Efficacy Of Live Attenuated Influenza Vaccine Research Articles

Cost-Effectiveness of Intranasal Live-Attenuated Influenza Vaccine for Children: A Systematic Review.

Introduction: The public health burden of seasonal influenza is significant, and influenza vaccination is the most effective preventive strategy. Nonetheless, the recommendation of influenza immunization in the pediatric population is still underrepresented. Our work aimed to assess the cost-effectiveness of pediatric influenza vaccination with the intranasal live-attenuated influenza vaccine (LAIV). Methods: We performed a systematic review of publications from PubMed/MEDLINE, Embase, and Scopus, covering the period from 1 January 2000 to 30 April 2022. We searched for economic evaluations that studied the impacts of LAIV among children or the pediatric population. Studies that considered incremental cost-effectiveness ratios (ICERs), in terms of cost per gain in life years, quality adjusted life years, or disability-adjusted life years, were covered. The Consensus Health Economic Criteria (CHEC) Extended Checklist was adopted to check the quality of the included studies. Results: Thirteen studies were included for the final review that were of good or excellent quality. The implementation of influenza vaccination with intranasal LAIV in the pediatric population was cost-effective when compared to the immunization strategies for the elderly and the high-risk groups alone or with no vaccination. The efficacy of LAIV for children, vaccination coverage, and the vaccine price were significant factors to the cost-effectiveness of influenza vaccination for children. Another significant contribution to the cost-effectiveness was the herd immunity arising from pediatric immunization against influenza. Conclusions: The implementation of influenza vaccination in the pediatric population with LAIV is cost-effective. Policymakers and health authorities may consider the evidence on the development of the pediatric influenza vaccination in their immunization schedules.

Detrimental impact of allergic airway disease on live attenuated influenza vaccine.

Historically, live attenuated, as opposed to inactivated, vaccines have been highly successful against many infectious diseases (see Ref. 1). However, curiously, seasonal live attenuated influenza vaccines (LAIV) or “Flumist” have not demonstrated superior efficacy when compared to inactivated influenza vaccines (IIV), especially in the past several influenza seasons.2, 3 This is in striking contrast to animal models in which Flumist consistently exhibits a clear advantage over IIV in inducing not only robust humoral immunity but also cytotoxic T cell immunity,4-7 which is believed to be important in cross-protection against mismatched influenza viruses.8-11 The reason for this discrepancy between human and animal data is not fully understood, but host factors have been suggested to contribute to highly variable LAIV efficacy.12 Given that chronic conditions, such as asthma, are highly prevalent among adults, that is, 1 in 13 (7.7%) adults in the United States according to centers for disease control and prevention (CDC),13 we propose that they can negatively impact vaccine efficacy. To test our hypothesis, we utilized mouse models of allergic airway disease (AAD) to assess LAIV efficacy in asthmatic mice (Figure 1A). LAIV-elicited systemic IgG responses were significantly diminished in AAD mice (Figure 1B,C). Antibody class switching is a complex process that involves a number of different stimuli.14 In particular, cytokines are known stimuli that direct antibody isotype switching. For example, the type 1 cytokine IFN-γ drives class switching to IgG2a and the type 2 cytokine IL-4 promotes switching to IgG1.15 Since mouse models of asthma are known to trigger type 2-biased immune responses,16, 17 it is plausible that the type 2 cytokine environment in AAD mice is suppressing type 1 immunity-based LAIV. Indeed, analysis of IgG subclasses shows that type 1 immunity-associated IgG2a was downregulated in AAD mice following intranasal (i.n.) LAIV vaccination (Figure 1B,C). Consistent with the systemic antibody profile, mucosal IgG and IgG2a antibodies were also suppressed in AAD mice (Figure 1D). In addition, mucosal IgA titer was reduced in mice with AAD (Figure 1D). We next investigated the protective efficacy of LAIV in AAD vs non-AAD mice. While LAIV-immunized AAD mice were protected against homologous challenge (data not shown), the cross-protective efficacy against heterologous infection was severely compromised (Figure 1E). This observation is consistent with our previous report that live influenza virus infection establishes inferior mucosal antibody immunity in AAD mice.18 Taken together, our results show that AAD is a host-associated factor that can negatively impact LAIV efficacy. Our finding may help explain why LAIV efficacy is highly variable in humans. The implication of our finding is that vaccine research should consider the impact of host factors such as chronic diseases for evaluation of experimental vaccines because the magnitude of interference may differ depending on the vaccine type. It is important to note that LAIV is not recommended for individuals with asthma due to increased incidence of wheezing post LAIV administration.19, 20 Further, people with severe asthma are often excluded from clinical trials that evaluate LAIV efficacy. Therefore, the use of LAIV among asthmatics has been relatively limited and whether asthma exacerbation has a negative effect on the efficacy of LAIV in humans remains unknown. In addition to asthma, other conditions that induce lung inflammation may also impact the efficacy of LAIV, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.21, 22 SARS-CoV-2 is particularly concerning given the high prevalence of asymptomatic infections, and therefore vaccine recipients may unknowingly receive LAIV vaccination while infected with SARS-CoV-2. Further research efforts are clearly warranted to elucidate the precise mechanism by which allergic lung inflammation interferes with the B cell immunogenicity of LAIV. Knowing the detrimental immune pathway that exists in AAD mice may help design a better vaccination approach to circumvent the negative interference imposed by host factors. Yoichi Furuya is supported by R56 AI146434 and American Heart Association Scientist Development Grant. Yoichi Furuya and Sreeja Roy are supported through The American Association of Immunologists Careers in Immunology Fellowship Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare no competing interests. Conceptualization: Yoichi Furuya, Sreeja Roy Data Curation: Yoichi Furuya, Clare M. Williams Formal Analysis: Yoichi Furuya Funding Acquisition: Yoichi Furuya Writing—Original Draft Preparation: Yoichi Furuya, Sreeja Roy, Clare M. Williams Writing—Review & Editing: Yoichi Furuya, Sreeja Roy, Clare M. Williams Yoichi Furuya had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis. The data that support the findings of the study are available from the corresponding author upon request.

Efficacy of live attenuated and inactivated influenza vaccines among children in rural India: A 2-year, randomized, triple-blind, placebo-controlled trial.

BackgroundInfluenza is a cause of febrile acute respiratory infection (FARI) in India; however, few influenza vaccine trials have been conducted in India. We assessed absolute and relative efficacy of live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) among children aged 2 to 10 years in rural India through a randomized, triple-blind, placebo-controlled trial conducted over 2 years.Methods and findingsIn June 2015, children were randomly allocated to LAIV, IIV, intranasal placebo, or inactivated polio vaccine (IPV) in a 2:2:1:1 ratio. In June 2016, vaccination was repeated per original allocation. Overall, 3,041 children received LAIV (n = 1,015), IIV (n = 1,010), nasal placebo (n = 507), or IPV (n = 509). Mean age of children was 6.5 years with 20% aged 9 to 10 years.Through weekly home visits, nasal and throat swabs were collected from children with FARI and tested for influenza virus by polymerase chain reaction. The primary outcome was laboratory-confirmed influenza-associated FARI; vaccine efficacy (VE) was calculated using modified intention-to-treat (mITT) analysis by Cox proportional hazards model (PH) for each year.In Year 1, VE was 40.0% (95% confidence interval (CI) 25.2 to 51.9) for LAIV and 59.0% (95% CI 47.8 to 67.9) for IIV compared with controls; relative efficacy of LAIV compared with IIV was −46.2% (95% CI −88.9 to −13.1). In Year 2, VE was 51.9% (95% CI 42.0 to 60.1) for LAIV and 49.9% (95% CI 39.2 to 58.7) for IIV; relative efficacy of LAIV compared with IIV was 4.2% (95% CI −19.9 to 23.5). No serious adverse vaccine-attributable events were reported. Study limitations include differing dosage requirements for children between nasal and injectable vaccines (single dose of LAIV versus 2 doses of IIV) in Year 1 and the fact that immunogenicity studies were not conducted.ConclusionsIn this study, we found that LAIV and IIV vaccines were safe and moderately efficacious against influenza virus infection among Indian children.Trial registrationClinical Trials Registry of India CTRI/2015/06/005902.

Impact of Pre-Existing Immunity to Influenza on Live-Attenuated Influenza Vaccine (LAIV) Immunogenicity.

During the previous influenza seasons, between 2010 and 2016, the live attenuated influenza vaccine (LAIV) provided variable efficacy against influenza in the U.S., causing the recommendation against the use of the LAIV. In striking contrast, pre-clinical studies have repeatedly demonstrated superior efficacy of LAIV against mismatched influenza viruses, compared to inactivated influenza vaccines (IIV). This disparity in reported vaccine efficacies between pre-clinical and clinical studies may in part be explained by limitations of the animal models of influenza. In particular, the absence of pre-existing immunity in animal models has recently emerged as a potential explanation for the discrepancies between preclinical findings and human studies. This commentary focuses on the potential impact of pre-existing immunity on LAIV induced immunogenicity with an emphasis on cross-protective immunity.

HAI and NAI titer correlates of inactivated and live attenuated influenza vaccine efficacy

BackgroundHigh hemagglutination inhibition (HAI) and neuraminidase inhibition (NAI) titers are generally associated with reduced influenza risk. While repeated influenza vaccination reduces seroresponse, vaccine effectiveness is not always reduced.MethodsDuring the 2007-2008 influenza season, a randomized, placebo-controlled trial (FLUVACS) evaluated the efficacies of live-attenuated (LAIV) and inactivated influenza vaccines (IIV) among healthy adults aged 18-49 in Michigan; IIV vaccine efficacy (VE) and LAIV VE against influenza disease were estimated at 68% and 36%. Using the principal stratification/VE moderation framework, we analyzed data from this trial to assess how each VE varied by HAI or NAI responses to vaccination observed for vaccinated individuals and predicted counterfactually for placebo recipients. We also assessed how each VE varied with pre-vaccination/baseline variables including HAI titer, NAI titer, and vaccination history.ResultsIIV VE appeared to increase with Day 30 post-vaccination HAI titer, albeit not significantly (p=0.20 and estimated VE 14.4%, 70.5%, and 85.5% at titer below the assay lower quantification limit, 512, and 4096 (maximum)). Moreover, IIV VE increased significantly with Day 30 post-vaccination NAI titer (p=0.040), with estimated VE zero at titer 10 and 92.2% at highest titer 640. There was no evidence that fold-change in post-vaccination HAI or NAI titer associated with IIV VE (p=0.76, 0.38). For LAIV, there was no evidence that VE associated with post-vaccination or fold-rise HAI or NAI titers (p-values >0.40). For IIV, VE increased with increasing baseline NAI titer in those previously vaccinated, but VE decreased with increasing baseline NAI titer in those previously unvaccinated. In contrast, for LAIV, VE did not depend on previous vaccination or baseline HAI or NAI titer.Conclusions: Future efficacy trials should measure baseline and post-vaccination antibody titers in both vaccine and control/placebo recipients, enabling analyses to better elucidate correlates of vaccine- and natural-protection.Trial registration: ClinicalTrials.gov NCT00538512. October 1, 2007.

Successes and Failures of the Live-attenuated Influenza Vaccine: Can We Do Better?

BackgroundThe effectiveness of the live-attenuated influenza vaccine (LAIV) can vary widely, ranging from 0% to 50%. The reasons for these discrepancies remain largely unclear.MethodsWe use mathematical models to explore how the efficacy of LAIV is affected by the degree of mismatch with the currently circulating influenza strain and interference with pre-existing immunity. The models incorporate 3 key antigenic distances: the distances between the vaccine strain, pre-existing immunity, and the challenge strain.ResultsOur models show that an LAIV that is matched with the currently circulating strain is likely to have only modest efficacy. Our results suggest that the efficacy of the vaccine would be increased (optimized) if, rather than being matched to the circulating strain, it is antigenically slightly further from pre-existing immunity than the circulating strain. The models also suggest 2 regimes in which LAIV that is matched to circulating strains may be protective: in children before they have built immunity to circulating strains and in response to novel strains (such as antigenic shifts) which are at substantial antigenic distance from previously circulating strains. We provide an explanation for the variation in vaccine effectiveness between studies and countries of vaccine effectiveness observed during the 2014–2015 influenza season.ConclusionsLAIV is offered to children across the world; however, its effectiveness significantly varies between studies. Here, we propose a mechanistic explanation to understand these differences. We further propose a way to select the LAIV strain that would have a higher chance of being protective.

Perspectives from the Society for Pediatric Research: Decreased Effectiveness of the Live Attenuated Influenza Vaccine.

The intranasal live attenuated influenza vaccine (LAIV), FluMist, has been widely appreciated by pediatricians, parents, and children alike for its ease of administration. However, concerns regarding lack of effectiveness in recent influenza seasons led to the CDC Advisory Committee on Immunization Practices (ACIP) recommendation to administer inactivated influenza vaccines (IIVs), and not LAIV, during the 2016-17 and 2017-18 seasons. Given that data from previous years demonstrated equivalent and even improved efficacy of LAIV compared with IIV, these recent data were surprising, raising many questions about the potential mechanisms underlying this change. This review seeks to summarize the history of LAIV studies and ACIP recommendations with a focus on the recent decrease in vaccine effectiveness (VE) and discordant results among studies performed in different countries. Decreased VE for A/H1N1pdm09 viruses represents the most consistent finding across studies, as VE has been low every season these viruses predominated since 2010-11. Potential explanations underlying diminished effectiveness include the hypothesis that prior vaccination, reduced thermostability of A/H1N1pdm09, addition of a fourth virus, or reduced replication fitness of A/H1N1pdm09 strains may have contributed to this phenomenon. Ongoing studies and potential alterations to LAIV formulations provide hope for a return of effective LAIV in future influenza seasons.

Efficacy of a Russian-backbone live attenuated influenza vaccine among young children in Bangladesh: a randomised, double-blind, placebo-controlled trial.

SummaryBackgroundThe rates of influenza illness and associated complications are high among children in Bangladesh. We assessed the clinical efficacy and safety of a Russian-backbone live attenuated influenza vaccine (LAIV) at two field sites in Bangladesh.MethodsBetween Feb 27 and April 9, 2013, children aged 2–4 years in urban Kamalapur and rural Matlab, Bangladesh, were randomly assigned in a 2:1 ratio, according to a computer-generated schedule, to receive one intranasal dose of LAIV or placebo. After vaccination, we monitored children in weekly home visits until Dec 31, 2013, with study clinic surveillance for influenza illness. The primary outcome was symptomatic, laboratory-confirmed influenza illness due to vaccine-matched strains. Analysis was per protocol. The trial is registered with ClinicalTrials.gov, number NCT01797029.FindingsOf 1761 children enrolled, 1174 received LAIV and 587 received placebo. Laboratory-confirmed influenza illness due to vaccine-matched strains was seen in 93 (15·8%) children in the placebo group and 79 (6·7%) in the LAIV group. Vaccine efficacy of LAIV for vaccine-matched strains was 57·5% (95% CI 43·6–68·0). The vaccine was well tolerated, and adverse events were balanced between the groups. The most frequent adverse events were tachypnoea (n=86 in the LAIV group and n=54 in the placebo group), cough (n=73 and n=43), and runny nose (n=68 and n=39), most of which were mild.InterpretationThis single-dose Russian-backbone LAIV was safe and efficacious at preventing symptomatic laboratory-confirmed influenza illness due to vaccine-matched strains. LAIV programmes might reduce the burden of influenza illness in Bangladesh.FundingThe Bill & Melinda Gates Foundation.

Influence of maternally-derived antibodies on live attenuated influenza vaccine efficacy in pigs

Vaccination during pregnancy is practiced in swine farms as one measure to control swine influenza virus (SIV) infection in piglets at an early age. Vaccine-induced maternal antibodies transfer to piglets through colostrum and stabilize the herd: however, maternally derived antibodies (MDA) interfere with immune response following influenza vaccination in piglets at the later stage of life. In addition, MDA is related to enhanced respiratory disease in SIV infection. Previously, we have developed a bivalent live attenuated influenza vaccine (LAIV) which harbors both H1 and H3 HAs. We demonstrated vaccination of this LAIV provided protection to homologous and heterologous SIV infection in pigs. In this study we aimed to investigate the influence of MDA on LAIV efficacy. To this end, SIV sero-negative sows were vaccinated with a commercial vaccine. After parturition, nursery piglets were vaccinated with LAIV intranasally or intramuscularly, and were then challenged with SIV. We report that MDA hampered serum antibody response induced by intramuscular vaccination but not by intranasal vaccination of the LAIV. Viral challenge in the presence of MDA caused exacerbated respiratory disease in unvaccinated piglets. In contrast, all LAIV vaccinated piglets were protected from homologous viral infection regardless of the route of vaccination and the presence of MDA. Our results demonstrated that LAIV conferred protection in the presence of MDA without inciting exacerbated respiratory disease.

Efficacy of live attenuated influenza vaccine against influenza illness in children as a function of illness severity

A recent study of inactivated influenza vaccine (IIV) in children aged 3–8 years demonstrated higher efficacy against moderate/severe influenza. A meta-analysis of all previous published randomized clinical trials of live attenuated influenza vaccine (LAIV) that collected information on illness severity in children aged 24–71 months was conducted. Moderate/severe influenza was defined as fever >39°C, acute otitis media, or lower respiratory tract illness; other cases were classified as milder influenza. LAIV efficacy versus placebo was 95.4% [95% confidence interval: 88.5, 98.1] (year 1) and 88.5% [77.4, 94.9] (year 2) against moderate/severe influenza and 91.4% [77.9, 96.7] (year 1) and 84.2% [56.7, 94.3] (year 2) against milder influenza. The relative efficacy of LAIV versus IIV was 52.2% [31.6, 66.6] for moderate/severe influenza and 45.0% [28.6, 57.5] for milder influenza. Efficacy against all influenza illnesses, regardless of severity, is critical to prevent influenza illness and transmission in the community.

Background paper to the recommendation for the preferential use of live-attenuated influenza vaccine in children aged 2–6 years in Germany

The German Standing Committee on Vaccination (STIKO) recommends seasonal influenza vaccination for children and adolescents with chronic medical conditions that put them at risk for severe influenza illness. In addition to trivalent inactivated influenza vaccines (TIV), a trivalent live-attenuated influenza vaccine (LAIV) was licensed for children and adolescents aged 2-17 years in the European Union in 2011. Employing the methodology of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group, we examined the evidence for efficacy and safety of LAIV relative to TIV to guide STIKO's decision on whether LAIV should be preferentially recommended for at-risk children. In our meta-analysis of data from two randomized trials directly comparing LAIV and TIV in children aged ≤ 6 years, the protective efficacy of LAIV against laboratory-confirmed influenza was 53 % [95 % confidence interval (CI): 45-61 %] higher than that of TIV. A similar study in individuals aged 6-17 years showed a 32 % (95 % CI: 3-52 %) higher efficacy of LAIV. The quality of the evidence for a superior protective efficacy of LAIV against all relevant clinical outcomes was rated 'moderate' for children aged 2-6 years and 'low' for the age group 7-17 years. Regarding safety outcomes, the available data suggest no significant differences between LAIV and TIV. Based on these results, STIKO recommends that LAIV should be used preferentially for influenza vaccination of at-risk children aged 2-6 years. In children and adolescents aged 7-17 years, either LAIV or TIV may be used without specific preference. Possible contraindications and the vaccinee's and his/her guardians' preferences should be taken into account.

Effectiveness of Intranasal Live Attenuated Influenza Vaccine Against All-cause Acute Otitis Media in Children

Acute otitis media (AOM) is a frequent complication of influenza in children, and influenza vaccination helps protect against influenza-associated AOM. A live attenuated influenza vaccine (LAIV) approved for eligible children aged ≥2 years for the prevention of influenza also effectively reduces influenza-associated AOM. However, the annual effectiveness of LAIV against all-cause AOM is unknown. AOM rates in children aged 6-83 months from 6 randomized, placebo-controlled trials and 2 randomized, inactivated influenza vaccine-controlled trials were pooled and analyzed. To enable comparison with studies of AOM prevention by pneumococcal conjugate vaccines, 12-month effectiveness was calculated assuming that LAIV had no effect outside of influenza seasons. During influenza seasons, LAIV efficacy compared with placebo against all-cause AOM in children aged 6-71 months (N = 9497) was 12.4% (95% confidence interval [CI]: 2.0%, 21.6%) in year 1. In year 2, the efficacy in children aged 18-83 months (N = 4142) was 6.2% (95% CI: -12.4%, 21.7%). Compared with inactivated influenza vaccine, the efficacy of LAIV in children aged 6-71 months (N = 9901) against febrile all-cause AOM was 9.7% (95% CI: -2.1%, 20.1%). The estimated 12-month effectiveness of LAIV compared with placebo against all-cause AOM was 7.5% (95% CI: -2.4%, 16.2%). LAIV reduced the incidence of all-cause AOM compared with placebo in children. The estimated 12-month effectiveness of LAIV was comparable with 7-valent pneumococcal conjugate vaccine. The effects of the vaccines will overlap somewhat; however, because pneumococcal conjugate vaccines only prevent a fraction of all pneumococcal AOM and influenza-associated AOM can be caused by other pathogens, LAIV could further reduce the incidence of AOM in children.

Influenza vaccine recommendations for children and youth for the 2012/2013 season.

Influenza vaccine recommendations for children and youth for the 2012/2013 season.

The role of nasal IgA in children vaccinated with live attenuated influenza vaccine

BackgroundImmunoglobulin A (IgA) is the predominant antibody produced in response to mucosal infections. The role of IgA in providing protection against influenza in children vaccinated with live attenuated influenza vaccine (LAIV) has not been well described. MethodsNasal IgA responses were assessed using data from 3 prospective, 2-year, randomized studies comparing LAIV with placebo in children 6–36 months of age. In each study, samples were collected in a subset of patients; a new cohort was enrolled each year. Ratios of strain-specific nasal IgA to total nasal IgA were calculated and prevaccination to postvaccination geometric mean fold-rises (GMFRs) were evaluated. Mean postvaccination IgA ratios were compared for subjects with and without confirmed influenza illness by study and in pooled analyses. ResultsAcross studies, a higher percentage of children receiving LAIV had a ≥2-fold increase in strain-specific IgA ratio compared with placebo recipients. GMFRs after LAIV in years 1 and 2 ranged from 1.2 to 6.2, compared with 0.5–2.2 among placebo recipients. Similar responses were observed in subjects who were baseline seronegative and seropositive based on serum hemagglutination inhibition antibody titers. In years 1 and 2, the mean postvaccination strain-specific to total IgA ratio was 3.1-fold (P<0.01) and 2.0-fold (P<0.03) higher among LAIV recipients with no evidence of culture-confirmed influenza illness compared with LAIV recipients who developed culture-confirmed influenza illness; a similar and consistent trend was observed for each individual study and type/subtype. ConclusionsThe current analysis demonstrates that nasal IgA contributes to the efficacy of LAIV and can provide evidence of vaccine-induced immunity. However, the inherent heterogeneity in nasal antibody levels and variability in nasal specimen collection hinders the precise evaluation of mucosal antibody responses. Other studies have demonstrated that LAIV-induced immunity is also partially explained by T-cell immunity, serum antibody responses, and innate immunity, consistent with the multi-faceted nature of immunity induced by wild-type influenza infection and other live virus vaccines.

Influenza Vaccine Effectiveness – We Can Do Better

The perception that vaccines are currently good enough is a barrier to development of vaccines that are much better. Are current vaccines only just good enough? A recent, rigorous analysis has raised questions regarding the evidence for effectiveness of the present generation of influenza vaccines in the elderly and those at risk for medical complications. Applying strict criteria to attempt to eliminate bias, the authors screened 5,707 studies published from January 1, 1967 to February 15, 2011 that used RT-PCR (reverse transcriptase-polymerase chain reaction) or culture for confirmation of influenza. Authors searched MEDLINE for randomized controlled trials (RCTs) evaluating a reduction in influenza risk of all circulating influenza viruses during flu seasons after vaccination (efficacy) as well as observational studies meeting strict inclusion criteria (effectiveness). A US research team identified only 31 eligible studies they felt provided reliable evidence regarding efficacy and effectiveness of flu vaccines. Seventeen RCTs and 14 observational studies were identified. They estimated pooled efficacy for trivalent inactivated vaccine (TIV) and live attenuated influenza vaccine (LAIV) when these data were available for statistical analysis. The team found efficacy of TIV was demonstrated in 8 of the 12 (67%) seasons analyzed in 10 RCTs with a pooled efficacy of 59% in adults aged 18 to 65 years. No trials met the inclusion criteria for children aged 2 to 17 years or adults 65 years or older. Efficacy of LAIV was demonstrated in 9 (75%) of 12 seasons analyzed in 10 RCTs in children aged 6 months to 7 years. No trials met inclusion criteria for children aged 8 to 17 years. Vaccine effectiveness was variable for seasonal influenza with 6 of 17 analyses in 9 studies showing significant protection against influenza in the outpatient or inpatient settings. This meta-analysis differs from others published in that eligible studies of both vaccines were restricted to those that used virus detection as primary endpoints. Second, it excluded RTCs in which the comparison group did not receive either placebo or a vaccine other than for influenza. In summary, what does this mean? It means that flu vaccines work, but not as well as is needed. Osterholm and colleagues conclude that ‘‘based on a track record of substantial safety and moderate efficacy in many seasons, we believe the current influenza vaccines will continue to have a role in reduction of influenza morbidity until more effective interventions are available. However, evidence for consistent high-level protection is elusive for the present generation of vaccines, especially in individuals at risk of medical complications or those aged 65 years or older.’’ The authors also call for a new generation of more effective and cross-protective vaccines that can be manufactured rapidly. We must keep in mind that current vaccines provide a moderate level of protection and the evidence still supports their use but that a partnership between industry and government may be required to guarantee the prospects for much better flu vaccines. Pandemic influenza would seriously threaten the global economy. There is optimism in the scientific community that better vaccines are within reach if we have the will to develop them. By targeting sections of the virus that rarely mutate, it may be possible to develop a single influenza vaccination with only follow-up boosters necessary.

The safety and efficacy of live attenuated influenza vaccine in young children with asthma or prior wheezing

In the European Union and Canada, an Ann Arbor strain live attenuated influenza vaccine (LAIV) is approved for use in children aged 2–17 years, including those with mild to moderate asthma or prior wheezing. The safety and efficacy of LAIV versus trivalent inactivated influenza vaccine (TIV) in children with asthma aged 6–17 years have been demonstrated. However, few data are available for children younger than 6 years of age with asthma or prior wheezing. Safety and efficacy data were collected for children aged 2–5 years with asthma or prior wheezing from two randomized, multinational trials of LAIV and TIV (N = 1,940). Wheezing, lower respiratory illness, and hospitalization were not significantly increased among children receiving LAIV compared with TIV. Increased upper respiratory symptoms and irritability were observed among LAIV recipients (p < 0.05). Relative efficacies were consistent with the results observed in the overall study populations, which demonstrated fewer cases of culture-confirmed influenza illness in LAIV compared with TIV recipients. Study results support the safety and efficacy of LAIV among children aged 2–17 years with mild to moderate asthma or a history of wheezing. Data regarding LAIV use are limited among individuals with severe asthma or active wheezing within the 7 days before vaccination.

Qualitative Differences in T cell responses to Live, Attenuated and Inactivated Influenza Vaccines

Annual epidemics of influenza cause considerable morbidity and mortality. Trivalent inactivated vaccine (TIV) and live, attenuated influenza vaccine (LAIV) are licensed in the United States, and both are effective in preventing disease in persons younger than 49. Serum hemagglutination inhibition (HI) titers correlate with TIV but not LAIV efficacy, suggesting that additional effector mechanisms are induced to the live, attenuated vaccine and play an important role in protection against disease. For this reason there is a need to identify surrogate markers of LAIV efficacy that are easily measured in robust assays. We have compared the immunogenicity of TIV and LAIV in a small clinical study (16 age-matched volunteers in each vaccine group) by measuring serologic responses using traditional HI and NA inhibition assays as well as a sensitive cell-based neutralization assay. In addition, we evaluated cellular responses by measuring the quantity and quality of antigen-specific CD4+ and CD8+ T cells following vaccination. The quality of the CD4+ T cell response was different for each vaccination group, with CD4+ T cell proliferation and increased secretion of IFN-γ characteristic of responses following immunization with LAIV, while antigen-specific T cells that secreted IL-5 were more frequently measured from TIV recipients. Our results suggest that sensitive, serologic assays with broad specificity, together with CD4+ T cell proliferation and IFN-γ secretion provide a more complete measure of the immunogenicity of LAIV in adults, and could be used to enhance the identification of vaccine responders.

The efficacy of intranasal live attenuated influenza vaccine in children 2 through 17 years of age: A meta-analysis of 8 randomized controlled studies

Nine randomized controlled clinical trials, including approximately 26,000 children aged 6 months to 17 years, have evaluated the efficacy of live attenuated influenza vaccine (LAIV) against culture-confirmed influenza illness compared with placebo or trivalent inactivated influenza vaccine (TIV). The objective of the current analysis was to integrate available LAIV efficacy data in children aged 2-17 years, the group for whom LAIV is approved for use. A meta-analysis was conducted using all available randomized controlled trials and a fixed-effects model. Cases caused by drifted influenza B were analyzed as originally classified and with all antigenic variants classified as dissimilar. Five placebo-controlled trials (4 were 2-season trials) and 3 single-season TIV-controlled trials were analyzed. Compared with placebo, year 1 efficacy of 2 doses of LAIV was 83% (95% CI: 78, 87) against antigenically similar strains; efficacy was 87% (95% CI: 78, 93), 86% (95% CI: 79, 91), and 76% (95% CI: 63, 84) for A/H1N1, A/H3N2, and B, respectively. Classifying B variants as dissimilar, efficacy against all similar strains was 87% (95% CI: 83, 91) and 93% (95% CI: 83, 97) against similar B strains. Year 2 efficacy was 87% (95% CI: 82, 91) against similar strains. Compared with TIV, LAIV recipients experienced 44% (95% CI: 28, 56) and 48% (95% CI: 38, 57) fewer cases of influenza illness caused by similar strains and all strains, respectively. LAIV efficacy estimates for children from Europe, the United States, and Middle East were robust and were similar to or higher than those for the overall population. In children aged 2-17 years, LAIV demonstrated high efficacy after 2 doses in year 1 and revaccination in year 2, and greater efficacy compared with TIV. This meta-analysis provides precise estimates of LAIV efficacy among the approved pediatric age group.

Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis

No published meta-analyses have assessed efficacy and effectiveness of licensed influenza vaccines in the USA with sensitive and highly specific diagnostic tests to confirm influenza. We searched Medline for randomised controlled trials assessing a relative reduction in influenza risk of all circulating influenza viruses during individual seasons after vaccination (efficacy) and observational studies meeting inclusion criteria (effectiveness). Eligible articles were published between Jan 1, 1967, and Feb 15, 2011, and used RT-PCR or culture for confirmation of influenza. We excluded some studies on the basis of study design and vaccine characteristics. We estimated random-effects pooled efficacy for trivalent inactivated vaccine (TIV) and live attenuated influenza vaccine (LAIV) when data were available for statistical analysis (eg, at least three studies that assessed comparable age groups). We screened 5707 articles and identified 31 eligible studies (17 randomised controlled trials and 14 observational studies). Efficacy of TIV was shown in eight (67%) of the 12 seasons analysed in ten randomised controlled trials (pooled efficacy 59% [95% CI 51-67] in adults aged 18-65 years). No such trials met inclusion criteria for children aged 2-17 years or adults aged 65 years or older. Efficacy of LAIV was shown in nine (75%) of the 12 seasons analysed in ten randomised controlled trials (pooled efficacy 83% [69-91]) in children aged 6 months to 7 years. No such trials met inclusion criteria for children aged 8-17 years. Vaccine effectiveness was variable for seasonal influenza: six (35%) of 17 analyses in nine studies showed significant protection against medically attended influenza in the outpatient or inpatient setting. Median monovalent pandemic H1N1 vaccine effectiveness in five observational studies was 69% (range 60-93). Influenza vaccines can provide moderate protection against virologically confirmed influenza, but such protection is greatly reduced or absent in some seasons. Evidence for protection in adults aged 65 years or older is lacking. LAIVs consistently show highest efficacy in young children (aged 6 months to 7 years). New vaccines with improved clinical efficacy and effectiveness are needed to further reduce influenza-related morbidity and mortality. Alfred P Sloan Foundation.

Protective efficacy of live-attenuated influenza vaccine (multivalent, Ann Arbor strain): a literature review addressing interference

Selecting the B strain for inclusion in a trivalent seasonal influenza vaccine has been difficult because two distinct influenza B lineages frequently co-circulate, prompting consideration of a quadrivalent vaccine containing two A and two B strains. Because interference among wild-type influenza viruses is a well-documented phenomenon and viral replication is required to elicit protection by the licensed live-attenuated influenza vaccine (LAIV; MedImmune, LLC, Gaithersburg, MD, USA), a potential quadrivalent formulation raises considerations of interference among the LAIV strains contained in the vaccine. We reviewed the available clinical and nonclinical literature to understand the potential impact of viral interference on immunogenicity, efficacy and shedding of LAIV strains. We have found no clinically significant evidence of viral or immune interference affecting efficacy of LAIV strains in multivalent vaccine formulations. Future clinical studies should compare the safety and immune responses of children and adults to licensed trivalent and investigational quadrivalent LAIV formulations.