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Safety Review of Hepatitis B Birth Dose Vaccination
CDC Advisory Committee on Immunization Practices meeting
Mark F. Blaxill, MBA
December 4, 2025Office of the Director
Safety of the hepatitis B vaccine
•Clinical trials
•Post -licensure safety studies
•IOM and VICP on vaccine -related injuries
•Animal models
•There were no randomized placebo -controlled trials in infants; cited trials used
short follow up periods of 7 days or less and discounted safety concerns
•CDC/ISO’s “rapid systematic review” of post -licensure safety studies reveals
concerns but evidence of chronic, late -onset effects was not presented
•IOM Safety of Vaccine reports have highlighted the absence of evidence to
assess potential adverse effects in over 30 endpoints
•VICP has processed large numbers of HBV related claims, compensating many
•Mechanisms of injury, especially immune activation, reported in animal models Overview of Hepatitis B Vaccine (HBV) Safety:
Safety evidence is limited and often concerning
Clinical trials on infants/children cited for birth dose of
Recombivax HB or Engerix -B in 1991 ACIP recommendation
Trial
publicationVaccine Control
groupSample size and
compositionSafety follow up
periodSafety findings
Zajac et al,
1986Recombivax HB None 79 children, ages 1 -12 years5 days after each dose18% “systemic” complaints:
“fatigue, weakness,
diarrhoea or irritability. ”
Stevens et al,
1987Re co m b iva x HB Plasma vaccine122 infants
39 plasma/83 recombinantAsia n -Am e rica n
HBs Ag + / HBe Ag + mothers7 days after each dose1 death in recombinant group due to “ inoperable congenital malformation”
A ndre et al, 1989En g e rix -B None 1187 neonates Up to 3 days after each dose96% “had no reaction to the
vaccine. ”
2.5% mild/moderate fever
“Symptoms of encephalitis…
“Encephalitis can be dangerous in infants. Watch for fever , lethargy ( weakness or drowsiness), poor feeding,
vomiting, body stiffness, unexplained/unusual irritability or crying”
Source: Encephalitis | National Institute of Neurological Disorders and Stroke“Systemic” clinical complaints in children reported in Zajac et al (1986)
ISO’s “rapid systematic review” of hepatitis B post -licensure safety data
(ISO, 9/18/25) included 20 studies— presented findings from 9 of 20
Categories Unvaccinated or no vaccine as control Vaccine(s) as control
Birth dose defined as <24 hours
Linder et al, 1999
Lewis et al, 2001 (VSD)
Morgan et al, 2025Bassily et al, 1995
Yerushalmi et al, 1997
Birth dose defined as 0 -8 days
Eriksen et al, 2004 (VSD) Greenberg et al, 2002Lopez et al, 2002
Wood et al, 2018
Birth dose defined as <30 days
Gallagher & Goodman, 2010 (NHIS, ASD)Geier et al, 2015 (VSD, Tics)Geier et al, 2016 (VSD, Dev Delay)
Geier et al, 2017 (VSD, Emot Disturb)
Geier et al, 2018 (VSD, prem puberty)Verstraeten et al, 2003 (VSD)
VAERS studies (3)
-Niu et al, 1996
-Niu et al, 1999 (death)
-Haber et al, 2018Sapru et al, 2007
Geier et al, 2013 (ASD)
ISO’s “rapid systematic review” of hepatitis B post -licensure safety data
(ISO, 9/18/25) included 20 studies— presented findings from 9 of 20
Categories Unvaccinated or no vaccine as control Vaccine(s) as control
Birth dose defined as <24 hours
Linder et al, 1999
Lewis et al, 2001 (VSD)
Morgan et al, 2025Bassily et al, 1995
Yerushalmi et al, 1997
Birth dose defined as 0 -8 days
Eriksen et al, 2004 (VSD) Greenberg et al, 2002Lopez et al, 2002
Wood et al, 2018
Birth dose defined as <30 days
Gallagher & Goodman, 2010 (NHIS, ASD)Geier et al, 2015 (VSD, Tics)Geier et al, 2016 (VSD, Dev Delay)
Geier et al, 2017 (VSD, Emot Disturb)
Geier et al, 2018 (VSD, prem puberty)Verstraeten et al, 2003 (VSD)
VAERS studies (3)
-Niu et al, 1996
-Niu et al, 1999 (death)
-Haber et al, 2018Sapru et al, 2007
Geier et al, 2013 (ASD)
Early post -licensure study described unexplained fever
in neonates in the year after HBV introduction in Israel
OR= 2.16“In conclusion, we found that an
increased incidence of unexplained
neonatal fever, which resulted in
evaluation for sepsis, administration of
intravenous antibiotics, and prolonged
hospital stay, may be associated with
vaccination against hepatitis B on the
first day of life. “
Post -licensure safety studies with unvaccinated group and
negative/protective findings show healthy vaccinee effect (HVE)
Study Condition(s)
examinedFinding HVE effects in sample
selection
Included in 9/2025 ACIP safety review
1. Lewis et al, 2001 ( VSD) Fever, sepsis, allergies, seizures
Testing frequencyNo differences0.73 OR for testsExclusions of preterm, LBWUnexplained testing frequency
2. Ericksen et al, 2004 ( VSD)Death Lower death rate
in exposedUnvaccinated sample mean birth wgt <44% of vaccinated
3. Morgan et al 2025
(Australia)Bronchopulmonary dysplasia in preterm0.83 RR “it is not known how clinician perception of the stability of the newborn affects the decision to vaccinate or not”
Eriksen et al, 2004 (VSD)
HVE effect: unvaccinated vs. vaccinated neonates
•<44% of median birth weight
•11 weeks lower median gestational age
•Only 5% of 1993- 98 cohort deaths were in
vaccinated infants, 72 of 1363
Study design
(1) identified all neonatal deaths in NCK and SCK from 1993 -98
(2) determined cases that had been vaccinated with HBV
(3) selected 2– 4 matched HBV -unvaccinated controls for each HBV -vaccinated neonatal death
Matching based on “days of life” category (0 -1, 2- 5 and 6 -28), birth year, sex and HMO
(4) determined pre -existing illness and the causes of death
(5) Categorized deaths as “expected” or “unexpected” in a blinded review
(6) assessed the clinical plausibility that HBV contributed to death
(7) assessed SIDS rates, searched for unvaccinated SIDS cases beyond matched sample
(8) Compared maternal and perinatal factors in both groupsEriksen et al, 2004: death assessment method
Eriksen et al, 2004: Death assessment in matched samples
Primary cause of death Vaccinated Unvaccinated
Total deaths 72 196
“Expected” 50 (69%) 128 (65%)
“Unexpected” 22 (31%) 68 (35%)
SIDS 8 0
Sepsis after birth 7 4
Necrotizing enterocolitis (NEC) 3 29
Insufficient information 2
CNS hemorrhage 1 15
Laryngeal edema 1
Pulmonary/other hemorrhage 0 5
Other - 15
ISO’s “rapid systematic review” of hepatitis B post -licensure safety data
(ISO, 9/18/25) included 20 studies— presented findings from 9 of 20
Categories Unvaccinated or no vaccine as control Vaccine(s) as control
Birth dose defined as <24 hours
Linder et al, 1999
Lewis et al, 2001 (VSD)
Morgan et al, 2025Bassily et al, 1995
Yerushalmi et al, 1997
Birth dose defined as 0 -8 days
Eriksen et al, 2004 (VSD) Greenberg et al, 2002Lopez et al, 2002
Wood et al, 2018
Birth dose defined as <30 days
Gallagher & Goodman, 2010 (NHIS, ASD)Geier et al, 2015 (VSD, Tics)Geier et al, 2016 (VSD, Dev Delay)
Geier et al, 2017 (VSD, Emot Disturb)
Geier et al, 2018 (VSD, prem puberty)Verstraeten et al, 2003 (VSD)
VAERS studies (3)
-Niu et al, 1996
-Niu et al, 1999 (death)
-Haber et al, 2018Sapru et al, 2007
Geier et al, 2013 (ASD)
Additional studies with unvaccinated comparisons listed—but
not presented —in 9/2025 ACIP safety review presentation
Study Condition(s) examined Finding Comments
1. Verstraeten et al, 2003 Neurodevelopmental disorders (VSD) No significant associations Hg/HBV exposure within 1st month
2. Gallagher & Goodman, 2010 Autism (NHIS) 3.002 OR in males Vaccinated w/in 1st month
3. Geier et al, 2015 Tics (VSD) 1.59 OR total
•1.65 OR in malesHg/HBV exposure within 1st month
4. Geier et al, 2016 Developmental delay (VSD) 1.22 RR Hg/HBV exposure within 1st month
5. Geier et al, 2017 Emotional disturbance (VSD) 1.34 OR
•1.36 OR in malesHg/HBV exposure within 1st month
6. Geier et al 2018 Premature puberty (VSD) 1.80 OR
•1.87 OR in femalesHg/HBV exposure within 1st month
7. Niu et al, 1996 VAERS reports: 1/1991 -5/1995
“neonates” <1 month and
“infants” < 1 year“No unexpected adverse
events in neonates and
infants”Neonates:13 of 24 SAEs were fever, 4 seizures3 of 6 deaths were SIDS
8. Niu et al, 1999 VAERS reports: 1/1991 -10/1998 No “clear increase in neonatal deaths”18 death reports within 1st month12 SIDS cases, 3 initially SIDS
9. Haber et al 2017 VAERS reports, inc. infants: 2005 -15 No “new or unexpected safety concerns”27 deaths, 64 SAEs in 1
st month,
197 SIDS cases
4 VSD studies with consistent methodologies found increased risk of injury
for chronic, late -onset conditions from HBV in 1st month
0.511.52
Tics
Developm
delayEmotional
disturbancePremature
pubertyT M F
T M F T M FT M FOdds
RatioLegend
T= total
M= maleF= female
IOM studies of causal relationships with HBV (1)
Condition 1994 2002 2012
Death
Death following anaphylaxis Y
SIDS
All other causes
Arthritis
Acute Arthropathy
Chronic Arthropathy
Psoriatic, onset or exacerbation
Reactive, onset or exacerbation
Rheumatoid, onset or exacerbation
Juvenile Idiopathic, onset or exacerbation
Anaphylaxis Y Y
Brachial Neuritis
Erythema Nodosum
Systemic Lupus Erythematosus, Onset or ExacerbationVasculitis, onset or exacerbationPolyarteritis Nodusa , onset or exacerbation
Diabetes, Type 1
FibromyalgiaEvidence is:
insufficient to accept
or reject ,
establishes (Y), or
favors rejection of (N)causality
IOM studies of causal relationships with HBV (2)
Condition 1994 2002 2012
Encephalitis
Encephalopathy
Seizures
Guillain -Barre Syndrome
Encephalomyelitis, Acute Disseminated
Demyelinating Disorder, Central Nervous System, 1st episode
Demyelinating Event, first episode, ADULTS
Demyelinating Event, first episode, CHILDREN
Optic Neuritis
Multiple Sclerosis
Multiple sclerosis, incident/onset, ADULTS N
Multiple sclerosis, incident/onset, CHILDREN
Multiple sclerosis relapse, ADULTS N
Multiple sclerosis relapse, CHILDREN
Transverse Myelitis Neuromyelitis OpticaChronic Inflammatory Disseminated PolyneuropathyEvidence is:
insufficient to accept
or reject ,
establishes (Y), or
favors rejection of (N)causality
Vaccine Injury Compensation Program (VICP)
Adult compensation claims for hepatitis B vaccine total $92 million
Multiple sclerosis, transverse myelitis, GBS, encephalitis,
alopecia, fibromyalgia, thrombocytopenia, hypotension, arthritis, uveitis, and optic neuritis are outcomes both compensated by V I C P and listed in the Re co m b iva x HB
and/or En g e rix -B package inserts.
Vaccine Injury Compensation Program (VICP)
Children’s compensation claims for hepatitis B vaccine
$18 million in payments for hepatitis B vaccine alone.
VICP has p aid an additional $80 million for claims due to hepatitis B in combination with other vaccines.
Children’s claims for hepatitis B vaccine are more
commonly denied than compensated by VICP
Animal models of hepatitis vaccine birth dose
Study Model Selected findings
Immune Brain Behavioral
Studies finding altered development
Yang et al, 2016 mice Th2 bias ↓ hippocampal neurogenesis ↑ anxiety ↓locomotor activity
Wang et al, 2018 mice ↑ IL-4 levels ↑ neuroinflammation ↓ spatial learning & memory
Zhou et al, 2024 mice CD8+ infiltrate CNS ↓ hippocampal neurogenesis ↑ anxiety
Li et al, 2015 rats Th2 shift ↓ synaptic plasticity --
Hewitson et al 2010a macaques -- -- Delayed neonatal reflexes
Hewitson et al 2010b macaques -- Altered amygdala maturation --
Studies finding no changes
Curtis et al 2015 macaques -- -- No consistent evidence of deficits
Gadad et al 2015 macaques -- No evidence of neuropathology No evidence of aberrant behavior
Immune activation after infant birth dose in rodent models
leads to neurodevelopmental and behavioral impairments
Study Immune findings Immune ->
brainBrain findings Brain ->
behaviorBehavioral
findings
Li et al, 2015
(rats)• Anti -HBs response; Th2 bias at 8
wks
• ↑ TNF-α, ↑IL-6, ↓ IFN-γ, ↓BDNF, ↓
IGF-1• Serum & hippocampal
cytokines track together• IFN -γ/IL-4 ratio tracks with
hi ppocampal B DN F & I G F -1I mpai red DG L T P
• ↓ dendritic spine density,
↓ stubby spi nes
• ↓ synaptophysin, PSD -95,
NR2 A, NR2 B-- --
Y ang et al
2016 (mice)• H i ppocampus ( 6 wks ): ↓ IFN-γ, ↓
BDNF, ↓ IGF-1; ↑ TNF-α, ↑IL-1β, ↑
IL-6
• Serum T h2 bias ( ↓ IFN-γ/IL-4)
• HEL+ a lu m reproduces
phenotype; alum alone does not• IFN -γ/IL-4 correlates with
hi ppocampal B DN F /I G F -1
& neurogenesis markers• ↓ Brd U +, ↓ Brd U +/DCX +, ↓
Brd U +/NeuN+
• Impaired CA1 L TP at 8
wks• E arly neurogenesis &
cytokine changes precede
behavior• OFT: ↓ distance, ↓ rearing,
↓ center time
• EPM: ↓ open- arm activity
• MWM: im paired learning & memory ( normal swi m speed)• Deficits only at 8 wks
W ang et al,
2018 (mice)• Sustained ↑ IL-4 in serum &
hippocampus
• Delayed neuroinflammation ( ↑
TNF-α, IL-1β, IL-6)
• Se ru m IL -4 correlates with
hi ppocampal I L -4• Neonatal IL-4 reproduces
HBV outcome
• HBV & IL -4 ↑BBB
perm eability t o IL -4
• ↓IL-4 R in hippocampus• Delayed hi ppocampal
neuroinflammation• Ea rly IL -4 surge → later
neuroinflammation →
behavior deficitsDelayed spatial cognition
Zhou et al,
2024 (mice)• HB V induces effector memory
CD8+ T -cells
• CD8+ T cells: ↑ CXCR6; ↓ Arid 5a ,
Mc1r, Flt3, etc.
• ↑ effector -memory C D4+ and
CD8+ T cells• ↑ TNF-α+ / IFN-γ+ CD8+ cells• C D8+ T cells enter C NS
via CXCL16/ CXCR6 axis• A doptive transfer of HB V -
T cells → ↓ neurogenesis• ↓ K i67+ and ↓ DCX+ cells
in DG
• CXCL16 from glia recruits CD8+ cells• CD8 infiltration →
anxiety -like behavior• OFT: ↓ center time, ↓
exploration
• EPM: ↓ open- arm activity
• ↑ anxiety -like behavior
The safety of the universal birth dose (UBD) was not studied, pre -licensure,
in randomized, placebo -controlled, extended follow -up trials.
Post -licensure studies have in some cases been confounded by the healthy
vaccinee affect; others have found evidence of chronic, late onset adverse
effects.
IOM Safety of Vaccine reports have highlighted the absence of evidence to
assess potential adverse effects in over 30 endpoints
Animal models provide evidence for risk of immunological activation and
neurobehavioral impairment. Conclusions