Vaccines and Childhood Illnesses: Beyond Thimerosal

David Ayoub, MDSpringfield, IllinoisAugust 5th, 2009

raypoke@mac.com

disclosure: no financial conflicts

Aluminum MSDSIngestion: Chronic ingestion of aluminum may cause Aluminum Related Bone Disease or aluminum-induced Osteomalacia with fracturing Osteodystrophy, microcytic anemia, weakness, fatigue, visual and auditory hallucinations, memory loss, speech and language impairment (dysarthria, stuttering, stammering, anomia, hypofluency, aphasia and  eventually, mutism), epileptic seizures (focal or grand mal), motor disturbance (tremors, myoclonic jerks, ataxia, convulsions, asterixis, motor apraxia, muscle fatigue), and dementia (personality changes, altered mood, depression, diminished alertness, lethargy, 'clouding of the sensorium', intellectual deterioration, obtundation, coma), and altered EEG.

http://www.sciencelab.com/xMSDS-Aluminum-9922844

“Now the presentations we heard yesterday clearly demonstrate that there are huge gaps in our information about what we know about the toxicology of aluminum. I would like to just reiterate what Neal Halsey said, the differences between adults and infants, there appears to be practically no[t] even animal data never mind human data.”

May 11th - 12th, 2000

What is aluminum?

• 3rd most abundant element

• food, water, air, soil, medicine

• ~8% of earth’s crust

• no biological role

• a poison

published1928

Dr Charles T Betts

“All salts of aluminum are poisonous when injected subcutaneously or intravenously”

Dr. Victor Vaughn, Toxicologist, University of Michigan before US Federal Trade Commission Hearings on aluminum, 1927

Adjuvant

“agents that act nonspecifically to increase the specific immune response to an antigen”

Dictionary of Immunology

(How) do aluminium adjuvants work?Brewer JM. Immunol Lett. 2006 15;102(1):10-5.

The aluminium compounds, originally identified as adjuvants over 70 years ago, remain unique in their widespread application to human vaccines. Given this history, it is surprising that the physicochemical interactions between aluminium compounds and antigens are relatively poorly understood. This has clearly been a contributing factor to vaccine failures, for example, through inappropriate selection of aluminium species or buffers. Similarly, the mechanism(s) of action of aluminium adjuvants are relatively unstudied, although it appears that these agents fail to fit within the current principles underlying activation of the immune response. This review aims to examine recent developments in our understanding of the physicochemical and biological aspects of research into aluminium adjuvants

Aluminum Salts Adjuvants

aluminum hydroxide

aluminum phosphate

aluminum sulfate

aluminum hydroxyphosphate sulfate

mercury-containing shots

aluminum-containing shots

Number of administered vaccines containing aluminum increased after

Thimerosal reduced (by 18 months age)

source: David Ayoub, MD, Prairie Collaborative, Inc

• DTaP Infanrix 625 micrograms

• Hep B Engerix 250 micrograms

• HiB PedVax 225 micrograms

• Pediarix 850 micrograms

• Prevnar 125 micrograms

• DTaP Daptacel 330 micrograms

• DTaP Tripedia 170 micrograms

• HepB HiB Comvax 225 micrograms

• HepB Recombivax 500 micrograms

• Hep A Havrix 250 micrograms

• HepA-B Twinrix 450 micrograms

Aluminum content of some vaccines

Aluminum Exposure Safety Limits

TITLE 21--FOOD AND DRUGSCHAPTER I--FOOD AND DRUG ADMINISTRATION

DEPARTMENT OF HEALTH AND HUMAN SERVICESSUBCHAPTER F--BIOLOGICS

PART 610 -- GENERAL BIOLOGICAL PRODUCTS STANDARDSSec. 610.15 Constituent materials.

(a) Ingredients, preservatives, diluents, adjuvants. An adjuvant shall not be introduced into a product unless there is satisfactory evidence that it does not affect adversely the safety or potency of the product. The amount of aluminum in the recommended individual dose of a biological product shall not exceed:

(1) 0.85 milligrams if determined by assay;

(2) 1.14 milligrams if determined by calculation on the basis of the amount of aluminum compound added; or

(3) 1.25 milligrams determined by assay provided that data demonstrating that the amount of aluminum used is safe and necessary to produce the intended effect are submitted to and approved by the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing addresses in 600.2 of this chapter).

"The amount of 15 mg of alum or 0.85 mg aluminum per dose was selected empirically from data that demonstrated that this amount of aluminum enhanced the antigenicity and effectiveness of the vaccine (Joan May, FDA/CBER, personal communication)."

from NW Baylor, W Egan and Paul Richman,

FDA, CBER; VACCINE; 20 (2002), S18-23

FDA limits NOT based upon safety data!

50 - 250 µg/kg

2 methods:

acute toxicity:1) maximum blood levels

chronic toxicity:2) weight adjusted total exposures

250 -1225 µg

Aluminum Exposure Defined

blood volume

aluminum in shot

Aluminum blood levels

K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Children With Chronic Kidney Disease

12.2.b Baseline levels of serum aluminum should be <20 µg/L. (OPINION)

12.2.c If levels of serum aluminum are between 20-60 µg/L, a search for and elimination of all sources of aluminum should be performed. (OPINION)

12.3 A deferoxamine (DFO) test should be performed if there are elevated serum aluminum levels (60-200 µg/L) or clinical signs and symptoms of aluminum toxicity

newborn: 250 μg/ 250ml blood = 1,000 μg/L

2 month infant*:1225 μg/ 340ml blood = 3,603 μg/L

adult:1225 μg/ 5L blood = 245 μg/L

potential aluminum blood levels post vaccine

*70cc/kg blood volume

weight adjusted exposure

“Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.”

from: http://www.fda.gov/cder/foi/appletter/2004/19626scs019ltr.pdf

“....I5 and 30 mcg/kg/day of aluminum from TPN solutions. This amount resulted in tissue loading with aluminum but not in clearly associated disease. Thus, this rate of aluminum administration could be defined as unsafe. Finally,.....60 mcg/kg/d of aluminum (32). This rate could be considered toxic.”

Gordon Klein, et al 1991

Al-containing vaccine

03.30 kg

2mo4.86 kg

4mo6.54 kg

6mo7.80 kg

12 mo10.1 kg

15 mo10.9 kg

18 mo11.5 kg

HepBEnergix

250 250 - 250 250 -

DTaPInfanrix

- 625 625 625 625 625

HiBPedvax

- 225 225 225 225 225

PCVPrevnar

- 125 125 125 125 125

HepAHavrix

- - - - 250 250

Max dose

(μg)250 1225 975 1225 850 975 875

Max weight adjusted dose

μg/kg/day

75.8 252 149 157 84.1 89.4 76.1

Finally,.....60 mcg/kg/d of aluminum (32). This rate could be considered toxic.”

Gordon Klein, et al 1991

23-55 kg (50-120 lbs)225 µg/shot x 3 shots= 675 µg total

*blood volume (70 cc/kg)

1.6-3.9 L blood volume*

58-140 µg/L potential blood aluminum

4-10 µg/kg per shot (12-30 µg/kg total)

Calculating the dose of aluminum exposure

9-11 y/o:

Calculating the potential peak blood level

9-11 y/o:

Al-containing

vaccine

content(micrograms)

HepBEnergix

250

DTaPInfanrix

625

HepAHavrix

250

PCVPrevnar 125

HPV 225

total 1475 27-64 µg/kg on day of vaccines

> 800 µg/L blood level

vaccine

note: This is a smaller dose than children now receive

breast milk

formula

MRL

MRL violation with just 2 vaccines!

syringe

interstitialfluid

blood/lymph

dissolved by alpha-hydroxycarboxylic acids

citratemalatelactate

urine

excretion

tissue

retention

transferrin

ferritinbrainbone

spleen/livermyocardium

endocrine

Solubilization of aluminum-containing adjuvants by constituents of interstitial fluid. Seeber SJ, White JL, Hem SL. J Parenter Sci Technol. 1991 May-Jun;45(3):156-9.

Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiania.

The solubilization of three commercially available aluminum-containing adjuvants by citrate anion was studied. Amorphous aluminum hydroxyphosphate and boehmite were both solubilized, however, amorphous aluminum hydroxyphosphate dissolved significantly faster than boehmite. The results suggest that citrate and other alpha-hydroxy carboxylate anions in the interstitial fluid are able to solubilize and thereby facilitate the excretion of aluminum from aluminum-containing adjuvants which are administered by intramuscular injection. The results also suggest that the release of antigen following administration may be significantly more rapid from an amorphous aluminum hydroxyphosphate-adjuvanted vaccine in comparison to a boehmite-adjuvanted vaccine.

Gardasil’s aluminum adjuvant may be solubilized faster and thus peak serum

aluminum levels may appear higher and sooner than with other adjuvants

toxic

n=17

blood levels of aluminum after Hep B vaccine in adults on dialysis: significant blood levels achieved with inter-individual variability

baseline

so where is the rest of the aluminum? 78-95% retained in 1 month!

In viva absorption of aluminium-containing vaccine adjuvants using 26AlRE Flarend SL Hem, JL White. et al. Vaccine 1997:15(12-13);1314-18.

less than vaccine exposureaverage 78% of aluminum still retained in 5 infants exposed for at least 2 weeks (range 60-95%)

Premies

Evidence of aluminum loading in infants receiving intravenous therapy. Sedman AB, Klein GL, Merritt RJ, Miller NL, Weber KO, Gill WL, Anand H, Alfrey AC.N Engl J Med. 1985 May 23;312(21):1337-43.

• aluminum hydroxide in young adult

mice

• 50 μg/kg per dose x 2 shots

• 100 μg/kg fully vaccinated

infants: 50-250 μg/kgGardasil: 27-64μg/kg

• Behavioral effects of aluminum

• 50% reduction in strength/endurance (wire-mesh

hanging)

• 138% increase in anxiety(open-field testing)

• increase memory errors (water maze; ns)

• 20% hair loss at injection site

histopathology

• spinal cord:

• 255% increase in apoptosis in spinal cord neurons

• 35% reduction in motor neurons in cord

• 350% increase astrocytes

• motor cortex neurons

• 192% increase in apoptosis

Morin stain for aluminum

myelin

mitochondria

microsomes

synapses

Are their similarities between aluminum toxicity and neurodevelopmental

disorders?

renal insufficiency•oral phosphate binders•contaminated dialysate•oral antacids•TPN•infant formula

normal renal function•aluminum containing vaccines and MMF•antacids/TPN/formula

..............................................47 cases

.............34 cases................................................4 cases

85 cases

interval to presentation 0-156 mo

developmental delay 95%

small head (<-2 sd) 75%

EEG abnormal 94%

seizures 65%

hypotonia 65%

dyskinesia 55%corticol atrophy/ventriculomegaly 47%

chorea 20%

gait/ataxia 20%

myoclonus 15%

lethargy/dec LOC 15%

weakness 10%

Progressive encephalopathy in children with chronic renal insufficiency in infancy. Rotundo A, Nevins TE, Lipton M, Lockman LA, Mauer SM, Michael AF. Kidney Int. 1982 Mar;21(3):486-91.

n=20

ASD and Aluminum Toxicity

•seizures•myoclonus•hypotonia•motor development •autonomic/cholinergic dysfunction•mitochondrial dysfunction•oxidative stress•ADD/ADHD•iron deficiency and anemia•calcium homeostasis•bone metabolism/microcephaly•melatonin, seratonin and sleep disorders•neuropathology•immune dysfunction•systemic infections/ bacterial binding/immunity

A Random Case SurveyAluminum in Autism Spectrum Disorders

David Ayoub, MDAnju Usman, MD

October 10, 2007Fall DAN! Think Tank

n-38

76.3%

upper limits normal

mean 12.9 µg/g

Aluminum in Hair

• Iron: 10.5% above upper limits

• Manganese: 13.2% above upper limits

Urinary Provocative Challenge

IV Ca-EDTA

• n-34, profile with the highest metals recorded if multiple done

post IV Ca EDTAchallenge

measuring urinary metals

Aluminum in Urinerandom vs EDTA vs other agents*

n-4 n-10

410

18

0-210-31

177.0

n-4 n-10 n-34

13.9 10.0

mean

* DMSA, DMPS, glutathione

mean

97%

Urinary Porphyrins

•First 2 intermediates analyzed-Uroporphyrin III (UP)-66% elevated

-Hepatocarboxy porphyrin (7cxP)-50% elevated

•Levels expressed as ratio with “upper limits” value

Aluminum Aluminum

Toxic Metals in Red Cells of Children (ng/ml)

modified from Adams, 2006

unpublished data from Dr T. Audhya:

n-46 n-21

Numerous studies show glutathione depletion in autistics

Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, Neubrander JA. Am J Clin Nutr. 2004 Dec;80(6):1611-7.

Al(maltol)3

Maltate control

Maltate control

High cell death

Al(maltol)3

low glutathione

High cell death

oral Al chloride (100mg/kg)8 weeks

Brain weight

Control

al(Cl)3

adults

1.676 +/- 0.07

1.679 +/- 0.21

pups

1.742 +/- 0.007

1.4939 =/- 0.08

- 17.4%p <0.001

mercury-containing shots

aluminum-containing shots

Number of administered vaccines containing aluminum increased after

Thimerosal reduced (by 18 months age)

source: David Ayoub, MD, Prairie Collaborative, Inc

Treatment