Combination Vaccines

Sayenna Uduman*, M I Sahadulla**, Raja Lakshmi***, Pretty G tharakan****
*MD, FAAP

Visiting Professor, Infection Control Committee & ID Division of the KIMS

Thiruvananthapuram, Kerala, India


**CMD, ID Division, KIMS

***ID Consultant, KIMS

****Clinical Pharmacist, KIMS

First Created: 03/11/2016 

Foreword

During the past two decades, the number of injections that are required per clinic visit to fulfill the recommended childhood immunization schedule has been increasing dramatically. This has created problems for patients and practitioners, sometimes risking a missed opportunity for vaccination. Simplifying immunization schedules and to reduce the number of injections, combination vaccines have been developed by combining multiple vaccines into a single syringe. In this review, the combination of vaccines (combos’) is defined as those containing various antigens to prevent different diseases or to protect against multiple strains of infectious agents causing the same disease.

Combos’ are available for many years include diphtheria and tetanus toxoids and pertussis vaccine (DTP); and measles-mumps-rubella (MMR). Also, the vaccines containing immunizing antigens against more than one serogroup or serotype of the same disease i.e. the pneumococcal, quadrivalent meningococcal and human papillomavirus (HPV) vaccines are symbolic. Improved vaccines are evolving continually & expected to be marketed for immunization purposes. The Health Ministry in each country has its own combos' preference and there have been no universally acceptable schedules in use.

Combos

  • A single injection that includes immunizations against two or more diseases.

  • Represent one solution to the issue of increased numbers of injections during single clinic visits and generally, combo’s are preferred over separate injections of equivalent component vaccines.

  • Can be used whenever any components of the combination are indicated and its other components are not contraindicated and got approved for use by the health and professional authorities (i.e. CDC, ACIP, COIDs, WHO, IAP, etc) for that dose in the series.

Combination Vaccines Authorised in The US

There are many combo preparations available for immunization use with different antigen components & formulations. The names of the new combo’s can be confusing, and some parents worry that their children may be vaccinated more than once for the same disease. Vaccine providers and pediatricians should be familiar with each combo’s components they choose and one should avoid using trade names that could be misinterpreted or may be banned after use for some time. The best way to avoid this is to maintain clear, up-to-date immunization records. Parents should keep all records together and bring them to their children’s doctor appointments. The approved Combo’s that are authorized for use in the US is provided in table 1.

Table 1 : Combination Vaccines licensed by the US Food and Drug Administration (FDA) - Redbook (2016)

# Combo Vaccines Trade name (Yr licensed) Age group Use in immunization schedule
1 Hib-rHepB Comvax (1996) Merck. 6 wk through 71 months Three-dose series administered at 2, 4, and 12 through 15 months of age.
2 HepA-rHepB Twinrix (2001) GSK =18 y Three doses on a 0-, 1-, and 6-mo schedule
3 DTaP-rHepB-IPV Pediarix (2002) 6 wk through 6 y Three-dose series at 2, 4, and 6 mo. of age
4 MMRV ProQuad (2005). Merck >12 months 12 months through 12 years, Two doses
5 DTaP-IPV Kinrix (2008) 4 y through 6 y Booster for fifth dose of DTaP and fourth dose of IPV
6 DTaP-IPV/ Hib Pentacel (2008) 6 wks through 4 y Four-dose series administered at 2, 4, 6, and 15 through 18 mon of age
7 Hib-MenCY MenHibrix (2013) GSK 6 wks through 18 months Four-dose series administered at 2, 4, 6, and 12 through 15 months of age
Dash (-) indicates products are supplied in their final form by the manufacturer and do not require mixing or reconstitution by user; slash (/) indicates products are mixed or reconstituted in which active components must be mixed by the user.

Hib= Haemophilus influenzae type b ; HepA=hepatitis A; rHepB = recombinant hepatitis B ; DTaP= Diphtheria–tetanus-acellular pertussis; IPV= inactivated poliovirus; MMRV= measles-mumps-rubella-varicella ; MenCY= meningococcal conjugate vaccine Serogroup C and Y.

Overview of Licensed DTP-based Pediatric Combinations in the US and Europe

  • Three diphtheria, tetanus, and acellular pertussis (DTaP) combinations are licensed for use in the pediatric population: Tripedia and Daptacel from Sanofi Pasteur and Infanrix from GSK.

  • Two larger licensed combinations currently in use are pentavalent Pediarix, a DTaP-HepB-IPV vaccine from GSK and pentavalent Pentacel, a DTaP-IPV/Hib combination from Sanofi Pasteur.

  • In addition, there is the tetravalent booster DTaP-IPV vaccine Kinrix for use in 4- to 6-year-old children and adult booster DTaP vaccines Adacel and Boostrix. Further details of these vaccines are outlined in Table 2.

Table 2: Available DTaP-based Combo’s in North American settings

Vaccines Trade name Manufacturer No. of doses in series Schedules Remarks
Childhood          
DTaP Tripedia

Infanrix

Daptacel
Sanofi Pasteur

GSK biolog

Sanofi
5

5

5
2, 4, 6, 15-18 mon, 4 to 6 y

2, 4, 6, 15-20 mon, 4 to 6 y

2, 4, 6, 15-20 mon, 4 to 6 y
Adjuvant; alum

Adju: aluminum hydroxide

Adju: aluminum hydroxide
DTaP-rHepB-IPV Pediarix GSK 3 2, 4, 6 mon Adju: aluminum hydroxide
DTaP-IPV Kinrix GSK >1 at 4 to 6 y (used as booster) Adju: aluminum hydroxide
DTaP-IPV/Hib Pentacel Sanofi 4 2-4-6, 15 to 18 mon Adju: aluminum hydroxide
Adult type          
DTap Adacel

Boosterix
Sanofi

GSK
1

1
1 dose at 10-64 y as booster

1 dose at 10-64 y as booster
Adju: aluminum hydroxide

Adju: aluminum hydroxide

Combination Vaccines Authorised in India and Middle East

The combo’s formulation licensed in each country is different and the pharmaceutical has adopted dissimilar trade names. To complicate further every vaccine has multiple brand names and each combo vaccine has a different schedule and dosage. In India, there isn’t a proper web site that lists out the combos according to the Immunization schedule in an orderly manner. One should read & learn from the package inserts before using the vaccine. If you have any questions or clarification, contact your regional health authority or to seek an ID consult.

Reconstitution of HIB Containing Combination Vaccines

The common versions of hexavalent/pentad valent/tetravalent formulations are packaged in 2 separate vials (a liquid DTP-HepB-IPV and another lyophilized Hib vial). Hib vaccine should be reconstituted just before administration. Lyophilized Hib vaccine can be stored either frozen at -20°C or refrigerated between 2°C and 8°C; however, liquid DTP or DTP-HepB vaccine MUST NOT BE FROZEN. To ensure that Hib is correctly reconstituted with DTP-rHepB it is recommended that both vials of the pentavalent DTP-rHepB/Hib formulation are stored together between 2°C and 8°C, and both vials should be shipped and distributed together. Reconstituted monovalent Hib vaccine or reconstituted Hib vaccine combined with other vaccines (DTP, rHepB, or DTP-IPV) should be destroyed after an immunization session or within six hours.

General Principles of Combination Vaccines (Combos’)

  • The decision to implement using the combos’ into immunization schedules involves complex economic and logistical considerations.

  • Vaccine provider should discuss with the parents on vaccine safety & availability, interchangeability, and whether the patient is likely to return for follow up.

  • Combos could be adopted in the recommended immunization schedule and should not be used outside the age groups for which they are licensed.

  • Should use only those combinations that have been demonstrated to be safe and efficacious that are authorized for use.

  • Combos are preferred over separate injections of the single component vaccines to keep the number of injections to a minimum.

  • Can be used for children who have fallen behind the schedule (lapsed immunization schedule).

  • Vaccines that are intended for separate administration should never be combined by vaccine providers. (i.e. PCV13 always to be administered separately)

  • Vaccine Information Statement (VIS’s) on each vaccine components of the combos should be known and available for any or all of the routine vaccines given from birth-6 months (DTaP, IPV, Hib, PCV, rHepB)

  • Should observe the nomenclature for combo’s contain either hyphens '-' or, sometimes, a forward slash '/' that are intended to indicate that the antigens are mixed '-' together by the manufacturer before the product is sold and the forward-slash '/' indicates that the two products are to be reconstituted by the user.

  • Switching between combination and single-antigen vaccines poses no problem as long as the recommended minimum intervals for all vaccines are maintained.

  • For example, if a child is given separate DTaP, IPV, rHepB- Hib -PCV13 vaccines during 2-month (6 to 8 week) visit, combo’s of either DTaP-IPV/Hib (Pentacel) with a separate two additional shots are be given for rHepB & PCV13 OR a DTaP- rHepB-IPV (Pediarix) combo given, the child need a separate shot of Hib & PCV13 has to be given at the 4-month (14 to 16 week) visit.

  • And, these days, more and more new combos are being introduced - and depending on the preference of your pediatrician, your child might be in line for one or more of these combos choices.

Efficacy of Combination Vaccines

The efficacy of each component in a combos’ is compared with established parameters of protection before the product was authorized for immunization purposes. Antibody responses to specific antigens in combination products may be either stronger or weaker than responses to separately administered single antigens, but these differences are not considered to have any clinical impact.

Safety of Combination Vaccines

Prior to authorization, combos go through careful testing to make sure the products are as safe and effective as each of the individual vaccines given separately. There may be differences in minor adverse events compared to single component vaccines, but they are not considered to be clinically significant and do not cause any lasting damage. In case of an adverse event following immunization, determining which component of a combination vaccine is responsible may be more challenging than in single component vaccines.

Potential Advantages & Benefits of Combos

Simplifying immunization schedules by combining multiple vaccines into a single syringe has been reported to have numerous positive effects. A US study reporting increased coverage rates with a pentavalent DTaP- rHepB-IPV (Pediarix) vaccine than with multiple lower-valent vaccines containing the same antigens. The combos’ benefit includes:

  • Fewer injections and reduced trauma to the infant

  • The Hexavalent (DTaP-rHepB-IPV/Hib) is especially exciting; since that might be just 2 shots for a child during infancy (Hexavalent and PCV13) visit for immunization.

  • Higher rates of compliance with complex vaccine schedule & a better vaccine coverage.

  • Timely vaccination- vaccination schedule are completed on time.

  • Reduced administration cost and lower storage space requirement.

  • Allows incorporation of new vaccines in the immunization schedules i.e. varicella vaccine incorporated with MMR (eg. MMRV).

  • reduced risk of injury to vaccine providers related to multiple injections of separate vaccines.

Future of Combo Vaccines

  • Now, the ACIP recommending Hexavac (DTaP-rHepB-IPV/Hib) vaccine is especially exciting, since that might be just 2 shots for your child during infancy (Hexavac and PCV13).

  • Other good combinations might include putting PCV & Hexavac together. That would mean just one shot at 2, 4 and 6 months!

Fewer shots are good, but even more exciting would be the development of edible vaccines. Early research showed that producing edible vaccines is theoretically possible, but the production of the first edible vaccines is likely way off.

Summary

Combos are necessary and important for the success of our immunization program, especially when more vaccines are added to the already crowded immunization schedule. The recommended vaccines have been shown to be as effective in combination as they are individually, but further progress in this direction is warranted. Combos can help overcome some of the key challenges to maintaining coverage through the universalization of vaccine schedules. To conclude, this is not the end of the story, as other waiting candidate vaccines for the newly emerging diseases, one day will need to be added to the combos' used.

Potential Disadvantages and Complexities of Combos

Although there are clear benefits with combination vaccines, the main challenge in their development is the risk that the efficacy or safety of the combination would be less than that seen with the administration of the vaccines separately

  • Misunderstanding, mix-up, and uncertainty about selection of vaccine combinations and schedules for subsequent doses, especially when vaccinations are given by multiple providers who might be using different products.

  • From a practical standpoint, uncommon transport and storage conditions and complicated bedside mixing could hamper the development of a combination vaccine.

  • Monovalent rHepB vaccine MUST BE USED for the birth dose. Combination vaccines that include HepB vaccine must not be used to give the birth dose because the DTP and Hib vaccines are not recommended to be given at birth.

  • Extra doses of certain antigens in the fixed combo product (an extra dose of hepB component, i.e. instead of a total 3 doses schedules, an additional 4th doses will be administered with the Combos use). An extra dose of a live-virus vaccine component, or Hib or reps vaccine, has not been found to be harmful.

  • It can be difficult to determine which component of a combination vaccine is responsible for an allergic reaction or another adverse event following immunization.

  • Combos may raise babies’ risk for fever-caused seizures. The study finds overall risk associated with combo still low. Indeed, the study also found no evidence that the vaccine increases the risk that a child will develop epilepsy disorder.

  • A shorter shelf-life than the individual component vaccines

  • The economic impact of the use of combos is unclear because combination products have the potential for either increased or decreased costs compared with single-antigen component vaccines.

  • Combination products may be more expensive than separate vaccines; however, combos' might represent a better overall economic value if the direct and indirect costs of extra injections, delayed or missed vaccinations, and additional handling and storage are taken into consideration.


1. CDC and P; Multiple Vaccines and the Immune System. 2016 http://www.cdc.gov/vaccinesafety/concerns/multiple-vaccines-immunity.html
2. Scheifele DW. Combining vaccines: does it make sense and does it work? Accessed July 2012 at: http://www.onehealth.ca/r_alberta_nwt/video_conferences/R080312B-HOb.pdf
3. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Morb Mortal Wkly Rep 2011;60(2):1-61.


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