 4 dose hepatitis B
vaccination series  among all infants  in all countries irrespective of HBsAg prevalence . Those vaccination
recommendations  have evolved based on global goals which focused in the 1990s and early 2000s on
controlling  hepatitis B through scale up of childhood immunization and then progressed  in 2015 to focus
on eliminating viral hepatitis as a public health threat  by 2030 through the scale up of prevention,
screening and treatment . The United States has endorsed the global goals of elimination of viral hepatitis
by 2030  and developed national strategies to achieve the targets .
Globally , of the 194 WHO  member states, 116 countries recommend universal hepatitis B birth dose
vaccination to all newborns , in alignment with global recommendations. Relatively f ew countries (3 3)
provide selective hepatitis B birth dose to infants born to mothers who are either HBsAg -positive o r of
HBsAg -unknown status . Two countries have partially introduced universal HepB -BD. In Canada , New
Brunswick, the Northwest territories and Nunavut provide universal HepB -BD while other provinces
provide selective HepB -BD. Pakistan introduced universal HepB -BD in two of its most populated
provinces (Punjab and Sindh).
The 43 c ountries that have not introduced HepB -BD are mostl y countries  in Sub -Saharan Africa , but this
is changing and in 2024, many countries  have either initiated introduc tion this year  or expressed interest
in introducing HepB-BD in their immunization schedule  in the next 3 -5 years .
10
 Map : Hepatitis B vaccine birth dose vaccination policy by county, 2025

Sources: Provincial and territorial routine and catch -up vaccination schedule for infants and children in Canada -
Canada.ca ; Hepatitis B vaccine – NHS ; Vaccine Scheduler | ECDC ; 9. Hepatitis B – Health New Zealand | Te Whatu
Ora; Introduction of Hepatitis B vaccine ; Hepatitis B | The Australian Immunisation  Handbook ;
20240220_Immunization_Schedule_english.pdf ; National Immunization Program for children | Policy&Services  :
KDCA ; Hepatitis B
Universal HepB -BD:  Hepatitis B birth dose  vaccine  provided to all newborns .
Selective HepB -BD:  Hepatitis B birth dose vaccine provided only to infants  born to women who test positive for
HBsAg.
Partially  introduced universal HepB -BD:  Hepatitis B vaccine strategy among infants  varies by geographic location
within the country.

Based on the request from the ACIP chair, we analyzed hepatitis B vaccination policies and schedule in 37
countries which include , Canada, countries in the European Union  (EU)  (n=27)  and European Economic
Area (EEA ) (Iceland, Liechtenstein, and Norway ), the United Kingdom  (UK) , Switzerland, Australia, New
Zealand, South Korea and Japan and compared them to the United States.
Among infants born to women with known HBV infection  (HBsAg positive women) , the  U.S. is aligned
with  Canada, all EU /EEA countries ,  the United Kingdo m (UK), Switzerland, Australia, New Zealand, South
Korea and Japan  which  all recommend the hepatitis B birth dose to be given at birth simultaneously with
HBIG , either before discharge from the hospital or within 24 hours of birth.

11
 For infants born to  HBsAg -negative women , countries with a universal hepatitis B birth dose vaccination
policy give all children the first dose following the same schedule as children born to HBsAg positive
mothers.
Among the 37 countries assessed,  26 implement selective HepB -BD for infants born to HBsAg -positive
women  and the universal infant vaccination with three doses of hepatitis B vaccine to all infants
irrespective of mothers ’ HBsAg status . Children born to HBsAg -negative mothers receive the first dose of
hepatitis B vaccine by 3 months of age in 24 of the 26 countries  (18 countries at 2 months of age and 6
countries at 3 months of age) .
Table: age at receipt of first dose of hepatitis B vaccine in selected countries *

*United States, Canada, all EU/EEA countries, UK, Norway, Switzerland, Iceland, Australia, New Zealand, South
Korea and Japan.
Sources: Provincial and territorial routine and catch -up vaccination schedule for infants and children in Canada -
Canada.ca ; Hepatitis B vaccine – NHS ; Vaccine Scheduler | ECDC ; 9. Hepatitis B – Health New Zealand | Te Whatu
Ora;  The Australian Immunisation  Handbook ; 20240220_Immunization_Schedule_english.pdf ; National
Immunization Program for children | Policy&Services  : KDCA ; Hepatitis B
High -income  countries base their decisions on vaccination schedule using cost -benefit and cost -
effectiveness assessments , especially countries  that provide free universal health care , along with
epidemiological profile and high levels of maternal hepatitis B screening in the population. For example ,
in 2016 -2017, Japan and the United Kingdom switched from selective infant hepatitis B vaccination to
universal infant vaccination after reviewing country -specific  epidemiological and cost -effectiveness data.
In 2020, Slovenia switched from providing the first dose of hepatitis B at school entry to providing
universal hepatitis B infant vaccination starting at 3 months of age.  To date, n o country in the world has
reverted  from universal to selective hepatitis B vaccination schedules.

12
 Hepatitis B prevalence  and screening  in pregnant women
Based on the request from the ACIP chair, we analyzed hepatitis B prevalence and screening among
pregnant women in  37 countries which include: Canada, countries in the European Union (EU) (n=27)
and European Economic Area (EEA) (Iceland, Liechtenstein, and Norway), the United Kingdom (UK),
Switzerland, Australia, New Zealand, South Korea and Japan and compared them to  the United States.
Prevalence estimates of hepatitis B among pregnant women were available in 20 of the 37 assessed
countries. Overall, 9 countries had less than 0.5% prevalence of hepatitis B surface antigen among
pregnant women while 8 countries reported a prevalence ranging from 0.5 to 0.9% and 3 countries
reported a prevalence greater than 2% in pregnant women.  There are no data on the prevalence of
hepatitis B in pregnant women in the United States in the last 10 years.
Only 6 of the 3 7 selected countries have national registries that can track hepatitis B screening among
pregnant women and estimate prevalence on an annual basis. The other 31 countries and the United
States  do not track hepatitis B screening during pregnancy. In those countries, hepatitis B prevalence
estimates when available  are based on surveys or special studies completed in previous years.
Figure: Prevalence of hepatitis B surface antigen  among pregnant women  in selected countries*

* United States, Canada, all EU/EEA countries, UK, Norway, Switzerland, Iceland, Australia, New Zealand, South
Korea and Japan.
Sources: Hepatitis B in England 2024 - GOV.UK ; Hepatitis B and C in Pregnancy and Children: A Canadian
Perspective – PMC ; Evidence brief - prevention of hepatitis B and C in Europe and the UK ; Uptake of perinatal
immunoprophylaxis  for infants born to women with a record of hepatitis B in Victoria (2009 –2017) – ScienceDirect ;
Updated -National Hepatitis Elimination Profile - Switerland -July2023_0.pdf ; Gaps in Prenatal Hepatitis B Screening
and Management of HBsAg Positive Pregnant Persons in the U.S., 2015 –2020 - PMC
All of the 37 selected countries, except two, provide universal health care access to all citizens (includ ing
residents and migrants) .

13
 Of the 29 countries that provide selective HepB -BD, five countries have national registries that can track
the percentage of pregnant women screened for hepatitis B and subsequent care cascade of mother and
infant. The remaining countries either have systems similar to the  perinatal hepatitis B  prevention
program in the  U.S. or report positive hepatitis B test results to a national notifiable disease surveillance
system . Unlike countries that provide selective HepB -BD, the United States does not have universal
healthcare coverage with free access to antenatal care and vaccinations to the population. This is a
critical difference between the United States and the countries that provide selective HepB -BD.
As a result  of lack of adequate systems  to track screening in pregnant women and subsequent post -
exposure prophylaxis  in exposed infants , most of the countries with selective HepB -BD policies cannot
track whether they are succeeding in preventing perinatal transmission of hepatitis B  on a regular basis
(outside of special studies) . However, they provide universal healthcare to all the population with access
to free antenatal care and vaccination services.
To highlight the limited data availability in the 37 assessed countries, we compiled publicly available data
on the percentage of pregnant women who are screened for hepatitis B surface antigen during
pregnancy in each of those countries. Of the 37 countries selected to compare to the United States, only
19 had publicly available data on percentage of pregnant women screened for hepatitis B.  Overall, 15
countries reported that more than 90% of pregnant women are screened  for hepatitis B , which is the
2030 g lobal indicator for validation of elimination.  The United States is one of five countries not meeting
the 2030 global screening target . All countries that provide selective hepatitis B birth dose vaccination
that have available antenatal screening data  have achieved the 90% global antenatal screening coverage
target for hepatitis B.
Figure: Coverage of antenatal screening for hepatitis B in selected countries

*No universal healthcare coverage
2023 data except for the following countries:  Lithuania, 2021; United States, 2015 -2019; France, Germany, and Poland,
data >5 but <10 years old.
No data is publicly available for Austria, Belgium, Croatia, Cyprus, Greece, Iceland, Italy, Japan, Latvia, Lichtenstein,
Luxembourg, Malta, New Zealand, Norway, Romania, South Korea, Spain, or Sweden.

14

Sources: Hepatitis B in England 2024 - GOV.UK ; Hepatitis B and C in Pregnancy and Children: A Canadian
Perspective – PMC ; Evidence brief - prevention of hepatitis B and C in Europe and the UK ; Uptake of perinatal
immunoprophylaxis  for infants born to women with a record of hepatitis B in Victoria (2009 –2017) – ScienceDirect ;
Updated -National Hepatitis Elimination Profile - Switerland -July2023_0.pdf ; Gaps in Prenatal Hepatitis B Screening
and Management of HBsAg Positive Pregnant Persons in the U.S., 2015 –2020 - PMC

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Summary: 1   ACIP Meeting Materials for Public Posting:  Hepatitis B Birth Dose Briefing Document     Contents   1. Background   2. Epidemiology   3. Systematic Review s for studies  on hepatitis B birth dose vaccine   4. Appendices   Appendix 1 ACIP Recommendations   Appendix 2 Global Recommendations     1. Background     Introduction   Hepatitis B virus (HBV) infection can be transmitted from mother -to-child during pregnancy and delivery.  Without any interventions, up to 85% of infants born to…