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Considerations and Query for the
Advisory Committee for Immunization Practices
Presented by Dr. Evelyn Griffin, MD, FACOG, IFMCP
Child/Adolescent Immunization Schedule Work Group
Vaccinations during Pregnancy Work Group
HPV Work GroupVaccines
and Aluminum Adjuvants
Background
Child/Adolescent Immunization Schedule Work Group Discussion
Objectives
ACIP Charter: provide “advice and guidance to the
Director of the CDC regarding the use of vaccines and
related agents”
•Consideration of an ACIP Adjuvant Work Group
•Educational forum
Some categories of vaccines:
•live attenuated (ie MMR), killed/subunit/recombinant, gene therapy -based
Many ingredients in vaccine products:
•Antigens
•Adjuvants
•Preservatives
•Stabilizers
•Surfactants
•Residuals
•Diluents
•(Adulterants in rare cases)Vaccine Overview
Some categories of vaccines:
•live attenuated (ie MMR), killed/subunit/recombinant, gene therapy -based
Many ingredients in vaccine products:
•Antigens
•Adjuvants
•Preservatives
•Stabilizers
•Surfactants
•Residuals
•Diluents
•(Adulterants in rare cases)
Each vaccine is unique, and each component may contribute to risk, safety, efficacy,
and effectiveness of a vaccine final drug product.Vaccine Overview
What is an Adjuvant?
•An adjuvant is any substance or compound added to a vaccine to enhance the
body’s immune response to the antigen (portion that mimics the pathogen).
•It stimulates the innate and adaptive immune responses to augment vaccine efficacy and longterm effectiveness.
Vaccine Overview:
Adjuvants
•Typically, only killed/subunit/recombinant – type vaccines include adjuvants.
•A large portion of the childhood and adolescent vaccine schedule and
vaccines given during pregnancy are formulated with adjuvants.
Does the FDA approve adjuvants?
•FDA approves final drug products, it does not approve adjuvants.
•There are no “FDA approved” adjuvants.Vaccine Overview:
Adjuvants
•Typically, only killed/subunit/recombinant – type vaccines include adjuvants.
•A large portion of the childhood and adolescent vaccine schedule and
vaccines given during pregnancy are formulated with adjuvants.
Are there Different Types of Adjuvants?
•Some adjuvants and adjuvant categories:
•Aluminum salts
•Oil-in-water emulsions
•Liposome-based
•Toll-Like Receptor (TLR) agonists
•Saponin (plant) -based
•Most killed/subunit/recombinant vaccines rely on aluminum salt -based
adjuvants (ABA). Since the 1920s, these have been the most widely used
adjuvants in FDA-licensed human vaccines.
•Examples of ABA: aluminum oxyhydroxide (Alhydrogel®) and aluminum hydroxyphosphate (Adju-Phos®)
Aluminum and Aluminum Salt Adjuvants
The only published/peer -reviewed study of aluminum blood levels observed in
infants after aluminum -adjuvant containing vaccine administration.
•Sample size (n= 15), serum aluminum levels measured before and 24 hours
after vaccination
•No significant detectable mean increase at 24h relative to pre-vax levels
•No long -term data, or organ distribution dataBiodistribution and Pharmacokinetics
Movsas et al. 2013
Current US Aluminum Exposure Limits
US Agency for Toxic Substances and Disease Registry (ATSDR) determined a
Minimum Risk Level (MRL) for orally ingested aluminum:
•Oral MRL ≈ 1 mg (1,000 mcg) Al/kg/day based on animal data
•Assumes ~0.1% oral absorption
•Converted to an injected -equivalent threshold,
this approximates 1 mcg/kg/day
Current US Aluminum Exposure Limits
The U.S. Code of Federal Regulations (21 CFR 610.15(a)) limits aluminum in
vaccines to ≤0.85 mg (850mcg) per dose, regardless of age group.
•Flarend et al., 1997: Doses up to 850 mcg total IM aluminum (including aluminium hydroxide and aluminium phosphate adjuvants) in rabbits resulted in transient blood level increases that resolved quickly, with no acute or chronic adverse effects observed.
•This is still the current FDA -accepted benchmark for human vaccine adjuvant
dosing.
•Masson et al., 2018 examined the limitations of using the Flarend study as a basis for regulatory threshold setting.
Why Focus on Aluminum Dose in Vaccines?
•Infants receive multiple aluminum- containing vaccines in a single visit under the
current schedule.
•Dose per kilogram body weight is far higher in early infancy than in adults.
•Neonatal kidneys, blood –brain barrier, and detoxification systems are immature.
Why Focus on Aluminum Dose in Vaccines?
•Infants receive multiple aluminum- containing vaccines in a single visit under the
current schedule.
•Dose per kilogram body weight is far higher in early infancy than in adults.
•Neonatal kidneys, blood –brain barrier, and detoxification systems are immature.
*There are similar considerations for children
and fetuses through pregnancy vaccination.
Multiple Aluminum Adjuvanted Vaccine Doses
Results in Cumulative Aluminum Exposure
The administration of one dose
each of Prevnar 20, PedvaxHIB,
Engerix -B, and Infanrix at one
visit delivers 1,225 mcg of
aluminum.
PCV, Hib, HepB, and DTaP
vaccines are administered multiple times by 6mo of age.
The rate at which aluminum
from vaccines migrates from human muscle to the bloodstream is not known.
Vaccine Selection Can Double Aluminum
Exposure on the Same Schedule
"Term infants with normal renal function may also be at risk because of their
rapidly growing and immature brain and skeleton, and an immature blood -
brain barrier. Until they are 1 to 2 years old, infants have lower glomerular filtration rates than adults, which affects their kidney function. The agency is concerned that young children and children with immature renal function are at a higher risk resulting from any exposure to aluminum.”
Cited in the Federal RegisterUS FDA Child Health Concerns, June 2003
Aluminum Biodistribution
Experimental and clinical data suggest intramuscular injected aluminum
and aluminum salts can persist at the injection site, then migrate via immune cells to liver, spleen, and other organs including the brain.
"The distribution profile of aluminium
to tissues was the same for both adjuvants (AH and AP) kidney > spleen > liver > heart > lymph node > brain."
Gherardi RK et al
Macrophagic myofasciitis (MMF)
•Muscle biopsies show aluminum- containing macrophages in
granulomas at prior IM vaccination injection sites (MMF lesions).
•Symptoms in many MMF patients: chronic myalgias, fatigue, and
cognitive difficulties.
•Causal link between injected aluminum or aluminum salts (aluminum oxyhydroxide) to systemic symptoms is not universally accepted.
•Demonstrates long -term persistence of aluminum in human tissue.Persistence and Macrophagic Myofasciitis
•Exley and Mold, 2019: Aluminum in postmortem brain tissue of neurological
patients, reflecting cumulative environmental exposure
•Shoenfeld and Agmon- Levin, 2011: Auto Immune/Inflammatory Syndrome
Induced by Adjuvants
•Shaw and Tomljenovic, 2014: aluminum neurotoxicity
•Daley et al., 2023: Association between aluminum exposure from vaccines before age 24 months and persistent asthma at age 24 to 59 Months
•Emerging research in mechanisms of aluminum oxidative stress: mitochondrial dysfunction, and impaired energy metabolism, pro -inflammatory effects and
microglial activation, promotion of amyloidogenesis and disruption of metal homeostasis (i.e. iron)Aluminum Based Adjuvants:
Biocompatible and Always Well Tolerated?
Aluminum Adjuvant Toxicology:
Data Gaps and Ambiguity
•Currently available infant safety assessments rely on a small number of
toxicokinetic studies and modeled assumptions.
•No long -term human studies tracking vaccine- derived aluminum kinetics in infants
or children have been published.
•Critical reviews challenge absorption factors and clearance assumptions in influential models (e.g., Mitkus 2011)
•No large, prospective, well- controlled studies comparing neurodevelopmental or
autoimmune outcomes by cumulative aluminum dose have been performed or
published.
•No established safe dose of injected aluminum for fetuses, neonates and preterm
infants has been established.
•Existing toxicology and pharmacokinetic data are too sparse and model- dependent
to support definitive conclusions of safety at current cumulative doses.
Query for ACIP
How should ACIP continue to assess effectiveness and safety
of adjuvants in currently authorized vaccines on the schedule
(childhood/adolescent, adult, and vaccines during pregnancy),
and related implications of the entire schedule?
Additional discussion
•Should multiple aluminum- containing vaccines be administered on the same
day in early infancy?
•Should lower- aluminum formulations and spacing strategies be preferred
when possible?
•What research is needed to define a genuinely evidence- based safety
margin for injected aluminum?
•What prudent policy would reduce peak and cumulative aluminum exposure
in the most vulnerable while urgent research gaps are addressed?
Acknowledgement & Invitation
For Collaboration