6

Allergen-Specific Immunotherapy
Helen E. Smith, Aziz Sheikh, and Robyn E. O’Hehir

CHAPTER OUTLINE
Summary of Important Concepts, 111 Adverse Reactions to SIT, 117
Introduction, 111 SIT in Pregnancy, 117
Historical Perspective, 112 Adherence to SIT, 117
Indications for Specific Allergen Immunotherapy, 112 Sublingual Immunotherapy, 117
Clinical Efficacy With Specific Allergens, 113 Mechanisms of SLIT, 117
Grass, Tree, and Weed Pollens, 113 Side Effects of SLIT, 119
House-Dust Mites, 113 Efficacy of SLIT, 119
Domestic Pets, 113 SLIT for Asthma, 119
Fungi, 113 Durability of Treatment, 119
Cockroach, 113 Effects of SLIT on the Natural History of
Multiple Allergen Mixtures, 113 Allergic Disease, 119
Specificity of Allergen Immunotherapy, 113 Safety and Cost-Effectiveness of SLIT, 120
Evidence of Disease Modification, 114 Modified Allergen Extracts and Adjuvants (Box 6.6), 120
Persistence of Clinical Improvement After Recombinant Allergen Vaccines, 121
Cessation of Immunotherapy, 114 Unmodified Allergens, 121
Pharmacoeconomics of SIT, 114 Modified Allergens, 121
Immunologic Response to Inhalant SIT, 114 The Future of SLIT, 121
Overview of the Immune Response to Immunotherapy, 115 Conclusions, 121
Indications for SIT, 116 References, 121
Injection Schedules, 116 Suggested Reading, 122

of allergen extracts and alternative routes of administration,

SUMMARY OF IMPORTANT CONCEPTS
with sublingual SIT (SLIT) being very popular and effective.
• Allergen immunotherapy is an effective treatment both for
allergic rhinitis and for allergic asthma.
• Sustained clinical effectiveness requires several years of
INTRODUCTION
treatment. Allergic rhinitis is common and, in many cases, not adequately
• Initially, specific immunotherapy (SIT) induces allergen- controlled by standard drug therapy. Specific immunotherapy
specific regulatory T cells that decrease T cell responses to (SIT) offers a way to desensitize patients, rendering them less
allergens. Over time, there is immune deviation from a pre- sensitive to inhalation of seasonal or perennial allergens. This
dominantly Th2 to a predominantly Th1 pattern of cytokine decreases their symptoms and improves quality of life, as well
production. as decreases the need to use disease-suppressing medication
• Immunotherapy modifies the course of allergic disease, as such as nonsedating antihistamines and nasal corticosteroids.
evidenced by decreases in rates of new allergic sensitiza- SIT also helps in selected patients with allergic asthma, who
tions, and prevention of progression from allergic rhinitis to are especially affected by allergic triggers. SIT provides long-
asthma. lasting benefits, beyond the period of treatment, but SIT must
• A minimum of 3 years of SIT will result in persistent benefit be administered over several years to achieve maximal efficacy.
for several years after discontinuation. Traditional SIT involves a course of injections, typically start-
• Several approaches have been tried to improve the safety and ing with a build-up or initiation phase of 7 to 12 weekly injec-
convenience of SIT. These include chemical modifications tions followed by monthly maintenance injections for 3 years.

111
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112 Allergy Essentials

Research has explored modified vaccines to improve efficacy but effects on lung function have been inconsistent. However,
with shorter courses and to minimize the risk of adverse effects. some carefully conducted studies of seasonal and/or perennial
Alternative routes of administration have become popular, with asthma have yielded only limited evidence of clinical improve-
sublingual immunotherapy (SLIT) showing broadly compara- ment in patients with asthma. The critical issue is to be sure that
ble efficacy to subcutaneous injection SIT (SCIT). the chosen allergen is responsible for causing symptoms in the

HISTORICAL PERSPECTIVE SMD

Study (95% CI)
Interest in the use of vaccination to treat allergy dates back to
Mite immunotherapy
the late 19th century.1 It was well recognized that hay fever was Armentia Medina et ala
a reaction against grass pollen, and that it involved immune Torres Costa et alb
recognition of pollen components, so, although the exact Machiels et alc
mechanisms were unknown, different researchers attempted to Pichler et ald
Franco et ale
immunize patients with pollen extracts. When early attempts Subtotal (95% CI)
invoked anaphylaxis, incremental regimens were tried, start- Chi-square 16.30 (df = 4) Z = 2.09
ing with a very low dose, and increasing gradually until a large Pollen immunotherapy
dose could be administered safely. In 1911, Noon and Freeman Ortolani et alf
Bousquet et alg
published the first paper on successful injection immunother- Reid et alh
apy. Over the next decade, the practice of injection therapy for Kuna et ali
hay fever was widely adopted, especially in the US. The scope Bousquet et alj
of immunotherapy was extended to treat perennial rhinitis and Dolz et alk
Creticos et all
asthma, covering additional pollens and perennial allergens Bousquet et alm
such as house-dust mites (HDMs) and animal danders. SIT was Machielsn
one of the first treatments to be subjected to randomized con- Bruce et alo
Hill et alp
trolled trials, with trials beginning in the 1950s. Subtotal (95% CI)
For over 100 years, immunotherapy has been given by the Chi-square 33.63 (df = 10) Z = 3.40
same method developed by Noon, with injections at weekly Other immunotherapy
intervals of progressively greater concentrations of extract, fol- Alvarez-Cuesta et al.q
lowed by a period of several years of maintenance injections. Varney et alr
Valovirta et als
However, in the past 25 years, there has been increasing inter- Adkinson et alt
est in administering immunotherapy by other routes, espe- Subtotal (95% CI)
cially sublingual/oral, which is intended to decrease the risk of Chi-square 30.12 (df = 3) Z = 1.4
adverse reactions and increase patient convenience. Other areas Total (95% CI)
of research have focused on vaccine modifications so that opti- Chi-square 86.23 (df = 19) Z = 4.22
mum desensitization can be achieved with fewer injections.
–4 –2 0 2 4
Favors immunotherapy Favors placebo
Fig. 6.1 Odds ratios (standardized mean difference, SMD) and
INDICATIONS FOR SPECIFIC ALLERGEN 95% confidence intervals (CIs) for clinical improvement, as evi-
IMMUNOTHERAPY denced by reduction in asthmatic symptoms after allergen immu-
notherapy in placebo-controlled studies. df, Degrees of freedom.
SIT has three main indications: allergic rhinoconjunctivitis,
Modified from Abramson M, Puy R, Weiner J. Immunotherapy
allergic asthma, and anaphylaxis due to allergy to wasp and bee in asthma: an updated systematic review. Allergy 1999;54:1022–
venom (Box 6.1 and see Chapter 15 Insect Allergy). The efficacy 1041. Referenced studies: a, Armentia Medina et al. Allergo
of SIT in seasonal and perennial allergic rhinitis has been estab- Immunopathol (Madr) 1995;23:211; b, Torres Costa et al. Allergy
lished in many well-designed clinical trials.2 1996;51:238; c, Machiels et al. J Clin Invest 1990;85:1024;
SIT is also effective as an adjunct therapy in asthma, although d, Pichler et al. Allergy 1997;52:274; e, Franco et al. Allergo
its role in treating asthma is less important than in treating aller- Immunopathol (Madr) 1995;23:58; f, Ortolani et al. J Allergy Clin
gic rhinitis. In placebo-controlled studies, SIT has been shown Immunol 1984;73:283; g, Bousquet et al. J Allergy Clin Immunol
to be effective in carefully selected patients with asthma caused 1990;85:490; h, Reid et al. J Allergy Clin Immunol 1986;78:590;
by grass pollen, cats, and HDM (Fig. 6.1). The effect is most i, Kuna et al. J Allergy Clin Immunol 1989;83:816; j, Bousquet
marked on allergen-specific bronchial hyperresponsiveness, et al. J Allergy Clin Immunol 1989;84:546; k, Dolz et al. Allergy
1996;51:489; l, Creticos et al. N Engl J Med 1996;334:501; m,
Bousquet et al. Clin Allergy 1985;25:179; n, Machiels et al. Clin
BOX 6.1 Indications for SIT Exp Allergy 1990;20:653; o, Bruce et al. J Allergy Clin Immunol
• Allergic rhinitis 1977;59:449; p, Hill et al. BMJ 1982;284:306; q, Alvarez-Cuesta
• Allergic asthma (if well controlled) et al. J Allergy Clin Immunol 1994;93:556; r, Varney et al. Clin Exp
• Hymenoptera sensitivity Allergy 1997;27:860; s, Valovirta et al. Ann Allergy 1986;57:173;
t, Adkinson et al. N Engl J Med 1997;336:324.

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 CHAPTER 6 Allergen-Specific Immunotherapy 113

individual patient, and that other contributory treatable traits allergy was only considered appropriate for people with occu-
have already been addressed. Unstable asthma is a risk factor for pational exposure (e.g., veterinarians and social workers).
adverse reactions to SIT, so patients must be carefully selected Clinical trials have shown decreases in asthma symptoms and
and optimally managed, and the right allergens must be chosen medication usage, as well as improvements in nonspecific bron-
if immunotherapy is to be of benefit for asthma.3 chial hyperresponsiveness in cat-allergic patients who do not
Systemic reactions to hymenoptera venom are relatively have cats at home, supporting the use of cat immunotherapy.
rare but can be fatal. If there are no contraindications, SIT is Currently, there are no corresponding data for dog allergy.
the treatment of choice for this group of patients. The decision
to treat is based on exposure risk and likely benefit, so these Fungi
patients require specialist assessment and careful consideration Airborne fungal spores are recognized causes of life-threat-
of the risk-to-benefit ratio (see Chapter 15 Insect Allergy). ening asthma attacks and “epidemic outbreaks” of asthma.
Unfortunately, there is little accurate information on exposure
patterns to most fungal species, and as there are thousands of
CLINICAL EFFICACY WITH SPECIFIC different species of fungi, it is hard to establish which fungi are
ALLERGENS relevant to an individual’s allergic disease. Diagnosis is made
even more difficult because fungal extracts are of variable qual-
Grass, Tree, and Weed Pollens ity, and there are no allergen extracts available for many gen-
Patients with seasonal allergic rhinitis are typically sensitized to era of fungi because it is impossible to grow them in artificial
grass pollen, tree pollens, or ragweed. The specific trigger is usu- media. Some benefits on asthma and allergic rhinitis symptoms
ally clear from the history and can be confirmed by detection of have been reported in double-blind, controlled studies of SIT
serum-specific IgE by skin testing or laboratory testing (sometimes with extracts of Cladosporium herbarum and Alternaria alter-
colloquially called “RAST” testing from radio allergosorbent test- nata. With fungi, as with any allergen, the decision to use SIT
ing, now superceded by immunoassays). Patients with multiple is guided by the patient’s sensitization, a pattern of symptoms
allergies can also benefit from pollen SIT, but the impact is most consistent with the pattern of exposure, and the availability of
evident in those with a narrow range of sensitivities.2 Typically, an extract of sufficient standardization to allow delivery of a
treatment is given pre-seasonally for 3 years, but sometimes SIT therapeutically effective and safe dose. Currently, fungi SIT is
is given all year round, again for a total of 3 years. Improvement seldom prescribed in clinical practice.
can be expected in about 80% of patients if appropriately selected.
For these patients, their symptoms may be decreased rather than Cockroach
completely abolished, with a marked decrease in the number of Cockroach sensitization is now recognized as a major factor in
days with severe symptoms and less need for rescue medications the pathogenesis of asthma, particularly in those living in inner
(e.g., antihistamines) compared with untreated or placebo-treated cities, especially in warmer climates, but there have been no
controls. Patients who also have pollen-induced seasonal asthma adequately controlled trials of cockroach SIT.
will usually notice an improvement in their chest symptoms, as
well as in their nasal symptoms. Multiple Allergen Mixtures
Most of the double-blind, placebo-controlled studies that
House-Dust Mites have confirmed the effectiveness of SIT in allergic rhinitis and
HDM sensitization is common and has been implicated as a risk asthma were performed with single allergen extracts. However,
factor for developing asthma. However, unlike pollen allergy, it in the US, a typical immunotherapy prescription often contains
can be difficult to determine how much of a patient’s rhinitis multiple unrelated allergen extracts. Although current US guid-
symptoms are attributable to HDM. This is partly because expo- ance supports the use of allergen mixtures, it is recommended
sure to HDM allergens occurs all year round and partly because that patients should only be treated with relevant allergens. The
many patients with rhinitis also have symptoms due to struc- inclusion of too many allergens into a maintenance injection
tural changes and sinusitis that are independent of their HDM may decrease the overall effectiveness of the treatment.4 The
allergy and therefore will not respond to mite-specific treat- evidence supporting treatment with multiple allergens comes
ment. Nevertheless, SIT with HDM extracts may be effective in mainly from trials using mixtures of two allergens; very few
controlling symptoms of perennial allergic rhinitis. Most clini- studies have examined multi-allergen SIT mixes, and what evi-
cians would agree that if there is no benefit after 6 months, con- dence there is comes from studies performed over 40 years ago,
tinuing SIT is unlikely to achieve any benefits. In some cases, with different mixtures from today. However, clinical experience
an alternative allergen extract may be tried, but more often it is suggests that SIT with multiple allergen mixes can be effective if
necessary to discontinue SIT and revert to standard pharmaco- the number of allergens used does not dilute out the individual
logic treatment. constituents to ineffective concentrations.

Domestic Pets
Sensitization to domestic pet allergens is associated with an
SPECIFICITY OF ALLERGEN IMMUNOTHERAPY
increased risk of developing asthma. In theory, domestic pet SIT is most effective where there is a limited range of allergic sen-
allergen exposure is avoidable and, historically, SIT for pet sitivities and where there is clear evidence that those allergens

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114 Allergy Essentials

are responsible for triggering symptoms. Clinical improvement 35

Symptom and medication score
is generally only seen in the response to allergens contained

Symptom and medication score

within the treatment mixture. However, as some allergens have 30

overlapping proteins, for example, grasses, treatment with pol- 25

len from one grass species can decrease responses to pollens P <0.03*
20
from other grasses, but treating with grass pollen has no effect SIT 1989–91 No SIT
on sensitivity to ragweed, and vice versa. 15
Clarity about which allergens are triggering symptoms is
10
easier to establish for seasonal pollen allergens and for occu-
pational exposure to domestic animals; it is more difficult to 5
be sure that perennial allergens or people’s own pets are truly
0
responsible for ongoing symptoms. Where there is doubt about 1 2 3 4 5 6 7 8 9 10 11 12 13 14
the role of allergens in causing symptoms or a large number of
Week
allergens are implicated, optimizing dose and compliance with
Fig. 6.2 Persistence of the effect of specific immunotherapy
nonsedating antihistamines and nasal corticosteroids may be
(SIT) 12 years after completing therapy. The graph shows symp-
preferable to SIT. toms’ scores during the pollen season in patients treated in
childhood 12 years earlier (blue circles) compared with matched
EVIDENCE OF DISEASE MODIFICATION control group (red squares). From Eng PA, et al. Three-year follow-
up after discontinuation of pre-seasonal grass pollen immuno-
Part of the argument in favor of SIT is that it may have long- therapy in childhood. Allergy 2006;61:198–201.
term benefits by modifying the course of the disease, whereas
drug therapies only suppress the symptoms for as long as they including conjunctival and skin sensitivity to grass pollen.
are taken (Box 6.2). Two outcomes are cited as evidence of The longest follow-up data have been reported in a 12-year
disease modification—the prevention of emergent asthma in open study of grass immunotherapy in children, in which the
patients treated for allergic rhinitis and the prevention of new treated children continued to have decreased symptom and
allergic sensitizations. A multicenter European study found medication scores during the grass season and fewer new sen-
that SIT with birch and/or Timothy grass for 3 years decreased sitizations compared with untreated controls (Fig. 6.2). Similar
the risk of developing asthma by 2.5-fold in children who only persistence of the effect was reported after immunotherapy
had symptoms of rhinitis at the initiation of SIT.5 This benefit with HDM extract. Over a 3-year period after discontinuation,
was still apparent 7 years after completing SIT. Several studies approximately half experienced a relapse in symptoms, but half
have reported decreased rates of development of new sensiti- remained symptom-free.
zations after SIT, as indicated by newly positive skin-prick test
results. In the two larger studies, the rate of new sensitization
was decreased by 56%–65% compared with the control group,
PHARMACOECONOMICS OF SIT
and this effect persisted for 3 years after completion of 3 to 4 The fact that the benefits of SIT extend far beyond the period of
years of treatment with SIT. It seems unlikely that SIT with one treatment is a key element of the economic argument for SIT.
allergen directly affects B cells that recognize unrelated aller- The possible cost benefits of SIT in children with newly diag-
gens. However, SIT might decrease nasal inflammation and nosed allergic rhinitis have been assessed. Highly significant
thereby alter the local environment, decreasing the likelihood reductions were achieved in pharmacy claims, outpatient vis-
that exposure to other allergens would lead to sensitization. its, and hospital admissions after SIT, compared with data for
Overall, although there is a promising line of enquiry, there is a similar children not receiving SIT. The total medical costs were
need for more evidence from high-quality clinical trials before reduced by 25%, even when the cost of the immunotherapy was
SIT can be recommended to prevent clinical allergy.6,7 included. Another study compared 2771 children with newly
diagnosed allergic rhinitis who received SIT and 11,010 who
did not. Healthcare utilization for the 18 months after starting
Persistence of Clinical Improvement After SIT was US$3247 (including the cost of SIT) compared with
Cessation of Immunotherapy US$4872 in the control group.
Both open and blinded studies have indicated a slow recurrence
of grass pollen symptoms after completing 3 or 4 years of SIT.
This recurrence reached 31% by the third year after treatment,
IMMUNOLOGIC RESPONSE TO INHALANT SIT
but with no appreciable increase thereafter. The persistence Much effort has focused on dissecting the mechanisms of suc-
of benefit is supported by subjective and objective measures, cessful immunotherapy, partly to try to improve the efficacy
and safety of SIT, and partly to try to find markers of treatment
failure so that ineffective courses can be stopped early. Box 6.3
BOX 6.2 Evidence of Disease Modification
summarizes current understanding of the immunologic changes
• Prevention of asthma
associated with successful injection immunotherapy for inhalant
• Prevention of new allergic sensitizations
allergies.

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 CHAPTER 6 Allergen-Specific Immunotherapy 115

BOX 6.3 The Immunologic Response to Immunotherapy

End-Organ Response Lymphocytes and Peripheral Blood Mononuclear Cells
Decreased Early and Late Responses to Specific Allergen • Decreased serum IL-2R
• Conjunctiva • Decreased lymphocyte proliferation
• Skin: early; late • Generation of specific suppressor cells
• Nose • Regulatory T lymphocytes
• Bronchi: early; late • Increased expression of Foxp3
• Secreting IL-10
Decreased Nonspecific Reaction to Bronchial Challenge • Secreting TGF-β
• Histamine
• Methacholine Evidence of Immune Deviation
• Decreased stimulated release of Th2 cytokines
Decreased Tissue Inflammation • IL-4
• Eosinophils • IL-13
• Metachromatic cells • Preferential deletion of Th2 T cells
• Increased stimulated release of Th1 cytokines
Humoral Response • IFN-γ
IgE • Increased stimulated mRNA for Th1 cytokines
• Early rise in specific IgE • IFN-γ
• Suppression of seasonal rise in specific IgE • IL-12
• Late decline in specific IgE
Other Immunologic Changes
IgG • Decrease in FcεRII/CD23 and B cell activation markers
• Increase in specific IgG • Decreased costimulatory molecules
• Early predominantly IgG1 • Decreased release of cytokines
• Late predominantly IgG4 • IL-2
• TNF
Cellular Response
• Histamine-releasing factors
Basophils
• Platelet-activating factor
• Nonspecific loss of responsiveness

IFN, interferon; IgE, IgG, immunoglobulins E and G; IL, interleukin; IL-2R, interleukin type 2 receptor; mRNA, messenger RNA; TGF-β, transforming
growth factor-β; TNF, tumor necrosis factor.

OVERVIEW OF THE IMMUNE RESPONSE • Allergen-specific IgE levels increase early and then decrease
slowly after SIT, but the rate of change is much less than
TO IMMUNOTHERAPY
would be expected if this were an important mechanism.
The effect of SIT on cellular inflammation has been studied • In contrast, allergen-specific IgG4 levels rise steeply after SIT.
extensively with findings on immunologic responses to SIT This is generally considered to be a direct consequence of the
reported that may appear contradictory. There are some studies injection of foreign material rather than the mechanism by
reporting induction of regulatory T cells (Treg) that suppress which SIT works. The immediate cause of IgG4 production
both Th1 and Th2 cytokine responses to specific allergen stimu- is likely to be induction of Treg producing IL-10.
lation, whereas other studies report an immune deviation from Both during and after SIT, there is a general suppression
a Th2 to a Th1 response such that allergen stimulation of T cells of allergen-specific T cell responses, which is now thought to
results in increased synthesis of IL-12 and interferon-γ (IFN-γ) be due to induction of allergen-specific Treg, which produce
and decreased synthesis of IL-4. Current perspectives are that two key cytokines: IL-10 and transforming growth factor-β
the Treg response occurs very early in the course of subcuta- (TGF-β). In parallel, there is suppression of allergen-specific
neous immunotherapy (SCIT), but with time there is a more lymphocyte proliferation and decreased production of IFN-γ,
general suppression of T cell reactivity to the injected allergen. IL-5, and IL-13. IL-10 is an inhibitor of proliferative and cyto-
While a detailed discussion of the immunologic mechanisms kine responses in T cells, which inhibits IgE production and
of SIT is beyond the scope of this chapter, the mechanisms enhances IgG4 production. TGF-β induces an isotype switch
involved can be summarized briefly as follows: toward IgA. At present, increased allergen-specific IL-10 pro-
• Eosinophils, basophils, and mast cells are the main effector duction is considered a marker of successful SIT and may also
cells of the allergic response. be a marker of adherence.
• The increased levels of eosinophils seen during natural aller- Two types of CD4+ helper T lymphocytes have been
gen exposure are decreased by SIT. described: Th2 cells, which preferentially secrete IL-4; and Th1
• Seasonal increases in nasal basophils and mast cells are also cells, which preferentially secrete IFN-γ in response to aller-
blunted. gen stimulation. Allergic individuals have increased numbers

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116 Allergy Essentials

of allergen-specific Th2 cells in their peripheral circulation to typically every 4 weeks. The basic treatment regimen may
but normal levels of antigen-specific Th1 and Treg. SIT leads require modification because of either missed visits or reactions
to a decrease in allergen-specific Th2 cells, suggesting that SIT to the previous injection. Dosage reductions are usually not
may work by deviating the immune response away from the needed during a pollen season.
Th2 pattern. This may be mediated through induction of cells
producing IL-12. Increased numbers of cells expressing IL-12
mRNA have been noted in skin sites challenged with allergen BOX 6.4 Example of a Conventional
after SIT. IL-12 promotes Th1 lymphocyte proliferation and US-Style Allergen Extract Treatment Schedule
suppresses Th2 cells, so the finding of increased IL-12-secreting The following schedule should be used, with modification if necessary, as out-
cells is consistent with a shift from Th2 to Th1 allergen-specific lined in the accompanying instructions.
responses after SIT.
Instructions for the Injection of Allergenic Extracts
Begin with vial #4 and progress to vial #1, which is the most concentrated or
INDICATIONS FOR SIT “maintenance” solution. The injections should be given every week. Once
While anaphylaxis to Hymenoptera venom is an absolute indica- maintenance is reached, the injection should be given every 3–4 weeks, with
the following exceptions: give weekly for first month and every
tions for SIT, there are no such absolute indications for inhal-
2 weeks for the second month.
ant allergens. Broadly speaking, SIT should be considered for
patients who have troublesome symptoms of allergic rhinitis, Schedule
rhinoconjunctivitis, or allergic asthma after natural exposure to Vial #5 Vial #4 Vial #3 Vial #2 Vial #1
allergens and who demonstrate specific IgE antibodies to rel-
0.05 mL 0.05 mL 0.05 mL 0.05 mL 0.05 mL
evant allergens. Other factors to consider are the severity and
0.10 mL 0.10 mL 0.10 mL 0.07 mL 0.07 mL
duration of symptoms, medication requirements, and patient
0.20 mL 0.20 mL 0.20 mL 0.10 mL 0.10 mL
preference. Because of the increased risk of adverse effects in
patients with poorly controlled asthma, SCIT should only be 0.40 mL 0.40 mL 0.40 mL 0.15 mL 0.15 mL
offered to patients with asthma if their asthma is well controlled 0.25 mL 0.20 mL
and their forced expiratory volume in 1 second (FEV1) is greater 0.35 mL 0.30 mL
than 80% predicted. 0.50 mL 0.40 mL
Outside the US, most SIT injections involve single allergens, 0.50 mL
which are obtained commercially and used individually. In con-
trast, in the US, it is common to use combinations of extracts The bold-underlined entries are representative instructions that
would be placed in the blank spaces in the schedule.
and to mix the allergens in a single maintenance vial tailored to
that patient. However, some caution is needed, because extracts
from fungi and cockroaches contain proteases that can degrade
the proteins in other extracts they are mixed with. Current
best advice is not to mix cockroach or any fungal extract with TABLE 6.1 A European-style Injection
extracts of pollens, HDM, or danders, but other combinations Immunotherapy Schedule for Hay Fever,
may be acceptable. Giving Two Injections Each Week for 6 Weeks
Effective SIT requires administration of sufficient allergenic Week Injection Allergen Volume Amount of
protein. A variety of methods have been used to define the no. no. concentration (mL) allergen (SQ-U)
potency of allergen extracts. Experience gained over many years 1 1 1000 0.1 100
and many trials has shown that a maintenance dose of approxi- 1 2 10,000 0.1 1000
mately 6–20 µg of major allergen is needed to achieve clinical 2 3 10,000 0.2 2000
efficacy. The actual amount varies between manufacturers and 2 4 10,000 0.4 4000
between allergens, and the lack of clarity on this point remains a
3 5 10,000 0.6 6000
matter of concern to practitioners and regulators alike.
3 6 100,000 0.1 10,000
Injection Schedules 4 7 100,000 0.1 10,000
A SIT schedule consists of two phases: the build-up or initia- 4 8 100,000 0.2 20,000
tion phase going from very low dose to the full maintenance 5 9 100,000 0.3 30,000
dose, and then a maintenance phase, in which the same dose is 5 10 100,000 0.3 30,000
given at intervals over a number of years. Typically, the build-up 6 11 100,000 0.5 50,000
phase is achieved by injections twice-weekly, weekly, or alter- 6 12 100,000 0.5 50,000
nate weeks (Box 6.4, Table 6.1). Various alternative regimens
Adapted from Frew et al. Clinical efficacy and safety of specific allergy
have been devised, with clusters of injections given at intervals
vaccination with Alutard grass in seasonal allergic rhinoconjunctivitis:
or rush protocols, in which the full build-up phase is achieved a large-scale randomised double-blind placebo-controlled multi-centre
in 1 to 2 days. Once patients reach the maintenance dose of their study [UKIS—The UK Immunotherapy Study]. J Allergy Clin Immunol
immunotherapy extract, injection frequencies are decreased 2006;117:319–25. 2006.2

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 CHAPTER 6 Allergen-Specific Immunotherapy 117

Adverse Reactions to SIT SUBLINGUAL IMMUNOTHERAPY

Localized and systemic reactions may occur after SIT. Local It has been known for many years that immunologic toler-
reactions are more frequent during the build-up phase than ance can be achieved by mucosal application of proteins. SLIT
during maintenance and, if large, may warrant adjustment to exploits this by applying relatively large doses of allergen to
the schedule (e.g., repeating the previous dose before progress- the buccal mucosa before swallowing. As this is safe and can
ing to the next and higher dose) or premedication with nonse- be done at home, it is much more convenient for patients than
dating antihistamines. The occurrence of local reactions after standard injection immunotherapy (SCIT). The immunologic
SIT does not predict subsequent systemic reactions, so if the mechanisms of successful SLIT are like those of SCIT, but den-
concern is solely about the possible occurrence of a systemic dritic cells in the buccal mucosa are thought to play a key role
reaction, no dose adjustment is needed after a local reaction. in inducing tolerance, most likely through Treg (Fig. 6.3). SLIT
Systemic reactions are more serious and can occasionally achieves decreased symptoms and medication requirements, as
prove fatal. The fatality rate in the US between 1985 and 2001 well as disease modification, similar to the outcomes associated
has been estimated to be about 1 per 2.5 million injections. In with successful SCIT. Economic considerations may influence
a national survey, three-quarters of systemic reactions were the type of immunotherapy used, as the vaccine costs are rela-
cutaneous or upper respiratory, while one-quarter exacerbated tively expensive compared with SCIT.
asthma, and 3% involved life-threatening respiratory com- Recent interest in SLIT has been driven in part by a percep-
promise or hypotension. Although it used to be thought that tion that injection SCIT is hazardous. When treating a rela-
patients were at increased risk for systemic reactions during tively benign disease such as allergic rhinitis, the risk of serious
the relevant pollen season, this has not been substantiated in adverse reactions weighs more heavily than when treating can-
large observational studies. Patients with asthma are at greater cer or life-threatening autoimmune disease.
risk of adverse reactions, especially if their asthma is labile or Over the past 30 years, several different preparations of aque-
symptomatic at the time of the injection, requires oral corti- ous allergen extracts have been tried for sublingual use, includ-
costeroid treatment, or has resulted in recent hospitalization ing sprays and drops. Standardized extracts for SLIT are available
or emergency room visits. With proper care and attention, it for HDM (Dermatophagoides farinae and Dermatophagoides
is reasonable to treat people whose asthma is mild and stable, pteronyssinus), cat dander, weeds (ragweed, Parietaria, mug-
but symptoms and peak flow readings should be checked prior wort), grasses, and tree pollens. To improve reliability of dosing
to each dose. Almost all severe reactions start within 20 min of and compliance, tablet formulations were developed; grass pol-
the injection, and a minimum observation period of 30–45 min len SLIT tablets have been commercially available and approved
after injections is widely accepted as appropriate. Late-onset sys- for treating allergic rhinitis since 2009. The tablet formulation
temic reactions are relatively rare, but when they do occur, they increases the stability of the product and improves standard-
are usually mild and subside spontaneously, without requiring ization of doses; tablets also simplify SLIT administration and
epinephrine (adrenaline) or emergency department attendance. minimize the potential risks of errors in dose administration.
Several large clinical trials have shown SLIT to be clinically
SIT in Pregnancy effective, improving allergic rhinitis and asthma symptoms and
There are two specific concerns during pregnancy: the risk to reducing requirements for rescue medication.8 SLIT is now
the fetus should there be an anaphylactic reaction to SIT, and widely used in Europe, especially in France, Germany, and
the potential effects of SIT on the development of the fetus’s Italy, but also in the US and Oceania. Different regimens are
immune system. Current advice is that SIT should not be initi- employed: some include a rapid build-up phase, while others
ated during pregnancy, but maintenance treatment may be con- start directly at the maintenance dose. Depending on the man-
tinued in the absence of a history of systemic reactions. There is ufacturer and preparation, SLIT doses are 50–110 times those
no evidence of any increase in the rates of prematurity, toxemia, used in SCIT. SLIT has a safer profile than SCIT; serious side
abortion, neonatal death, or congenital malformations when effects are very rare, and the more common local side effects are
SIT is continued in pregnancy. Whether maternal SIT has any usually confined to the early weeks of treatment and are respon-
beneficial effects on the unborn child in terms of preventing the sive to intercurrent nonsedating antihistamines. In addition to
development of allergic disease is not known, and it is unlikely its safer profile, SLIT is administered at home after the first dose
ever to be studied formally. under observation—an additional advantage over SCIT, which
requires clinic visits.
Adherence to SIT Long-term data are lacking, but based on SCIT practice and
The long duration of SIT and dosing fatigue are important con- available clinical trials with seasonal allergens, 3 years or more
tributors to patients stopping their therapy prematurely. The of treatment is recommended.9
number of patients not completing their course of SIT ranges
from 10% to 46%. These poor completion rates have stimulated Mechanisms of SLIT
research into developing vaccines that can achieve the same When allergens are placed in contact with the oral mucosa for
benefits as conventional SIT but within a shorter time frame several minutes before swallowing, a small amount of the aller-
and using alternative routes of administration that are easier for genic material is absorbed into the mucosa (the rest is swal-
the patient. lowed and digested, never reaching immunocompetent cells).

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118 Allergy Essentials

SLIT Re-exposure - challenge

Allergen

Mast cell
Release of
– inflammatory
mediators
IL-4
DC IL-5 B IgE
IL-13 Allergic mucosal
Th2 inflammation and
IL-4 symptoms
– – –
+
– Foxp3
IL-10 IL-10
Th Treg TGF-β T-cell anergy
+ +

+ + –
IL-12
Th1
IFN-γ B
IL-2 IgG, IgA ‘blocking antibodies’

–
Fig. 6.3 Immunologic mechanisms of specific sublingual immunotherapy (SLIT). Locally administered allergen using SLIT is taken up
by mucosal dendritic cells (DCs) and then presented to T cells together with interleukin (IL)-12, biasing the response toward a Th1-like
profile and away from the pro-IgE Th2 profile arbitrated by protolerogenic mechanisms mediated by the increased release of IL-10.
There is enhanced secretion of interferon-γ (IFN-γ) and IL-2, which drive specific B cell production of nonpathogenic and protective
IgG1 and IgG4 antibodies and decreased release of the Th2 pro-IgE cytokine IL-4. Oral mucosal DCs actively upregulate regulatory
T cell (Treg) subtypes, including Forkhead box P3 protein (Foxp3)-expressing T cells, contributing to T cell anergy mediated by IL-10
and transforming growth factor-β (TGF-β). These interconnected pathways lead to reduction in allergic inflammation and symptoms.

The fraction that is retained in the oral mucosa is taken up by cells toward the Th1 phenotype, whereas IL-10 suppresses aller-
dendritic cells that migrate to the regional lymph nodes. Both gen-specific Th2 and Th17 responses, induces IgG4, and inhib-
standard allergens and chemically modified allergoids persist its recruitment of mast cells, basophils, and eosinophils. Lastly,
in the mouth for several hours, and small amounts can still TGF-β1 blocks the Th2 response and decreases the activation of
be identified in the oral cavity up to 20 hours later. In theory, mast cells and eosinophils. Research in this area is now focused
absorption from sites other than the oral mucosa might also on identifying more efficient ways of inducing allergen-specific
contribute to the immunologic stimulus from SLIT, but there is Treg, including the use of appropriate immunologic adjuvants.
minimal clinical benefit from allergens given orally and simply Most of these phenomena are also found after SLIT (Box
swallowed without a period of retention under the tongue. 6.5), albeit with smaller changes in specific IgE, specific IgG, and
The immunologic changes associated with successful SLIT cytokines compared with those identified in patients treated by
are similar to those observed with SCIT (Fig. 6.3). These include injection SIT.10 Induction of allergen-specific IgG4 is a consis-
enhanced suppressor activity of IL-10-secreting Treg; suppres- tent finding in most SLIT studies using large doses of allergen,
sion of eosinophils, mast cells, and basophils; and antibody but some studies reporting good clinical responses to SLIT have
isotype switching from IgE to IgG4 and possibly IgG2. Current not detected any change in allergen-specific IgE, IgG, or IgG4.
data suggest that IL-10-producing Treg are pivotal to the various This may partly reflect the timing of the immunologic analy-
changes induced by SIT. Once induced, chronic allergen expo- sis relative to administration of SLIT, but some doubts remain
sure may favor expansion of Tr1 cells through IL-12 and IL-27 about the relationship between changes in these immunologic
synthesis. Recruitment of these cells into areas of inflammation measures and the delivery of clinical benefit.11 Current and
will lead to amplification of local cytokine responses, including ongoing research suggests late induction of allergen-specific
IL-12, IL-10, and TGF-β1. The IL-12 will skew any Th2 and Th17 IgG2, which may provide a biomarker of effective SLIT.12

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 CHAPTER 6 Allergen-Specific Immunotherapy 119

BOX 6.5 Possible Mechanisms of SLIT practice that benefits are maintained for at least 7 years after
ceasing SLIT. Lasting benefit seems to be more likely in those
• Induction of IgG antibodies (early sustained IgG4 and late IgG2)
• Reduction in specific IgE (long-term)
with more severe disease at enrolment.
• Reduced recruitment of effector cells SLIT with grass pollen tablets has also been studied in chil-
• Altered helper T cell cytokine balance (shift to Th1 from Th2) dren and adolescents, in both Europe and North America.
• T cell anergy Grass pollen tablets were well tolerated, and the levels of benefit
• B cell suppression achieved were comparable with those found in adults.
• Increased regulatory T cell (Treg) function SLIT has been most extensively tested in grass pollen allergy,
but tablet-based therapies are now available for HDM, and
ones for tree pollen allergy and animal dander are under devel-
Although there is considerable overlap in the immune opment. Further large-scale trials are needed in well-defined
responses found in individual studies of SCIT and SLIT, some patient groups.
differences have been identified between SCIT and SLIT.
Because not all the phenomena reported after SCIT occur after SLIT for Asthma
SLIT, it is possible that different or additional mechanisms may Most clinical trials of SLIT have focused on evaluating its efficacy
occur in SLIT. in allergic rhinitis.13 Some trials included patients with asthma,
and SLIT appears to decrease asthma symptoms and medication
Side Effects of SLIT scores after 2 years of treatment. A study of HDM SLIT tablets
SLIT has a much safer profile than SCIT, but local side effects are in patients with asthma who were not well controlled in Global
common, most frequently local irritation of the oral mucosa and Initiative for Asthma (GINA) treatment steps 2–4 demonstrated
sometimes local swelling. Systemic reactions are extremely rare, efficacy and has resulted in inclusion of consideration of HDM
but caution is advised in patients who have experienced systemic SIT in the GINA guidelines for asthma management.14 SLIT is
side effects to other forms of SIT. Local side effects ease with currently recommended for patients with allergic rhinitis, with
accompanying nonsedating antihistamines during early weeks or without asthma, but is not currently recommended specifi-
and repeated use, and rarely lead patients to discontinue therapy. cally for treatment of asthma. Importantly, current guidelines
To avoid unnecessary discontinuation, patients should be super- recommend that SLIT should only be initiated in patients with
vised when they take their first doses. This allows any potential side asthma who are stable with an FEV1 >70% predicted.
effects to be discussed and the therapeutic regimen to be explained. SIT for grass pollen allergy may offer protection against epi-
demic thunderstorm asthma in regions that are geographically
Efficacy of SLIT susceptible and where ryegrass is the prevalent pasture grass
Several well-conducted clinical trials have shown 30%–40% associated with seasonal rhinitis.15
decreases in symptom score and rescue medication use in
patients with seasonal allergic rhinitis after SLIT. In general, the Durability of Treatment
trials show that clinically significant benefits are achieved in the A key question in deciding whether to use SLIT is how long
first year of SLIT, and the magnitude of benefit does not increase the benefits of therapy extend beyond the period of treatment.
much in the second and third years. However, it is likely that the Maintaining double-blind trials for years is extremely difficult,16
second and third years of SLIT contribute to the overall dura- both for the investigators and for the control group participants
bility of the response, which we know from double-blind, pla- who have to go without treatment for years to answer the ques-
cebo-controlled trials extends for at least 2 years after 3 years of tion properly. Evidence from long-term follow-up of open-label
therapy (Fig. 6.4), supporting reports from open-label clinical therapy has shown that the longer the course of treatment, the
longer the benefit persists. Five years of SLIT gave benefits for at
100 least 7 years, whereas the benefit of 3 to 4 years of SLIT seemed
32% 40% 37% 31% 31% to wane more quickly. The more recent double-blind, placebo-
80 controlled studies continued for 2 years after completing
Median placebo (%)

therapy have demonstrated a durable response. Unfortunately,

60
accurate cost–benefit analysis requires an estimate of the dura-
40 bility of therapeutic effect, so the lack of long-term data remains
a problem for policymakers and manufacturers alike.
20

0 Effects of SLIT on the Natural History of

Placebo Year 1 Year 2 Year 3 FU Y1 FU Y2
Allergic Disease
Fig. 6.4 Efficacy of sublingual allergen tablets on rhinitis symp-
toms over 3 years of treatment and 2 further years on placebo. As discussed earlier, there is considerable interest in the pos-
Adapted from Durham SR et al. SQ-standardised sublingual sibility that SIT may modify the course of allergic disease. If
grass immunotherapy: confirmation of disease modification unequivocally substantiated, this effect would dramatically
2 years after 3 years of treatment in a randomised trial. J Allergy swing the economic argument in favor of SIT because one could
Clin Immunol 2012;129:717–725. discount the costs of treatment against the costs of the future

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 120 Allergy Essentials

80 No discussion of new therapeutic options is complete with-

70 out consideration of the economic aspects. Rhinoconjunctivitis
19/79 vs 32/72 is a common condition, and standard therapies such as non-
60
Asthma after 3 years (%)

Odds Ratio: 2.52

sedating antihistamines and even nasal corticosteroids are
50 relatively inexpensive compared with forms of SIT. SLIT offers
40
improvements that cannot be achieved by standard pharma-
cotherapy, but it is relatively expensive compared with anti-
30 histamine therapy, which is adjusted according to symptoms.
20 Cost-effectiveness analysis requires assumptions on the likely
10
durability of benefits and the period of impact on relevant
financial outcomes. Some evidence of cost-effectiveness has
0 been presented, indicating a cost of 13,000–18,000 Euros
SIT Control
(US$17,000–25,000) per quality-adjusted life year (QALY)
Fig. 6.5 Pollen SIT reduces asthma in children with seasonal
allergic rhinitis. Adapted from Möller C et al. Pollen immunother-
gained. The benefit consisted of decreases in rescue medication
apy reduces the development of asthma in children with seasonal and fewer hours lost from work (production loss). The analysis
rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 2002; used a horizon of 9 years and assumed that the clinical ben-
109:251–256. efit achieved in the first years of therapy would be sustained
throughout. On this basis, tablet-based SLIT could be consid-
condition that has been avoided. Data have been presented ered as cost-effective at current prices compared with standard
in two areas: prevention of new sensitizations and prevention thresholds applied by national regulatory bodies.18,19
of asthma. As with SCIT, atopic children treated with SLIT In summary, there is evidence of favorable cost–benefit anal-
acquire fewer new sensitizations over 3 years, compared with ysis, but this has not yet resulted in major changes in the devel-
untreated children.17 SLIT also may prevent children with rhi- opment and reconfiguration of allergy health services. SLIT is
nitis from developing asthma later. In a 3-year study, 18 of 44 relatively expensive, especially compared with standard drug
control children developed asthma versus only 8 of 45 SLIT- treatment for allergic rhinitis. Currently, SLIT needs to be tar-
treated children (Fig. 6.5). geted to patients with significant disease.17
Thus, both SCIT and SLIT appear to modify the course of
allergic disease by decreasing the incidence of new sensitiza-
tions, preventing the development of clinical asthma, and/or MODIFIED ALLERGEN EXTRACTS AND
accelerating its resolution. The mechanism remains unclear but
probably involves a combination of immunologic effects and
ADJUVANTS (BOX 6.6)
downstream changes to the structure and function of the small A major disadvantage of conventional SIT is the consider-
airways. Better data are needed, but if confirmed, these disease- able investment in time and money required on the part of
modifying and preventive effects of SIT would have a major the patient to achieve and maintain effective doses of allergen
impact on any cost–benefit analysis. extract. To address this, allergists began experimenting over 60
years ago with ways of slowing the absorption of allergen from
Safety and Cost-Effectiveness of SLIT the injection site to both decrease the number of injections
One of the main drivers behind the development of SLIT was
awareness of risks associated with SCIT. Although SCIT is usually
BOX 6.6 Modifications to Allergen
quite safe in patients without asthma, occasional serious adverse
events do occur, but these are rarely fatal. In most reports, the rate Extracts and Routes of Administration
of serious systemic reactions in patients with rhinitis is about 1 in • Depot preparations
500 injections. Most clinical trials of SLIT report local side effects, • Aluminum adsorption
• Tyrosine adsorption
particularly itching of the mouth and palate, but there were few
• Liposome-encapsulated
serious systemic side effects. Since SLIT preparations became • Allergoids
available commercially, a small number of serious adverse events • Recombinant technology
have been reported, mainly in patients who had already experi- • Unmodified major allergens
enced problems with conventional SCIT. These isolated episodes • Mutated or deleted major allergens
were typically not witnessed by medical personnel, so some doubt • TLR stimulation
remains regarding their precise nature, but clearly some caution • 3-Deacylated MPL
is required if SLIT is given to such patients. The first dose of SLIT • CpG (type A and type B): combined with allergen or administered without
should normally be taken in the physician’s office, particularly allergen
in patients who previously experienced problems with SCIT. In • Transcutaneous
some series, up to 11.6% of patients had experienced wheezing • Transmucosal
• Oral
or worsening of nasal symptoms on one or more occasions after
• Intranasal
a SLIT dose, although the overall frequency of systemic adverse • Sublingual
reactions was only 1 in 3000 doses.

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 CHAPTER 6 Allergen-Specific Immunotherapy 121

required and to improve safety. Various depot preparations

THE FUTURE OF SLIT
have been tried; alum precipitation reduces the risk of systemic
side effects, but trials indicate that even with modified vaccines Future developments in SLIT may take several forms, including
3 years of treatment is still needed for maximum efficacy. mucoadhesives, allergoids, adjuvants, and new allergens (latex,
Various adjuvants have been tried to increase the immuno- foods). The delivery of allergen to the mucosa may be improved
logic effect of a given amount of allergen. Two of these involved by creating formulations that adhere better to the mucosa
stimulation of Toll-like receptors (TLRs), which are cell surface and deliver the necessary amount of allergen more efficiently.
receptors that recognize molecular patterns commonly found Such mucoadhesives could allow smaller amounts of allergen,
in bacteria and viruses. When allergens are given together with thereby decreasing the risk of local side effects and adverse reac-
TLR stimulation, the immunologic effect is altered, biasing the tions. The efficiency of SLIT might also be improved by more
response toward a Th1 pattern. Unmethylated CpG DNA motifs persistent presence of the allergen.
stimulate TLR9, and lipopolysaccharides and a derivative, As with SCIT, it may be possible to use modified allergens,
monophosphoryl lipid A (MPL), stimulate TLR4. SIT studies for example, allergoids, which retain the ability to stimulate
using MPL as an adjuvant have shown clinical efficacy after only T cells while having decreased binding to IgE. This should
four injections, but further data on durability are needed before decrease side effects, and has been tested in patients with
this can be adopted into routine use. Immunostimulation with grass pollen allergy, in whom it appears effective, both when
CpG-containing DNA sequences has been tested for ragweed given all year round and when used pre-seasonally. Adjuvants
and HDM allergy. Initial trials were promising, although later that selectively induce IL-10 could also enhance the efficacy
ragweed studies proved less effective. of SLIT vaccines. Another adjuvant, Lactobacillus plantarum,
Allergenic proteins can be cross-linked with formaldehyde or deviates T cells toward a mixed Th1/Treg pattern. Both these
glutaraldehyde to produce larger molecules, which are less able adjuvants have enhanced the efficacy of SLIT in a mouse
to react with IgE antibodies. Such allergen extracts are called model of asthma.
“allergoids” and have proved effective in clinical trials, although
their clinical use has been limited to the US. In contrast, aller-
goids have proved more popular in Europe, allowing rapid
CONCLUSIONS
build-up regimens and delivery of large amounts of allergen in Allergen immunotherapy has been practiced with only rela-
fewer injections. Encapsulation of unmodified HDM allergen tively modest changes for more than 100 years. The clinical
extracts in liposomes has also been investigated. Liposomes are effectiveness of adequate doses in appropriate patients for
lipid vesicles formed by one or more phospholipid bilayers that both allergic rhinitis and bronchial asthma has been repeat-
entrap the water-soluble extract in their internal aqueous com- edly confirmed. Treatment by the sublingual route is becoming
partment. They are biodegradable and stable and prolong the increasingly popular. SLIT appears to be as effective as SCIT for
half-life of the encapsulated drug while acting as an adjuvant, allergic rhinitis and is certainly more convenient for patients.
inducing a Th1 response. The precise mechanisms of SIT action remain uncertain. Both
SCIT and SLIT are associated with induction of Treg, expres-
Recombinant Allergen Vaccines sion of IL-10 and TGF-β1, and secretion of allergen-specific
In theory, recombinant technology offers the possibility of IgG4 and possibly IgG2. The major threat to future use of SCIT
improving the standardization and safety of allergen SIT. Most and SLIT is the lack of comprehensive cost-effectiveness data,
of the key components of inhaled allergens have been identi- which are increasingly required by healthcare commissioners
fied, cloned, sequenced, and expressed in various systems. This when deciding which treatments to fund. Future developments
allows production of virtually unlimited quantities of allergenic will include a wider range of allergens, adaptations with muco-
proteins, mutated proteins, or fragments of allergenic proteins. adhesives and adjuvants to refine the immunologic response,
and research into the durability of responses to determine
Unmodified Allergens cost-effectiveness.
There have been several trials of SIT with unmodified purified As well as confirming primary efficacy, clinical trials of
major allergens. To date, the trials have shown efficacy but no SCIT and SLIT have confirmed a persisting beneficial effect
real superiority to standard SIT. In theory, SIT vaccines could after immunotherapy is discontinued. These findings suggest
be personalized to the individual’s serologic pattern of reaction, that immunotherapy has the potential to be used more widely.
but this approach raises awkward regulatory questions yet to be Increased utilization would be facilitated by alternative extracts
addressed. and better methods of administration making SIT safer and
more convenient for the patient.
Modified Allergens
Genetic modification can produce hypoallergenic variants of
allergenic proteins, which may decrease the risk of IgE-mediated
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