Adverse Effects of Adjuvants in Vaccines by Viera Scheibner (Part 1)

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ADVERSE EFFECTS OF ADJUVANTS IN VACCINES by Viera Scheibner (Part 1)

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ADVERSE EFFECTS OF ADJUVANTS IN VACCINES

by Viera Scheibner, Ph.D. Ó 2000

Nexus Dec 2000 (Vol 8, No1) & Feb 2001 (Vol 8, Number 2)

ADJUVANTS, PRESERVATIVES AND TISSUE FIXATIVES IN VACCINES

Vaccines contain a number of substances which can

be divided into the following groups:

1. Micro-organisms, either bacteria or viruses,

thought to be causing certain infectious diseases

and which the vaccine is supposed to prevent.

These are whole-cell proteins or just the

broken-cell protein envelopes, and are called antigens.

2. Chemical substances which are supposed to

enhance the immune response to the vaccine, called adjuvants.

3. Chemical substances which act as preservatives

and tissue fixatives, which are supposed to halt

any further chemical reactions and putrefaction

(decomposition or multiplication) of the live or

attenuated (or killed) biological constituents of the vaccine.

All these constituents of vaccines are toxic, and

their toxicity may vary, as a rule, from one batch of vaccine to another.

In this article, the first of a two-part series,

we shall deal with adjuvants, their expects role

and the reactions (side effects).

ADJUVANTS

The desired immune response to vaccines is the

production of antibodies, and this is enhanced by

adding certain substances to the vaccines. These

are called adjuvants (from the Latin adjuvare, meaning " to help " ).

The chemical nature of adjuvants, their mode of

action and their reactions (side effect) are

highly variable. According to Gupta et al.

(1993), some of the side effects can be ascribed

to an unintentional stimulation of different

mechanisms of the immune system whereas others

may reflect general adverse pharmacological

reactions which are more less expected.

There are several types of adjuvants. Today the

most common adjuvants for human use are aluminium

hydroxide, aluminium phosphate and calcium

phosphate. However, there are a number of other

adjuvants based on oil emulsions, products from

bacteria (their synthetic derivatives as well as

liposomes) or gram-negative bacteria, endotoxins,

cholesterol, fatty acids, aliphatic amines,

paraffinic and vegetable oils. Recently,

monophosphoryl lipid A, ISCOMs with Quil-A, and

Syntex adjuvant formulations (SAFs) containing

the threonyl derivative or muramyl dipeptide have

been under consideration for use in human vaccines.

Chemically, the adjuvants are a highly

heterogenous group of compounds with only one

thing in common: their ability to enhance the

immune response—their adjuvanticity. They are

highly variable in terms of how they affect the

immune system and how serious their adverse

effects are due to the resultant hyperactivation of the immune system.

The mode of action of adjuvants was described by

Chedid (1985) as: the formation of a depot of

antigen at the site of inoculation, with slow

release; the presentation of antigen

immunocompetent cells; and the production of

various and different lymphokines (interleukins and tumour necrosis factor).

The choice of any of these adjuvants reflects a

compromise between a requirement for

adjuvanticity and an acceptable low level of adverse reactions.

The discovery of adjuvants dates back to 1925 and

1926, when Ramon (quoted by Gupta et al., 1993)

showed that the antitoxin response to tetanus and

diphtheria was increased by injection of these

vaccines, together with other compounds such as

agar, tapioca, lecithin, starch oil, saponin or even breadcrumbs.

The term adjuvant has been used for any material

that can increase the humoral or cellular immune

response. to an antigen. In the conventional

vaccines, adjuvants are used to elicit an early,

high and long-lasting immune response. The newly

developed purified subunit or synthetic vaccines

using biosynthetic, recombinant and other modern

technology are poor immunogens and require

adjuvants to evoke the immune response.

The use of adjuvants enables the use of less

antigen to achieve the desired immune response,

and this reduces vaccine production costs. With a

few exceptions, adjuvants are foreign to the body and cause adverse reactions.

Part 1 deals with the following types of adjuvants (after Gupta et al, 1993):

Oil emulsions

Freund’s emulsified oil adjuvants (complete and incomplete)

Arlacel A

Mineral oil

Emulsified peanut oil adjuvant (adjuvant 65)

Mineral compounds

Bacterial products

Bordetella pertussis

Corynebacterium granulosumderived P40 component

Lipopolysaccharide

Mycobacteriwn and its components

Cholera toxin

Liposomes

Immunostimulating complexes (ISCOMs)

Other adjuvants

Squalene

Oil Emulsions

In the 1960s, emulsified water-in-oil and

water-in-vegetable-oil adjuvant preparations used

experimentally showed special promise in

providing exalted " immunity " of long duration

(Hilleman, 1966). The development of Freund’s

adjuvants emerged from studies of tuberculosis.

Several researchers noticed that immunological

responses in animals to various antigens were

enhanced by introduction into the animal of

living Mycobacterium tuberculosis. In the

presence of Mycobacterium, the reaction obtained

was of the delayed type, transferrable with

leukocytes. Freund measured the effect of mineral

oil in causing delayed-type hypersensitivity to

killed mycobacteria. There was a remarkable

increase in complement-fixing antibody response

as well as in delayed hypersensitivity reaction.

Freund’s adjuvant consists of a water-in-oil

emulsion of aqueous antigen in paraffin (mineral)

oil of low specific gravity and low viscosity.

Drakeol 6VR and Arlacel A (mannide monooleate)

are commonly used as emulsifiers.

There are two Freund’s adjuvants: incomplete and

complete. The incomplete Freund’s adjuvant

consists of water-in-oil emulsion without added

mycobacteria; the complete Freund’s adjuvant

consists of the same components but with 5 mg of

dried, heat-killed Mycobacterium tuberculosis or butyricum added.

The mechanism of action of Freund’s adjuvants is

associated with the following three phenomena:

1. The establishment of a portion of the antigen

in a persistent form at the injection site,

enabling a gradual and continuous release of

antigen for stimulating the antibody;

2. The provision of a vehicle for transport of

emulsified antigen throughout the lymphatic

system to distant places, such as lymph nodes and

spleen, where new foci of antibody formation can be established; and,

3. Formation and accumulation of cells of the

mononuclear series which are appropriate to the

production of antibody at the local and distal sites.

The pathologic reaction to the Freund’s adjuvants

starts at the injection site with mild erythema

and swelling followed by tissue necrosis, intense

inflammation and the usual progression to the

formation of a granulomatous lesion. Scar and

abscess formation may occur. The reactions

observed following the administration of the

complete adjuvant are generally far more

extensive than with the incomplete adjuvant. The

earliest cellular response is polymorphonuclear,

then it changes into mononuclear and later

includes plasmocytes. The adjuvant emulsion may

be widely disseminated in varrious organs,

depending on the route of inoculation, with the

development of focal granulomatous lesions at

distal places. Various gram-negative organisms

may show a potentiating effect of the adjuvant,

similar to that displayed by mycobacteria.

The earliest use of oil emulsion adjuvants was

made with the influenza, vaccine by Friedwald

(1944) and by Henle and Henle (1945). Following

their promising results on animals, Salk (1951)

experimented with such adjuvants on soldiers

under the auspices of the US Armed Forces

Epidemiological Board. He used a highly refined

mineral oil, and developed a purified Arlacel A

emulsifier which was free of toxic substances,

such as oleic acid which had caused sterile

abscesses at the injection site, and he

administered the vaccine by intramuscular route.

Subsequently, et al. (1965) reported

their, failure to enhance the antibody and

protective response to types 3, 4 and 7

adenovirus vaccines in mineral oil adjuvant

compared with aqueous vaccine. Unpublished

studies have revealed the need for an adequate

minimal amount of antigen to trigger an antibody

response to the emulsified preparations.

Salk et al. (1953) applied Freund’s adjuvant to

poliomyelitis vaccine, and later followed with

extensive testing of killed crude as well as

purified polio virus vaccine in animals and

humans, where the reactions in humans were considered inconsequential.

Grayston et al. (1964) reported highly promising

results with the trachoma vaccine using an oil

adjuvant. However, the trachoma vaccine lost its

relevance because, as demonstrated by Dolin et

al. (1997) in their 37 years of research in a

sub-Saharan village, the dramatic fall in the

disease occurrence was closely connected with

improvements in sanitation, water supply,

education and access to health care. According to

Dolin et al. (1997), the decline in trachoma

occurred without any trachoma-specific intervention.

Allergens in Freund’s adjuvant deserve special

attention because they can be dangerous. These

dangers include an overdose, i.e., the immediate

release of more than the tolerated amount of

properly emulsified vaccine in sensitive persons,

or the breaking of the emulsion with the release

of all or part of the full content of the

allergen within a brief period of time. Long-term

delayed reactions include the development of

nodules, cysts or sterile abscesses requiring

surgical incision. It is also likely that some

allergens used, such as house dust or mould,

might have acted like mycobacteria to potentiate

the inflammatory response. Such reactions have

been reduced with the use of properly tested and standardised reagins.

One must also consider that the first application

of Freund’s adjuvants was made at a time when

modern concepts of safety were non-existent

Indeed, mineral oil adjuvants have not been

approved for human use in some countries, including the USA.

Mineral Compounds

Aluminium phosphate or aluminium hydroxide (alum)

are the mineral compounds most commonly used as

adjuvants in human vaccines. Calcium phosphate is

another adjuvant that is used in many vaccines.

Mineral salts of metals such as cerium nitrate,

zinc sulphate, colloidal iron hydroxide and

calcium chloride were observed to increase the

antigenicity of’ the toxoids, but alum gave the best results.

The use of alum was applied more than 70 years

ago by Glenny et al. (1926), who discovered that

a suspension of alum-precipitated diphtheria

toxoid had a much higher immunogenicity than the

fluid toxoid. Even though a number of reports

stated that alum-adjuvanted vaccines were no

better than plain vaccines (Aprile and Wardlaw,

1966), the use of alum as an adjuvant is now well

established. The most widely used is the antigen

solution mixed with pre-formed aluminium

hydroxide or aluminium phosohate under controlled

conditions. Such vaccines are now called

aluminium-adsorbed or aluminium-adjuvanted.

However, they are difficult to manufacture in a

physico-chemically reproducible way, which

results in a batch-to-batch variation of the same

vaccine. Also, the degree of antigen absorption

to the gels of aluminium phosphate and aluminium

hydroxide varies. To minimise the variation and

avoid the non-reproducibility, a specific

preparation of aluminium hydroxide (Alhydrogel)

was chosen as the standard in 1988 (Gupta et al., 1993).

The aluminium adjuvants allow the slow release of

antigen, prolonging the time for interaction

between antigen and antigen-presenting cells and

lymphocytes. However, in some studies, the

potency of adjuvanted pertussis vaccines was more

than that of the plain pertussis vaccines, while

in others no effect was noted. The serum

agglutinin titres, after vaccination with

adjuvanted pertussis vaccines, were higher than

those of the plain vaccines, with no difference

in regard to protection against the disease

( et al., 1962). Despite these conflicting

results, aluminium compounds are universally used

as adjuvants for the DPT

(diphtheriapertussis-tetanus) vaccine.

Hypersensitivity reactions following their

administration have been reported which could be

attributed to a number of factors, one of which

is the production of IgE along with IgG antibodies.

It was suggested that polymerased toxoids, such

as the so-called glutaraldehyde-detoxifled

purified tetanus and diphtheria toxins, should be

used instead of aluminium compounds. They are

used combined with glutaraldehyde-inactivated pertussis vaccine.

Calcium phosphate adjuvant has been used for

simultaneous vaccination with diphtheria,

pertussis, tetanus, polio, BCG, yellow fever,

measles and hepatitis B vaccines and with

allergen (Coursaget et al., 1986). The advantage

of this adjuvant has been seen to be that it is a

normal constituent of the body and is better

tolerated and absorbed than other adjuvants. It

entraps antigens very efficiently and allows slow

release of the antigen. Additionally, it elicits

high amounts of IgG-type antibodies an much less

of IgE-type (reaginic) antibodies.

Bacterial Products

Micro-organisms in bacterial infections and the

administration of vaccines containing whole

killed bacteria and some metabolic products and

components of various micro-organisms have been

known to elicit antibody response and act as

immunostimulants. The addition of such

micro-organisms and substances into vaccines

augments the immune response to other antigens in such vaccines.

The most commonly used micro-organisms, whole or

their parts, are Bordetella pertussis components,

Corenybacterium derived P40 component, cholera toxin and mycobacteria.

•B. pertussis components

The killed Bordetella pertussis has a strong

adjuvant effect on the diptheria and tetanus

toxoids in the DPT vaccines. However, there are a

number of admitted and well-describe reactions to

it, such as convulsion, infantile spasms,

epilepsy, sudden infant death syndrome (SIDS),

Reye syndrome, Guilain-Barre syndrome, transverse

myelitis and cerebral ataxia. Needless to say,

the causal link to it is often (even though not

always) vehemently disputed and generally considered " coincidental " .

Paradoxically, in one case of shaken baby

syndrome in which the baby developed subdural and

retinal haemorrhages from the disease whooping

cough, doctors accused the father of causing

these injuries and strenuously denied that the

disease pertussis can and does cause such

haemorrhages—forgetting that this is the very

reason why pertussis vaccine was developed

against such potentially devastating disease in

the first place. Such devastating effects are

caused by the pertussis toxin, the causative

agent of the disease (pertussis is a

toxin-mediated disease), employed as the active

ingredient in all pertussis vaccines whether

whole-cell or acellular (Pittman, 1984).

Gupta et al. (1993) concluded that PT is too

toxic to be administered to humans, but

chemically detoxified or genetically inactivated

PT may not exhibit the adjuvant effects comparable to the native PT.

•Corynebacterium-derived P40

P40 is a particulate fraction isolated from

Corynebacterium granulosum, composed of the cell

wall peptidoglycan associate with a glycoprotein.

In animals, it displays a number of activities

such as stimulation of the reticulo-endothelial

system, enhancement of phagocytosis and activation of macrophages.

P40 abolishes drug-induced immunosuppression and

increase non-specific resistance to bacterial,

viral, fungal and parasitic infections. It

induces the formation of IL-2, tumour necrosis

factor, and interferon alpha and gamma (Bizzini

et al., 1992). In clinical trials, P40 was

claimed to be efficacious in the treatment of

recurrent infections of the respiratory and

genito-urinary tracts. Allergens coupled to P40

have been said to be instrumental in

desensitising allergic patients without any side effects.

•Lipopolysaccharide (LPS)

LPS is an adjuvant for both humoral and

cell-mediated immunity. It augments the immune

response to both protein and polysaccharide

antigens. It is too toxic and pyrogenic, even in

minute doses, to be used as an adjuvant in humans.

•Mycobacterium and its components

Interestingly, Mycobacterium and its components,

as originally formulated, were too toxic to be

used as adjuvants in humans. However, the efforts

to detoxify them resulted in the development of

N-acetyl muramyl-L-alanyl-D-isoglutamine, or

muramyl dipeptide (MDP). When given without

antigen, it increased nonspecific resistance

against infections with bacteria, fungi,

parasites, viruses, and even against certain

tumours (McLaughlin et al., 1980). However, MDPs

are potent pyrogens (maybe that’s why they may be

effective against certain tumours—my comment) and

their action is not completely understood; hence

they are not acceptable for use in humans.

•Cholera Toxin

A major drawback with cholera toxin as a mucosal

adjuvant is its intrinsic toxicity.

Liposomes

Liposomes are particles made up of concentric

lipid membranes containing phospholipids and

other lipids in a bilayer configuration separated

by aqueous compartments. They have been used

parenterally in people as carriers of

biologically active substances (Gregoriadis, 1976) and considered safe.

Immunostimulating complexes (ISCOMs)

ISCOMs (DeVries et al., 1988; Morein et al.,

199 & , Lovgren : al., 1991) represent an

interesting approach to stimulation of the

humoral and cell-mediated immune response towards

amphipathic antigens. It is a relatively stable

but non-covalently-bound complex of saponin

adjuvant Quil-A, cholesterol and amphipathic

antigen in a molar ratio of approximately 1:1:1.

The spectrum of viral capsid antigens and

non-viral amphipathic antigens of relevance for

human vaccination, incorporated into ISCOMs,

comprises influenza, measles, rabies, gp340 from

EB-virus, gp120 from HIV, Plasmodium falciparum and Trypanosoma cruzi.

ISCOMs have been shown to induce cytotoxic

T-lymphocyte (CTL). Following oral

administration, some types of CTLs were found in

mesenteric lymph nodes and in the spleen, and

specific IgA response could be induced.

ISCOMs have only been used in veterinary

vaccines, partly due to their haemolytic activity

and some local reactions all reflecting the

detergent activity of the Quil-A molecule.

CONTINUED IN PART 2

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Sheri Nakken, former R.N., MA, Hahnemannian Homeopath

Vaccination Information & Choice Network, Nevada City CA & Wales UK

Vaccines - http://www.wellwithin1.com/vaccine.htm

Vaccine Dangers & Homeopathy Online/email courses