Prevention and Control of Influenza, Recommendations of the Advisory Committee on Immunization Practices (ACIP)

Nicole M. Smith, PhD; Joseph S. Bresee, MD; David K. Shay, MD; Timothy M. Uyeki, MD; Nancy J. Cox, PhD; Raymond A. Strikas, MD

Disclosures

Morbidity and Mortality Weekly Report. 2006;55(27):1-41. 

In This Article

Live, Attenuated Influenza Vaccine Recommendations

LAIV is an option for vaccination of healthy, nonpregnant persons aged 5-49 years who want to avoid influenza, and those who might be in close contact with persons at high risk for severe complications, including health-care workers. During periods when inactivated vaccine is in short supply, use of LAIV is encouraged when feasible for eligible persons (including health-care workers) because use of LAIV by these persons might increase availability of inactivated vaccine for persons in groups at high risk. Possible advantages of LAIV include its potential to induce a broad mucosal and systemic immune response, its ease of administration, and the acceptability of an intranasal rather than intramuscular route of administration.

LAIV is intended for intranasal administration only and should not be administered by the intramuscular, intradermal, or intravenous route. LAIV must be thawed before administration. This can be accomplished by holding an individual sprayer in the palm of the hand until thawed, with subsequent immediate administration. Alternatively, the vaccine can be thawed in a refrigerator and stored at 2ºC-8ºC for ≤60 hours before use. Vaccine should not be refrozen after thawing. LAIV is supplied in a prefilled single-use sprayer containing 0.5 mL of vaccine. Approximately 0.25 mL (i.e., half of the total sprayer contents) is sprayed into the first nostril while the recipient is in the upright position. An attached dose-divider clip is removed from the sprayer to administer the second half of the dose into the other nostril. If the vaccine recipient sneezes after administration, the dose should not be repeated.

LAIV should be administered annually according to the following schedule:

  • Children aged 5-<9 years previously unvaccinated at any time with either LAIV or inactivated influenza vaccine should receive 2 doses* of LAIV separated by 6-10 weeks; if possible, the second dose of vaccine should be administered before the onset of influenza season.

  • Children aged 5-<9 years previously vaccinated at any time with either LAIV or inactivated influenza vaccine should receive 1 dose of LAIV. They do not require a second dose.

  • Persons aged 9-49 years should receive 1 dose of LAIV.

LAIV can be administered to persons with minor acute illnesses (e.g., diarrhea or mild upper respiratory tract infection with or without fever). However, if clinical judgment indicates nasal congestion is present that might impede delivery of the vaccine to the nasopharyngeal mucosa, deferral of administration should be considered until resolution of the illness.

Whether concurrent administration of LAIV with other vaccines affects the safety or efficacy of either LAIV or the simultaneously administered vaccine is unknown. In the absence of specific data indicating interference, following the ACIP general recommendations for immunization is prudent.[210] Inactivated vaccines do not interfere with the immune response to other inactivated vaccines or to live vaccines. Inactivated or live vaccines can be administered simultaneously with LAIV. However, after administration of a live vaccine, at least 4 weeks should pass before another live vaccine is administered (see Persons Who Should Not Be Vaccinated with LAIV).

The effect on safety and efficacy of LAIV coadministration with influenza antiviral medications has not been studied. However, because influenza antivirals reduce replication of influenza viruses, LAIV should not be administered until 48 hours after cessation of influenza antiviral therapy, and influenza antiviral medications should not be administered for 2 weeks after receipt of LAIV.

LAIV must be stored at -15ºC or colder. A manufacturer-supplied freezer box was formerly required for storage of LAIV in a frost-free freezer; however, the freezer box is now optional, and LAIV may now be stored in frost-free freezers without using a freezer box. LAIV can be thawed in a refrigerator and stored at 2ºC-8ºC for ≤60 hours before use. It should not be refrozen after thawing because of decreased vaccine potency.

Available data indicate that both children and adults vaccinated with LAIV can shed vaccine viruses for ≥2 days after vaccination, although in lower titers than typically occur with shedding of wild-type influenza viruses. Shedding should not be equated with person-to-person transmission of vaccine viruses, although, in rare instances, shed vaccine viruses can be transmitted from vaccinees to nonvaccinated persons.

One unpublished study of a child care center setting assessed transmissibility of vaccine viruses from 98 vaccinated to 99 unvaccinated children, all aged 8-36 months. Eighty percent of vaccine recipients shed one or more virus strains, with a mean of 7.6 days' duration.[249] One vaccine type influenza type B isolate was recovered from a placebo recipient and was confirmed to be vaccine-type virus. The type B isolate retained the cold-adapted, temperature-sensitive, attenuated phenotype, and it possessed the same genetic sequence as a virus shed from a vaccine recipient in the same children's play group. The placebo recipient from whom the influenza type B vaccine virus was isolated did not exhibit symptoms that were different from those experienced by vaccine recipients. The estimated probability of acquiring vaccine virus after close contact with a single LAIV recipient in this child care population was 0.58%-2.4%.

One study assessing shedding of vaccine viruses in 20 healthy vaccinated adults aged 18-49 years demonstrated that the majority of shedding occurred within the first 3 days after vaccination, although one participant was noted to shed virus on day 7 after vaccine receipt. No study participants shed vaccine viruses ≥10 days after vaccination. Duration or type of symptoms associated with receipt of LAIV did not correlate with duration of shedding vaccine viruses. Person-to-person transmission of vaccine viruses was not assessed in this study.[250]

Another study assessing shedding of vaccine viruses in 14 healthy adults aged 18-49 years indicated that 50% of these adults had viral antigen detected by direct immunofluorescence or rapid antigen tests within 7 days of vaccination. The majority of viral shedding was detected on day 2 or 3. Person-to-person transmission of vaccine viruses was not assessed in this study.[251]

In clinical trials, viruses shed by vaccine recipients have been phenotypically stable. In one study, nasal and throat swab specimens were collected from 17 study participants for 2 weeks after vaccine receipt.[252] Virus isolates were analyzed by multiple genetic techniques. All isolates retained the LAIV genotype after replication in the human host, and all retained the cold-adapted and temperature-sensitive phenotypes. A study conducted in a day care setting found that limited genetic change occurred in the LAIV strains after replication in the vaccine recipients.[253]

Twenty prelicensure clinical trials assessed the safety of the approved LAIV. In these combined studies, approximately 28,000 doses of the vaccine were administered to approximately 20,000 persons. A subset of these trials were randomized, placebo-controlled studies in which an estimated 4,000 healthy children aged 5-17 years and 2,000 healthy adults aged 18-49 years were vaccinated. The incidence of adverse events possibly complicating influenza (e.g., pneumonia, bronchitis, bronchiolitis, or central nervous system events) was not statistically different among LAIV and placebo recipients aged 5-49 years. LAIV is made from attenuated viruses and does not cause influenza in vaccine recipients.

Children. In a subset of healthy children aged 60-71 months from one clinical trial,[111,112] certain signs and symptoms were reported more often among LAIV recipients after the first dose (n = 214) than placebo recipients (n = 95) (e.g., runny nose, 48.1% versus 44.2%; headache, 17.8% versus 11.6%; vomiting, 4.7% versus 3.2%; and myalgias, 6.1% versus 4.2%), but these differences were not statistically significant. In other trials, signs and symptoms reported after LAIV administration have included runny nose or nasal congestion (20%-75%), headache (2%-46%), fever (0-26%), vomiting (3%-13%), abdominal pain (2%), and myalgias (0-21%).[105,108,110,254,255,256] These symptoms were associated more often with the first dose and were self-limited. Data from a study of children aged 1-17 years indicated an increase in asthma or reactive airways disease in the subset aged 1-<5 years.[257,258] Because of these data, LAIV is not approved for use among children aged <5 years. Another study was conducted among more than 11,000 children aged 18 months-18 years in which 18,780 doses of vaccine were administered over a 4-year period. This study did not observe an increase in asthma visits 0-15 days after vaccination for children who were aged 18 months-4 years compared with the prevaccination period; however, a significant increase in asthma events was observed 15-42 days after vaccination but only in vaccine year 1.[259]

Adults. Among adults, runny nose or nasal congestion (28%-78%), headache (16%-44%), and sore throat (15%-27%) have been reported more often among vaccine recipients than placebo recipients.[114,260,261] In one clinical trial[114] among a subset of healthy adults aged 18-49 years, signs and symptoms reported more frequently among LAIV recipients (n = 2,548) than placebo recipients (n = 1,290) within 7 days after each dose included cough (13.9% versus 10.8%), runny nose (44.5% versus 27.1%), sore throat (27.8% versus 17.1%), chills (8.6% versus 6.0%), and tiredness/weakness (25.7% versus 21.6%).

Safety Among Groups at High Risk from Influenza-Related Morbidity. Until additional data are acquired and analyzed, persons at high risk for experiencing complications from influenza virus infection (e.g., immunocompromised patients; patients with asthma, cystic fibrosis, or chronic obstructive pulmonary disease; or persons aged ≥65 years) should not be vaccinated with LAIV. Protection from influenza among these groups should be accomplished using inactivated influenza vaccine.

Serious Adverse Events. Serious adverse events requiring medical attention among healthy children aged 5-17 years or healthy adults aged 18-49 years occurred at a rate of <1%. Surveillance will continue for adverse events that might not have been detected in previous studies. Reviews of reports to VAERS after vaccination of approximately 2,500,000 persons during the 2003-04 and 2004-05 influenza seasons did not reveal any substantial new safety concerns.[262,263] Health-care professionals should promptly report all clinically significant adverse events after LAIV administration to VAERS, as recommended for inactivated influenza vaccine.

The following populations should not be vaccinated with LAIV:

  • persons aged <5 years or those aged≥50 years;†

  • persons with asthma, reactive airways disease, or other chronic disorders of the pulmonary or cardiovascular systems; persons with other underlying medical conditions, including such metabolic diseases as diabetes, renal dysfunction, and hemoglobinopathies; or persons with known or suspected immunodeficiency diseases or who are receiving immunosuppressive therapies;†

  • children or adolescents receiving aspirin or other salicylates (because of the association of Reye syndrome with wild-type influenza virus infection);†

  • persons with a history of GBS;

  • pregnant women;† or

  • persons with a history of hypersensitivity, including anaphylaxis, to any of the components of LAIV or to eggs.

Close contacts of persons at high risk for complications from influenza should receive influenza vaccine to reduce transmission of wild-type influenza viruses to persons at high risk. Use of inactivated influenza vaccine is preferred for vaccinating household members, health-care workers, and others who have close contact with severely immunocompromised persons (e.g., patients with hematopoietic stem cell transplants) during those periods in which the immunocompromised person requires care in a protective environment. The rationale for not using LAIV among health-care workers caring for such patients is the theoretical risk that a live, attenuated vaccine virus could be transmitted to the severely immunocompromised person. If a health-care worker receives LAIV, that worker should refrain from contact with severely immunocompromised patients for 7 days after vaccine receipt. Hospital visitors who have received LAIV should refrain from contact with severely immunocompromised persons for 7 days after vaccination; however, such persons need not be excluded from visitation of patients who are not severely immunocompromised. ACIP has not indicated a preference for inactivated influenza vaccine use by health-care workers or other persons who have close contact with persons with lesser degrees of immunodeficiency (e.g., persons with diabetes, persons with asthma taking corticosteroids, or persons infected with HIV) or for inactivated influenza vaccine use by health-care workers or other healthy persons aged 5-49 years in close contact with all other groups at high risk.

Low-level introduction of vaccine viruses into the environment is likely unavoidable when administering LAIV. The risk for acquiring vaccine viruses from the environment is unknown but likely to be limited. Severely immunocompromised persons should not administer LAIV. However, other persons at high risk for influenza complications may administer LAIV. These include persons with underlying medical conditions placing them at high risk or who are likely to be at risk, including pregnant women, persons with asthma, and persons aged ≥50 years.

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