ARCHIVED - Interchangeability of Diphtheria, Tetanus, Acellular Pertussis, Polio, haemophilus Influenzae Type B Combination Vaccines Presently Approved for Use in Canada for Children < 7 Years of Age

Introduction 

In Canada, there are two manufacturers that supply three combination vaccines against diphtheria, tetanus, pertussis, polio and Haemophilus influenzae type b (Hib), for use in infancy through early childhood. While these products offer equivalent protection against these diseases, they differ slightly in composition. The recommendations within this statement focus on the interchangeability of the presently approved products based on current scientific data, experiences of other countries and expert opinion. 

Given the nature of this statement and the similarities between different vaccines, trade names of vaccines will be used to minimize product confusion.  

General Principles of Vaccine Interchangeability 

As the number of combination vaccine products being developed and marketed in Canada increases, it is important to consider the issue of vaccine interchangeability. While combination products reduce the number of injections given to each child, their introduction necessitates switching from single antigen vaccinations. Where combination products are already the standard of care, several factors may necessitate giving different products to the same child over time. If the previously administered product is not known, or is not available, a switch may be required. Even when faced with vaccine product shortages, deferring vaccination is not desirable as one study demonstrated that 25% of deferred children never return for the indicated vaccination^{Footnote 1}.

When examining candidate vaccines for potential interchangeability, there are several factors that should be taken into account. The vaccines should be approved with the same indications and should be equally acceptable in terms of safety, reactogenicity, immunogenicity and efficacy. Even when approved for the same indications, different manufacturers use different production methods, antigen concentrations, stabilizers and preservatives. Each of these could potentially impact on the immunogenicity, safety or efficacy profile of the product. In addition, if an immunization regimen is to be changed to use different vaccine products interchangeably, the new regimen should be equally acceptable from the perspective of safety and efficacy, as well as scheduling.

Ideally, as new combination vaccines become available, there should be randomized controlled clinical trials evaluating their interchangeability with existing products. To date, this has not been routinely done. Most of our knowledge has resulted from situations of vaccine shortage, immigration to areas where different vaccine products are available, and new product purchases with the negotiation of new contracts. Given the importance of this issue and the limited data available regarding the inter- changeability of early childhood vaccines, every opportunity should be taken to encourage further research in this area.

Review of Combination Vaccine Products Approved for Use in Canada for the Prevention of Diphtheria, Tetanus, Pertussis, Polio and Haemophilus influenzae type b (see Table 1)

The three pentavalent combination diphtheria, tetanus, acellular pertussis, polio and Haemophilus influenzae type b (DTaP-IPV/ Hib) vaccines presently approved for use in Canada have all demonstrated less reactogenicity compared with whole-cell pertussis combination vaccines and adequate immunogenicity against component antigens in pre-licensure studies. They all contain small amounts of aluminum and are thimerosal free. Each must be stored between 2 °C and 8 °C and must not be frozen. While all target the same diseases, there are some differences with regard to component antigens, their concentrations and the vaccine formulations, as outlined below.

Pentacel™ (Aventis Pasteur Limited) 

Since 1997, Pentacel^TM has been used for the primary immunization and 18-month booster injection of all children living in Canada. Pentacel^TM is reconstituted immediately prior to administra- tion by combining a lyophilized powder containing Haemophilus influenzae type b tetanus protein-conjugate vaccine (Act-Hib^TM) with Quadracel^TM, a liquid product containing acellular pertussis vaccine, adsorbed diphtheria and tetanus toxoids and inactivated polio vaccine. The pertussis vaccine has five components: pertussis toxoid (PT), filamentous hemagglutinin (FHA), pertactin (PRN) and fimbrial proteins 2 and 3 (FIM2 and FIM3). The diphtheria and tetanus toxoids are denatured with formaldehyde. The three poliovirus types are propagated in human diploid cells and formalin inactivated. 

Pediacel™ (Aventis Pasteur Limited) 

PediacelTM was approved for use in Canada in 2000 but has not been marketed. It differs from PentacelTM in that the Hib component comes pre-mixed in a liquid formulation with the other components in an ampoule. While the concentrations and types of the three poliovirus strains in PediacelTM are identical to those in PentacelTM, they are grown in Vero monkey kidney cell lines. The pertussis vaccine contains the five component antigens at the same concentrations as PentacelTM; the amounts of tetanus and diphtheria toxoids are also the same. 

Infanrix™ -IPV/Hib [GlaxoSmithKline (GSK) Inc.] 

InfanrixTM-IPV/Hib is a pentavalent vaccine that also requires reconstitution prior to administration. This is done by combining tetanus protein conjugate adsorbed Hib vaccine (HiberixTM) with the InfanrixTM-IPV, a product composed of acellular pertussis, adsorbed diphtheria and tetanus toxoids and inactivated polio vaccines. This vaccine differs from the PediacelTM and PentacelTM vaccines in that the pertussis portion is derived from only three component antigens: pertussis toxoid, pertactin, and FHA. The concentrations of each of these antigens are each 5 µg greater than in the five-component pertussis vaccines. The tetanus and diphtheria concentrations are 5 µg and 10 µg greater per dose, respectively, than in PentacelTM; however, there does not appear to be greater reactogenicity with this product based on reported adverse effects. The poliovirus strains, as in PentacelTM, are propagated in human diploid cells and inactivated. 

Evidence Regarding Vaccine Comparability and Interchangeability 

To date, no clinical trials have been performed that directly compare the three pentavalent combination vaccine products described above when used for the primary immunization series. There are also no studies directly examining their interchangeability for the 2-, 4- and 6-month immunizations. Pentacel^TM and Pediacel^TM have demonstrated similar immunogenicity. The reactogenicity of all three vaccines appears comparable in pre-licensure studies. The results from a recent Canadian randomized controlled non-inferiority trial comparing Pentacel^TM and Infanrix^TM-IPV/Hib for the 18-month booster injection after primary immunization with Pentacel^TM have shown that the two products are equivalent with regard to immunogenicity to component antigens 1 month after vaccination. They also have comparable safety profiles (data on file at GlaxoSmithKline). 

Haemophilus influenzae type b

Several different protein carriers have been used in the conjugation process for Hib vaccines. In the Canadian context, all of the currently approved combination vaccines use Hib conjugated to tetanus toxoid (PRP-T). PRP-T has been shown to cause fewer local reactions than many of the other protein carriers used^{Footnote 2-3}. 

An anti-PRP concentration of 1 µg/mL or higher is considered to be a serologic correlate of protection against disease. Several studies have demonstrated lower immunogenicity to the Hib component of combination whole-cell pertussis vaccine products that include Hib antigens when compared with individually administered Hib conjugate vaccine. Several studies evaluating acellular pertussis combination products containing Hib have demonstrated decreased titres when compared with individually administered Hib vaccine. This appears to be particularly evident with the combination vaccines containing fewer pertussis antigens, including Infanrix^{TM Footnote 4-7}. 

However, given that the anti-Hib titres of the acellular pertussis combination vaccines are in the range of what is believed to be protective, the functional activity of antibodies remains unchanged and immune memory is not decreased by the combined products, there has been an acceptance of their use as a combination vaccine. In Canada, no increase in invasive Hib disease has been observed with the use of pentavalent products^{Footnote 8}. In fact, by 2000 there had been a 99% reduction in Hib meningitis compared with pre-vaccine levels. In Germany, the first country to introduce combination acellular pertussis products with Hib on a national scale, there was a continued decline in invasive disease with vaccine efficacy estimated at > 98.8% following completion of the primary series^{Footnote 9}. These rates are similar to those reported for monovalent Hib conjugate vaccines in several other countries. The one exception is in the United Kingdom, where an increase in breakthrough Hib disease was observed between 1999 and 2002, when they introduced a three-dose primary series at 2, 3 and 4 months without a booster dose. However, the early primary series scheduling and the lack of a booster dose are likely key contributing factors to this finding^{Footnote 10-11}.

Multiple studies have been undertaken to assess the inter- changeability of Hib conjugate combination vaccine products in Canada and elsewhere. Scheifele et al, randomly selected 319 Canadian children who had received three doses of either HbOC (HibTITER^TM) or PRP-T (Act-HIB^TM) at 2, 4 and 6 months to receive one of these two vaccines for the 18-month booster. No differences in reactogenicity were observed and better immunogenicity was seen in those primed with PRP-T regardless of which product they received as a booster^{Footnote 12}. Bewley et al.^{Footnote 13} also demonstrated similar reactogenicity between Hib conjugated to meningococcal protein, tetanus toxoid or diphtheria toxoid. All three vaccines demonstrated the ability to prime the immune system adequately even when given as mixed products to complete the primary series.

Diphtheria, Tetanus and Polio 

Combination vaccines with acellular pertussis and Hib do not result in diminished immune responses to either the diphtheria, tetanus or polio components. While the higher antigen concentrations of diphtheria and tetanus in some products such as Infanrix^TM could theoretically result in increased reactogenicity and adverse events, this has not been demonstrated in the clinical trial setting to date. A Canadian study comparing polio vaccines made in Vero monkey kidney cell lines with those in human diploid cell lines when given in combination with DTaP demonstrated no differences in adverse reactions or immunogenicity between the two^{Footnote 14}.

Pertussis 

Immunologic correlates of protection against pertussis are still not well defined, making it difficult to compare immune responses to different combination acellular pertussis vaccines. The pertussis antigens that have been used in acellular vaccines developed to date include PT, FHA, PRN, FIM2 and FIM3. Debate persists as to which antigens are needed to confer both adequate and optimal immunity against the disease.

In a study comparing pertussis incidence among persons having household exposures using antibody titres to the different antigens, antibodies to PRN were found to be most correlated with protection^{Footnote 15}. Some protection was also conferred with antibodies to PT and FIM 2. Anti-FHA did not seem to have added protection. In a nested household study in Sweden comparing infants who had received two or five component DTaP vaccines, Storesaeter et al.^{Footnote 16} also found that antibodies to PRN and FIM2/3 conferred protection, as did PT to a lesser degree. In yet another study, Taranger et al.^{Footnote 17} administered a single component DTaP vaccine with PT and found that the number of pertussis cases decreased dramatically in the population, indicating that the PT antibody alone conferred significant protection.

In general, all of the currently approved acellular pertussis combination vaccines have demonstrated good immunogenicity to their component antigens and decreased reactogenicity when compared with the previously used, whole-cell products. Studies have evaluated whether single versus multiple antigen products have equal efficacy against disease. When examining cases of laboratory-confirmed pertussis with cough (7 days), single component PT vaccines have been shown to be less effective than two component PT/FHA vaccines. Three or four component vaccines containing PRN in addition to PT and FHA are more effective than either single- or two-component vaccines^{Footnote 18}. In a double-blind, cohort study comparing five-component, two-component and whole-cell pertussis vaccines, there were significant differences in efficacy, with the five-component product demonstrating an 85% efficacy, the two-component a 59% efficacy, and the whole-cell, a 48% efficacy^{Footnote 19}. It is likely, therefore, that antibodies to the different component antigens all play a role in protection against clinical disease, with PT being a major contributor. Immunogenicity to PT appears to depend not only on antigen concentration but also possibly on antigen derivation and formulation^{Footnote 20}.

Several studies have demonstrated adequate immunologic responses to pertussis antibodies and comparable reactogenecity when different vaccine products have been used interchangeably for both the primary series and booster doses^{Footnote 21-23}. Unfortunately, none has involved all of the three products presently approved in Canada. Tripedia^TM is a trivalent acellular pertussis, diphtheria and tetanus toxoids vaccine product manufactured by Aventis Pasteur Limited that has similar tetanus toxoid and slightly decreased diphtheria toxoid concentrations compared to Pentacel^TM. There are only two component pertussis antigens in Tripedia^TM. In a study evaluating the interchangeability of Tripedia^TM and Infanrix^TM at 2, 4 and 6 months of age, non-inferiority was demonstrated with regard to reactogenicity and immunogenicity^{Footnote 22}. Pichichero et al.^{Footnote 23} demonstrated that, in infants who had received mixed acellular pertussis vaccine products for the primary series and/or 18-month booster injection, antibody titres to component antigens were not significantly different than those in children who received the same acellular product at each immunization when evaluated just prior to the 4- to 6-year booster dose. In this same cohort of children, no differences were found in antibody responses or reactogenicity following the fifth booster dose. This finding demonstrated that completing a DTaP vaccine regimen with an alternative product did not compromise the immune response to the vaccine antigens contained within the original vaccine^{Footnote 24}. 

Recommendations in Other Countries 

Canada is not the first country to examine the issue of vaccine interchangeability. While it is clear that evidence from published literature is still lacking, other countries have adopted permissive approaches. In the United States, all types of Hib conjugate vaccines are deemed interchangeable once the primary series has been completed^{Footnote 25}. The Advisory Committee on Immunization Practices recommends that, wherever possible, the same DTaP vaccine should be used for the primary series given the lack of good immunologic correlates of pertussis protection. If the initial product is either not known or not available, the American Academy of Pediatrics' 2003 recommendations state that an alternative product may be used to complete the primary DTaP series. Feldman et al.^{Footnote 26} in a review on vaccine interchangeability, reiterates the general principle that providers not miss immunization opportunities. 

Australia's latest recommendations state that with the exception of acellular pertussis vaccines, products from different manufacturers that protect against the same disease may be used interchangeably. However, with regard to acellular pertussis products, they state that until more data become available, vaccines from the same manufacturers should be used for the primary series. If the previous acellular pertussis vaccine type is unknown or not available, it is advised that vaccination should proceed with any registered product^{Footnote 27}. 

New Zealand plans to change from Infanrix^TM-IPV to Quadracel^TM. Citing an absence of clinical data to support interchangeability, they have recommended that infants who have already initiated the primary series complete it with Infanrix^TM-IPV. If this is not possible, then Quadracel^TM should be used to complete the series (Dr. A. Roberts, Public Health Directorate, Ministry of Health, Australia: personal communication, 2004). 

NACI Recommendations 

1. A regularly scheduled primary or booster vaccination should not be deferred due to the lack of availability of a particular product.

2. The primary immunization series should, wherever possible, be completed with the same combination product. However, based on expert opinion, if the original vaccine is not known or not available, it is recommended that an alternative combination DTaP-IPV/Hib product be used to complete the primary immunization series.

3. Based on expert opinion and using the limited data available to date, NACI recommends that the DTaP-IPV/Hib and DTaP-IPV combination vaccine products currently approved for sale in Canada may be used interchangeably for the 18-month and 4- to 6-year booster, respectively. 

   • There is good evidence that using the currently available combination vaccine products interchangeably for the 18-month and 4- to 6-year booster, does not adversely affect the immunogenicity and effectiveness of the diphtheria, tetanus and polio components. 
   • There is good evidence that Hib combination vaccine products can be used interchangeably for the 12- to 18-month booster, as long as a single combination vaccine product was used for the primary series. Based on expert opinion and in the absence of conclusive scientific data, if the primary series has been completed using more than one combination vaccine, any combination DTaP-IPV/Hib product can be used for the 12- to 18-month booster. 
   • Based on expert opinion, and in the absence of conclusive scientific data, alternate combination acellular pertussis vaccine products can be used for the 18-month and/or 4- to 6-year booster immunizations for the prevention of pertussis. 

Research Needs 

Every opportunity should be taken to evaluate the safety and effectiveness of the interchangeability of combination vaccine products in the context of the Canadian childhood immunization program. 

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*Members: Dr. M. Naus (Chairperson), Dr. T. Tam (Executive Secretary), Dr. I. Bowmer, Dr. S. Dobson, Dr. B. Duval, Dr. J. Embree, Ms. A. Hanrahan, Dr. J. Langley, Dr. A. McGeer, Dr. P. Orr, Dr. M.N. Primeau, Dr. B. Tan, Dr. B. Warshawsky, A. Zierler. 

Liaison Representatives: S. Callery (CHICA), Dr. J. Carsley (CPHA), Dr. L. Chapman (CDC), Dr. A. Gruslin (SOGC), A. Honish (CNCI), Dr. B. Larke (CCMOH), Dr. B. Law (ACCA), Dr. A. McCarthy (AMMI Canada), Dr. S. Rechner (CFPC), Dr. J. Salzman (CATMAT), Dr. L. Samson (CPS), Dr. D. Scheifele (CAIRE). 

Ex-Officio Representatives: Dr. S. Deeks (CIDPC), Dr. A. Klein and Dr. H. Rode (BREC), Dr. M. Lem (FNIHB), Dr. M. Tepper (DND). 

This statement was prepared by Dr. Lindy Samson with assistance from Dr. Shelley Deeks and approved by NACI.