Timing and Spacing of Vaccines : Antibody–Vaccine Interactions , Live Injected Vaccines and Live Oral and Intranasal Vaccines
The timing and spacing of vaccine doses are two of the most important issues in the appropriate use of vaccines. Specific circumstances that are commonly encountered in immunization practice are the timing of antibody-containing blood products and live vaccines (particularly measles and varicella-containing vaccines), simultaneous and nonsimultaneous administration of different vaccines, and the interval between subsequent doses of the same vaccine.
Antibody–Vaccine Interactions
The presence of circulating antibody to a vaccine antigen may reduce or completely eliminate the immune response to the vaccine. The amount of interference produced by circulating antibody generally depends on the type of vaccine administered and the amount of antibody.
Inactivated antigens, which include recombinant vaccines, are generally not affected by circulating antibody, so they can be administered before, after, or at the same time as the antibody. Simultaneous administration of antibody (in the form of immune globulin) and vaccine is recommended for postexposure prophylaxis of certain diseases, such as hepatitis B, rabies, and tetanus.
Live Injected Vaccines
Live vaccines must replicate in order to cause an immune response. Antibody against injected live vaccine antigen may interfere with replication. If a live injectable vaccine (measles-mumps-rubella [MMR], varicella, or combination measles-mumps-rubella-varicella [MMRV]) must be given around the time that antibody is given, the two must be separated by enough time so that the antibody does not interfere with viral replication. If the live vaccine is given first, it is necessary to wait at least 2 weeks (i.e., an incubation period) before giving the antibody. If the interval between the vaccine and antibody is less than 2 weeks, the recipient should be tested for immunity or the vaccine dose should be repeated.
If the antibody is given before a dose of MMR or varicella-containing vaccine, it is necessary to wait until the antibody has waned (degraded) before giving the vaccine to reduce the chance of interference by the antibody. The necessary interval between an antibody-containing product and MMR or varicella-containing vaccine (except zoster vaccine) depends on the concentration of antibody in the product, but is always 3 months or longer. A table listing the recommended intervals between administration of antibody products and live vaccines (MMR and varicella-containing) is included in Appendix A and in the General Recommendations on Immunization (2011). The interval between administration of an antibody product and MMR or varicella vaccination can be as long as 11 months. Zoster vaccine is not known to be affected by circulating antibody so it can be administered at any time before or after receipt of an antibody-containing blood product.
Yellow fever vaccine also is not known to be affected by circulating antibody. Because few North Americans are immune to yellow fever, these products do not contain significant amounts of antibody to yellow fever virus.
Although passively acquired antibodies can interfere with the response to rubella vaccine, the low dose of anti-Rho(D) globulin administered to postpartum women has not been demonstrated to reduce the response to the rubella vaccine. Because of the importance of rubella and varicella immunity among childbearing age women, women without evidence of immunity to rubella or varicella should receive MMR or varicella vaccine (but not MMRV) in the postpartum period.
Vaccination should not be delayed because of receipt of anti-Rho(D) globulin or any other blood product during the last trimester of pregnancy or at delivery. These women should be vaccinated immediately after delivery and, if possible, tested 3 months later to ensure immunity to rubella and, if necessary, to measles.
Live Oral and Intranasal Vaccines
Oral typhoid vaccine is not known to be affected by the administration of immune globulin or blood products. Oral typhoid vaccine may be given simultaneously with blood products, or separated by any interval. The replication of live attenuated influenza (LAIV) and rotavirus vaccines are not believed to be affected by antibody-containing blood products. These can be given any time before or after administration of antibody-containing blood products.
Interval Between Doses of the Same Vaccine
Immunizations are recommended for members of the youngest age group at risk for a disease for whom efficacy and safety of a vaccine have been demonstrated. Most vaccines in the childhood immunization schedule require two or more doses for development of an adequate and persisting antibody response. Studies have demonstrated that recommended ages and intervals between doses of the same antigen(s) provide optimal protection or have the best evidence of efficacy.
Administering doses of a multidose vaccine at shorter than the recommended intervals might be necessary when an infant or child is behind schedule and needs to be brought up-to-date quickly or when international travel is pending. In these cases, an accelerated schedule using the minimum age or minimum interval criteria can be used. Accelerated schedules should not be used routinely.
For routine vaccination, vaccine doses should not be administered at intervals less than the recommended minimal intervals or earlier than the minimal ages. Two exceptions to this may occur. The first is for measles vaccine during a measles outbreak or before travelling abroad. Infants 6 through 11 months should receive one MMR dose, and this dose should not be counted (should be repeated at 12 months of age or older). The second exception involves administering a dose a few days earlier than the minimum interval or age, which is unlikely to have a substantially negative effect on the immune response to that dose.
Although vaccinations should not be scheduled at an interval or age less than the recommended minimums, a child may have erroneously been brought to the office early, or may have come for an appointment not specifically for vaccination. In these situations, the clinician can consider administering the vaccine earlier than the minimum interval or age. If the parent/child is known to the clinician and the physician has confidence that the child will return for a visit, it is preferable to reschedule the child for vaccination closer to the recommended interval. If the parent/child is not known to the clinician or is not reliable (e.g., habitually misses appointments), it may be preferable to administer the vaccine at that visit than to reschedule a later appointment that may not be kept.
Number of Doses
For live injected vaccines, the first dose administered at the recommended age usually provides protection. An additional dose is given to provide another opportunity for vaccine response in the small proportion of recipients who do not respond to the first dose. For instance, approximately 95% of recipients will respond to a single dose of measles vaccine. The second dose is given to ensure that nearly 100% of persons are immune (i.e., the second dose is “insurance”). Immunity following live vaccines is long-lasting, and booster doses are not necessary.
For inactivated vaccines, the first dose administered at the recommended age usually does not provide protection (hepatitis A vaccine is an exception). A protective immune response may not develop until the second or third dose. For inactivated vaccines, antibody titers may decrease (wane) below protective levels after a few years. This phenomenon is most notable for pertussis vaccine; tetanus and diphtheria vaccine immunity also wanes. For these vaccines, periodic “boosting” is required. An additional dose is given to raise antibody back to protective levels.
Not all inactivated vaccines require boosting throughout life. For example, additional doses of Hib vaccine are not required after completion of the infant primary series and 12-15 month old booster dose because Hib disease is very rare in children older than 5 years of age. Hepatitis B vaccine does not require boosting because of immunologic memory to the vaccine and the long incubation period of hepatitis B (which can produce an “autoboost”).
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