Recommendations for UseThe IAPCOI concludes that all currently licensed combination vaccines in India have an immunogenicity, efficacy and safety profile comparable to separately administered vaccines as of currently available data. However manufacturer’s recommendation for mixing the vaccines in the same syringe should be strictly followed. |
A combination vaccine consists of two or more separate immunogens that have been physically combined in a single preparation. These immunogens may pertain to the many antigens/serotypes of the given pathogen (e.g. poliovirus vaccines) or of multiple pathogens (e.g. DTP vaccine). This concept differs from that of simultaneous vaccines, which, although administered concurrently, are physically separate.
The combining of multiple related or unrelated antigens into a single vaccine is not a new concept. Several combination vaccines have been in use including the trivalent influenza vaccines, diphtheria, pertussis and tetanus toxoids (DTwP, DTaP, DT, Td, Tdap), the polio vaccines, MMR and meningococcal vaccines. Additionally several other multivalent vaccines have been recently introduced including the pneumococcal, rotavirus and HPV vaccines. Further discussion on combination vaccines here refers to vaccines against multiple pathogens combined in a single injection. The advantages of combination vaccines are multiple and include fewer injections, reduced burden on the cold chain, reduced requirement of syringes and needles and easier record keeping. The concern is stability of the product and immune interference between the various antigens leading to suboptimal immunogenicity
DTwP+Hib, DTwP+Hep B, DTwP+Hib+Hep B
These are available in two forms.
1) As ready to use liquid
preparations: DTwP+ Hep B (Tritanrix HBTM, SII Q-VacR,
ComvacTM4-HB, Shantetra), DTwP+Hib (Easy four, ShanHib-
DPT), DTwP+Hep B+ Hib (Shan5, Easy five, ComvacTM5) and
2) When lyophilized Hib needs to be reconstituted with DTwP/
DTwP + Hep B from the same manufacturer: DTwP + Hib
(Tetraact Hib), DTwP+ Hib + Hep B (Tritanrix HBTM +
HiberixTM, SII Q-VacR + HibproR, ComvacTM4-HB + BioHibTM).
Though the antibody response to Hib is reduced in these combination vaccines as compared to separate administration, most subjects attain the seroprotective level of 1 ìg/ml and there is no reduced efficacy against Hib disease. The antibody responses to diphtheria, pertussis, tetanus and Hep B are unchanged. The liquid and the lyophilized formulations have similar immunogenicity and safety for both primary and booster immunization.
DTaP+Hib, DTaP+Hib+IPV
Currently the DTaP/Hib is available as lyophilized Hib which needs to be reconstituted with liquid DTaP just prior to administration (InfanrixTM + HiberixTM, TripacelTM + ActHibTM) or with DTaP + IPV (PentaximTM). Antibody responses to diphtheria, pertussis, tetanus and if applicable polio are satisfactory and comparable to those obtained after administration as separate doses.
The primary concern and debate with these vaccines is Hib immunogenicity as studies showed a significant reduction in Hib titer/percentage of children achieving the long term protective level of 1 ìg/ml, when these combination vaccines are used as compared to separate administration of Hib vaccines in primary immunization. This reduction in Hib immunogenicity is not noted when these vaccines are used for booster vaccination even in subjects who had been administered combination vaccines for primary immunization. The reduction in Hib antibody titers was noted across all studies with different formulations of DTaP (exception Canadian five component DTaP vaccine) and different Hib conjugate vaccines and was more significant when vaccination was administered earlier in life and in premature babies. Studies with the five component Canadian vaccine combination vaccine with Hib did not show reduced Hib immunogenicity. Experts did not attach much significance to lower Hib immunogenicity of these combination vaccines as the serologic correlates of protection for Hib were derived from studies with the polysaccharide vaccines which provided poor quality antibodies and no immunologic memory. Hence DTaP+ Hib combination vaccines were initially licensed in Europe for both primary and booster immunization but in the USA only for booster vaccination.
An increased incidence of Hib disease was noted in the UK but not in other European countries following shift to DTaP+ Hib combination vaccines. This was initially attributed to the lower immunogenicity of the combination vaccine but later conclusively attributed to other factors mainly non administration of a booster dose at 18 months. The US FDA and ACIP has recently approved DTaP (5 component) + IPV + Hib combination vaccine (Pentacel TM) for primary immunization (June 2008).
Hep A + Hep B
Available in adult formulation (for those aged 18 and above, TwinrixTM) and pediatric formulation (Twinrix juniorTM). The recommended schedule is three doses at 0, 1 and 6 months. These combination vaccines show acceptable and comparable immune response against Hep A and Hep B as compared to separate administration. A rapid immunization schedule particularly suitable for travelers at 0, 7 and 21 days has acceptable short and long term efficacy. The adult formulation may also be used effectively in children aged 1-15 years as two doses at 0 and 6 months.
DTwP+IPV, DTwP+IPV+Hib
These vaccines are available internationally and show acceptable immunogenicity (against all components) and safety. These vaccines are potentially of immense importance in the Indian EPI to facilitate a shift from OPV to IPV as polio eradication nears.
DTaP+IPV, DTaP+Hep B, DTaP+IPV+Hep B, DTaP+Hib+Hep B, DTaP+IPV +Hep B+Hib
These quadrivalent, pentavalent and hexavalent combination vaccines show acceptable and comparable immunogenicity against diphtheria, pertussis, tetanus and polio. The responses against Hib are lower as discussed earlier. The Hep B antibody titers following primary immunization are also lower than when Hep B is administered separately which is believed to be due to close spacing of the doses at 1 mth interval rather than immune interference. The hexavalent vaccines are available internationally in two different formulations; one is lyophilized Hib which needs to be reconstituted with liquid DTaP+IPV+Hep B (Infanrix HexaTM) and the other as a ready to use liquid vaccine (HexavacTM).
MMRV Vaccine
A combination MMR and varicella vaccine (ProQuad) was licensed in USA in 2005 for healthy children aged 12 months to 12 years. The antigen content of varicella is higher than single antigen varicella vaccine. The vaccine demonstrates comparable immunogenicity and efficacy against all components but greater side effects of fever and rash as compared to separate administration of the vaccines. Post marketing surveillance reports indicate an increased (double) risk of febrile seizures following the receipt of this vaccine as compared to separate MMR and varicella vaccines. Another combination MMRV vaccine licensed in Europe is Priorix tetra with comparable immunogenicity and efficacy but an increased risk of fever as compared to separate administration of vaccines.
Hep A+Typhoid
These vaccines particularly for use in travelers to endemic countries show comparable immunogenicity and safety as compared to separate administration of vaccines.
Hep B+Hib
These vaccines show acceptable immunogenicity against
Hib and Hep B as compared to separate administration of
vaccines.