Current Status of Live Attenuated Influenza Vaccine in the United States for Seasonal and Pandemic Influenza

Christopher S. Ambrose; Catherine Luke; Kathleen Coelingh

Disclosures

Influenza Resp Viruses. 2008;2(6):193-202. 

In This Article

LAIV Safety Profile

The safety of LAIV has been evaluated in approximately 49 000 individuals in 48 completed studies, including more than 18 000 children younger than 5 years. Additionally, more than 10 million doses have been commercially distributed in the United States since licensure. In clinical studies, the most common adverse reactions (= 10% in LAIV recipients and at least 5% greater than in controls) were runny nose or nasal congestion in all ages, fever >100ºF in children 2–6 years of age, and sore throat in adults ( Table 4 and Table 5 ).[23] Rates of reactogenicity events generally decline upon revaccination with LAIV, either in the same or subsequent seasons.

Study MI-CP111[22] was prospectively designed to evaluate wheezing in children 6–59 months of age. The incidence of medically significant wheezing (MSW) was analyzed through 42 days after vaccination with LAIV or TIV; MSW was defined as a medical diagnosis of wheezing associated with other respiratory findings (e.g., hypoxemia, respiratory distress, or initiation of daily bronchodilator therapy). MSW was reported in more subjects 6–23 months of age who had received LAIV than in those given TIV (LAIV, 5·9%; TIV, 3·8%; P = 0·002). Among children aged 24–59 months, rates of MSW were comparable in LAIV and TIV recipients (LAIV, 2·1%; TIV, 2·5%; P = 0·38). In this same study, hospitalization rates were higher in LAIV recipients 6–23 months of age compared with TIV recipients (4·2% versus 3·2%, P = 0·09) with no increase among children 24–59 months of age (2·1% versus 2·5%; P = 0·33). The increase in hospitalizations in children < 2 years was driven by children 6–11 months of age (LAIV, 6·1%; TIV, 2·6%; P = 0·002) and most of the hospitalizations occurred > 42 days after the last dose, were not temporally clustered, and were accounted for by events commonly expected in this population (e.g., respiratory tract and gastrointestinal tract infections). A biological rationale for this increase in late-occurring hospitalizations cannot be readily explained. In older subgroups of children 12–23 and 24–59 months of age, hospitalization rates were not increased in LAIV versus TIV recipients.

In the University of Michigan multi-year comparative study of LAIV and TIV in adults < 50 years of age,[27,30] year 1 reactogenicity results showed an increased rate of arm soreness in TIV recipients and increased rates of runny nose/congestion, cough, and headache in LAIV recipients. In year 2, TIV recipients had increased rates of arm soreness, arm redness, muscle aches, as well as trouble breathing and red eyes (reported in other studies as ocular respiratory syndrome); LAIV recipients had increased rates of sore throat and runny nose/congestion.

The vaccine viruses in LAIV replicate in the cells of the nasal mucosa and can at times be isolated from nasal secretions post-vaccination. Based on two prospective studies, shedding of vaccine virus on at least 1 day is frequent in young children (e.g., 89% and 69% of subjects aged 6–23 and 24–59 months, respectively) and decreases with advancing age (44%, 27%, and 17% in individuals aged 5–8, 9–17, and 18–49 years, respectively).[42,43] In these studies, peak shedding incidence occurred on day 2, with the average subject with shedding having virus recoverable for 1·5–3 days and with titers below 1·5 log10 TCID50/ml after 13, 10, and 6 days post-vaccination for individuals 6–23 months, 2–8 years, and = 9 years of age.

Based on available information, transmission of vaccine virus from a vaccine recipient to an unvaccinated contact is likely to be a rare event, even in young children, and without negative clinical consequences. In a daycare study in children (n = 98) designed to optimize the occurrence and detection of transmission, one documented case of transmission was observed. The transmitted type B vaccine strain was only detected on 1 day, retained its ca, ts phenotype, and did not cause disease. Based on this study, the probability of transmission to a child following daycare contact with a single vaccinated child was calculated to be 0·58%.[9] Four additional type A strains from placebo recipients could not be characterized as vaccine or wild-type; inclusion of these four isolates as possible cases yields a transmission probability of 2·4%.[23]

Live attenuated influenza vaccine is not approved for use in immunocompromised individuals. However, because of concerns regarding inadvertent exposure to the vaccine, studies were conducted in relatively asymptomatic or mildly symptomatic adults and children with HIV infection. These studies demonstrated that LAIV was not associated with significant adverse events in HIV-infected individuals.[44,45] Similarly, a recent comparative safety study conducted in 243 children 5–17 years of age with HIV disease (viral load < 60 000 and CD4 count > 15%) demonstrated that there were no unexpected toxicities, prolonged shedding, or serious adverse events associated with either LAIV or TIV.[46]

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