Proportion of IgE-mediated allergic reactions to the

2009-2010 pH1N1 vaccine

Isabelle Rouleau, PhD(c)Faculté de médecine, Université Laval

Research Team

Authors: Rouleau I (1), Drolet JP (1), Benoit M (1), Lemire C (2), Moore A (3), Banerjee D (4), Paradis L (5), Alizadehfar R (4), Des Roches (6), Chan ES (7) Stark D (7), Warrington R (8), Skowronski DM (9) and De Serres G (1).

Affiliation: (1) Centre hospitalier universitaire de Québec, Université Laval (2) Université de Sherbrooke (3) Centre affilié universitaire Hôpital Charles Lemoyne, Université de Sherbrooke (4) McGill University Health Centre, McGill University (5) Centre hospitalier de l’Université de Montréal, Université de Montréal (6) Centre hospitalier Universitaire Sainte-Justine, Université de Montréal (7) University of British Columbia (8) University of Manitoba (9) British Columbia Centre for Disease Control.

Allergy to pH1N1 vaccine

After 2009-2010 vaccination: number of cases of anaphylaxis number of cases of allergic reactions No increase in frequency of ORS

ORS is not an IgE dependent reaction

True« Vaccine allergy » (IgE-mediated) Probably rare, but too few studies

Important distiction

Allergy and ORS may look alike: Presentation is fairly similar Delay to onset is similar One is IgE mediated, the other is not

IgE-mediation dictates recommendations Dangerous to revaccinate if IgE mediated Not contraindicated for most cases of ORS

Recurrences are of similar or milder severity

Allergy diagnostic testing

Skin testing as a two step process: Prick test (drop of allergen) Intradermal injection

A positive response is evaluated by Wheal (papule - effect of histamine) Flare (erythema – axonal reflex)

False positives can occur More often with intradermal test (irritant effect)

Wheal and flare

Study design and participants

Objective Estimate the % of patients with IgE

mediated reactions to pH1N1 vaccine

Case control study: Cases of anaphylaxis, allergy and ORS

with onset < 24 hours after vaccination Controls vaccinated w/o any allergic-like

reaction < 24 hours after vaccination

Participating Centres

Hospitals (Quebec) Centre hospitalier universitaire de Québec Centre hospitalier de l’Université de Sherbrooke Centre hospitalier Charles Lemoyne McGill University Health Centre (General / Children’s) Centre hospitalier de l’Université de Montréal Centre hospitalier universitaire Sainte-Justine

Hospitals (British Columbia) Children’s and Women’s Health Centre

Collaborating Centres University of British Columbia BC Centre for Disease Control University of Manitoba

Testing conditions

Following conditions were tested: Pos. (Histamine)/Neg. control (Saline) pH1N1 antigen AS03 adjuvant Reconstituted vaccine (same day) Reconstituted vaccine (day old) 2010-2011 seasonal vaccine (subsample) Egg protein (if indicated)

2009-10 Antigens were supplied by GSK Lot under monitoring to ensure stability

Study outcomes

Prick test was positive if: Wheal ≥ 3 mm over saline, AND Visible flare (erythema)

Intradermal test was positive if: Wheal ≥ 5 mm over saline, AND Visible flare (erythema)

Proportion of positive is a composite of Positive prick or intradermal test

Results

From January 18 to March 31st

94 cases and 37 controls (N=131) 65% reported cases of allergy 25% reported cases of ORS 7% reported cases of anaphylaxis 3% clinic referrals

3 cases and 1 controls were excluded No response to histamine

Surveillance reports vs. allergists

ReportsAllergists

Anaphylaxis

N (col. %)

AllergyN (col. %)

ORSN (col. %)

TOTALN (col. %)

Anaphylaxis

4 (57.1) 15 (25.4) 2 (9.1) 22 (24.2)

Allergy 0 (0.0) 13 (22.0) 0 (0.0) 14 (15.4)

ORS 1 (14.3) 2 (3.4) 7 (70.0) 10 (11.0)

Other 2 (4.8) 26 (44.1) 13 (59.1) 42 (46.2)

TOTAL 7 (7.7) 59 (64.8) 22 (24.2) N=91

Proportion of positive skin tests

N (%) Positive (ID 3 mm)

N (%) Positive (ID 5 mm)

Cases Controls Cases Controls

N (%) N (%) N (%) N (%)

pH1N1 antigen 6 (6.6) 1 (2.8) 4 (4.4) 0 (0.0)

AS03 adjuvant 11 (12.1) 1 (2.8) 6 (6.6) 1 (2.8)

Reconstituted vaccine (same day)

10 (11.0) 2 (5.6) 9 (9.9) 2 (5.6)

Reconstituted vaccine (day old)

7 (9.7) 2 (5.7) 7 (9.7) 1 (2.9)

To any vaccine component

17 (18.7) 2 (5.6) 14 (15.4) 2 (5.6)

Proportion of positive toprick tests among positives

N (%) Positive (ID 5 mm)

Positive to Prick test

Cases Controls Cases Controls

N (%) N (%) N (%) N (%)

pH1N1 antigen 4 (4.4) None 3/4 (75%) None

AS03 adjuvant 6 (6.6) 1 (2.8) 2/6 (33%) None

Reconstituted vaccine (same day)

9 (9.9) 2 (5.6) 2/9 (22%) None

Reconstituted vaccine (day old)

7 (9.7) 1 (2.9) 0/7 None

Positive skin tests (prick or ID of 5 mm) by type of case

Controls Anaphyl.

Allergy

ORS Other

N (%) N (%) N (%) N (%) N (%)

pH1N1 antigen 0 (0.0) 1 (4.6) 1 (7.1) 0 (0.0) 2 (4.4)

AS03 adjuvant 1 (2.8) 2 (9.1) 1 (7.1) 1 (10.0) 2 (4.4)

Reconstituted vaccine (same day)

2 (5.6) 3 (13.6) 0 (0.0) 0 (0.0) 6 (13.3)

Reconstituted vaccine (day old)

2 (5.7) 3 (15.8) 0 (0.0) 1 (12.5) 3 (7.7)

To any vaccine component

2 (5.6) 5 (22.7) 1 (7.1) 1 (10.0) 7(15.6)

Positive skin tests (ID 5mm), by component and type of reaction

0

5

10

15

20

25

Antigen Adjuvant Vaccine (Same day)

Vaccine (Day old)

At least 1component

% P

osit

ive

Anaphylaxis Allergy ORS Other Controls

Positives to reconstituted vaccine

Our primary outcome is being positive to reconstituted vaccine Skin tests may have false positives

Among 9 cases positive to reconstituted vaccine 1 positive to antigen in vaccine 2 positive to adjuvant in vaccine 1 positive to both antigen and adjuvant 5 are negative to both antigen and adjuvant

Only 4 are probably « true positives » Proportion of IgE mediated reactions = 4% Reported Anaphylaxis (1); Allergy (2) ; ORS (1)

Revaccination of positive cases

4 cases with positive skin tests None had immediate symptoms (< 60

min) 1 reported symptoms (1-24 hours)

« Bumpy » rash on neck/face, palpitations, dyspnea (attributed to anxiety) and exacerbated cough 6 hours post vaccination. (Case 161)

Revaccination of negative cases

21 cases with positive skin tests 2 had immediate symptoms (< 60 min)

Pruritus on neck, hoarse voice, nausea and headache (Allergy, Case 080)

Sensation of sublingual edema and pruriginous rash at injection site (Allergy/Anaphylaxis, Case 086)

4 had reported reaction (1-24 hours) Bilateral conjunctivitis with ocular pruritus, sore

throat and cough at 20 hours (Case 086) Urticaria with hoarse voice at 8

hours.(Allergy/Anaphylaxis Case 110) Angioedema around, but not at the injection site.

(Allergy/Anaphylaxis Case 227) Bilateral conjunctivitis with ocular pruritus, eyelid

edema at 24 hours. (ORS, Case 249) Urticaria at the injection site. (Allergy, Case 255)

Conclusions

Few cases have IgE mediated reactions Similar to basophil activation tests 10% of cases positive to the vaccine Only 4% are allergic to a component

Cases classified as anaphylaxis by allergist have more positive skin tests than others

Most reactions are not Ig-E mediated Similar to basophil activation tests

Conclusions

When revaccinated 25-30% of cases experienced an adverse event Similar to basophil activation tests 25% of test positive cases 20-30% of test negative cases

If not IgE mediated, what mechanism? Coincidental – postviral immune response Non-specific immune activation (most often) Complement, kinins Late T-cell responses (seems unlikely) Other?

PHAC-sponsored components

Review of medical consultation by non-participating allergists Obtain allergist and patient consent Copy of medical records of patients tested

outside our study protocol

In vitro studies Activation of the contact system (kinins)

Pandemic vaccine activates contact system Complement pathway

In the next few months

Any questions or comments?