Canadian Immunization Guide: Part 5 - Passive Immunization

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  • This CIG chapter has not been updated to contain information regarding COVID-19 vaccines. For this information, refer to the COVID-19 vaccine chapter.

Last partial content update (see Table of Updates): June 2022

June 2022:

The content on respiratory syncytial virus (RSV) monoclonal antibody (palivizumab [SYNAGIS®]) has been removed from this chapter. For information on the use of palivizumab, refer to the National Advisory Committee on Immunization (NACI) Statement on Recommended use of palivizumab to reduce complications of respiratory syncytial virus infection in infants.

Last complete chapter revision: November 2013

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Introduction

Passive immunizing agents are preparations containing pre-formed antibodies derived from humans or animals, or produced by recombinant DNA technology (refer to Table 1). Administration of passive immunizing agents can prevent certain infections or reduce the severity of illness caused by the infectious agent.

This chapter describes the types and uses of passive immunizing agents and discusses product administration and storage requirements. The safety profile of standard immunoglobulin, including common adverse events, is presented.

Passive immunizing agents

Passive immunization should be considered when vaccines for active immunization are unavailable or contraindicated, or in certain instances when unimmunized individuals have been exposed to the infective agent and require immediate protection. Passive immunization may also have a role in the management of immunocompromised people unable to adequately respond to a vaccine. The duration of the beneficial effects provided by passive immunizing agents is relatively short-lived and protection may be incomplete.

There are two types of antibody preparations available:

  • Standard immunoglobulin (Ig) of human origin - sometimes referred to as "immunoserum globulin", "serum immunoglobulin" or "gamma globulin"
  • Specific immunoglobulins of human or animal origin, or produced by recombinant DNA technology - containing high titres of specific antibodies against a particular microorganism or its toxin. Products of human origin are preferred over those of animal origin because of the high incidence of adverse reactions to animal sera and the longer lasting protection conferred by human immunoglobulins.
Table 1: Passive immunizing agents - origin of antibodies
Passive immunizing agent Origin of antibodies
Standard immunoglobulin
Standard human Ig Human plasma
Specific immunoglobulins
Botulism antitoxin Horse serum (equine)
Botulism Ig Human plasma
Cytomegalovirus Ig Human plasma
Diphtheria antitoxin Horse serum (equine)
Hepatitis B Ig Human plasma
Rabies Ig Human plasma
Respiratory syncytial virus monoclonal antibody (palivizumab) Recombinant DNA technology
Tetanus Ig Human plasma
Vaccinia Ig Human plasma
Varicella zoster Ig Human plasma

For complete prescribing information, consult the product leaflet or information contained within the product monographs available through Health Canada's Drug Product Database. Refer to Contents of Immunizing Agents Authorized for Use in Canada in Part 1 for a list of passive immunizing agents available for use in Canada and their contents.

Standard immunoglobulin (human)

Standard human immunoglobulin (GamaSTAN®) is a sterile, concentrated solution for intramuscular (IM) injection containing 15% to 18% immunoglobulin. It is obtained from pooled human plasma from screened donors and contains mainly IgG with small amounts of IgA and IgM. The potency of each lot of immunoglobulin product is tested against international standards or reference preparations for at least two different antibodies, one viral and one bacterial. Specific measles and hepatitis A antibody content in standard human immunoglobulin is not regulated by Health Canada.

Subcutaneous (Sc) and intravenous (IV) immunoglobulin (IVIg) are used for continuous passive immunization for persons with selected congenital or acquired immunoglobulin deficiency states and as an immunomodulator in certain diseases. Discussion of uses of these products is beyond the scope of the Canadian Immunization Guide. Consult appropriate resources such as the manufacturer's product leaflet or the product monographs.

Recommendations for use

Prophylactic use of IM Ig has been shown to be effective in a limited number of clinical situations, including exposure to measles and hepatitis A. The dose varies by indication.

Measles

Refer to Post-exposure prophylaxis (PEP) and outbreak control in Measles Vaccine, Part 4 for information.

Hepatitis A

Refer to Human immunoglobulin (pre-exposure prophylaxis) and (post-exposure prophylaxis) in Hepatitis A Vaccine, Part 4 for information.

Rubella

Passive immunization with Ig is not effective in preventing rubella. Ig given soon after exposure to rubella may modify or suppress symptoms but may not prevent infection, including congenital infection. Therefore, the routine use of Ig in susceptible women exposed to rubella early in pregnancy is not recommended.

Specific immunoglobulins

Specific immunoglobulins are derived from the pooled sera of people with antibodies to specific infectious agents; antisera from animals (usually horses that are hyper-immunized against a specific organism) when human products are not available; or recombinant DNA technology. Immunoglobulins from human or animal sources are made by more than one B cell clone (polyclonal) and can bind to heterogeneous antigens. Antibodies produced through recombinant DNA technology originate from a single clone of B cells (monoclonal) and are specific to only one antigen. A monoclonal antibody product is available for the prevention of respiratory syncytial virus (RSV) infection. Because of the relatively high risk of a specific type of immunological reaction (known as serum sickness) following the use of animal products, human Ig should be used whenever possible.

Some specific Ig products are only available on an emergency basis and require application to Health Canada's Special Access Programme (SAP). The SAP provides access to non-marketed drugs for health care providers treating people with serious or life-threatening conditions when conventional therapies have failed, are unsuitable, or unavailable. The SAP authorizes a manufacturer to sell a product that cannot otherwise be sold or distributed in Canada based on the submitted Special Access Request Form which can be obtained from the SAP website or by contacting the SAP office (telephone: 613-941-2108; fax: 613-941-3194 - available 24 hours a day, 7 days a week). The health care provider should be prepared to provide the information required on the Special Access Request Form to the SAP on-call officer. Public health should be contacted for assistance in obtaining specific Ig products.

Botulism antitoxin (BAtx, equine) and botulism immunoglobulin (BIG-IV, human)

Botulism antitoxin or botulism immunoglobulin is used therapeutically in people with established or suspected botulism as well as prophylactically in asymptomatic people strongly suspected of having eaten food contaminated with the botulism toxin. Health Canada's Botulism-Guide for Health Care Professionals provides information about botulism including clinical specimen collection and submission. Botulism antitoxin and botulism immunoglobulin are not authorized for sale in Canada and are currently only available through the SAP. Only the following four products can be accessed through the SAP:

  1. Novartis trivalent Types ABE
  2. NP-018 (heptavalent) Types A to G
  3. BabyBIG®, Botulism immunoglobulin Intravenous; accessed from the Infant Botulism Treatment and Prevention Program at the California Department of Public Health
  4. Botulism antitoxin Type AB and Type E; accessed from the Butantan Institute in Brazil

BabyBIG® is a human-derived botulism antitoxin indicated in the treatment of infant botulism for infants up to one year of age. The manufacturers of BabyBIG® do not permit pre-orders of this product and it can only be obtained by directly contacting the SAP. For additional information on BabyBIG®, health care providers can contact the California Department of Public Health, Infant Botulism Treatment and Prevention Program at 510-231-7600.

Health care providers should request botulism antitoxin through their local public health officials. Public health officials will provide the botulism antitoxin from the Provincial/Territorial antitoxin stockpile or request it through the Public Health Agency of Canada's (PHAC) National Emergency Stockpile System or SAP.

Testing for hypersensitivity to the equine antitoxin preparations should be carried out in accordance with the manufacturer's recommendations before the antitoxin is administered. If sensitivity tests are positive, desensitization must be undertaken according to the manufacturer's recommendations.

Cytomegalovirus immunoglobulin (CMVIg)

Cytomegalovirus immunoglobulin (Cytogam®) is a solution of cytomegalovirus (CMV) Ig for IV administration. It is prepared from pooled human plasma from screened donors and contains relatively high levels of antibody against CMV. CMVIg can be used for:

  • reduction of the risk of primary CMV disease in CMV seronegative transplant recipients
  • adjunctive therapy for CMV pneumonitis in transplant recipients

The maximum recommended dose per infusion is 150 mg/kg of body weight. Since CMVIg is indicated in specific circumstances only, it should be used in consultation with a specialist in immunodeficiency. Further discussion of CMVIg is beyond the scope of the Canadian Immunization Guide.

Diphtheria antitoxin (DAtx, equine)

Anti-diphtheria serum is a specific immunoglobulin preparation for IM or IV administration, obtained from the plasma of horses hyper-immunized with diphtheria toxoid. The antitoxin is available on an emergency basis through local public health officials.

Diphtheria antitoxin should be administered when there is clinical suspicion of diphtheria. Bacteriologic confirmation is not required to initiate treatment. Testing for hypersensitivity to the preparation should be carried out before diphtheria antitoxin is administered. If sensitivity tests are positive, desensitization must be undertaken according to the manufacturer's recommendations. The method of testing for sensitivity to equine serum, as well as the dose and route of administration, are described in the manufacturer's product leaflet.

Diphtheria antitoxin is not recommended for prophylaxis of close contacts of diphtheria cases, whether immunized or not, given the substantial risk of allergic reaction to equine serum and lack of evidence of additional benefit of antitoxin for contacts who have received antimicrobial prophylaxis.

Refer to Diphtheria Toxoid in Part 4 for additional information.

Hepatitis B immunoglobulin (HBIg)

Hepatitis B immunoglobulin preparations (HyperHEP B® S/D, HepaGam B®) are solutions of hepatitis B Ig for IM administration, prepared from pooled human plasma from screened donors with a high level of antibody to hepatitis B surface antigen. HBIg provides immediate short-term passive immunity.

For post-exposure prophylaxis, hepatitis B (HB) vaccine is the most important intervention, providing 90% of the protection from hepatitis B; HBIg may provide additional protection and should be offered to susceptible individuals (refer to Table 2). HBIg may be given at the same time as HB vaccine but at different injection sites, using separate needles and syringes. HBIg administered concurrently with vaccine does not interfere with the antibody response to the vaccine. The timing and use of HBIg is currently under review by the National Advisory Committee on Immunization (NACI).

Table 2: Hepatitis B post-exposure prophylaxis, recommendations for use of HBIg
Post-exposure prophylaxis circumstance Recommendations

Infant born to a mother with acute or chronic hepatitis B infection

  • All infants born to infected mothers should be given an IM dose of 0.5 mL HBIg as soon as possible after birth (preferably within 12 hours) in addition to the first of a three dose series of HB vaccine (premature infants weighing less than 2,000 grams at birth require four doses of vaccine). The efficacy of HBIg decreases significantly after 48 hours, but HBIg may be given up to 7 days after birth.

Percutaneous or mucosal exposure to blood or body fluids potentially containing hepatitis B virus

  • HBIg should be given to susceptible individuals (based on their immunization and antibody status, and the infectious status, if known, of the source) within 48 hours after exposure1. Efficacy of HBIg decreases significantly after 48 hours, but HBIg may be given up to 7 days after exposure.
  • Dose of HBIg for older infants, children and adults is 0.06 mL/kg of body weight IM.

Sexual contacts of an acute case or chronic carrier of hepatitis B

  • A singleTabel 2 - Footnote 1 IM dose of HBIg (0.06 mL/kg of body weight) should be given within 48 hours after exposure.
  • Efficacy of HBIg decreases significantly after 48 hours, but may be given up to 14 days from the last sexual contact.

Refer to Hepatitis B Vaccine in Part 4 for additional information.

Rabies immunoglobulin (RabIg)

Rabies immunoglobulin products (IMOGAM®Rabies Pasteurized, HYPERRAB®) are solutions of anti-rabies Ig for IM administration, prepared from the pooled human plasma of screened donors immunized with rabies vaccine. RabIg is available on an emergency basis through local public health officials.

Post-exposure rabies prophylaxis of previously unimmunized individuals consists of both RabIg and rabies vaccine. RabIg provides immediate passive protection that persists for a short period of time (half-life of about 21 days) until the exposed person mounts an immunoresponse to the rabies vaccine.

The recommended dose of RabIg is 20 IU/kg of body weight for all age groups given on the first day of initiation of therapy. Because of possible interference of RabIg with the immunoresponse to the rabies vaccine, the dose of RabIg should not be exceeded. If possible, the full dose of RabIg should be thoroughly infiltrated into the wound and surrounding area. Any remaining volume of RabIg should be injected, using a different needle, intramuscularly at a site distant from the site of vaccine administration. When more than one wound exists, each wound should be locally infiltrated with a portion of the RabIg using a separate needle. In such instances, the RabIg can be diluted in a diluent permitted by the specific product labelling in order to provide the full amount of RabIg required for thorough infiltration of all wounds. If the site of the wound is unknown, the entire dose should be administered intramuscularly at a separate site from where the rabies vaccine is administered.

Rabies vaccine and RabIg may be given at the same time but at different injection sites, using separate needles and syringes. Rabies vaccine and RabIg should never be mixed in the same syringe. If RabIg is not administered as recommended at the initiation of the rabies vaccine series, RabIg can be administered up to day 7 after vaccine is initiated.

Refer to Rabies Vaccine in Part 4 for additional information.

Tetanus immunoglobulin (TIg)

Tetanus immunoglobulin (HYPERTET® S/D) is a solution of tetanus Ig for IM administration prepared from pooled human plasma of screened donors immunized with tetanus toxoid. TIg provides immediate passive protection until the exposed person mounts an immunoresponse to the tetanus toxoid.

Individuals who are previously unimmunized or incompletely immunized (unknown or less than 3 doses of tetanus-toxoid containing vaccine) and sustain a wound that is other than minor and clean should receive both TIg and tetanus toxoid-containing vaccine (as appropriate for age and immunization history) given at different injection sites using separate needles and syringes. Indications for post-exposure prophylaxis are outlined in Table 3.

Table 3: Guide to tetanus prophylaxis in wound management
History of tetanus immunization Clean, minor wounds All other wounds
Tetanus toxoid-containing vaccineTable 3 - Footnote 1 TIg Tetanus toxoid-containing vaccineTable 3 - Footnote 1 TIgTable 3 - Footnote 2
Unknown or less than 3 doses in a vaccine seriesTable 3 - Footnote 3 Yes No Yes Yes
3 or more doses in a vaccine series and less than 5 years since last booster dose No No No NoTable 3 - Footnote 4
3 or more doses in a vaccine series and more than 5 years but less than 10 years since last booster dose No No Yes NoTable 3 - Footnote 4
3 or more doses in a vaccine series and more than 10 years since last booster dose Yes No Yes NoTable 3 - Footnote 4

Some individuals with humoral immunodeficiency (e.g., HIV, agammaglobulinemia or hypogammaglobulinemia) may not respond adequately to tetanus toxoid-containing vaccine. Individuals with humoral immunodeficiency who have wounds that are not minor and clean should receive both TIg and tetanus toxoid-containing vaccine, regardless of the time elapsed since the last booster.

The recommended dose of TIg for adults and children is 250 units by IM injection. It is advisable to administer the entire contents of the vial of TIg regardless of the child's size; theoretically the same amount of toxin will be produced in a child or adult's body by the infecting tetanus organism.

Refer to Tetanus Toxoid in Part 4 for additional information.

Vaccinia immunoglobulin (VIG)

Vaccinia immunoglobulin intravenous is a solution of gamma globulin from the serum of individuals recently immunized with smallpox vaccine. It is indicated to treat severe smallpox vaccine-associated adverse events: eczema vaccinatum, progressive vaccinia, severe or recurrent generalized vaccinia, and extensive lesions resulting from accidental implantation (transfer of vaccinia virus from the primary vaccination site to other parts of the body). VIG is ineffective in the treatment of post-vaccinial encephalitis and has no role in the treatment of smallpox.

The PHAC Centre for Emergency Preparedness and Response has a supply of VIG based on a requirement of 1 dose of VIG for every 10,000 doses of smallpox vaccine. The Canadian Smallpox Contingency Plan indicates that VIG would be sent to the provinces/territories at the same time as smallpox vaccine and related supplies if smallpox occurs in Canada. Refer to Smallpox Vaccine in Part 4 for additional information.

Varicella zoster immunoglobulin (VarIg)

Varicella zoster immunoglobulin (VariZIG®) is a freeze-dried preparation of varicella zoster Ig prepared from the pooled human plasma of screened donors with high titres of antibodies to varicella zoster virus.

VarIg is recommended for the prevention or reduction in severity of infection within 4 days (96 hours) of the most recent exposure to the varicella zoster virus. The decision to administer VarIg should be based on fulfilling all of the following four criteria:

  1. The exposed person is susceptible to varicella (except for recipients of HSCT).
  2. There has been a significant exposure to a person with varicella or herpes zoster (HZ). The following situations are significant exposures to varicella zoster virus:
    • continuous household contact (living in the same dwelling) with a person with varicella or being indoors for more than 1 hour with a case of varicella
    • being in the same hospital room for more than 1 hour, or more than 15 minutes of face-to-face contact with a person with varicella
    • touching the lesions of a person with active varicella
    • close contact with a person with HZ. Close contact with HZ includes:
      • touching the rash, exposed lesion or vesicle fluid
      • contact with an individual who has disseminated HZ
      • contact with articles freshly soiled by discharges from vesicles
      • contact with articles freshly soiled by mucous membrane secretions of a person with disseminated HZ
      • exposure to an immunocompromised person with localized HZ anywhere on the body as their viral shedding may be greater.
  3. The exposed person is at increased risk of severe varicella including:
    • pregnant women
    • newborn infants of mothers who develop varicella during the 5 days before to 48 hours after delivery
    • selected neonates in intensive care settings
    • immunocompromised persons (including those with HIV with CD4 cell count < 200 × 106/L or CD4 percentage < 15%)
    • recipients of HSCT regardless of pre-transplant varicella immunostatus, history of varicella disease or vaccination, or positive serologic test results
  4. Post-exposure immunization with univalent varicella vaccine is contraindicated.

VarIg may be used within 96 hours from the most recent exposure. Protection conferred by VarIg lasts approximately 3 weeks. Subsequent exposures occurring more than 3 weeks after a dose of VarIg require additional doses of VarIg if the criteria for administration, as specified above, are met.

The recommended dose of VarIg is 125 IU/10 kg of body weight up to a maximum of 625 IU. The minimum dose is 125 IU. VarIg should be given by the IM route.

Individuals receiving replacement IVIg (400 mg/kg of body weight or higher) are considered protected and do not require VarIg if the last dose of IVIg was received within the three weeks prior to varicella exposure.

Refer to Varicella Vaccine in Part 4 for additional information.

Human immunoglobulin administration and storage

Large volumes of immunoglobulin for IM injection (greater than 2 mL for children or greater than 3-5 mL for adults, depending on muscle mass) should be divided and injected at two or more sites. Currently available human Ig preparations, with the exception of IVIg, VarIg, CMVIg, VIG, and BIG-IG, must not be given IV because of the risk of rare anaphylactic reactions.

Human Ig preparations should be stored at +2°C to +8°C. Do not freeze.

Human immunoglobulin safety and adverse events

Human Ig preparations are among the safest blood-derived products available. Plasma donors undergo a comprehensive screening process prior to donation and individuals with known risks for blood-borne pathogens are excluded from donating plasma for Ig preparations. Donated plasma is tested (at a minimum) for HIV, hepatitis B, hepatitis C and other infectious agents, and, if positive, is not used for the manufacturing of Ig products. In addition, donated plasma undergoes multiple purification procedures for human virus inactivation or removal during preparation of Ig products.

For safety information about products prepared from animal serum, consult the product leaflet. For safety information about specific Ig products consult the product leaflet or information contained within the product monographs available through Health Canada's Drug Product Database.

Common and local adverse events

Injection site reactions following receipt of standard human Ig include tenderness, erythema and stiffness of local muscles, which may persist for several hours. Mild fever or malaise may occasionally occur.

Less common and serious or severe adverse events

Less common side effects following receipt of standard human Ig include flushing, headache, chills and nausea. Urticaria, angioedema and anaphylactic reactions may occur rarely.

Guidance on reporting Adverse Events Following Immunization (AEFI)

Health care providers are asked to report, through local public health officials, any serious or unexpected adverse event felt to be temporally related to immunization with a passive immunizing agent. An unexpected AEFI is an event that is not listed in available product information but may be due to the immunization, or a change in the frequency of a known AEFI. Refer to Adverse Events Following Immunization in Part 2 and Reporting Adverse Events Following Immunization (AEFI) in Canada for additional information about AEFI reporting.

Contraindications and precautions

HBIg, VarIg and standard human Ig preparations are contraindicated in persons with history of anaphylaxis after previous administration of the product and in persons with proven immediate or anaphylactic hypersensitivity to any component of the product or its container. Refer to Contents of Immunizing Agents Available for Use in Canada in Part 1 for a list of passive immunizing agents available for use in Canada and their contents. If indicated, TIg and RabIg should be given with caution to persons with a history of prior systemic allergic reactions following the administration of human Ig preparations.

In situations of suspected hypersensitivity or non-anaphylactic allergy to product components, investigation that may involve administration in a controlled setting is indicated. Consultation with an allergist is advised.

Human Ig preparations should not be given to people with known isolated IgA deficiency unless the benefit outweighs the risk, in which case the product should be given with caution and under close observation.

For people with bleeding disorders, special measures need to be considered before administering IM injections. Any bleeding disorder should be optimally controlled. For example, hemophiliacs may receive clotting factor concentrates to optimize their clotting factor level. There is evidence to suggest that IM administration is safe when given with a small gauge needle (23 gauge or smaller) and firm pressure is applied to the injection site for ≥ 2 minutes.

Drug interactions

Passive immunization with human Ig preparations can interfere with the immunoresponse to MMR, measles-mumps-rubella-varicella (MMRV) and univalent varicella vaccines. These vaccines should be given at least 14 days prior to administration of a human Ig preparation, or delayed until the antibodies in the Ig preparation have degraded. Refer to Blood Products, Human immunoglobulin and Timing of Immunization in Part 1 for additional information.

Selected references

  • Buckley RH, Schiff RI. The use of intravenous immunoglobulin in immunodeficiency diseases. N Engl J Med 1991;325(2):110-17.
  • Canadian Paediatric Society, Infectious Diseases and Immunization Committee. Position statement: Transfusion and risk of infection in Canada: Update 2006; accessed July 2012 at: http://www.cps.ca/english/statements/ID/PIDNoteTransfusion06.htm
  • Cangene Corp. Product Monograph - HepaGam B™. April 2009.
  • Cangene Corp. Product Monograph - VariZIG™. January 2008.
  • CSL Behring Canada Inc. Product Monograph - Cytogam® March 2011.
  • Grifols Therapeutics LLC. Product Monograph - GamaSTAN®. March 2019.
  • Grifols Therapeutics LLC. Product Monograph - HyperHEP B™ S/D. February 2012.
  • Grifols Therapeutics LLC. Product Monograph - HYPERTET™ S/D. February 2012.
  • Grifols Therapeutics LLC. Product Monograph - HYPERRAB®. March 2019.
  • Mclntosh D, Isaacs D. Varicella zoster virus infection in pregnancy. Arch Dis Child 1993;68:1-2.
  • Miller E, Cradock-Watson JE, Ridehalgh MK. Outcome in newborn babies given anti-varicella-zoster immunoglobulin after perinatal maternal infection with varicella-zoster virus. Lancet 1989;2(8659):371-73.
  • Novartis Vaccines and Diagnostics GmbH & Co. Product Leaflet - Botulism Antitoxin Behring. September 2006.
  • Sanofi Pasteur Ltd. Product Monograph - IMOGAM®Rabies Pasteurized, October 2005.
  • Siber GR, Werner BC, Halsey NA et al. Interference of immunoglobulin with measles and rubella immunization. J Pediatr 1993;122(2):204-11.
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