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 immune globulin, including common adverse events, is presented.
Several changes have been made to the chapter since the publication of the 2006 Canadian Immunization Guide. Information on the indications and use of the cytomegalovirus immune globulin and the vaccinia immune globulin has been added. The chapter has also been expanded to include information about administration and storage of human immune globulin products. Finally, all recommendations have been updated following the release of Part 4 chapters containing comprehensive information on the use of specific immunizing agents available in Canada.
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:
|Passive immunizing agent||Origin of antibodies|
|Standard immune globulin|
|Standard human Ig||Human plasma|
|Specific immune globulins|
|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
|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 Available for Use in Canada in Part 1 for a list of passive immunizing agents available for use in Canada and their contents.
Standard human immune globulin (GamaSTAN® S/D) is a sterile, concentrated solution for intramuscular (IM) injection containing 15% to 18% immune globulin. 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 immune globulin 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 immune globulin is not regulated by Health Canada. Theoretically, the concentrations of specific measles and hepatitis A antibody in standard human immune globulin may be insufficient due to lower levels of antibody in the general population as a result of decreased rates of natural infection. This issue is under NACI review. Maximum plasma levels are reached approximately 2 days after IM injection, and the half-life in the circulation of individuals with normal IgG levels is 23 days.
Subcutaneous (Sc) and intravenous (IV) immune globulin (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, and recommendations in the product leaflet or product monograph should be followed.
Prophylactic use of Ig has been shown to be effective in modifying or preventing disease if administered within 6 days after exposure to measles, however, it should be given as soon as possible after exposure when indicated. Ig should be considered for susceptible pregnant women and susceptible immunocompromised contacts of measles, and for children less than 6 months of age; measles-containing vaccine is contraindicated in the two former groups and effectiveness and safety has not been established in the latter group. Ig should also be considered for susceptible immunocompetent contacts of measles who are 6 months of age and older and who present more than 72 hours after exposure (when MMR vaccine no longer provides post-exposure protection) but within 6 days after exposure (when Ig may still provide post-exposure protection).
The recommended dose of Ig for healthy individuals exposed to measles is 0.25 mL/kg of body weight given by the IM route. The dose for exposed individuals who are immunocompromised is 0.5 mL/kg of body weight. A maximum dose of 15 mL should not be exceeded.
Individuals receiving replacement IVIg (400 mg/kg of body weight or higher) are considered protected and do not require Ig if the last dose of IVIg was received within the three weeks prior to measles exposure.
Unless it is contraindicated, individuals who receive Ig for the prevention of measles should receive measles-containing vaccine after specified intervals, once the measles antibodies administered passively have degraded. Refer to Blood products, human immune globulin and timing of immunization in Part 1 for additional information.
Refer to Measles Vaccine in Part 4 for additional information.
Hepatitis A (HA) vaccine is the preferred agent for pre-exposure prophylaxis. Ig will provide protection against HA when administered IM before exposure. Ig is indicated for pre-exposure prophylaxis for:
Administering Ig immediately before travel will ensure that protective concentrations of antibody are adequate for short-term (up to 6 months) travel.
The recommended dose of Ig varies according to the duration of required protection. In general, for protection lasting less than 3 months the dose is 0.02 mL/kg of body weight. If protection is required for 3 months or longer, 0.06 mL/kg of body weight should be administered and repeated every 6 months.
Hepatitis A (HA) vaccine is the preferred agent for post-exposure prophylaxis. Ig is the recommended post-exposure immunoprophylactic agent:
For post-exposure prophylaxis, the dose of Ig is usually 0.02 mL/kg of body weight, given as soon as possible after an exposure. Efficacy of Ig is unknown if more than 14 days have elapsed since the last exposure.
Refer to Hepatitis A Vaccine in Part 4 for more information about HA vaccine.
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 immune globulins 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. Immune globulins 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 immune globulin (BIG-IV, human)
Botulism antitoxin or botulism immune globulin 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 immune globulin 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:
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 immune globulin (CMVIg)
Cytomegalovirus immune globulin (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:
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 immune globulin 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 immune globulin (HBIg)
Hepatitis B immune globulin 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).
|Post-exposure prophylaxis circumstance||Recommendations|
|Infant born to a mother with acute or chronic hepatitis B infection||
|Percutaneous or mucosal exposure to blood or body fluids potentially containing hepatitis B virus||
|Sexual contacts of an acute case or chronic carrier of hepatitis B||
Refer to Hepatitis B Vaccine in Part 4 for additional information.
Rabies immune globulin (RabIg)
Rabies immune globulin products (IMOGAM® Rabies Pasteurized, HYPERRAB® S/D) 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 immune response 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 immune response 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 two-fold to three-fold in a solution of 0.9% sodium chloride 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.
Respiratory syncytial virus (RSV) monoclonal antibody (RSVAb)
Respiratory syncytial virus monoclonal antibody (SYNAGIS® [palivizumab]) is a humanized monoclonal antibody to RSV produced by recombinant DNA technology and composed of 95% human and 5% murine amino acid sequences. RSVAb is not derived from human Ig, and is free of potential contamination from blood-borne infectious agents.
RSVAb prophylaxis is recommended for children who are at high risk of severe RSV disease as outlined in Table 3.
|Infants born prematurely|
|Infants born prematurely at 32 weeks or less gestational age||
|Infants born prematurely between 33 and 35 weeks gestational age||
|Children with lung disease|
|Children younger than 24 months of age with chronic lung disease of prematurity or bronchopulmonary dysplasia||
|Children with heart disease|
|Children younger than 24 months of age with hemodynamically significant cyanotic and acyanotic heart disease||
|Children living in rural and remote communities|
|Infants born prematurely between 33 and 35 weeks gestational age who live in rural or remote communities||
|Inuit children younger than 6 months of age at start of RSV season||
RSVAb is administered by the IM route only; the preferred site of injection is the anterolateral thigh. RSVab is administered every 4 weeks at a dose of 15 mg/kg of body weight for each of the five months during the period of high risk of exposure to RSV (maximum of 5 doses). Providing the first dose at least 2 weeks prior to the onset of the local RSV season is recommended; for neonates, initial dosing just prior to hospital discharge during the RSV season is recommended.
Children who become infected with RSV while taking RSVAb prophylaxis should continue to receive their scheduled monthly doses of RSVAb throughout the RSV season, because RSV infection itself does not confer protective immunity.
Tetanus immune globulin (TIg)
Tetanus immune globulin (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 immune response 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 4.
|History of tetanus immunization||Clean, minor wounds||All other wounds|
|Unknown or less than 3 doses in a vaccine seriesFootnote 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||NoFootnote 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||NoFootnote 4|
|3 or more doses in a vaccine series and more than 10 years since last booster dose||Yes||No||Yes||NoFootnote 4|
Some individuals with humoral immune deficiency (e.g., HIV, agammaglobulinemia or hypogammaglobulinemia) may not respond adequately to tetanus toxoid-containing vaccine. Individuals with humoral immune deficiency 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 immune globulin (VIG)
Vaccinia immune globulin 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 immune globulin (VarIg)
Varicella zoster immune globulin (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:
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.
Large volumes of immune globulin 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 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 Vaccine Safety 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 some evidence to suggest that IM administration may generally be safe when given with a small gauge needle (23 gauge or smaller) and firm pressure is applied to the injection site for 5-10 minutes.
Passive immunization with human Ig preparations can interfere with the immune response 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 Immune Globulin and Timing of Immunization in Part 1 for additional information.