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Spacing of Immunobiologics - Health-Care Provider Information

Date last rev'd: October 21, 1996

Multiple doses of same antigens

Some products require more than 1 dose for adequate protection. The use of multiple reduced doses or the use of doses given at less than recommended intervals may lessen the antibody response and is not endorsed or recommended; such doses should not be counted as part of the vaccination series. It is unnecessary to restart an interrupted series of a vaccine or toxoid or to add extra doses. However, some products require periodic booster doses to maintain protection.

Simultaneous administration

Most of the widely used antigens can safely and effectively be given simultaneously (i.e., on the same day) without impairing antibody responses or increasing rates of adverse reactions. This is particularly helpful for international travelers for whom exposure to several infectious diseases may be imminent.

In general, inactivated vaccines can be administered simultaneously at separate sites. However, when vaccines commonly associated with local or systemic reactions e.g., cholera, parenteral typhoid, and plague are given simultaneously, reactions may be accentuated. It is preferable to administer these vaccines on separate occasions.

When administered at the same time and at separate sites, DTP, OPV, and MMR have produced seroconversion rates and rates of side effects similar to those observed when the vaccines are administered separately. Simultaneous vaccination of infants with DTP, OPV (or IPV), and either Hib vaccine or hepatitis B vaccine has resulted in acceptable response to all antigens. Routine simultaneous administration of DTP (or DTaP), OPV (or IPV), Hib vaccine, MMR, and hepatitis B vaccine is encouraged for children who are the recommended age to receive these vaccines and for whom no specific contraindications exist at the time of the visit. Administration of MMR and Hib vaccine at 12 to 15 months of age, followed by DTP (or DTaP, if indicated) at 15-18 months, remains an acceptable alternative for children with caregivers known to be compliant with other health-care recommendations and who are likely to return for future visits; hepatitis B vaccine can be administered at either of these two visits. DTaP may be used instead of DTP only for the fourth and fifth dose in children 15 months of age through 6 years (i.e., before the seventh birthday).

Hepatitis B vaccine administered with yellow fever vaccine is as safe and efficacious as when these vaccines are administered separately. Measles and yellow fever vaccines have been administered together safely and with full efficacy of each of the components.

The antibody response of yellow fever and cholera vaccines is decreased if administered simultaneously or within a short time of each other. If possible, yellow fever and cholera vaccinations should be separated by at least 3 weeks. If there are time constraints and both vaccines are necessary, the injections can be administered simultaneously or within a 3-week period with the understanding that antibody response may not be optimal.

Decisions on the need for yellow fever and/or cholera immunizations should take into account the amount of protection afforded by the vaccine, the importance of vaccination versus environmental or hygienic practices in avoiding disease exposure, and whether there is an actual vaccination requirement for entry into a country. Certain countries require yellow fever vaccination with documentation in an International Certificate of Vaccination. Yellow fever vaccine is highly effective in protecting against a disease with substantial mortality for which no therapy exists. The currently used cholera vaccine provides only limited protection of brief duration; few indications exist for its use.

Limited data suggest that the immunogenicity and safety of Japanese encephalitis (JE) vaccine is not compromised by simultaneous administration with DTP vaccine. No data exist on the effect of concurrent administration of other vaccines, drugs (e.g., chloroquine, mefloquine), or biologicals on the safety and immunogenicity of JE Vaccine.

Non-Simultaneous Administration

Inactivated vaccines generally do not interfere with the immune response to other inactivated or live vaccines. In general, an inactivated vaccine can be given either simultaneously or at any time before or after a different inactivated vaccine or a live vaccine. An exception, as noted above, is the recommendation that yellow fever and cholera vaccines should be separated by at least 3 weeks, if possible.

Theoretically, the immune response to one live-virus vaccine might be impaired if administered within 30 days of another live-virus vaccine; however no evidence exists for currently available vaccines to support this concern, whenever possible, live virus vaccines administered on different days should be administered at least 30 days apart. However, OPV and MMR vaccine can be administered at any time before, with, or after each other, if indicated.

Live virus vaccines can interfere with an individual's response to tuberculin testing. Tuberculin testing, if otherwise indicated, can be done on the day that live viral vaccines are administered or 4-6 weeks later.

Immune globulin (IG preparations)*

When certain live attenuated vaccines are given with immune globulin (IG) preparations, and antibody response can be diminished. IG preparations do not interfere with the immune response to either OPV or yellow fever vaccine. However, immune globulin can inhibit the immune response to other parenterally-administered live-attenuated vaccine viruses (measles, mumps, rubella); the duration of inhibition is related to the dose of immune globulin. Administration of MMR and its component vaccines should be delayed for a) at least 3 months after IG administration given in doses to prevent hepatitis A, hepatitis B, or tetanus prophylaxis b) at least 4 months after rabies prophylaxis, c) at least 5 months after measles or varicella prophylaxis, and d) at least 6 months after receipt of whole blood or packed red blood cells or measles prophylaxis an immunocompromised person. Receipt of higher doses of immune globulins in immunocompromised persons or receipt of intravenous immune globulin or certain other blood products may interfere with the immune response to MMR vaccine for longer periods. The General Recommendations on Immunization (MMWR:1994;43(RR-1)) should be consulted for specific guidance on MMR vaccination following use of these products.

Because of imminent exposure to disease, immune globulin administration may become necessary after MMR or its individual component vaccines have been given, and interference can occur. Vaccine virus replication and stimulation of immunity usually will occur within 1-2 weeks after vaccination. If the interval between administration of these vaccines and the subsequent administration of an immune globulin preparation is 14 days or longer, vaccine need not be readministered. If the interval is less than 14 days, the vaccine should be readministered a) at least 3 months after hepatitis A, hepatitis B, or tetanus prophylaxis, b) at least 4 months after rabies prophylaxis, and c) at least 5 months after measles or varicella prophylaxis, unless serologic testing indicates that antibodies have been produced. If administration of immune globulin becomes necessary because of imminent exposure to disease, MMR or its component vaccines can be administered simultaneously with immune globulin, with the recognition that vaccine-induced immunity may be compromised. The vaccine should be administered in a site remote from that chosen for the immune globulin inoculation. Vaccination should be repeated after the interval noted above unless serologic testing indicates antibodies have been produced.

When immune globulin is given with the first dose of hepatitis A vaccine, the proportion of persons who develop protection levels of antibody is not affected, but antibody concentrations are lower. Because the final concentrations of anti-HAV are many-fold higher than that considered protective, this reduced immunogenicity is not expected to be clinically important. Immune globulin preparations interact minimally with other inactivated vaccines and toxoids. Therefore, other inactivated vaccines can be given simultaneously or at any time interval after or before an immune globulin product is used. However, vaccines should be administered at sites different than the immune globulin.

^*Formerly called immune serum globulin and immunoglobulin.

Division of Quarantine
National Center for Infectious Diseases
Centers for Disease Control and Prevention
Atlanta, GA

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