Combination Vaccines

Definition: A combination vaccine consists of two or more separate immunogens that have been physically combined in a single preparation. This concept differs from that of simultaneous vaccines, which, although administered concurrently, are physically separate.

History: The combining of multiple related or unrelated antigens into a single vaccine is not a new concept. Combination vaccines in common use include diphtheria and tetanus toxoid, available alone (DT or dT) or with pertussis vaccine (DTP), inactivated (IPV) or live oral (OPV) trivalent polio vaccine and MMR vaccine. The first combination vaccine was trivalent influenza vaccine approved in 1945 and the second was hexavalent pneumococcal vaccine in 1947, DTP was licensed in 1948, IPV in 1955, OPV in 1963 and MMR in 1971. More recently licensed combination vaccine incorporate newer components such as Hib, aP or HB antigens. DPT/Hib and DPTWC/HB combination vaccines are currently available in India.

Benefits: The benefits of Combination Vaccines include:

1. Reduced number of injections
   • reduced parental anxiety
   • reduced pain to child
   • reduced risk to vaccinator by less needle handling.
2. Ensures higher compliance, low dropout rates and enhanced coverage.
3. Reduced number of visits.
4. Successful implementation of immunization programmes.
5. Reduced storage space.
6. Reduced burden on cold chain.
7. Reduced documentation and logistics.
8. Reduced packaging, handling, transportation.

DPT and Conjugate Hib Combination: During the late 1980’s and early 1990’s a number of studies were launched to evaluate vaccines that combined DPT and conjugate Hib. Trials were conducted assessing antibody levels in subjects receiving combination vaccines and separate components. For every antigen except diphtheria, the combined vaccine produced substantially lower antibody levels but even though substantially reduced, these were well above those considered protective. Levels show a quantum jump when booster dose of the combined vaccine is given. None of the combination vaccines was associated with materially increased adverse reaction. For details of composition, dosage, schedule and brand names, see section as “Know your vaccines”.

DPTWC / HB Combination: A combined DPTWC/HB Vaccine containing per 0.5 ml dose 10 mcgm of Hepatitis B surface antigen and not less than 30 IU of adsorbed D-toxoid, not less than 60 IU of T-toxoid and not less than 4IU of PW, Pertussis whole cell component is available as a single 0.5 ml dose and 5 ml multi dose vial with ten pediatric doses suitable for administration at 6, 10,14 weeks or 2, 4, 6 months. The vaccine is now licensed in India.

Summary: Combination Vaccines

Histrocial Aspects

• Definition
• Historical Aspects

First CV Trivalent Influenza Vaccine 1945

Second CV Hexavalent Pneumococcal Vaccine 1947
DPT and IPV licensed 1948, OPV 1963, MMR 1971,
DPTwc / Hib 1995, DPTwc/HB 1998.

Current state of developement

Vaccine	Developed	Under development
DPTwc / IPV	+
DPTwc / Hib	+
DPTwc / HB	+
DPTwc / IPV / HIb	+
Hep A / Hep B	+
DPTac / Hib	+
DPTac / IPV	+
DPTac / Hib / IPV	+
DPTac / Hib / IPV / HB	+
MMR / Varicella	+
DPTac / Hib / IPV / HB / HA	+

Future Combination: A number of studies have evaluated combination vaccines that incorporate DPT, HB, and, more recently, Hib components. Results of these studies were variable. The combined vaccines were as likely to show higher as lower antibody responses compared with the separate vaccines for the various antigens. In general, the groups with the lowest antibody responses still attained levels considered protective (where applicable). One study, not yet published, evaluated the effect of a booster dose of DPT/ HB/ Hib given at 18 months of age to subjects who received DPT/ HB + Hib or DPT / HB / Hib for the primary series. Both groups had high antibody responses to the booster; mean levels tended to be higher in the group primed with DPT / HB / Hib and were significantly so for antibody to PRP.

New Thinking and Rethinking
There is no doubt that the coming era in vaccinology belongs to the new and wonderful concept of combination vaccines. However, various issues other than pharmaceutical and developmental aspects are to be considered and examined. Different countries follow different immunization schedules, either for social and administrative or epidemiological reasons. Since epidemiological situations and immunization schedules vary from country to country, the cost benefit of a combined vaccine will also vary. Since these vaccines seek to combine many more antigens from multiple different pathogens, it makes them difficult to study in controlled double blind, randomized trials because of the increased number of the study arms required for complete evaluation. Also, the determination of the serological response to different antigens should be evaluated in relation to protective immunological responses to the lowest antibody protection level rather than equivalent mean titre of antibodies towards individual components.

Newer Vaccines - Vaccines Already Available in India

• Live attenuated Varicella (Oka) vaccine
• Killed Hepatitis A virus vaccine
• Pneumococcal vaccine (23 valent polysaccharide)
• Influenza virus vaccine
• Combination vaccines DPTwc / Hib and DPT / HB

Vaccines Available in other Countries

• Conjugated Pneumococcal vaccine (7 valent)
• Conjugated S.typhi Vi vaccine
• Rotavirus vaccine
• Several other combination vaccines