How to Handle

an Adverse Reactions due to

Rabies Vaccine and

Rabies Immunoglobulin

Suda Punrin, MD

Outline

• What is adverse reactions ?

• Adverse reactions from rabies vaccine and RIG

• Management

Adverse reactions (AEs)

Definition

• One that is noxious, is unintended, and occurs at doses normally used in man

Classify

• Type A

• Type B

International drug monitoring. Report of a WHO meeting. World Health Organ Tech Rep Ser 1972;498:1-25

White KD. et. al. J Allergy Clin Immunol 2015;136:219-34

Access from www.topicalsteroidaddiction.weebly.com , August 23, 2016

Vaccine adverse reactions

Local reactions

- Pain

- Swelling

- Erythema

Systemic reactions

- Fever

- Headache

- Myalgia

- Lymphadenopathy

Allergic reactions

- Immediate/

IgE-mediated/

anaphylaxis

- Non-immediate/

Delayed

hypersensitivity

Moylett E. and Hanson C. J Allergy Clin Immunol 2004;114:1010-20

Disease attributable events

Often falsely labeled as allergic

สรุปรายงานอาการไม่พึงประสงค์จากการใช้ยา ประจ าปี 2557

ศูนย์เฝ้าระวังความปลอดภัยด้านผลิตภัณฑ์สุขภาพ ส านักงานคณะกรรมการอาหารและยา

≥ 9 Definite ใช่แน่

5-8 Probable ใช่

1-4 Possible อาจจะใช่

≤ 0 Doubtful น่าสงสัย

ศูนย์เฝ้าระวังความปลอดภัยด้านผลิตภัณฑ์สุขภาพ ส านักงานคณะกรรมการอาหารและยา 2557

Symptoms Certain Probable Possible Unlikely

Anaphylaxis 1 23 7 -

Angioedema 8 36 16 -

Urticaria 21 175 104 -

Rash 58 286 186 -

Symptoms Certain Probable Possible Unlikely

Anaphylaxis 5 49 10 -

Angioedema 2 23 10 -

Urticaria 8 134 67 -

Rash 24 267 98 -

Local reactions 4 73 21 -

Serum sickness - 11 4 -

Rabies vaccine

Rabies immunoglobulin

U.S., Vaccine Adverse Event Reporting System (VAERS)

• Human Diploid Cell Rabies Vaccine (HDCV, Imovax ®)

1990 – 2015: 1,611 reports

• Purified Chick Embryo Cell (PCEC, RabAvert®)

1997 – 2005: 336 reports

Dobardzic A, et. al. Vaccine 2007;25:4244-51 Moro PL, et. al. PLoS Negl Trop Dis 2016;10:e0004846

U.S., Vaccine Adverse Event Reporting System (VAERS)

• Most common adverse events (AEs) included pyrexia, headache, myalgia and nausea

• 5.8 – 7 % were serious AEs * (death, hospitalization, prolonged hospitalization, disability, life-threatening-illness)

Dobardzic A, et. al. Vaccine 2007;25:4244-51 Moro PL, et. al. PLoS Negl Trop Dis 2016;10:e0004846

*Some appeared to be unrelated to vaccination

U.S., Vaccine Adverse Event Reporting System (VAERS)

• Allergic reactions were mostly urticaria, rash and angioedema

Dobardzic A, et. al. Vaccine 2007;25:4244-51 Moro PL, et. al. PLoS Negl Trop Dis 2016;10:e0004846

Dobardzic A, et. al. Vaccine 2007;25:4244-51

*No pattern among 13 neurological AEs suggesting a plausible relationship to vaccination

Fulbright J. et. al. J Pediatr Hematol Oncol 2015;37:e427–8

Immune-mediated thrombocytopenia

Kaliner C. et. al. JAMA 1965;193:109-12 Access picture from www.fda.gov , August 23, 2016

Suwansrinon K, et. al. Trans R Soc Trop Med Hyg 2007;101:206-8

QSMI 1987 – 2005 ; 72,132 patients

60 % received purified ERIG : 40 % received HRIG

Adverse events ERIG HRIG

No. (%) 786 (1.8%) 26 (0.09%)

Local reactions 352 13

Serum sickness-like symptoms

312 2

Other systemic symptoms*

122 11

*Fever, headache, malaise § One case of anaphylaxis after ERIG administration

A. Neumayr, J. Blum IDCases 3 2016:1–2

Local reaction

Serum sickness

Access from www.studyblue.com , access August 23, 2016

Symptomatic treatment

Serum – sickness like reactions

How to manage ?

Vaccine adverse reactions

Local reactions

- Pain

- Swelling

- Erythema *record site of

vaccination

Systemic reactions

- Fever

- Headache

- Myalgia

- Lymphadenopathy

Allergic reactions

- Immediate/

IgE-mediated/

anaphylaxis

- Non-immediate/

Delayed

hypersensitivity

Moylett E. and Hanson C. J Allergy Clin Immunol 2004;114:1010-20

Disease attributable events

Often falsely labeled as allergic *record Lot.no. of vaccine

Immediate reaction Non – immediate reaction

Maculopapular rash

Angioedema

Urticaria

Corticosteroids should not be given !

Allergy ?

History Physical examination Timelines Casuality assessment: - Naranjo’s algorithm In vivo/ In vitro test

Allergy

What components ?

Virus or bacteria particle

Culture media: egg, milk

Additives: preservatives, adjuvants,

stabilizers, antibiotics

Contamination: latex

Fritsche P.,Helbling A.,Ballmer-Weber BK. Swiss Med Wkly 2010;140:238 – 46

Prevent further reactions and avoid unnecessary vaccine restriction

วัคซีน ส่วนประกอบของวัคซีน

PCECV (RABIPUR®)

เชื้อไวรัสโรคพิษสุนัขบ้าชนิดเชื้อตาย TRIS-hydroxymethyl, aminomethane, sodium chloride, EDTA

potassium-L-glutamate, saccharose, polygeline (เจลาติน)

PVRV (VERORAB®)

เชื้อไวรัสโรคพิษสุนัขบ้าชนิดเชื้อตาย มอลโตส sodium chloride และ ฮิวแมน แอลบูมิน

CPRV (TRCS SPEEDA®)

เชื้อไวรัสโรคพิษสุนัขบ้าชนิดเชื้อตาย เด๊กซแ์ทรน ฮิวแมน แอลบูมิน

ท่ีมา: เอกสารก ากับยา

Niclou M. et. al. Austin J Allergy 2014;1:3

21-year old German soldier: PrEP before a military mission in Afghanistan

10 min after 1st dose of PCEC: dizziness, sweats, pruritus, N/V,

hypotension and tachycardia

Dx: psychovegetative reaction

5 min after 2nd dose of PCEC: same symptoms with urticaria

A polygelin-free rabies vaccine was given for 3rd dose

without symptoms

แพ้ไข่ จะฉีดวัคซีนป้องกันโรคพิษสุนัขบ้า ได้หรือไม่ ?

Kelso J. et al. J Allergy Clin Immunol 2012;130:25–43

Vaccines Contains

HDCV (Imovax®) Human serum albumin, Beta-propiolactone, MRC-5 cellular protein, neomycin, phenol red (phenolsulfonphthalein), vitamins

PCEC (RabAvert®) Amphotericin B, Beta-propiolactone, bovine albumin or serum, potassium glutamate, chlortetracycline, EDTA, neomycin, chicken protein, egg albumin (ovalbumin)

Purified chick embryo cell rabies vaccine

Egg-containing vaccines Vaccine Egg protein content Approach in egg-

allergic patients

Measles & Mumps Picograms - nanograms

Administer in usual manner *

Rabies (PCEC) Picograms - nanograms

Administer in usual manner *

Influenza Micrograms To be discussed

Yellow fever Micrograms

Skin test prior giving

Caubet JC., et al. Pediatr Allergy Immunol 2014: 25: 394–403

* If nature of allergy is not severe reactions, e.g. anaphylaxis

If investigation could not be done…

U.S. ACIP recommendation (1)

• Once initiated, rabies prophylaxis should not be discontinued because of local or mild systemic AEs

• Usually, such reactions can be successfully managed with symptomatic treatment

Manning SE, et al. MMWR Recomm Rep 2008;57:1-28

U.S. ACIP recommendation (2)

• When a person with hypersensitivity to rabies vaccine must be revaccinated, empiric intervention such as pretreatment with antihistamines might be considered.

• Epinephrine should be readily available

• Person should be carefully observed after vaccination

Manning SE, et al. MMWR Recomm Rep 2008;57:1-28

Optional management in case of mild AEs

• Switch to other brand of rabies vaccine

วัคซีน ส่วนประกอบของวัคซีน

PCECV (RABIPUR®)

เชื้อไวรัสโรคพิษสุนัขบ้าชนิดเชื้อตาย TRIS-hydroxymethyl, aminomethane, sodium chloride, EDTA

potassium-L-glutamate, saccharose, polygeline (เจลาติน)

PVRV (VERORAB®)

เชื้อไวรัสโรคพิษสุนัขบ้าชนิดเชื้อตาย มอลโตส sodium chloride และ ฮิวแมน แอลบูมิน

CPRV (TRCS SPEEDA®) เชื้อไวรัสโรคพิษสุนัขบ้าชนิดเชื้อตาย เด๊กซแ์ทรน ฮิวแมน แอลบูมิน

Gupta M, et. al. J Allergy Clin Immunol Pract 2015;3:281-2

Graded challenge in immediate reactions

Other managements

• Observe responsible cat or dogs for 10 days

• Check rabies neutralizing antibody

Summary

• Local/mild reactions are common and do not contraindicate future doses

• Risk for acquiring rabies must be carefully considered before deciding to discontinue vaccination

• Allergy to rabies biologics are rare and should be further evaluated

Thank you for your attention

Thank you for your attention