Acne vaccines..

[Guest guest]

Hmm.. It gives no details on whether a 'vaccine' would be a

'traditional' vaccine (bug+aluminum), or some sort of immuno-

modulatory treatment.

My feeling is that the human neuro-endo-immune system can normally

deal with with the a. vulgaris bacterium just fine, and that acne

results from a lack of tolerance development to a more-or-less

indiginous bacterium that the immune system should just leave alone.

Thus acne would be a hyper-immune response something akin to asthma

or allergies.

Thus something disrupting the tolerance-induction process might

underlie it. Over-vaccination skewing the immune system? Mess-ups

in the endocrine influences on the immune system? Loss of tolerance

is seen in diabetes 1 and other acknowledged vaccine reactions..

The other big question is how much of acne is created by mal-micro-

nutrition - retinoic acid is used as a treatment, which is a form of

vitamin A. Hmm.. Perhaps kids aren't getting enough vitamin A to

begin with?

Jim

--

Acne Vaccines: Therapeutic Option for the Treatment of Acne Vulgaris?

Kim

J Invest Dermatol 2008 128: 2353-2354; 10.1038/jid.2008.221

Acne, one of the most common skin diseases, is caused by multiple

factors, including Propionibacterium acnes. Studies suggest that

responses to P. acnes by host immunity play important roles in its

pathogenesis. Identifying immune modulators that attenuate

inflammatory responses against P. acnes and the inhibition of

bacterial growth may lead to novel avenues of immunologic intervention.

Acne vulgaris is one of the most common skin diseases, affecting

approximately 50 million people in the United States. The disease is

important because it has significant morbidity and profoundly affects

patients' self-esteem. Although acne is common, its pathogenesis is

still uncertain. Multiple etiological factors, including follicular

hyperkeratinization, sebum, Propionibacterium acnes, and

inflammation, are thought to contribute. Perhaps it is the

multifactorial etiology of acne that makes it challenging to treat.

There is a high unmet clinical need for new and better treatments,

given the increase in antibiotic-resistant strains of P. acnes and

the restrictions placed on the use of isotretinoin. In this issue,

Nakatsuji et al. (2008b) describe an alternative strategy to

conventional therapy: a P. acnes vaccine that exerts protective

immunity.

Although P. acnes is present in normal skin, its importance in acne

pathogenesis has been well demonstrated because a reduction in

bacterial count with antibiotic therapy improves the clinical

outcome. What is less clear, however, is whether P. acnes is a true

pathogen or whether unwanted host immune responses to this commensal

microbe determine the disease outcome, because the number of bacteria

present in lesions does not always correlate with disease severity

(Leyden et al., 1988). Several previous studies have demonstrated

that both cellular and humoral immunity against P. acnes are present

in patients, and recent studies have provided a better understanding

of the innate immune response produced by hosts in response to P.

acnes. Upon activation, host innate cells elaborate a protective

antimicrobial response to P. acnes by inducing the production of

antimicrobial peptides such as human

-defensin 2 (Nagy et al., 2005, 2006). On the other hand, the same

mechanism may be responsible for producing inflammatory mediators by

innate cells such as keratinocytes, monocytes, and sebocytes in

response to P. acnes (Kim et al., 2002; Nagy et al., 2005, 2006),

causing tissue injury and inflammatory disease. The balance between

these innate responses, in addition to adaptive immune responses

elicited by P. acnes likely determines whether the host will present

with clinically active lesions.

Many of the current therapies focus on reducing the number of P.

acnes organisms, and most recent developments have been in the use of

combination therapies. Benzoyl peroxide and the retinoids have been

added to topical antibiotics with the hope that the frequency of

resistance will decrease, thereby improving the therapeutic outcome.

On the other hand, only a few therapies focus primarily on reducing

inflammation. The use of lower doses of antibiotics for their anti-

inflammatory properties is currently being evaluated. In addition,

recent studies suggest that in addition to its well-known effect on

" normalizing " the follicular epithelium, retinoic acid demonstrates

anti-inflammatory and antimicrobial effects (Liu et al., 2005, 2008),

underscoring the need to investigate further the immunomodulatory

effects of acne therapies. Despite substantial interest in basic acne

research, acne vaccines that modulate host immune responses to P.

acnes are not available.

In the study reported in this issue, Nakatsuji et al. (2008b)

generated antibodies using inactivated P. acnes, postulating that

they might provide protective immunity. The authors demonstrated that

intranasal immunization of mice with this inactivated vaccine

generated in vivo protective immunity against P. acnes challenge.

Specifically, the antibodies elicited by inactivated P. acnes

attenuated IL-8 production in human sebocytes; however, there was no

effect on P. acnes growth. The clinical improvement observed in this

P. acnes inflammatory murine model suggests that for acne treatment,

antibodies that primarily exhibit anti-inflammatory properties might

be sufficient for clinical improvement but without an antimicrobial

effect.

Immunization with P. acnes holds promise for acne therapy.

The inactivated P. acnes vaccine used in this study targeted the

whole bacterium, most likely without specificity. Therefore,

developing vaccines against specific P. acnes antigens might be even

more useful, as previously demonstrated by the same research group

(Nakatsuji et al., 2008a). This would require that P. acnes antigens

first be identified and then characterized for the types of response

that each antigen elicits; this information could then be used to

develop a component acne vaccine. Very few P. acnes antigens have

been identified and studied.

It will be important to evaluate the antibodies generated against P.

acnes for other immunomodulatory effects, including their ability to

induce proinflammatory mediators and cytotoxicity, which might lead

to tissue injury. It has been shown that some patients have

antibodies against P. acnes, and positive correlations between

antibody titers and the severity of the disease have been reported

(Webster et al., 1985; Ingham et al., 1987; Ashbee et al., 1997).

Thus, not all antibodies directed against P. acnes may be beneficial,

and they may even worsen the disease.

Part of the difficulty in developing any acne therapy is that there

is no perfect animal model. Although the mouse model used by

Nakatsuji et al. (2008b) demonstrated a decrease in ear swelling in

vaccinated mice, the lesions produced by injection of P. acnes into

the ears of mice do not reproduce clinical acne lesions exactly. For

this reason, it is not certain that similar clinical improvement will

occur in humans, in whom other varying factors, such as the presence

of inflammatory lipids in sebum, may influence the growth and

behavior of P. acnes. Nonetheless, the authors of this study offer an

important and interesting concept—that focusing on attenuating the

inflammatory component of the disease could be therapeutically

beneficial. Because the induction of cytokines, chemokines, and

metalloproteinases by P. acnes occurs via a Toll-like receptor 2

(TLR2)-dependent pathway, the development of vaccines or other immune

therapies that target TLR2 and other TLRs may provide other

alternatives to conventional therapy. We are already familiar with

agents that modulate TLR response, such as imiquimod, which enhances

TLR7 and TLR8 function, and retinoic acid, which downregulates TLR2

expression and function, suggesting that vaccines with potent anti-

TLR immunity may hold promise for the future of acne therapy.

Conflict of Interest:

The author serves as a consultant and is on a scientific advisory

board for Galderma, Medicis, Sanofi-Aventis and Stiefel.