General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 11

3. Timing and Spacing of Immunobiologics

Updates

Major changes to the best practice guidance for timing and spacing of immunobiologics 

include 1) guidance for simultaneous vaccination in the context of a risk for febrile seizures 

and 2) clarification of the use of the grace period between doses of MMRV.

General Principles for Vaccine Scheduling

Optimal response to a vaccine depends on multiple factors, including the type of vaccine, age 

of the recipient, and immune status of the recipient. Recommendations for the age at which 

vaccines are administered are influenced by age-specific risks for disease, age-specific risks 

for complications, age-specific responses to vaccination, and potential interference with the 

immune response by passively transferred maternal antibodies. Vaccines are generally 

recommended for members of the youngest age group at risk for experiencing the disease for 

which vaccine efficacy and safety have been demonstrated.

Vaccines can be divided into two general categories: live or non-live. Most live vaccines used 

in the United States are “live attenuated”, meaning that the microbe in the vaccine is alive but 

has been weakened (attenuated) through serial passage in cultures, or produced through 

genetic technology. One live vaccine licensed for use in the United States (oral adenovirus 

vaccine) is not attenuated. Live vaccines must replicate in order to induce an immune 

response. Several factors can interfere with replication, and these are a driving factor in the 

principles of timing and spacing of live vaccine. These principles will be discussed later in 

this chapter. Non-live vaccines can include whole or fractional vaccines produced by 

inactivating (killing) the microbe; or fractional vaccines such as recombinant vaccines, 

produced through genetic technologies. Also included under the category of non-live vaccines 

are toxoids, which generate an antibody response to toxins produced by a microbe rather 

than to the microbe itself. Several recently developed non-live vaccines do not contain 

antigen but employ RNA or DNA to instruct the recipient’s own cellular mechanism to 

generate antigenic material. Some vaccines described as “live attenuated” (e.g., Jynneos 

Smallpox/Monkeypox vaccine) do not replicate and for the purposes of timing and spacing 

recommendations behave like non-live vaccines. 
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 12

Certain vaccines available outside the U.S. might be categorized differently as to vaccine type 

(e.g., live attenuated JE vaccine and live oral polio vaccine) (Table 3-1).

Tetanus and diphtheria toxoids require booster doses to maintain protective antibody 

concentrations (1). Unconjugated polysaccharide vaccines do not induce T-cell memory, and 

additional doses (although they elicit the same or a lower antibody concentration) might 

increase the duration of protection. Conjugation with a protein carrier improves the 

effectiveness of polysaccharide vaccines by inducing T-lymphocyte–dependent immunologic 

function (2). Many vaccines that stimulate both cell-mediated immunity and neutralizing 

antibodies (e.g., live, attenuated virus vaccines) can usually induce prolonged immunity, even 

if antibody titers decline over time (3). Subsequent exposure to such viruses usually results in 

a rapid anamnestic antibody response without viremia.

Approximately 90%-95% of recipients of a single dose of certain live vaccines administered 

by injection at the recommended age (i.e., measles, rubella, and yellow fever vaccines) 

develop protective antibodies, generally within 14 days of the dose. For varicella and mumps 

vaccines, 80%-85% of vaccines are protected after a single dose. However, because a limited 

proportion (5%-20%) of measles, mumps, and rubella (MMR) or varicella vaccinees fail to 

respond to 1 dose, a second dose is recommended to provide another opportunity to develop 

immunity (4). 

Of those who do not respond to the first dose of the measles component of MMR or varicella 

vaccine, 97%-99% respond to a second dose (5,6).

The Recommended Immunization Schedules for Persons Aged 0 Through 18 Years and 

the Recommended Adult Immunization Schedule are revised annually. Physicians and other 

health-care providers should ensure that they are following the most up-to-date schedules, which 

are available from CDC at www.cdc.gov/vaccines/schedules/hcp/index.html. 

Spacing of Multiple Doses of the Same Antigen

Vaccination providers should adhere to recommended vaccination schedules (Table 3-2).

Administration at recommended ages and in accordance with recommended intervals 

between doses of multidose antigens provides optimal protection.
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 13

Administration of doses of a multidose vaccine using intervals that are shorter than 

recommended might be necessary in certain circumstances, such as impending international 

travel or when a person is behind schedule on vaccinations but needs rapid protection. In 

these situations, an accelerated schedule can be implemented using intervals between doses 

that are shorter than intervals recommended for routine vaccination (7). The accelerated or 

minimum intervals and ages for scheduling catch-up vaccinations are available at 

www.cdc.gov/vaccines/schedules/hcp/index.html. Vaccine doses should not be administered 

at intervals less than these minimum intervals or at an age that is younger than the minimum 

age.*(a)

Before administering a vaccine dose, providers might need to verify that all previous doses 

were administered after the minimum age and in accordance with minimum intervals (Table 

3-2). In clinical practice, vaccine doses occasionally are administered at intervals less than 

the minimum interval or at ages younger than the minimum age. Doses administered too 

close together or at too young an age can lead to a suboptimal immune response. However, 

administering a dose a few days earlier than the minimum interval or age is unlikely to have a 

substantially negative effect on the immune response to that dose. Known as the “grace 

period”, vaccine doses administered ≤4 days before the minimum interval or age are 

considered valid; however, local or state mandates might supersede this 4-day guideline 

(7).(b) (Day 1 is the day before the day that marks the minimum age or minimum interval for

a vaccine.) The scenario most applicable to the grace period is a visit to a provider several 

days prior to the date indicated by the minimum interval, such as for a mild illness. Followup is unlikely soon after or even for a longer period of time following this mild illness visit; 

this therefore raises the question of whether vaccines be administered during the mild illness 

visit to avoid missed opportunities to vaccinate. Because of the unique schedule for rabies 

vaccine and the accelerated Twinrix schedule the 4-day guideline does not apply to this 

vaccine (8, personal communication, Hepatitis A subject matter experts). Doses of any 

vaccine administered ≥5 days earlier than the minimum interval or age should not be 

counted as valid doses and should be repeated as age appropriate. The repeat dose should be 

spaced after the invalid dose by the recommended minimum interval (Table 3-2). For 

example, if the first and second doses of Haemophilus influenzae type b (Hib) were 

administered only 14 days apart, the second dose would be invalid and need to be repeated 

because the minimum interval from dose 1 to dose 2 is 4 weeks. 
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 14

The repeat dose should be administered ≥4 weeks after the invalid dose (in this case, the 

second) (7). The repeat dose is counted as the valid second dose. If the first and second doses 

of hepatitis A vaccine were administered less than 6 months apart, the second dose is invalid 

and should be repeated 6 months after the invalid second dose (7). However, if this repeat 

dose (the third dose) is administered anytime 6 months or more after the first dose, the 

series can be considered complete. If the minimum interval between the second and third 

dose of hepatitis B vaccine is violated, or if the minimum age of the third dose is violated, the 

third dose of hepatitis B vaccine is invalid. The repeat dose can be administered as early as 8 

weeks after the 2nd valid dose as long as the dose is also after 24 weeks of age and 16 weeks 

after the 1st dose. (9)

If the first dose in a series is given ≥5 days before the recommended minimum age, the dose 

should be repeated on or after the date when the child reaches at least the minimum age (7). 

If the vaccine is a live vaccine, ensuring that a minimum interval of 28 days has elapsed from 

the invalid dose is recommended (7). For example, if the first dose of varicella vaccine were 

inadvertently administered at age 10 months, the repeat dose would be administered no 

earlier than the child’s first birthday (the minimum age for the first dose). If the first dose of 

varicella vaccine were administered at age 11 months and 2 weeks, the repeat dose should be 

administered no earlier than 4 weeks thereafter, which would occur after the first birthday.

Certain vaccines (e.g., adult tetanus and diphtheria toxoids [Td], pediatric diphtheria and 

tetanus toxoids [DT], tetanus toxoid) produce increased rates of local or systemic reactions in 

certain recipients when administered more frequently than recommended (10, 11).

Careful record keeping, maintenance of patient histories, use of immunization information 

systems (IISs), and adherence to recommended schedules can decrease the incidence of such

reactions without adversely affecting immunity.

Simultaneous Administration

Simultaneous administration of vaccines is defined as administering more than one vaccine 

on the same clinic day, at different anatomic sites, and not combined in the same syringe. 

Experimental evidence and extensive clinical experience provide the scientific basis for 

administering vaccines simultaneously (12). 
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 15

Simultaneously administering all vaccines for which a person is eligible at the time of a visit 

increases the probability that a child, adolescent, or adult will be vaccinated fully by the 

appropriate age (13). A study conducted during a measles outbreak demonstrated that 

approximately one-third of measles cases among unvaccinated but vaccine-eligible preschool 

children might have been prevented if MMR had been administered at the same visit when 

another vaccine was administered (14). Simultaneous administration also is critical when 

preparing for foreign travel in the near future and when a health-care provider is uncertain 

that a patient will return for additional doses of vaccine.

With some exceptions, simultaneously administering the most widely used live and non-live 

vaccines has produced seroconversion rates and rates for adverse reactions similar to those 

observed when the vaccines are administered separately (12, 15-17). Routine administration 

of all age-appropriate doses of vaccines simultaneously is recommended for children for 

whom no specific contraindications exist at the time of the visit (7). MMR and varicella 

vaccine can be administered simultaneously (7). Live, attenuated influenza vaccine (LAIV) 

does not interfere with the immune response to MMR or varicella vaccines administered at 

the same visit (18). No data exist about the immunogenicity of oral Ty21a typhoid vaccine 

when administered concurrently or within 30 days of live-virus vaccines. In the absence of 

such data, if typhoid vaccination is warranted, administration should not be delayed because 

of recent administration of live, attenuated virus vaccines (19). 

Simultaneous administration of pneumococcal polysaccharide vaccine (PPSV) and 

inactivated influenza vaccine elicits a satisfactory antibody response without increasing the 

incidence or severity of adverse reactions (20). Simultaneous administration of PPSV23 and 

inactivated influenza vaccine is recommended for all persons for whom both vaccines are 

indicated. Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) 

and inactivated influenza vaccine (IIV) can be administered simultaneously (21). Hepatitis B 

vaccine administered with yellow fever vaccine is as safe and immunogenic as when these 

vaccines are administered separately (22). Measles and yellow fever vaccines have been 

administered safely at the same visit and without reduction of immunogenicity of either 

component (23,24).
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 16

During the 2010-2011 influenza season, surveillance systems detected safety signals for 

febrile seizures in young children following IIV and PCV13 vaccines (25). CDC studied the 

health-care visit records of more than 200,000 vaccinated children ages 6 months through 

59 months through the Vaccine Safety Datalink Project during the 2010-2011 influenza 

season. The analyses found that febrile seizures following IIV and PCV13 vaccines given to 

this age group were rare, but did occur at higher than expected rates. The risk for febrile 

seizures peaked in children age 16 months and were more common when the 2 vaccines were 

given during the same health-care visit. In this group, about one additional febrile seizure 

occurred among every 2,200 children vaccinated. After assessing benefits and risks, ACIP 

continues to recommend IIV and PCV13 be given concomitantly if both are recommended 

(25,26).

There are 2 exceptions to the recommendation that vaccines should be administered 

simultaneously. In persons with anatomic or functional asplenia and/or HIV infection, 

quadrivalent meningococcal conjugate vaccine (MCV4)-D (MenACWY-D, Menactra) and 

pneumococcal conjugate vaccine (PCV)13 (PCV13, Prevnar 13) should not be administered 

simultaneously (27). This is based on immunogenicity studies that showed reduced antibody 

concentrations for 3 serotypes of pneumococcus (subtypes 4, 6B, and 18C) when PCV7 was 

administered simultaneously with MenACWY-D. For persons with anatomic or functional 

asplenia and/or HIV, PCV13 should be administered first and MenACWY-D 4 weeks later.

In patients recommended to receive both PCV13 and PPSV23, the 2 vaccines should not be 

administered simultaneously (28). PCV13 should be administered first. If PPSV23 has been 

administered first, PCV13 should be administered no earlier than 8 weeks later in children 6-

18 years, and one year later in adults 19 years and older. Immunogenicity studies evaluating 

responses to PCV13 and PPSV23 administered in series showed a better immune response 

when PCV13 was administered first. An evaluation of immune response after a second 

pneumococcal vaccination administered 1 year after the initial study doses showed that 

subjects who received PPSV23 as the initial study dose had lower antibody responses after 

subsequent administration of PCV13 than those who had received PCV13 as the initial dose 

followed by a dose of PPSV23, regardless of the level of the initial response to PPSV23 

(29,30).
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 17

Depending on which vaccines are administered during the first year of life, a child might 

receive up to 9 injections at the 12- through 15-month visit (MMR, varicella, Hib, PCV13, 

pediatric diphtheria and tetanus toxoids and acellular pertussis [DTaP], inactivated 

poliovirus [IPV], hepatitis A, hepatitis B [HepB], and influenza vaccines). Although there is 

no exact limit on the number of injections, with a little flexibility, a provider can ensure that 

the primary series doses are given without administering too many injections at each visit. To 

reduce the number of injections at the 12- through 15-month visit, the hepatitis B series and 3 

doses of IPV (31) can be administered before the child’s first birthday.

There are many other examples of ways the vaccination schedule provides flexibility. The 

majority of children aged 1 year who have received 2 Hib vaccine doses (polyribosylribitol 

phosphate-meningococcal outer membrane protein [PRP-OMP]) or 3 Hib vaccine doses 

(PRP-tetanus [PRP-T]) and 3 previous doses of DTaP and PCV13 have protection against 

Hib, diphtheria, pertussis, tetanus, and pneumococcus, which lasts throughout infancy 

(2, 32). The third (PRP-OMP) or fourth (PRP-T) dose of the Hib series and the fourth doses 

of DTaP and PCV13 are critical in boosting antibody titer and ensuring continued protection 

(2, 33-35). The fourth dose of DTaP is recommended at age 15-18 months but may be 

administered as early as age 12 months if 6 months have elapsed since the third dose and if 

there is concern that the child might not return by age 18 months (33). For infants at low risk 

for infection with hepatitis B virus (i.e., mother tested negative for hepatitis B surface antigen 

[HBsAg] at the time of delivery and is not in a high risk group), the hepatitis B series can be 

completed at any time for children aged 6-18 months (36). The minimum age for 

administration of combination vaccines is the oldest minimum age for any of the individual 

components; the minimum interval between doses is equal to the greatest minimum interval 

of any of the individual components. Recommended spacing of doses should be 

maintained (Table 3-2).

Combination Vaccines

Combination vaccines merge equivalent component vaccines into single products to prevent 

more than one disease or to protect against multiple strains of infectious agents causing the 

same disease. Licensed combination vaccines can be used whenever any components of the 

combination are indicated and its other components are not contraindicated and if licensed 

by the Food and Drug Administration (FDA) for that dose in the series. 
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 18

Use of combination vaccines can reduce the number of injections patients receive and 

alleviate concern associated with the number of injections (29,37,38). Studies have 

demonstrated that parents and providers might be uncomfortable with multiple injections 

during single visits (39-41). Potential advantages of combination vaccines include 1) 

improved vaccine coverage rates (42), 2) timely vaccination coverage for children who are 

behind in the schedule (43, 44), 3) reduced shipping and stocking costs, 4) reduced costs for 

extra health care visits necessitated by deferral of vaccination, and 5) facilitation of 

additional new vaccines into vaccination programs.

Potential disadvantages of combination vaccines include the following: 1) adverse events that 

might occur more frequently after administration of a combination vaccine compared with 

administration of separate antigens at the same visit, such as fever that occurs with the 

combination MMRV vaccine and combination DTaP-HepB-IPV vaccine (45,46); 2) confusion 

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; 3) reduced pathogen coverage if the combination product covers fewer types of one 

particular vaccine-preventable disease-causing agent (47); 4) extra doses of certain antigens 

in the combination product (e.g., a provider who administers 4 doses of DTaP-HepB-IPV 

vaccine will give an extra dose of hepatitis B component); and 5) a shorter shelf-life than the 

individual component vaccines. The economic impact of the use of combination vaccines is 

unclear because combination products have the potential for either increased or decreased 

costs compared with single-antigen component vaccines. The price of a combination vaccine 

might exceed the total price of separate vaccines containing the same antigens. However, 

combination vaccines 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 (48).

Licensed Combination Vaccines

In this report, a combination vaccine is defined as a product containing components that can 

be divided equally into independently available routine vaccines. A dash ( – ) between 

vaccine products indicates that products are supplied in their final form by the manufacturer 

and do not require mixing or reconstitution by the user. A slash ( / ) indicates that the 

products must be mixed or reconstituted by the user. 
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 19

Seven combination vaccines for which separate antigens or antigen combinations exist have 

been licensed by FDA since 1996 in the United States (Table 3-3) (49-55). In the future, 

combination vaccines might include increasing numbers of components in different arrays to 

protect against these and other diseases. The use of a combination vaccine generally is 

preferred over separate injections of the equivalent component vaccines (56). Considerations 

should include provider assessment,(c) patient preference, and the potential for adverse 

events. An exception is the first dose of MMRV. Unless the parent or caregiver expresses a 

preference for MMRV vaccine, MMR and varicella vaccine should be administered for the 

first dose for children aged 12-47 months (see Contraindications and Precautions) (45).

Situations might arise in which one component of a combination vaccine is specifically 

preferred to another component in that same vaccine. Future research considerations for 

newly licensed combination vaccines should focus on safety of doses that are not needed 

because a patient is already vaccinated against the agents, whether the combination vaccine 

will improve the timeliness of vaccination, and potential reduced costs from disease 

prevention resulting from timely vaccination.

Combination Vaccines and FDA Licensure

Only combination vaccines licensed by FDA should be used (56). Vaccination providers 

should not combine separate vaccines into the same syringe to administer together unless 

mixing is indicated for the patient’s age and is explicitly specified on the FDA-approved 

product label inserts. Only 2 combination vaccines, (DTaP-IPV/Hib vaccine, marketed as 

Pentacel, and Hib-MenCY, marketed as MenHibrix) contain separate antigen components for 

which FDA approves mixing by the user. The safety, immunogenicity, and effectiveness of 

unlicensed combinations are unknown.

Interchangeability of Formulations

FDA generally licenses a combination vaccine based on studies demonstrating that the 

product’s immunogenicity (or efficacy) and safety are comparable or equivalent to 

monovalent or combination products licensed previously (38). 
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 20

FDA licensure also generally indicates that a combination vaccine may be used 

interchangeably with monovalent formulations and other combination products with similar 

component antigens produced by the same manufacturer to continue the vaccination series. 

For example, DTaP, DtaP-IPV/Hib, DtaP-HepB-IPV, and future DtaP vaccines that contain 

similar acellular pertussis antigens from the same manufacturer may be used 

interchangeably if licensed and indicated for the patient’s age (35).

Interchangeability of Combination Vaccines from Different 

Manufacturers

Licensure of a vaccine by FDA does not necessarily indicate that the vaccine is 

interchangeable with products from other manufacturers. Such data are ascertained and 

interpreted more readily for diseases with known correlates of protective immunity (e.g., 

specific serologic markers). For diseases without such surrogate laboratory markers, 

prelicensure field vaccine efficacy (phase III) trials or postlicensure surveillance generally are 

required to determine protection (57). ACIP prefers that doses of vaccine in a series come 

from the same manufacturer; however, if this is not possible or if the manufacturer of doses 

given previously is unknown, providers should administer the vaccine that they have 

available.

Vaccine Supply

Although vaccination providers should stock sufficient quantities of combination and 

monovalent vaccines needed to vaccinate children, adolescents, and adults against all 

diseases for which vaccines are recommended (29, 38), all available types or brand-name 

products need not be stocked. Potential advantages of stocking a limited number of vaccines 

include 1) reducing confusion and potential errors when staff members must handle 

redundant products and formulations, 2) minimizing waste when less commonly used 

products expire, 3) decreasing cold storage capacity requirements, and 4) minimizing 

administrative costs related to accounting, purchasing, and handling. The National Pediatric 

Vaccine Stockpile exists to offset supply challenges (58).
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 21

Extra Doses of Vaccine Antigens

Administering extra antigens contained in a combination vaccine should be avoided in most 

situations (56). Using combination vaccines containing certain antigens not indicated at the 

time of administration to a patient might be justified when 1) the extra antigen is not 

contraindicated, 2) products that contain only the needed antigens are not readily available, 

and 3) potential benefits to the patient outweigh the potential risk for adverse events 

associated with the extra antigens. An extra dose of many live-virus vaccines and Hib or 

hepatitis B vaccine has not been found to be harmful (59,60). However, the risk for an 

adverse event might increase when extra doses are administered at an earlier time than the 

recommended interval for certain vaccines (e.g., tetanus toxoid vaccines and PPSV) 

(20, 33, 61).

A vaccination provider might not have vaccines available that contain only the antigens 

needed as indicated by a child’s vaccination history. Alternatively, although the indicated 

vaccines might be available, the provider might prefer to use a combination vaccine to reduce 

the required number of injections. In such cases, the benefits and risks of administering the 

combination vaccine with an unneeded antigen should be carefully considered and discussed 

with the patient or parent.

When non-live vaccines (which are often adsorbed to aluminum-salt adjuvants) are 

administered, the reactogenicity of the vaccine must be considered in balancing the benefits 

and risks of extra doses (56). Because clinical experience suggests low reactogenicity, an 

extra dose of Hib or hepatitis B vaccine may be administered as part of a combination 

vaccine to complete a vaccination series for another component of the combination. 

Administration of extra doses of tetanus toxoid vaccines earlier than the recommended 

intervals can increase the risk for severe local reactions (21, 34). Examples of such vaccines 

include DtaP, DT (for children), and Td (for adolescents and adults). Extra doses of tetanustoxoid–containing vaccines might be appropriate for certain patients, including for children 

who previously received DT or Td vaccine and need protection from pertussis (in DtaP or 

Tdap) or for immigrants with uncertain vaccination histories.
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 22

Conjugate Vaccine Carrier Proteins

Protein conjugates used in Hib conjugate vaccines produced in the United States include 

tetanus toxoid (in PRP-T) which is also used as a component of DtaP and Tdap vaccines (21).

Simultaneous or sequential vaccination with Hib and these tetanus-toxoid containing 

vaccines is recommended when both are indicated (56). MCV4 and PCV13 both contain 

diphtheria-toxoid conjugates. There has been concern about simultaneous administration of 

vaccines containing like conjugates. One brand of MCV4, MenACWY-D (Menactra), 

demonstrates reduced immunogenicity of the antibody response to Streptococcal pneumonia 

strains when administered simultaneously with PCV13 compared with separate 

administration. It is recommended to space these vaccines by 28 days in a person with 

anatomic asplenia (47). Simultaneous or sequential vaccination of MCV4-CRM (Menveo), 

PCV13, and Tdap (34, 62), all of which contain diphtheria toxoid, is not associated with 

reduced immunogenicity or increase in local adverse events.

Nonsimultaneous Administration

There is no evidence that non-live vaccines interfere with the immune response to other nonlive vaccines or to live vaccines. Any non-live vaccine can be administered either 

simultaneously or at any time before or after a different non-live vaccine or live vaccine 

(Table 3-4). The 2 exceptions, as mentioned above, are a 4-week interval between PCV13 and 

MenACWY-D in a person with anatomic asplenia and the separation of doses between PCV13 

and PPSV23 (6-12 months recommended for non-high risk, 8 week minimum) if PCV13 is 

given first, 8 weeks in children 6-18 years, and 1 year minimum in adults 19 years and older if 

PPSV23 is given first (27). 

Limited data are available regarding interference between live vaccines used in the United 

States. The immune response to one live-virus vaccine might be impaired if administered 

within 28 days (i.e., 4 weeks) of another live-virus vaccine (63,64). In a study conducted in 2 

U.S. health maintenance organizations, the risk for varicella vaccine failure (i.e., varicella 

disease in a vaccinated person) among persons who received varicella vaccine within 28 days 

of MMR vaccination was threefold higher than among persons who received varicella vaccine 

>28 days after MMR vaccination (65). Another study determined that the response to yellow 

fever vaccine is not affected by monovalent measles vaccine administered 1-27 days earlier 

(23). 
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 23

The effect of nonsimultaneous administration of rubella, mumps, varicella, and yellow fever 

vaccines is unknown.

Two or more injectable or nasally administered live vaccines not administered on the same 

day should be separated by at least 4 weeks (Table 3-4), to minimize the potential risk for 

interference. If 2 such vaccines are separated by <4 weeks, the second vaccine administered 

should not be counted and the dose should be repeated at least 4 weeks later. On the day a 

live injectable or intranasal vaccine will be administered, providers should ensure that no live 

injectable or intranasal vaccine was given in the previous 28 days.

The 4-day grace period discussed earlier, which may be used to shorten the minimum 

interval between doses of the same vaccine, should not be applied to this 4-week interval 

between 2 different live vaccines (56). Confusion about this prohibition may arise when 2 live 

vaccines whose intervals are identical are administered simultaneously. For example, if MMR 

and varicella vaccines are administered on the same day, the second dose of each vaccine 

could come due 4 weeks later (depending on the patient’s age). If either vaccine had been 

given alone at both time points, the 4-day grace period could be applied to the second dose. 

But in this situation the live vaccine rule prevents the grace period from being applied to the 

second dose of either vaccine, because Varicella-2, if administered earlier than 4 weeks, could 

potentially be affected by MMR1, and likewise MMR2 could be affected by Varicella-1. Note 

that this prohibition also applies if the combination MMRV is used rather than individual 

MMR and varicella vaccines.

The oral vaccines Ty21a typhoid vaccine and rotavirus can be administered simultaneously 

with or at any interval before or after other live vaccines (injectable or intranasal) if indicated 

(66).

Spacing of Vaccines and Antibody-Containing Products

Live Vaccines

Ty21a typhoid, yellow fever, LAIV, and rotavirus vaccines may be administered at any time 

before, concurrent with, or after administration of any antibody-containing preparation such 

as immune globulin, hyperimmune globulin, or intravenous immune globulin (IGIV) (67). 
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 24

Blood (e.g., whole blood, packed red blood cells, and plasma) and other antibody-containing 

blood products (e.g., immune globulin, hyperimmune globulin, and IGIV) can inhibit the 

immune response to measles and rubella vaccines for ≥3 months. The effect of blood and 

immune globulin preparations on the response to mumps and varicella vaccines is unknown; 

however, commercial immune globulin preparations contain antibodies to these viruses. 

Blood products available in the United States are unlikely to contain a substantial amount of 

antibody to yellow fever virus. The length of time that interference with injectable live-virus 

vaccine (other than yellow fever) can persist after the antibody-containing product is a 

function of the amount of antigen-specific antibody contained in the product (68,70). 

Therefore, after an antibody-containing product is received, live vaccines (other than Ty21a 

typhoid, yellow fever, LAIV, and rotavirus vaccines) should be delayed until the passive 

antibody has degraded (Table 3-5). In circumstances where there is high-risk of vaccinepreventable disease it is acceptable to administer a dose of vaccine prior to completion of this 

interval. If a dose of injectable live-virus vaccine (other than yellow fever) is administered 

after an antibody-containing product but at an interval shorter than recommended in this 

report, the vaccine dose should be repeated. The repeat dose should be administered at the 

interval indicated for the antibody-containing product, after the invalid dose of vaccine 

(Table 3-6). Immunogenicity and safety of dengue vaccine after administration of 

intravenous immunoglobulin (IGIV) and other immunoglobulin containing products has not 

been studied. Clinicians considering dengue vaccine for persons who recently received blood 

products (including IGIV) or other immunoglobulin containing products should delay prevaccination testing and administration of vaccine doses by 12 months. 

Although passively acquired antibodies can interfere with the response to rubella vaccine, the 

low dose of anti-Rho(D) globulin or any other blood product administered to postpartum 

women have not been demonstrated to reduce the response to the RA27/3 strain rubella 

vaccine (71). Congenital rubella syndrome and congenital varicella are conditions with 

considerable morbidity and represent a true risk in future pregnancies. Because of the 

importance of rubella and varicella immunity among women of child-bearing age (4, 72), the 

postpartum vaccination of women without evidence of immunity to rubella or varicella with 

MMR, varicella, or MMRV vaccines 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. 
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 25

Any reduction in immunity caused by anti-Rho(D) globulin or other blood products is 

outweighed by the opportunity to generate immunity. These women should be vaccinated 

immediately after giving birth and, if possible, tested ≥3 months later to ensure immunity to 

rubella and, if appropriate, to measles (2). Measles and rubella serologies have a low falsepositive rate and are therefore acceptable for use in this limited postpartum context.

Interference might occur if administration of an antibody-containing product becomes 

necessary after administration of MMR or varicella vaccines. Usually, vaccine virus 

replication and stimulation of immunity occurs 1-2 weeks after vaccination. If the interval 

between administration of any of these vaccines and subsequent administration of an 

antibody-containing product is <14 days, vaccination should be repeated after the 

recommended interval (Tables 3-5 and 3-6) unless serologic testing indicates a protective 

antibody response (7).

A humanized mouse monoclonal antibody product (palivizumab) is available as prophylaxis 

for serious lower respiratory tract disease from respiratory syncytial virus among infants and 

young children. This product contains only antibody to respiratory syncytial virus and does 

not interfere with the immune response to licensed live or non-live vaccines.

Non-live Vaccines

Antibody-containing products interact less with non-live vaccines compared with live 

vaccines (73). Therefore, administering non-live vaccines either simultaneously with or at 

any interval before or after receipt of an antibody-containing product should not 

substantially impair development of a protective antibody response (Table 3-5). The vaccine 

or toxoid and antibody preparation should be administered at different sites using the 

standard recommended dose.

Interchangeability of Single-Component Vaccines from 

Different Manufacturers

Certain vaccines that provide protection from the same diseases are available from different 

manufacturers, and these vaccines usually are not identical in antigen content or in amount 

or method of formulation. 
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 26

Manufacturers use different production processes, and their products might contain different 

concentrations of antigen per dose or a different stabilizer or preservative.

Available data indicate that infants who receive sequential doses of different Hib conjugate, 

hepatitis B, and hepatitis A vaccines produce a satisfactory antibody response after a 

complete primary series (74-77). 

All brands of Hib conjugate, hepatitis B,(d)hepatitis A, rotavirus,(e) and quadrivalent 

meningococcal conjugate vaccines are interchangeable within their respective series. 

If different brands of a particular vaccine require a different number of doses for series 

completion (e.g., Hib and rotavirus vaccines) and a provider mixes brands in the primary 

series, the higher number of doses is recommended for series completion (e.g., doses of 

either rotavirus or Hib vaccine). For Hib vaccines, any monovalent or combination conjugate 

vaccine is acceptable for the booster dose of the series, if only one product was used for the 

primary series (56).

Limited data are available about the safety, immunogenicity, and efficacy of using acellular 

pertussis (i.e., DTaP) vaccines from different manufacturers for successive doses of the 

pertussis series. Data from one study indicate that for the first 3 doses of the DTaP series, 1-2 

doses of Tripedia (Sanofi Pasteur) followed by Infanrix (GlaxoSmithKline) for the remaining 

dose (or doses) is comparable to 3 doses of Tripedia with regard to immunogenicity, as 

measured by antibodies to diphtheria, tetanus, and pertussis toxoids, and filamentous 

hemagglutinin (78). However, in the absence of a clear serologic correlate of protection for 

pertussis, the relevance of these immunogenicity data for protection against pertussis is 

unknown. When feasible, the same brand of DTaP vaccine should be used for all doses of the 

vaccination series (56). If vaccination providers do not know or have available the type of 

DTaP vaccine previously administered to a child, any DTaP vaccine may be used to continue

or complete the series (56). For a child who needs 2 doses of influenza vaccine (IIV or LAIV), 

it is preferable to use the same type of vaccine for both doses. However, if the child is eligible 

for either IIV or LAIV, and the type of vaccine used for the first dose is not available, either 

vaccine can be used for the second dose (56). In a postlicensure study, meningococcal 

conjugate vaccines from different manufacturers were evaluated for successive doses of 

meningococcal conjugate vaccine. Persistence of antibodies were studied in recipients of 

MCV4-CRM after previous receipt of either MCV4-CRM or MenACWY-D. 
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 27

The percentage of persons with protective titers were the same for all serogroups. 

No data exist on the use of MenACWY-D after MCV4-CRM. Health-care providers should use 

every opportunity to provide a dose when indicated, regardless of the vaccine brand used for 

the previous dose or doses. For vaccines in general, vaccination should not be deferred 

because the brand used for previous doses is not available or is unknown (29, 79).

Lapsed Vaccination Schedule

Vaccination providers should administer vaccines as close to the recommended intervals as 

possible. However, intervals between doses that are longer than recommended typically do 

not reduce final antibody concentrations, although protection might not be attained until the 

recommended number of doses has been administered. With some exceptions (e.g. oral 

typhoid vaccine) an interruption in the vaccination schedule does not require restarting the 

entire series of a vaccine or toxoid or addition of extra doses (7).

Unknown or Uncertain Vaccination Status

Vaccination providers frequently encounter persons who do not have adequate 

documentation of vaccinations. With the exception of influenza vaccine and PPSV23, 

providers should only accept written, dated records as evidence of vaccination; self-reported 

doses of influenza vaccine and PPSV23 are acceptable (61,80). The rationale for acceptance 

for influenza vaccine is that the time period of recall is one year or less, making it very likely 

that correct recall will occur. The rationale for acceptance for PPSV23 is high frequency of 

vaccination leads to an increased rate of local reactions due to the reactogenicity of this 

vaccine. Although vaccinations should not be postponed if records cannot be found, an 

attempt to locate missing records should be made by contacting previous health care 

providers, reviewing state or local IISs, and searching for a personally held record. If records 

cannot be located within a reasonable time, these persons should be considered susceptible 

and started on the age-appropriate vaccination schedule. While serology should generally 

NOT be performed to ascertain evidence of immunity, serologic testing for immunity is an 

alternative to vaccination for certain antigens (e.g., measles, rubella, hepatitis A, and 

tetanus). 
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 28

However, commercial serologic testing might not always be sufficiently sensitive or 

standardized for detection of vaccine-induced immunity (with the exception of hepatitis B 

vaccination at 1-2 months after the final dose), and research laboratory testing might not be 

readily available. An exception to the prohibition on serologic testing is dengue. Laboratory 

testing to ascertain immunity to dengue (of which serology is one option) must be performed 

prior to vaccination, and only those individuals who are positive should be vaccinated.

(a) During measles outbreaks, if cases are occurring among infants aged <12 months, measles vaccination of infants as young as 6 months 

can be used as an outbreak control measure. However, doses administered at ages <12 months should not be counted as part of the 

series (81).

(b) In certain situations, local or state requirements might mandate that doses of selected vaccines be administered on or after specific 

ages. For example, a school entry requirement might not accept a dose of MMR or varicella vaccine administered before the child’s first 

birthday. ACIP recommends that physicians and other health-care providers comply with local or state vaccination requirements when

scheduling and administering vaccines.

(c) Provider assessment should include number of injections, vaccine availability, likelihood of improved coverage, likelihood of patient 

return, and storage and cost considerations.

(d) The exception is the 2-dose hepatitis B vaccination series for adolescents aged 11-15 years. Only Recombivax HB (Merck Vaccine 

Division) should be used in the schedule. Engerix-B (GlaxoSmithKline) is not approved by FDA for this schedule.

(e)Based on expert opinion.
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 29

TABLE 3-1 Types of Vaccines

Vaccine Category Examples

Live Oral adenovirus vaccine*

Live attenuated ACAM2000 smallpox vaccine

Bacille Calmette Guerin (BCG) vaccine

Dengue vaccine

Ebola vector vaccine

Live attenuated influenza vaccine (LAIV)

Live oral typhoid vaccine (Ty21a)

Measles-mumps-rubella – containing (MMR, 

MMRV)

Oral cholera vaccine

Rotavirus vaccines (RV1, RV5)

Varicella (Var) vaccine

Yellow Fever vaccine

Non-live Anthrax vaccine

COVID-19 vaccines (Pfizer, Moderna, 

Novavax)

Haemophilus influenzae type b (Hib) 

vaccines

Hepatitis A (HepA) vaccines

Hepatitis B (HepB) vaccines

Human papillomavirus (HPV) vaccines

Inactivated poliovirus vaccine (IPV)

Inactivated typhoid vaccine (Typhim Vi)

Influenza vaccines (IIV4, RIV4)

Japanese Encephalitis Vaccine (JEV)

Meningococcal conjugate (MenACWY) 

vaccine

Pneumococcal conjugate vaccines (PCV13, 

PCV20, PCV15)

Pneumococcal polysaccharide vaccine 

(PPSV23)

Rabies vaccine

Recombinant zoster vaccine (RZV)

Respiratory syncytial virus vaccine (RSV)

Serogroup B meningococcal (MenB) vaccines 

(MenB-FHbp, MenB-4C)

Tetanus-toxoid, diphtheria-toxoid, or 

pertussis-containing vaccines (DTaP, Tdap, 

DT, Td, DTaP-HepB-IPV, DTaP-IPV/Hib, 

DTaP-IPV, DTaP-IPV-Hib-HepB)†

Non-replicating§ COVID-19 vaccine (Janssen)

Jynneos smallpox/monkeypox vaccine * Oral adenovirus vaccine is used primarily in the military for prevention of adenovirus 

infection. It should not be confused with Janssen COVID-19 vaccine which is used for the 

prevention of SARS-CoV-2 infection

† The tetanus-toxoid components of these vaccines are toxoids, not vaccines.

§ These vaccines do not replicate and therefore behave like non-live vaccines.
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 30

TABLE 3-2. Recommended and minimum ages and intervals between 

vaccine doses(a),(b),(c),(d)

Known as the “grace period”, vaccine doses administered ≤4 days before the minimum 

interval or age are considered valid; however, local or state mandates might supersede 

this 4-day guideline

“3 calendar months” (or fewer) can be converted into weeks per the formula “1 month = 4 

weeks”

Vaccine and 

dose 

number

Recommended 

age for this dose

Minimum 

age for this 

dose

Recommended 

interval to next 

dose

Minimum 

interval to 

next dose

DEN4CYD-1 9—16 years 9 years 6 months 5 months after 

age at 1st dose

DEN4CYD-2 9—16 years 9 years + 5 

months

6 months 5 months after 

age at second 

dose

DEN4CYD-3 9—16 years 9 years +10 

months

— —

DTaP-1(e) 2 months 6 weeks 8 weeks 4 weeks

DTaP-2 4 months 10 weeks 8 weeks 4 weeks

DTaP-3 6 months 14 weeks 6-12 months(f) 6 months(f)

DTaP-4 15-18 months 15 months(f) 3 years 6 months

DTaP-5(g) 4-6 years 4 years — —

HepA-1(e) 12-23 months 12 months 6-18 months 6 months

HepA-2 ≥18 months 18 months — —

HepB-1(h) Birth Birth 4 weeks-4 months 4 weeks

HepB-2 1-2 months 4 weeks 8 weeks-17 months 8 weeks

HepB-3(i) 6-18 months 24 weeks — —

Hib-1(j) 2 months 6 weeks 8 weeks 4 weeks

Hib-2 4 months 10 weeks 8 weeks 4 weeks

Hib-3(k) 6 months 14 weeks 6-9 months 8 weeks

Hib-4 12-15 months 12 months — —

HPV Two Dose Series(l)
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 31

HPV-1 11-12 years 9 years 6 months 5 months

HPV-2 11-12 years (+6 

months)

9 years + 5 

months(m)

— —

HPV Three Dose Series

HPV-1(n) 11-12 years 9 years 1-2 months 4 weeks

HPV-2 11-12 years (+1-2 

months)

9 years (+4 

weeks)

4 months 12 weeks(n)

HPV-3(n) 11-12 years (+6 

months)

9 years (+5 

months)

— —

Influenza, 

inactivated(o)

≥6 months 6 months(p) 4 weeks 4 weeks

IPV-1(e) 2 months 6 weeks 8 weeks 4 weeks

IPV-2 4 months 10 weeks 8 weeks-14 months 4 weeks

IPV-3 6-18 months 14 weeks 3-5 years 6 months

IPV-4(q) 4-6 years 4 years — —

LAIV(o) 2-49 years(r) 2 years 4 weeks 4 weeks

MenACWY-1(s) 11-12 years 2 months(t) 4-5 years 8 weeks

MenACWY-2 16 years 11 years (+8 

weeks)(u)

— —

MenB-1 Healthy adolescents: 

16-23 years

16 years Bexsero: 4 weeks

Trumenba: 6 

months(c)

Bexsero: 4 

weeks

Trumenba: 6 

months(c)

Persons at increased 

risk: ≥10 years

10 years Bexsero: 4 weeks

Trumenba: 1-2 

months(c)

Bexsero: 4 

weeks

Trumenba: 1 

month

MenB-2 Healthy adolescents: 

16-23 years (+1 

month)

16 years (+1 

month)

— —

Persons at increased 

risk: ≥10 years (+1 

month)

10 years (+1 

month)

Bexsero: —

Trumenba: 4-5 

months(c)

Bexsero: —

Trumenba: 4 

months(c)
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 32

MenB-3(v) Persons at increased 

risk: ≥ 10 years (+ 6 

months(c))

10 years (+ 6 

months(c))

— —

MMR-1(w) 12-15 months 12 months 3-5 years 4 weeks

MMR-2(w) 4-6 years 13 months — —

PCV13-1(j, x) 2 months 6 weeks 8 weeks 4 weeks

PCV13-2 4 months 10 weeks 8 weeks 4 weeks

PCV13-3 6 months 14 weeks 6 months 8 weeks

PCV13-4 12-15 months 12 months — —

PCV15 See footnote x below

PCV20 See footnote x below

PPSV-1 — 2 years 5 years 5 years

PPSV-2(y) — 7 years — —

Rotavirus-1(z) 2 months 6 weeks 8 weeks 4 weeks

Rotavirus-2 4 months 10 weeks 8 weeks 4 weeks

Rotavirus-3(z) 6 months 14 weeks — —

Td 11-12 years 7 years 10 years 5 years

Tdap(aa) ≥11 years 7 years — —

Varicella-1(w) 12-15 months 12 months 3-5 years 12 weeks(bb)

Varicella-2(w) 4-6 years 15 months(cc) — —

RZV - 1 ≥50 years 50 years(dd) 2-6 months 4 weeks

RZV - 2 ≥50 years (+ 2-6 

months)

50 years — —
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 33

Abbreviations: DEN4CYD = dengue vaccine; DTaP = diphtheria and tetanus toxoids and acellular pertussis; HepA = 

hepatitis A; HepB = hepatitis B; Hib = Haemophilus influenzae type b; HPV = human papillomavirus; IPV = 

inactivated poliovirus; LAIV = live, attenuated influenza vaccine; MenACWY = quadrivalent meningococcal conjugate 

vaccine; MenB = serogroup B meningococcal vaccine; MenB-4C = Bexsero; MenB-FHbp = Trumenba; MMR = 

measles, mumps, and rubella; MMRV

= measles, mumps, rubella, and varicella; MPSV4 = quadrivalent meningococcal polysaccharide vaccine; PCV13 = 

pneumococcal conjugate vaccine; PPSV23= pneumococcal polysaccharide vaccine; PRP-OMP = polyribosylribitol 

phosphate-meningococcal outer membrane protein conjugate; RZV = recombinant zoster vaccine; Td = tetanus and 

diphtheria toxoids; Tdap = tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis.

(a) Combination vaccines are available. Use of licensed combination vaccines is generally preferred to separate 

injections of their equivalent component vaccines. When administering combination vaccines, the minimum age for 

administration is the oldest age for any of the individual components. The minimum interval between doses is equal to 

the greatest interval of any of the individual components.

(b) Information on travel vaccines, including typhoid, Japanese encephalitis, and yellow fever, is available at 

https://www.cdc.gov/travel. Information on other vaccines that are licensed in the United States but not distributed, 

including anthrax and smallpox, is available at http://emergency.cdc.gov/bioterrorism/ .

(c) “Months” refers to calendar months.

(d) Within a number range, a hyphen (-) should be read as “through.”

(e) Combination vaccines containing the hepatitis B component are available (see Table 3-3). These vaccines should not 

be administered to infants aged <6 weeks because of the other vaccine components (i.e., Hib, DTaP, HepA, and IPV).

(f) The minimum recommended age for DTaP-4 is 15 months, with a recommended 6 months from DTaP-3 (the 

recommended interval between DTaP-3 and DTaP-4 is 6 months). However, DTaP4 need not be repeated if given on 

or after 12 months of age and at least 4 months after DTaP-3. The 4-day grace period can be applied when validating 

past doses and can be applied to the minimum age of 12 months and the minimum interval of 4 months between 

DTaP-3 and DTaP-4. The 4-day grace period can be used when planning doses ahead of time, but should be applied to 

the minimum age of 15 months and the minimum interval between DTaP-3 and DTaP-4 of 6 months. 

(g) If a fourth dose of DTaP is given on or after the fourth birthday, a fifth dose is not needed if the interval between the 

third dose and fourth dose is at least 6 months. 

(h) Adjuvanted Hepatitis B vaccine (HepB-CgG) can be administered to adults 18 years old and older on a two dose 

schedule, the first and second dose separated by 4 weeks.

(i) HepB-3 should be administered at least 8 weeks after HepB-2 and at least 16 weeks after HepB-1 and should not be 

administered before age 24 weeks.

(j) For Hib and PCV13, children receiving the first dose of vaccine at age ≥7 months require fewer doses to complete the 

series.

(k) If PRP-OMP (Pedvax-Hib, Merck Vaccine Division) was administered at ages 2 and 4 months, a dose at age 6 

months is not necessary. The final dose has a minimum age of 12 months.

(l) A two-dose schedule of HPV vaccine is recommended for most persons beginning the series between 9 through 14 

years of age. See HPV vaccine-specific recommendations for details. 

www.cdc.gov/mmwr/volumes/65/wr/pdfs/mm6549a5.pdf

(m) If a patient is eligible for a 2-dose HPV series, and the second dose is given less than four weeks after the first dose, 

it is an invalid dose. Administer another dose 6-12 months after the first dose. If the second dose is given less than five 

months after the first dose, but more than four weeks after the first dose, the next dose should be administered at least 

12 weeks after the second dose, and at least 6-12 months after the first dose. The 4-day grace period may be used. If 

the third dose was administered before December 16, 2016, and was administered 12 weeks after the 2nd dose, and 16 

weeks after the first dose, it is a valid dose. The 4-day grace period may be used. If the third dose was administered on 

or after December 16, 2016, and was administered 12 weeks after the 2nd dose and 5 months after the first dose, it is a 

valid dose. The 4-day grace period may beused.

(n) The minimum age for HPV-3 is based on the baseline minimum age for the first dose (i.e., 9 years) and the 

minimum interval of 5 months between the first and third dose. If the third dose was administered before December 

16, 2016, and was administered 12 weeks after the 2nd dose, and 16 weeks after the first dose, it is a valid dose. The 4- 

day grace period may be used. If the third dose was administered on or after December 16, 2016, and was

administered.

(o) One dose of influenza vaccine per season is recommended for most persons. To determine which children younger 

than 9 years should receive 2 doses in a single season, please see influenza vaccine-specific recommendations (82). If a 

dose of LAIV is administered to a child 6 months to 2 years of age in error, the dose does not need to be repeated.
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 34

(p) The minimum age for inactivated influenza vaccine varies by vaccine manufacturer. See package insert for vaccinespecific minimum ages.

(q) A fourth dose is not needed if the third dose was administered at ≥4 years and at least 6 months after the previous 

dose.

(r) If a dose of LAIV is administered to someone 6 months to 2 years of age, the dose does NOT need to be repeated. If 

someone is still indicated for dose 2 of the prime-boost, and younger than 2 years of age, the second dose should be 

IIV.

(s) Revaccination with meningococcal vaccine is recommended for previously vaccinated persons who remain at high 

risk for meningococcal disease (47).

(t) MenACWY-D (Menactra) can be given as young as 9 months for high-risk persons. MenACWY-CRM (Menveo) can 

be given as young as 2 months for high-risk persons. Hib-MenCY can be given as young as 6 weeks for high-risk 

persons. Hib-MenCY is given as a 4-dose series at 2 months, 4 months, 6 months and 12-18 months. MenACWY-TT 

(MenQuadfi) can be given as young as 2 years for high-risk persons.

(u) For routine non-high risk adolescent vaccination, the minimum age for the booster dose is 16 years.

(v) This dose is not necessary if Bexsero is correctly administered, or if Trumenba is correctly administered to healthy 

adolescents.

(w) Combination MMRV vaccine can be used for children aged 12 months-12 years. See text for details.

(x) Infants and children can optionally receive PCV15 instead of PCV13. High-risk adults 19 years through 64 years 

who are known to have not received any pneumococcal vaccine or whose PCV13 history is unknown should receive 

either PCV20 or PCV15. Adults 65 years old and older who are known to have not received any pneumococcal 

vaccine or whose PCV13 history is unknown should receive either PCV20 or PCV15. If PCV15 is administered and if 

PPSV23 naïve, a dose of PPSV23 should be administered a year later. On the basis of shared clinical decisionmaking, adults 65 years old and older who have received a complete series of pneumococcal vaccine can receive a 

dose of PCV20 at least five years after the most recent dose. For adults who have started the recommended 

pneumococcal vaccine series with PCV13 but have not received all recommended doses, look at ACIP Vaccine 

Recommendations and Schedules for details.

(y) A second dose of PPSV23 5 years after the first dose is recommended for persons aged ≤65 years at highest risk for 

serious pneumococcal infection and those who are likely to have a rapid decline in pneumococcal antibody 

concentration (61).

(z) The first dose of rotavirus must be administered at age 6 weeks through 14 weeks and 6 days. The vaccine series 

should not be started for infants aged ≥15 weeks, 0 days. Rotavirus should not be administered to children older than 8 

months, 0 days of age regardless of the number of doses received between 6 weeks and 8 months, 0 days of age. If 2 

doses of Rotarix (GlaxoSmithKline) are administered as age appropriate, a third dose is not necessary.

(aa) Only 1 dose of Tdap is recommended. Subsequent doses should be given as Td or Tdap. For management of a 

tetanus-prone wound in persons who have received a primary series of tetanus-toxoid–containing vaccine, the 

minimum interval after a previous dose of any tetanus-containing vaccine is 5 years.

(bb) A special grace period of 2 months, based on expert opinion, can be applied to the minimum interval of 3 months, 

when evaluating records retrospectively, which results in an acceptable minimum interval of 4 weeks. An additional 4 

days should not be added on to this grace period.

(cc) A special grace period of 2 months, based on expert opinion, can be applied to the minimum age of 15 months when 

evaluating records retrospectively, which results in an acceptable minimum age of 13 months. An additional 4 days 

should not be added on to this grace period.

(dd) If a 1st dose of recombinant zoster vaccine is administered to someone 18 – 49 years of age, the dose does not need 

to be repeated. A 4 day grace period can be added to the absolute minimum age of 18 years when evaluating records 

retrospectively.
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 35

TABLE 3-3. FDA-licensed combination vaccines(a)

Vaccine(b) Trade name 

(year licensed)

Age range Routinely recommended 

ages

HepA-HepB Twinrix (2001) ≥18 years Three doses on a schedule of 

0, 1, and 6 months

DTaP-HepB-IPV Pediarix (2002) 6 weeks-6 years Three-dose series at 2, 4, 

and 6 months of age

MMRV ProQuad (2005) 12 months-12 

years

Two doses, the first at 12-15 

months, the second at 4-6 

years

DTaP-IPV Kinrix (2008) 4-6 years Fifth dose of DTaP and 

fourth dose of IPV

DTaP-IPV/Hib Pentacel (2008) 6 weeks-4 years Four-dose schedule at 2, 4,

6, and 15-18 months of age

Hib-MenCY MenHibrix (2012) 6 weeks-18 

months

Four-dose schedule at 2, 4,

6, and 12-15 months of age(c)

DTaP-IPV Quadracel (2015) 4-6 years Fifth dose of DTaP and 

fourth or fifth dose of IPV

DTaP-IPV-HibHepBVaxelis (2018) 6 weeks – 4 

years

Three-dose series at 2, 4, 

and 6 months of age

Abbreviations: DT = diphtheria and tetanus toxoids; DTaP = diphtheria and tetanus toxoids and acellular pertussis; 

FDA = Food and Drug Administration; HepA = hepatitis A; HepB = hepatitis B; Hib = Haemophilus influenzae type b; 

IPV = inactivated poliovirus; MMR = measles, mumps, and rubella; MMRV = measles, mumps, rubella, and varicella; 

Td = tetanus and diphtheria toxoids; Tdap = tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis.

Source: (82).

(a) Although MMR, DTaP, DT, Td, and Tdap are combination vaccines, they are not included on this list because they 

are not available in the United States as single-antigen products.

(b) In descriptions of combination vaccines, dash (-) indicates products in which the active components are supplied in 

their final (combined) form by the manufacturer; slash ( / ) indicates products in which active components must be 

mixed by the user.

(c) Hib-MenCY can be used for routine dosing of Hib vaccine but is recommended only for meningococcal vaccination 

in persons at high-risk of meningococcal disease.
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 36

TABLE 3-4. Guidelines for spacing of live and non-live antigens

Antigen combination Recommended minimum interval between doses

Two or more non-live (a),(b),(c) May be administered simultaneously or at any interval 

between doses

Non-live and live (d) May be administered simultaneously or at any interval 

between doses

Two or more live injectable (d) 28 days minimum interval, if not administered 

simultaneously

Source: (83).

(a) Certain experts suggest a 28-day interval between tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis 

(Tdap) vaccine and tetravalent meningococcal conjugate vaccine if they are not administered simultaneously.

(b) In persons with functional or anatomic asplenia, MCV-D and PCV13 should not be administered simultaneously and 

should be spaced by 4 weeks. Likewise for persons with immunosuppressive high-risk conditions indicated for PCV13 

and PPSV23, PCV13 should be administered first, and PPSV23 should be administered no earlier than 8 weeks later. 

For persons 65 years old or older indicated for PCV13 and PPSV23, PCV13 should be administered first and PPSV23 

should be administered 6-12 months later. For persons with high-risk conditions indicated for PCV15 and PPSV23, the 

interval between PCV15 and PPSV23 should be one year, for those with immunosuppressive high-risk conditions the 

interval may be shortened to 8 weeks.

(c) For providers who wish to use Menactra in patients indicated for DTaP, the two vaccines should be administered 

simultaneously. If they cannot be administered simultaneously, administer Menactra first, and then administer 

DTaP 6 months later.

(d) The live oral vaccines Ty21a typhoid vaccine and rotavirus vaccine may be administered simultaneously with or 

at any interval before or after non-live or live injectable vaccines.
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 37

TABLE 3-5. Guidelines for administering antibody-containing products(a) 

and vaccines

Type of 

administration

Products administered Recommended minimum 

interval between doses

Simultaneous 

(during the same 

clinic day)

Antibody-containing products and 

non-live antigen

Can be administered 

simultaneously at different 

anatomic sites or at any time 

interval between doses

Antibody-containing products and 

live antigen

Should not be administered 

simultaneously.(b) If 

simultaneous administration of 

measles-containing vaccine or 

varicella vaccine is unavoidable, 

administer at different sites and 

revaccinate or test for 

seroconversion after the 

recommended interval (see 

Table 3-6)

Nonsimultaneous Administered 

first

Administered 

second

Antibodycontaining 

products

Non-live 

antigen

No interval necessary

Non-live 

antigen

Antibodycontaining 

products

No interval necessary

Antibodycontaining 

products

measles, 

mumps, rubella 

vaccine, 

varicella 

vaccine, and 

combined 

measles, 

mumps, rubella, 

varicella vaccine 

antigens

Dose related(b),(c)
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 38

MMR vaccine, 

varicella vaccine, 

and combined 

measles, mumps, 

rubella, varicella 

vaccine antigens

Antibodycontaining 

products

2 weeks(b)

(a) Blood products containing substantial amounts of immune globulin include intramuscular, subcutaneous, and 

intravenous immune globulin, specific hyperimmune globulin (e.g., hepatitis B immune globulin, tetanus immune 

globulin, varicella zoster immune globulin, and rabies immune globulin), whole blood, packed red blood cells, plasma, 

and platelet products.

(b) Yellow fever vaccine; rotavirus vaccine; oral Ty21a typhoid vaccine; and live, attenuated influenza vaccine are 

exceptions to these recommendations. These live, attenuated vaccines can be administered at any time before or after 

or simultaneously with an antibody-containing product.

(c) The duration of interference of antibody-containing products with the immune response to the measles component 

of measles-containing vaccine, and possibly varicella vaccine, is dose related (see Table 3-6).
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 39

TABLE 3-6. Recommended intervals between administration of antibodycontaining products and measles- or varicella-containing vaccine, by 

product and indication for vaccination

Product/Indication Dose (mg IgG/kg) 

and route(a)

Recommended interval 

before measles- or live 

varicella-containing 

vaccine(b) administration 

(months)(c)

Blood transfusion

RBCs, washed 10 mL/kg, negligible 

IgG/kg IV

None

RBCs, adenine-saline added 10 mL/kg (10 mg 

IgG/kg) IV

3

Packed RBCs (hematocrit 65%)(d) 10 mL/kg (60 mg 

IgG/kg) IV

6

Whole blood (hematocrit 35%-

50%)(d)

10 mL/kg (80-100

mg IgG/kg) IV

6

Plasma/platelet products 10 mL/kg (160 mg 

IgG/kg) IV

7

Botulinum Immune Globulin 

Intravenous (Human)

1.0 mL/kg (50 mg 

IgG/kg) IV

6

Cytomegalovirus IGIV 150 mg/kg maximum 6

Hepatitis A IG

Contact prophylaxis 0.1 mL/kg (16.5

mg IgG/kg) IM

6(e)

International travel, <1 month stay 0.1 mL/kg (16.5

mg IgG/kg) IM

6(e)

International travel, ≥1 month stay 0.2 mL/kg (33 mg 

IgG/kg) IM

6(e)

Hepatitis B IG 0.06 mL/kg (10 mg 

IgG/kg) IM

3

IGIV

Replacement therapy for immune 

deficiencies(f)

300-400 mg/kg IV(e) 8
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 40

Immune thrombocytopenic 

purpura treatment

400 mg/kg IV 8

Postexposure varicella prophylaxis 400 mg/kg IV 8

Postexposure measles prophylaxis 

for immunocompromised contacts

400 mg/kg IV 8

Immune thrombocytopenic 

purpura treatment

1000 mg/kg IV 10

Kawasaki disease 2 g/kg IV 11

Measles prophylaxis IG

Standard (i.e., 

nonimmunocompromised) contact

0.50 mL/kg (80 mg 

IgG/kg) IM

6

Monoclonal antibody to 

respiratory syncytial virus F 

protein (e.g., Synagis 

[MedImmune])(g)

15 mg/kg IM None

Rabies IG 20 IU/kg (22 mg 

IgG/kg) IM

4

Tetanus IG 250 units (10 mg 

IgG/kg) IM

3

Varicella IG 125 units/10 kg (60-

200 mg IgG/kg) IM, 

maximum 625 units

5
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 41

Abbreviations: HIV = human immunodeficiency virus; IG = immune globulin; IgG = immune globulin G; IGIV = 

intravenous immune globulin; mg IgG/kg = milligrams of immune globulin G per kilogram of body weight; IM = 

intramuscular; IV = intravenous; RBCs = red blood cells.

(a) This table is not intended for determining the correct indications and dosages for using antibody-containing products. 

Unvaccinated persons might not be protected fully against measles during the entire recommended interval, and 

additional doses of IG or measles vaccine might be indicated after measles exposure. Concentrations of measles 

antibody in an IG preparation can vary by manufacturer’s lot. Rates of antibody clearance after receipt of an IG 

preparation also might vary. Recommended intervals are extrapolated from an estimated half-life of 30 days for 

passively acquired antibody and an observed interference with the immune response to measles vaccine for 5 months 

after a dose of 80 mg IgG/kg. Sources: Mason W, Takahashi M, Schneider T. Persisting passively acquired measles 

antibody following gamma globulin therapy for Kawasaki disease and response to live virus vaccination [Abstract 311]. 

Presented at the 32 meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy, Los Angeles, 

California, October, 1992, AND Siber GR, Werner BG, Halsey NA, et al. Interference of immune globulin with measles 

and rubella immunization. J Pediatr. 1993;122(2):204-211. DOI: 10.1016/S0022-3476(06)80114-9, AND Mason WH, 

Schneider TL, Takahashi M. Duration of passively acquired measles antibody and response to live virus vaccination 

allowing gamma globulintherapy for Kawasaki syndrome. Prog Pediatr Cardiol. 1992;1(1):82. DOI: 10.1016/S1058-

9813(06)80067-6. The extrapolation is performed by counting months from 80 mg down to (1-3 mg) (e.g. 80 >>> 40 

>> >20 >> >10 >>> 5>>>2.5....equal to FIVE intervals) and adding a grace month, so 80 mg values take a “6 month” 

interval)

(b) Does not include recombinant zoster vaccine, since this vaccine is non-live.

(c) The interval between blood/passive antibody products and testing for history of dengue infection (which is mandatory 

prior to administration of dengue vaccine) should be 12 months

(d) Assumes a serum IgG concentration of 16 mg/mL.

(e) The reason the interval is 6 months (and not 4 months) is that the quantity of 16.5 IgG/kg does not reflect the upper 

ceiling of the quantity of measles IgG in the product.

(f) Measles vaccination is recommended for children with mild or moderate immunosuppression from HIV infection, 

and varicella vaccination may be considered for children with mild or moderate immunosuppression from HIV 

infection, but both are contraindicated for persons with severe immunosuppression from HIV or any other 

immunosuppressive disorder.

(g) Contains antibody only to respiratory syncytial virus.
General Best Practice Guidelines for Immunization: Timing and Spacing of Immunobiologics 42

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