Canadian Immunization Guide
Seventh Edition - 2006

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Part 1
General Guidelines

Principles of Combination Vaccines

Combination vaccine products are already available for many immunizations conducted in Canada. Diphtheria, tetanus and polio vaccines have been available as a combination product for over 30 years. Since 1996, all infants in Canada have been vaccinated against diphtheria, tetanus, pertussis, polio and Haemophilus influenzae type b (DTaP-IPV-Hib ) with a single, pentavalent vaccine.

Over the past few years, the number of combination vaccine products has grown considerably, and this trend will continue with more vaccines being introduced to the routine immunization schedule for children and adults. As new products are recommended, it is important for the immunization provider to feel comfortable with the principles of combination vaccines. This chapter serves as a general overview of these principles. For details on specific combination vaccines, please refer to the individual chapters in this Guide.

What is a combination vaccine?

Combination vaccines are developed to protect against more than one infection. Polyvalent vaccines against multiple strains or serotypes of the same infectious agent are not considered to be combination vaccines. The term "combined vaccines" may also be used to describe the mixture of two separate vaccines in a single vial prior to administration or vaccines that are separately manufactured but combined into one product during the final packaging stages.

General principles of combination vaccines

• Combination vaccines are rigorously evaluated before approval for use in Canada. Only those combinations that are known to be safe and efficacious are recommended for routine use. For an overview of vaccine safety, including that of specific combination products, please refer to the chapter on Vaccine Safety.
• Ideal combination vaccines are as safe and effective as each of their single component counterparts.
• Combination vaccines should fit the currently recommended schedule, be easily stored and easy to administer.
• Combination vaccines facilitate adherence to recommended immunization schedules by reducing the number of immunization visits required as well as the number of injections a person receives.
• Combination products can potentially decrease the amount of adjuvants and preservatives when compared with multiple, single-antigen products.
• Health care providers should never combine products that are intended for separate administration.

Efficacy of combination vaccines

• The efficacy of each component in a combination vaccine is compared with established parameters of protection before approval.
• Antibody responses to specific antigens in combination products may be either stronger or weaker than those to separately administered single antigens.
• The impact of any observed changes in antibody titres is assessed against the known human protective levels of antibodies or other indicators of efficacy.
• Combination vaccines approved to date have an efficacy and safety record similar to that of single-component vaccines.
  • The addition of Hib to the combination vaccine with tetanus, diphtheria, acellular pertussis and polio did not result in diminished immune responses to the tetanus, diphtheria, acellular pertussis and polio components. The response to the Hib antigens was somewhat reduced; however, a significant impact on clinical efficacy when the vaccine was administered according to the Canadian immunization schedule was not demonstrated through post-marketing studies.

Safety of combination vaccines

• The currently available combination products in Canada have had excellent safety records.
• Ideal combination vaccines should have fewer adverse reactions or, at the very least, no more than if administering single-antigen products separately.
• The safety of each new combination product is rigorously evaluated prior to approval and compared against the safety of single-antigen products or existing combination vaccines.
• New combination vaccines help to further our knowledge regarding co-administration of antigens as combination vaccines, as they are all well evaluated before approval.
• The vaccine provider may face questions from parents about their feelings that multiple combination vaccines can weaken the immune system.
• With the refinement of vaccine development and production over past decades, children today are exposed to far fewer vaccine antigens than in the past, even though they are immunized against more infections with more combination vaccines.
• Children are naturally exposed to multiple antigens on a routine basis. They respond well to these persistent exposures with no untoward effects on their immune system.
• If multiple antigens posed a problem for the immune system, we would find that infants vaccinated with combination products had less protection against the infection than those vaccinated with single products. This has not been found.

Complexities of combination vaccines

• The efficacy and safety of each component in a combination must be evaluated separately and in its combined form, thereby increasing the complexity of pre-approval clinical trials.
• Clinically important interference between each component of a combination vaccine must be ruled out. Antibody responses to individual antigens in combination products may be diminished. Given that antibody responses are only a surrogate for clinical efficacy, assessing or estimating the clinical relevance of this is complex. In the development of new combination products, acceptable endpoints and immunization goals should be clearly defined.
• The measurement of potency and antigen content of combination products is more complex and difficult.
• Even a single, transient problem in the production of an individual component of a combination product could lead to a significant shortage in vaccine supply for multiple diseases.
• In the context of combination products, the effects of adjuvants can be difficult to assess.
• It can be difficult to determine which component is responsible for an allergic or other adverse event.
• There are usually increased costs associated with combination product procurement.

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