What is the Interval For Non-simultaneous Administration of Live Virus Vaccines?

Patient Presentation
A 1-year-old female came to clinic for her health supervision visit. She was healthy and developing well, and her family was going for an extended stay in China for the next few months. The mother had always been concerned about giving “so many vaccines at one time” but had always given all recommended vaccines on schedule. The mother was asking about spreading out the vaccine schedule again. The pertinent physical exam showed a smiling toddler who was just starting to walk. She had normal vital signs and growth parameters were in the 75-90%. The examination was normal.

The diagnosis of a healthy toddler was made. The pediatrician discussed which vaccines were recommended at the time. She noted that, “Especially as you are leaving for China, we can keep her current on her vaccines and you won’t need to receive any there. If we start to split them up, then you have to wait a few weeks between the vaccines and you will have to get more of them in China.” The mother agreed that it would be better to keep the child on the recommended schedule and also easier because of the travel. “Even if she doesn’t need vaccines in China, it still is important that she has her well child checks on time. Otherwise we will see you back when she is 15 months old,” the pediatrician reminded the mother.

Vaccines are a mainstay of infectious disease prevention and health promotion. Infants, children and adults benefit from vaccines the most when they are given on the recommended schedules. However there are times when this is not possible as children come to the physician a little early, or a little late, or had unavailable records and so received addition vaccine, etc. There are many questions that arise because of these timing issues such as the one above.

Standard vaccine schedules can be reviewed here.

Commonly administered vaccines includes:

  • Live-attenuated vaccines
    • Cholera
    • Measles, mumps, rubella (MMR combined vaccine)
    • Polio, oral
    • Rotavirus
    • Smallpox
    • Typhoid, oral
    • Varicella
    • Yellow fever
  • Inactivated vaccines
    • Hepatitis A
    • Influenza, injectable
    • Polio, injectable
    • Rabies
    • Typhoid, injectable
  • Subunit, recombinant, polysaccharide, and conjugate vaccines
    • Haemophilus influenzae type b (HIB) disease
    • Hepatitis B
    • Human papillomavirus (HPV)
    • Pertussis (part of the DTaP combined vaccine)
    • Pneumococcal disease
    • Meningococcal disease
    • Varicella zoster
  • Toxoid vaccines
    • Diphtheria
    • Tetanus

Simultaneous vaccine administration

  • Children can receive as many vaccines as needed at one time, so called simultaneous administration. There is no upper limit to the number of vaccines that can be given simultaneously. All vaccines that are indicated can be given simultaneously. There are no contraindications to this practice with 2 exceptions: 1) a patient needing both PCV13 (pneumococcal conjugate vaccine, recommended to be given first) and PPSV23 (pneumococcal polysaccharide vaccine, recommended to be given second) should be separated by at least 8 weeks, and 2) for patients with anatomic or functional asplenia, PCV13 and meningococcal conjugate vaccines may be given or not given together and have particular instructions depending on the vaccine brands being used. Combination vaccines with equivalent components are generally preferred over separate component vaccines.
    Simultaneous means given in the same clinic visit or same clinic day.

Minimum Intervals and Vaccine Deficiency

    Vaccines schedules have recommended intervals between vaccine administrations which provides the best timing for the vaccine to be effective. “A “minimum interval” is shorter than the recommended interval between doses, and is the shortest time between two doses of a vaccine series in which an adequate response to the second dose can be expected.” Minimal interval should not be used for scheduling routine vaccines, recommended intervals should be used instead. Minimal intervals are used for accelerating a vaccine schedule usually for children with immunization deficiency (i.e. the child is behind on their vaccines and needs to catch-up). Minimal intervals are also sometimes used because of unusual time restraints or circumstances such as international travel. Minimal intervals provide valid and effective immunizations, but are not as optimal and therefore following recommended schedules are best.

    An accelerated schedule should be used for any patient who is > 1 month or 1 dose behind the recommended dosing schedule. Minimal intervals can be used as many times as necessary until the patient is back on schedule.

    The Advisory Committee on Immunization Practice (ACIP) says “[f]or intervals of 3 months or less, you should use 28 days (4 weeks) as a “month.” For intervals of 4 months or longer, you should consider a month a “calendar month”: the interval from one calendar date to the next a month later.”

Vaccination Too Early

    When reviewing immunization records, there is a 4-day grace period instituted by the ACIP. If a vaccine was administered ≤ 4 days before the minimum age or minimum interval, it may be counted as a valid dose. The 4 day grace period is not for scheduling of vaccines but for reviewing records only. Vaccine administration even in this grace period window can cause problems with people who are less experienced or knowledgeable about vaccine timing. They can see vaccines given early and may believe them to be invalid. Documentation from a health care provider acknowledging vaccine validity may be needed or institutions may mistakenly insist on vaccine readministration even if given within the 4 day grace period. Therefore it is always best to not give vaccines early but on schedule.

Vaccination Too Late

    Do not start a vaccine series over. As long as the minimum interval and minimum age requirements have been met, then the patient usually can receive the vaccine. For some vaccines there are upper ages after which a vaccine should not be given. (e.g. HIB vaccine after 60 months of age) Oral typhoid may need to be restarted if the total doses are not completed in the recommended time frame.

Extra Vaccine Doses

    Complete vaccine records should be obtained and reviewed if possible. Unfortunately because of incomplete records, some children receive additional doses of vaccine which may be valid or invalid doses. The total number of valid vaccine doses should be determined (including review of the minimum intervals and ages). Doses that are not valid should be disregarded. If the valid doses still show the patient to be deficient, the patient should receive all indicated vaccine doses.

Learning Point
Dosing interval for non-simultaneous vaccine administration

    For 2 or more different, live viral, injectable vaccines not administered simultaneously, a minimum interval of 4 weeks should separate the vaccines. This is because the injectable, live virus vaccines may interfere with each other, decreasing the efficacy of the vaccines.
    MMR and Varicella administration specifically falls under this rule: do them all at one time or separate their administration by at least 4 weeks. If two different live virus injectable vaccines are given < 4 weeks, then the second vaccine given is considered invalid and should be repeated ≥ 28 days after the first vaccine was given. Serological testing can be obtained to determine immunity but this is costly and has other problems associated with it.

    Oral live virus vaccines including cholera, typhoid, and rotavirus can be given simultaneously with other vaccines (inactivated, or live virus injectable vaccines) and if not given simultaneously there is no minimal interval between administrations. One exception is that oral cholera should be given at least 8 hours before oral typhoid.

    Inactivated vaccines can be given simultaneously, and if not administered simultaneously, there is no minimum time intervals between administrations.

Questions for Further Discussion
1. List 2-3 references to obtain evidence-based scientific vaccine information?
2. Where can you find good evidence-based travel health information?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Immunization and Childhood Immunization.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Centers for Disease Control. General Recommendations. Epidemiology and Prevention of Vaccine-Preventable Diseases. Pink Book.
Available from the Internet at https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/genrec.pdf (2015, cited 5/16/18).

US Department of Health and Human Services. Vaccine Types.
Available from the Internet at https://www.vaccines.gov/basics/types/index.html (rev. 12/2017, cited 5/16/18).

Immunization Action Coalition. Scheduling Vaccines.
Available from the Internet at http://www.immunize.org/askexperts/scheduling-vaccines.asp (rev. 2/1/2018, cited 5/16/18).

Immunization Action Coalition. Administering Vaccines.
Available from the Internet at http://www.immunize.org/askexperts/administering-vaccines.asp (rev. 3/9/2018, cited 5/16/18).

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa