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

Christopher S. Ambrose; Catherine Luke; Kathleen Coelingh


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

In This Article

Efficacy/Effectiveness in Adults

LAIV Efficacy in Adults 18-64 Years of Age

Study AV009[24] was a randomized, double-blind, placebo-controlled study in adults 18–64 years of age (n = 4561) that evaluated the effectiveness of LAIV in preventing any febrile illness (AFI), as well as more influenza-specific syndromes such as severe febrile illness (SFI) and febrile upper respiratory illness (FURI); prevention of influenza-like illness (ILI) as defined by the Centers for Disease Control and Prevention (CDC), and the US Department of Defense (DOD) were analyzed post hoc. The study was conducted during a season dominated by an antigenically mismatched A/H3N2 strain. During the season, LAIV recipients had 9·7% fewer cases of AFI compared with placebo recipients (not significant). However, LAIV recipients experienced statistically significant reductions in SFI, FURI, CDC-ILI, and DOD-ILI (Figure 2). Significant reductions in illness were seen for subjects <40 years of age as well as for subjects = 40 years of age. However, in a post hoc analysis of adults 50–64 years of age (n = 641), effectiveness was not demonstrated; as a result, LAIV is not approved for use in the United States in adults 50 years of age and older.

Figure 2.

Effectiveness of LAIV in reducing illness in adults 18-64 years of age (study AV009). *P < 0·05; P < 0·001. CDC-ILI = influenza-like illness as defined by the Centers for Disease Control and Prevention guidelines; DOD-ILI = influenza-like illness as defined by the US Department of Defense guidelines; LAIV = live attenuated influenza vaccine; URI = upper respiratory tract illness.

From this study, which measured illness regardless of etiology and did not include laboratory diagnosis of influenza infection, it is not possible to generate an influenza-specific efficacy estimate. However, during the same season, the CDC conducted a placebo-controlled study of inactivated influenza vaccine in a similar population: healthy, working adults 18–64 years of age (n = 1184).[25] Although no effectiveness for inactivated vaccine was seen, results indicate that 18% of CDC-ILI cases in placebo recipients may have been caused by influenza (4·4% laboratory-confirmed influenza, 23·8% CDC-ILI). If this ratio is applied to the rates of CDC-ILI from study AV009 (data on file), the influenza-specific efficacy for LAIV can be projected to have been 75–94%.

The first study to directly assess the efficacy of the licensed formulation of LAIV in adults was an experimental challenge study. Among seronegative adults 18–40 years of age (n = 103), LAIV demonstrated 85% (95% CI: 28, 100) efficacy against culture-confirmed influenza illness;[26] the efficacy of TIV was estimated at 71% (95% CI: 2, 97).

Subsequently, investigators at the University of Michigan initiated a 3-year study of the efficacies of TIV and LAIV compared with placebo in healthy adults 18–48 years of age.[27] In year 1 (n = 1247), the absolute efficacies of TIV and LAIV against culture-confirmed illness were 77% (95% CI: 37, 92) and 57% (95% CI: -3, 82), respectively; results for culture- or PCR-confirmed illness were 75% (95% CI: 42, 90) and 48% (95% CI: -7, 74). The vaccines had similar efficacy against influenza A/H3N2 but LAIV had lower efficacy against influenza B; this may have resulted from poor immunity against influenza B or the chance occurrence of increased infections in LAIV recipients caused by influenza B viruses from the alternate genetic lineage, given that no influenza vaccine has demonstrated efficacy against cross-lineage B strains.[28,29] Analysis of results from year 2 of the study (2005–2006, n = 2058) were complicated by a low influenza attack rate; efficacies of the two vaccines were similar and highly variable across different analysis methods.[30]

Another study described the efficacy of LAIV and TIV in young healthy adults (US military trainees) in 2005–2006.[31] Using a methodology that compared influenza incidence within the 2 weeks following vaccination (before the development of adaptive immune responses) to the incidence 2 weeks or more after vaccination, researchers concluded that the overall efficacy for the influenza vaccines was 92% (95% CI: 85, 96); efficacy was 95% at a site that used LAIV exclusively.

LAIV Experience in Adults = 50 Years of Age

Although LAIV is not approved for use in adults 50 years or older, several studies have been conducted in adults = 50 years of age; these data are presented below for completeness.

In adults 60 years or older, two randomized controlled studies have been conducted, one placebo-controlled and one TIV-controlled. Study D153-P507 (n = 3242) was a randomized, double-blind study conducted in South Africa in 2001. LAIV efficacy against antigenically matched strains was 42·3% (95% CI: 21·6, 57·8) compared with placebo, with 52·5% (95% CI: 32·1, 67·2) efficacy against A/H3N2 and no efficacy against influenza B (1·4% LAIV, 1·3% placebo).[32] Study D153-P516 (n = 3009) was a randomized, open-label, TIV-controlled study conducted in South Africa in 2002[33] from which no efficacy conclusions could be drawn because of the few cases of culture-confirmed influenza illness. In these studies, rates of runny nose/nasal congestion, cough, sore throat, headache, muscle ache, tiredness, decreased appetite, and use of fever medication were increased in LAIV recipients.

The efficacy of LAIV in simultaneous combination with TIV has also been studied in the elderly. In a double-blind field trial conducted over a 3-year period in nursing home residents aged = 65 years, 523 residents (mean age, 84 years) received TIV and either monovalent A/H3N2 LAIV or placebo.[34] TIV+LAIV recipients experienced 61% (95% CI: 18, 82) fewer cases of laboratory-documented influenza A compared with TIV+placebo. A later study with a monovalent B LAIV suggested a similar trend, but attack rates were too low to allow definitive conclusions.[35] A third study was conducted among 2215 individuals = 50 years of age with COPD within the Veterans Affairs medical system.[36] In this study, the relative efficacy of TIV+LAIV compared with TIV+placebo in the prevention of laboratory-documented influenza illness was 16% (95% CI: -22, 43) for any influenza strain, 26% (95% CI: -17, 53) for A/H3N2, and -5% (95% CI: -113, 48) for B. However, TIV+LAIV recipients were shown to have an improvement in chronic lung disease severity index scores over the course of the study.[37] TIV+LAIV recipients reported higher rates of increased sputum, stuffy/runny nose, increased shortness of breath, chills, and itchiness at the intramuscular injection site compared with TIV+placebo recipients.


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