Presentation to the CSACI Meeting  in Toronto on September 9, 2000

What Are The Relevant Antigens?

In choosing the components for a clinically relevant allergen extract, one must  be acquainted with the local and regional aerobiology with respect to pollens, moulds and indoor allergens. Additionally there may be specific allergens in the patient’s own environment which may be important. The allergist must be aware, through the patient’s history and skin testing record, of the total allergenic load facing the patient. Since a patient may travel, there may be allergens other than in the patient’s home locale that may be important, depending on the length of stay and the degree of exposure possible. That is to say, the omission of any clinically relevant allergens from the therapeutic vaccine may not allow the patient to receive maximum benefit. Equally important is that the inclusion of allergens merely because of a positive skin test without a history of sensitivity to that antigen could dilute the required antigens leading to poor therapeutic efficacy. The potency and stability of the extracts to be used is of great importance. To a certain extent, the use of standardized antigens will help to assure that a single batch will be consistent from vial to vial as long as the manufacturer is the same, but this does not necessarily apply from one manufacturer to another.

The most commonly used components in a therapeutic vaccine are the pollens of trees, grasses, ragweed, and in some cases other weeds. Moulds may be found indoors and outdoors and may be specific to a patient’s environment, but it is often difficult to establish a link between their presence and the occurrence of a patient’s symptoms. Therefore, the selection of moulds, many of which have not proven to cause allergy symptoms, is often difficult. Dust mites are found virtually all over the world and the Toronto area has one of the highest levels in North America. House Dust is not specific and contains innumerable and indefinable antigens. Many do not treat for cat and dog because they can be avoided but there are cases where this is not possible, such as split families, animal care workers, or families that continue to refuse to give up the pets. Other animals represent individualized cases and there is no good documentation as to efficacy. Hymenoptera venoms have been shown to be highly effective. Bacterial vaccine is a thing of the past and should not be used as there is no evidence of efficacy.

Compatibility of mixed antigens is not always present. Cockroach and mite extracts contain digestive enzymes while moulds and insects contain proteases which can denature other antigens. In addition to cockroach enzymes, among the moulds, alternaria, cladosporium, aspergillus, helminthosporium and penicillium are known to have protease activity that can interfere with the potency of other antigens in a mixture. Mites do not seem to have this activity as one would have thought, but this may have been due to glycerine in the diluent. There is no proteolytic activity in pollens or animal danders and this may render them susceptible to denaturation. Interestingly, moulds and cockroach can be mixed. Pollens and danders, however, should not be mixed with cockroach or moulds.

Cross reactivity among trees is somewhat selective:

•Cypress family (cypress, cedar, juniper,arbor vitae) strongly cross react.

•Birch family (birch, alder, hazelnut,hornbeam) cross-react

•Beech family (beech,oak) strongly cross-react

•Walnut, pecan, hickory have strong similarities

•Olive, ash, privet; olive and Russian olive cross react

•Populus family (poplar, aspen, cottonwood) cross react

•Other trees have great diversity

This probably means that we should take a close look at the trees which pollinate in our area, check those that cross react, and treat for those which are significant and do not cross react along with one of the members of any of the cross reacting groups.

 

Grass cross reactivities

•Two groups – Northern pasture (timothy, Kentucky bluegrass, June, Red top, etc.) & Bermuda

•Bahia and Johnson grasses share allergens with northern pasture grasses

•Bermuda cross reacts with native prairie grasses

•Immunotherapy with timothy and Bermuda alone covered 10 different grasses in all 3 classes in one study and this probably means that we do not have to use multi- grass mixtures

  Weed cross reactivities:

  •4 major ragweeds (short, giant, western, false - not southern and slender ragweed),cocklebur and burweed strongly cross react

•Sages, wormwood, and mugwort strongly cross react

•Chenopods (Lamb’s quarters, Russian thistle, kochia) and Amaranths (Pigweed, Palmer’s amaranth, western water hemp) varying degrees of cross reactivity

•Russian thistle has some unique antigens

There are two major MITE groups Der p1/Der f1 (digestive) and Der p2/Der f2 (somatic). There is a high degree of cross reactivity  between the two major species of dermatophagoides (farinae and pteronynissinus).

ANIMAL DANDERS are generally effective.Cat has been shown to be effective even in homes without cats, so this type of immunotherapy is not just for occupational use. One should, however, be aware that  cat immunotherapy may increase asthma.

  Grasses, ragweed, and house dust mite in adequate doses are effective for rhinitis and asthma treatment.

  The major CAT allergen Fel d1 found in all breeds of cat; the major DOG allergens

Can f1 and Can f2 and albumin are responsible for significant cross reactivity between dog species.

  COCKROACH is important in inner city asthma but there is poor information on its immunotherapy efficacy. There is only partial cross reactivity between different cockroaches’ allergens, therefore, one should immunize with all of the significant representatives.

  There are many different species of MOULDS, however, the exposure pattern information is lacking Many are hard to grow and their extracts are, therefore, of variable quality. Some studies do show efficacy for cladosporium, alternaria & aspergillus.

  The North American potency of standardized extracts is defined in bioequivalent allergy units (BAU)

A large number of sensitive subjects are skin tested to the antigen to be standardized and the designation of 100,000 BAU is given to an extract which gives a 2.5 cm. average erythema  when diluted 1:5 million. !0,000 BAU is a 10 fold dilution of this. For safety extracts are used at a 10,000 BAU concentrate. A Safe I.D. test can be done using  0.01 BAU/ml.  Short ragweed has rarely induced a systemic reaction below 1000 – 2000 BAU/ml. Efficacy can be obtained in highly sensitive individuals at doses as low as 100 BAU.Maximum tolerated peak doses are usually 1000 – 4000 BAU

One can determine an unstandardized extract’s potency compared to a  standardized one through side by side skin testing – a similar dose induces a  similar response. If a standardized extract is part of an equally proportioned mixture, the final standardized concentration is the BAU rate of the standardized portion divided by the number of portions. The unstandardized portions are each listed as their original designation divided by the number of ingredients

European extracts are standardized by the content of major allergens in mass units (ug)

The amino acid sequences of approximately 140 antigens are known. Studies have shown that the dose to be aimed at for the antigens listed  are:

Cat – 11-17 ug Fel d1 (13.8, 1.3, 17.3,15 ug in various studies)

Grass –18.6 ug Phl pV (15-18.6 in two studies )

Short Ragweed – 11-24.8 ug Amb a11 (1.0, 12.4, 6, 24.8 ug  in several studies)

Mites –7.0 ug Der p1 (11.9, 7.0, 7.0 ug in several studies)

 

•Our membership survey showed that 17.5% of us mix 5 or more antigens in a mixture, while 4 antigens are the maximum for most. A minimum  number of  us of  use one or two antigens. Dust mite and pollen are rarely mixed except in pediatric use. This raises the question “Should we be keeping antigens separate in view of proteases, dilution factors, and reaction prevention?”

  A second question to be considered is “Are moulds of any use given their difficulty in production, generally unproven efficacy with three exceptions, and possible toxicity?”

  The third question is “ For weeds other than ragweed, do they actually work?”

  Another question is “In switching patients from unstandardized extracts to the newer standardized ones, should we just be cutting back or starting the patients all over again on a new schedule from the very beginning?”

  Lastly, “Will this changeover differ with mixed extracts as opposed to single antigens?”

  These are some of the questions that we will have to discuss and answer. Thank you for your attention.

 

Ronald B. Filderman, M.D., M.Sc., FRCPC