Document text
Non -specific effects following hepatitis B
vaccinationNational Center for Emerging and Zoonotic Infectious Diseases
John Su
Acting DirectorImmunization Safety OfficeCenters for Disease Control and Prevention
September 18, 2025
1
Request to CDC from ACIP chair
Present the results for the HepB vaccine from the study by Garly ML,
Jensen H, Martins CL, Balé C, Baldé MA, Lisse IM, Aaby P . Hepatitis B
vaccination associated with higher female than male mortality in Guinea -
Bissau: an observational study. The Pediatric infectious disease journal.
2004 Dec 1;23(12):1086 -92.
2
Outline
•Review non -specific effects following vaccination
•Summarize Garly, et al. 2004 paper
•Through a rapid systematic review of non- specific effects following hepatitis
B vaccination, provide available evidence related to mortality following
hepatitis B vaccination
3
Non-specific effects following vaccination
Pittet L, Netea MG, Curtis N. Chapter 3 - Non-specific Effects of Vaccines. In: Stanley A. Plotkin WAO, Paul A. Offit, and Kathryn M. Edwards, ed.Plotkin's Vaccines. 8 ed. Elsevier; 2023:37 -44.e7:chap 3.•In addition to protecting against their target disease, vaccines may
induce changes in the immune system that have broader effects
•Non -specific effects (NSE) are distinct from adverse events, cross -
protective, and downstream indirect effects
•Clinical manifestations of NSE
-All-cause mortality
-Unrelated infections
-Risk of allergic and autoimmune disease
•Live -attenuated and non-live vaccines may have differential NSE
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Summary of Garly, et al. 2004 article
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Background
•Several studies have examined the non- specific effects of
vaccines on all -cause mortality
•Few studies had examined a potential impact of hepatitis B
vaccination and mortality
•Objective of Garly, et al. 2004 paper:
-Is hepatitis B vaccine associated with sex -specific differences in
mortality?
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Methods
•Study setting:
-Guinea -Bissau Bandim Health Project surveillance system
-Enrolled inmeasles vaccine trial1
•Study population:
-Birth cohorts, March 1994 – February 2000
-Children born March 1996 –February 1997, eligible for hepatitis B vaccine
•Study design: prospective cohort
•Exposure:
-3 doses of hepatitis B vaccine given at 7.5, 9, and 10.5 months of age
-Human plasma- derived hepatitis B vaccine, Hepaccine (not a U.S. licensed vaccine)2
1. Garly ML, Martins CL, Balé C, da Costa F, Dias F, Whittle H, Aaby P. Early two -dose measles vaccination schedule in Guinea -Bissau: good protection and cov erage in infancy. Int J
Epidemiol. 1999 Apr;28(2):347 -52. doi: 10.1093/ ije/28.2.347. PMID: 10342702.
2. Heppacine is not approved for use in the United States; HEPACCINE -B INJECTION - 27/30.1/0128; HEPACCINE -B MULTIDOSE INJECTION - 27/30.1/0129; HEPACCINE -B PAEDIATRIC
INJECTION - 27/30.1/0127; HEPACCINE -B PAEDIATRIC 2 DOSE INJECTION - 27/30.1/0422; HEPACCINE -B PAEDIATRIC MULTIDOSE INJECTION - 27/30.1/0423 7
Methods
•Three mortality comparisons:
1.Children aged 7.5 - 12 vs 1.5 - 7.5 months, all birth cohorts
2.Hepatitis B -vaccinated vs hepatitis B -unvaccinated (subset in 2-dose
measles vaccine (MV) trial)
3.Female -to-male , hepatitis B -vaccinated vs hepatitis B -unvaccinated
(among those who received MV; HBV+MV vs MV alone)
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Results
•Comparison 1 (N = 8,906)
-Mortality rate ratio (MRR) was 0.97 (95% CI, 0.77- 1.23) for the HBV -unvaccinated cohorts comparing
7.5- 12-month to 1.5- 7.5 month age groups
-Among the birth cohorts when most children received HBV (7.5 months of age ),children had
increased mortality [MRR 1.62 (95% CI 1.09, 2.41)] comparing 7.5- 12-month to 1.5- 7.5 month age
groups
•Comparison 2 (N= 5,441)
-Among children enrolled in the MV trial, compared with HBV -unvaccinated children, the MRR for
children 7.5- 12 months of age from the HBV -vaccinated cohort was 1.81 (95% CI 1.19, 2.75)
•Comparison 3 (N=5,061)
-The female -to-male MRR was 1.66 (95% CI 0.80- 3.45) in the cohort who received both HBV and MV
through 12 months of age
-The female -to-male MRR was 2.20 (95% CI 1.07, 4.54) in cohort who received both HBV and MV and
0.96 (95% CI 0.70, 1.32) in the MV only cohort through 24 months of age
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Conclusions
•Garly, et al. concludes, using 3 different tests of the same intervention:
-Changes in the mortality pattern after the introduction of hepatitis B vaccine in a
high mortality setting
-Higher mortality between 7.5 and 12 months of age among children who
received hepatitis B vaccine compared to those who did not, within a 2 -dose
measles vaccine trial
-The effect was found to be stronger for females than for males
-Hepatitis B vaccine may have sex -differential non -specific effects
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Limitations and Implications
•Analyses were not planned when the trial was designed
•The study was not randomized, so an unbiased comparison of hepatitis B -
vaccinated and unvaccinated children from the same period could not
bemade
•Effects may differ when hepatitis B vaccine is given at birth and with BCG
•An increase in the female -to-male mortality ratio could also represent a
reduction in male mortality
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Rapid systematic review of non- specific
effects of hepatitis B vaccine
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Rapid systematic review of non- specific effects after
hepatitis B vaccination
•To inform the Garly et al. 2004 paper, we conducted a rapid systematic
review on the non -specific effects (e.g., mortality) after hepatitis B
vaccination in children
•The key question used to guide the review: What are the non-
specific effects of hepatitis B -containing vaccines administered in
childhood?
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Rapid systematic review of data on non- specific effects
•Key question: What are the non -
specific effects of hepatitis B -
containing vaccines administered in
childhood?
•Conducted a new rapid systematic
review of published literature through August 20, 2025
•Electronic databases
searched: MEDLINE, EMBASE,
CINAHL, and Cochrane LibraryPI/ECO(ST)
ELEMENTDescription for this Review
PopulationInfants and children through 6 years of age
Intervention or
Exposure*Hepatitis B (HBV) – Recombivax HB,Engerix -B
Combination vaccines –
Pediarix, Kinrix, Quadracel, Vaxelis, Pentacel, ProQuad
Comparator (if applicable)Any or none
Outcome(s)Non- specific effects
All-cause morbidity
All-cause mortality (death)
Non- targeted infection (sepsis, respiratory tract)
Allergic and atopic disease (asthma, eczema, atopic dermatitis, food allergy)
Autoimmune and immune- mediated disease (type 1 diabetes mellitus,
inflammatory bowel disease – ulcerative colitis and Crohn’s disease,
juvenile idiopathic arthritis, systemic lupus erythematosus, Hashimoto’s
thyroiditis, alopecia)Malignancy (cancer, leukemia)
SettingAny
Time Frame Any publication years
Any duration of follow up
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Results
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Systematic review inclusion and exclusion criteria
Inclusion Criteria Exclusion Criteria
• Clinical trials
• Observational studies
• Surveillance reports
• Systematic reviews• Case reports
• Case series
• Narrative reviews
• Animal studies
• Infants
•Children ≤ 6 years of age•Older children ≥7 years of age
• Adults
• Hepatitis B vaccines (Hepatitis B,
H BV, HepB, Engerix -
B,Recombivax HB, Pediarix, Vaxelis)• Other vaccines
• Outcomes include any of the following: non-specific effects, all -cause morbidity, all -
cause mortality, non- targeted infection,
allergic and atopic disease, autoimmune and
immune -mediated disease, malignancy• Any other outcome
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Results of systematic reviewIdentification Screening IncludedStudies from databases/registers (n = 2068)
Embase (n = 1105)
MEDLINE (n = 811)
Cochrane Library (n = 119)
CINAHL (n = 33)References removed (n = 0)
Duplicates identified manually (n = 0)
Key word screening for “hepatitis B,” “HBV,” “Hep B,”
“Engerix -B,” “Recombivax HB,” “ Pediarix ,” “Vaxelis ”(n
= 2068)Studies excluded (n = 1831)
Studies sought for retrieval (n = 16)Studies excluded (n = 221)
Studies assessed for eligibility (n = 16) Studies excluded (n = 8)
Wrong study design (case report, case series, etc.) (n=3)
Wrong patient population (children>/=7, adolescents, adults) (n=1)
Wrong intervention (does not evaluate hepatitis B -containing vaccines) (n=4)
Studies included in review (n = 8)
Studies screened (n = 237)
Studies not retrieved (n = 0)
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Summary of publications meeting search criteria
•Total of 8 studies included in review
-4 studies evaluated pentavalent, hepatitis B -
containing vaccines* and non -specific effects
-4 studies evaluated monovalent hepatitis B
vaccines and non- specific effects
•Study characteristics (N=8)
•Presenting results of studies
(N=4) evaluating monovalent hepatitis B
vaccination
*Pentavalent vaccine: Diphtheria- Tetanus -whole cell Pertussis- Hemophilus influenzae type B- Hepatitis BCharacteristic # of Studies
Study design Cohort 7
Nested case series 1
Vaccine adm inistered Pentavalent vaccine 4
M onovalent hepatitis B vaccine4
C ountry of study High income country 2
Lo w- and mi ddl e -
income country6
Non-specific effects Mortality 4
Fem ale -to-m ale
m ortality5
Other non- specific
effects1
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StudyStudy
TypeCountryOutcome and
WindowComparison armsNon -Specific Effects
Measure of
AssociationIntervention
Results
% (n/N or PT)Comparison
Results
% (n/N or PT)
He 2022 Cohort United StatesAll-cause mortality;
median follow -up of 8
yearsHepatitis B vaccine*
vs no hepatitis B
vaccine(390/10,785)2.6
(4,185/26,006)aHR 0.78 (95%CI: 0.
68-0.90)
Morgan
2025Cohort
(extrem
elypret
erm inf
ants)AustraliaAll-cause mortality;
within 3 months of lifeHepatitis B vaccine vs
no hepatitis B vaccine2.3 (7/306) 2.7 (14/512)aRR :
1.13 (95%CI: 0.42-
2.81)
Garly 2004 Cohort Guinea -BissauAll-cause mortality;
7.5 months –
12months of ageHepatitis B
vaccine [Hepaccine ]
+measles vaccine
vsmeasles vaccineNR/876 NR/4,565MRR
1.81 (95%CI: 1.19-
2.75)Studies evaluating mortality
Two cohort studies in high- income countries (HIC) showed no association between all -cause
mortality and hepatitis B vaccination, and one cohort study in a low -and middle -income
country (LMIC) suggested an increase in risk of all -cause mortality after hepatitis B vaccination.
PT = person -time; aHR = adjust hazard ratio; aRR = adjusted rate ratio; NR = not reported; MRR = mortality rate ratio
•*Unspecified manufacturer, thimerosal -free 19
StudyStudy
TypeCountryOutcome and
WindowComparison armsNon -Specific Effects
Measure of
AssociationIntervention
Results
% (n/N or PT)Comparison
Results
% (n/N or PT)
Garly 2004 Cohort Guinea -BissauFemale -to-
male mortality; 7.5
months – 12months
of ageHepatitis B vaccine
[Hepaccine] +
measles vaccine vs
measles vaccine12.5 (18/143.8
female person-
years)7.5 (12159.1
male person-
years)MRR 1.66 (95%CI: 0
.80- 3.45)
Garly 2004 Cohort Guinea -BissauFemale -to-
male mortality; 9 -24
monthsHepatitis B
vaccine [Hepaccine]
+ measles vaccine vs
measles vaccine6.1 (22/358
female person-
years)2.8 (11/394.3
male person-
years)MRR
2.20 (95%CI: 1.07-
4.54)
Aaby 2004Nested
case
seriesThe GambiaFemale -to-
male mortality; 18
months of ageHepatitis B as last
vaccine vs no
hepatitis B as last
vaccine7 (4/60) 0 (0/53) NRStudies evaluating female- to-male mortality
Evidence is inconsistent about sex -specific mortality after receipt of hepatitis B vaccines in
LMIC; one study suggests both no difference and an increase in the female -to-male mortality
ratio and one study suggests no difference in mortality by sex.
PT = person -time; MRR = mortality rate ratio; NR = not reported 20
StudyStudy
TypeCountryOutcome
and WindowComparison armsNon -Specific Effects
Measure of
AssociationIntervention
Results
% (n/N or PT)Comparison
Results
% (n/N or PT)
He 2022 Cohort United StatesCancer- related
mortality;
median follow -
up of 8 yearsHepatitis B
vaccine* vs no
hepatitis B vaccine0.7 (97/10,785)2.6
(881/26,006)aHR 0.76 (95%CI:
0.58 -1.00)
He 2022 Cohort United StatesCardiovascular
-related
mortality;
median follow -
up of 8 yearsHepatitis B vaccine*
vs no hepatitis B
vaccine0.4 (53/10,785)1.9
(732/26,006)aHR 0.83 (95%CI:
0.60 -1.15]Studies evaluating other mortality outcomes
One cohort study in a HIC suggests no effect of hepatitis B vaccines on
cancer -related mortality and cardiovascular -related mortality.
PT = person -time; aHR = adjusted hazard ratio
*Unspecified manufacturer, thimerosal -free 21
Conclusions
•Few studies exist to inform the non-specific effects of hepatitis B vaccination
•Two cohort studies in HIC showed no association between all -cause mortality
and hepatitis B vaccination
•One cohort study in an LMIC showed an increase in risk of all -cause mortality
after hepatitis B vaccination
•Evidence is inconsistent about sex -specific mortality after receipt of hepatitis B
vaccines
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CDC’s interpretation on limitations and implications
•Non -specific effects (NSE) may vary in settings with different background
mortality rates and infectious diseases burden
•NSE may not be generalizable across immunization programs
-Heppacine is not licensed for use in the United States
-In the United States , hepatitis B vaccine is given earlier and often in combination with
other routine vaccines
•Biologic molecular and immunological mechanisms for non-specific effects are
not fully understood
-The interval between vaccination and the onset of NSE, as well as the persistence
ofeffects are uncertain
-The duration of a vaccine's NSE is complicated by a subsequent vaccination with adifferent vaccine
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References
1.Pittet L, Netea MG, Curtis N. Chapter 3 - Non -specific Effects of Vaccines. In: Stanley A. Plotkin WAO, Paul A. Offit, and Kathryn M. Edwards,
ed. Plotkin's Vaccines . 8 ed. Elsevier; 2023:37- 44.e7:chap 3.
2.Aaby P, Jensen H, Walraven G. Age -specific changes in the female -male mortality ratio related to the pattern of vaccinations: An observational
study from rural Gambia. Vaccine . 29 May 2006;24(22):4701 -4708. doi:10.1016/j.vaccine.2006.03.038
3.Aamand T, Fisker AB, Correia C, Fernandes M, Clipet -Jensen C, Thysen SM. Do Pentavalent ( DTwP -Hib-HBV) vaccines have sex -differential
nonspecific effects? An observational study. Observational Study Research Support, Non -U.S. Gov't. Hum Vaccin Immunother . 12 15
2023;19(3):2288297. doi:10.1080/21645515.2023.2288297
4.Fisker AB, Biering -Sorensen S, Lund N, et al. Contrasting female -male mortality ratios after routine vaccinations with pentavale nt vaccine versus
measles and yellow fever vaccine. A cohort study from urban Guinea -Bissau. Research Support, Non -U.S. Gov't. Vaccine . 08 31 2016;34(38):4551 -
4557. doi:10.1016/j.vaccine.2016.07.034
5.Fisker AB, Thysen SM. Non -live pentavalent vaccines after live measles vaccine may increase mortality. Research Support, Non- U.S. Gov't. Vaccine .
10 01 2018;36(41):6039 -6042. doi:10.1016/j.vaccine.2018.08.083
6.Garly ML, Jensen H, Martins CL, et al. Hepatitis B vaccination associated with higher female than male mortality in Guinea- Bissa u: An observational
study. Pediatr Infect Dis J . December 2004;23(12):1086 -1092. doi:10.1097/01.inf.0000145700.77286.94
7.Hanifi SMA, Biering -Sorensen S, Jensen AKG, Aaby P, Bhuiya A. Penta is associated with an increased female -male mortality ratio: cohort study
from Bangladesh. Research Support, Non -U.S. Gov't. Hum Vaccin Immunother . 01 02 2021;17(1):197 -204. doi:10.1080/21645515.2020.1763084
8.He WQ, Guo GN, Li C. The impact of hepatitis B vaccination in the United States, 1999 -2018. Hepatology . 06 2022;75(6):1566 -1578.
doi:10.1002/hep.32265
9.Morgan HJ, Nold MF, Kattan GS, et al. Hepatitis B vaccination of preterm infants and risk of bronchopulmonary dysplasia: a co hort study, Australia.
Vaccination contre l'hepatite B de prematures et risque de dysplasie bronchopulmonaire : etude de cohorte en Australie , Vacunacion contra la
hepatitis B en neonatos prematuros y riesgo de displasia broncopulmonar : estudio de cohortes en Australia. Bull World Health Organ .
2025;103(3):187 -193. doi:10.2471/BLT.24.291683
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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.
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