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

Prevention and Control of Seasonal Influenza With Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP)—United States, 2014–15 Influenza Season

Safety of influenza vaccines in pregnant women

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.

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.

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.

Revisiting live attenuated influenza vaccine efficacy among children in developing countries

Since 2004, increasing numbers of military personnel have been immunized with the intranasal live attenuated influenza vaccine (LAIV) while most others received the trivalent inactivated vaccine (TIV). However, data about live virus vaccine effectiveness among healthy adults are limited. To monitor the effectiveness of vaccines to better inform military vaccination policy. Surveillance of population-based, propensity-matched, and/or vaccine-naive cohorts of more than a million active-duty, nonrecruit military service members aged 17 to 49 years stationed in the United States during the 2004-2005, 2005-2006, or 2006-2007 influenza season. Incidence of health care encounters resulting in a primary diagnostic code consistent with pneumonia or influenza. Incident hospitalizations was a secondary outcome. In all 3 seasons, immunization with TIV was associated with lower incidence rates of health care encounters for pneumonia and influenza when compared with no immunization: 8.6 vs 19.4 for 2004-2005, 7.8 vs 10.9 for 2005-2006, and 8.0 vs. 11.7 per 1000 person-years for 2006-2007 (all P < .001). Similar estimates were obtained from propensity-matched and/or vaccine-naive cohorts. Consistently lower vaccine effect following LAIV immunization was only seen during the 2006-2007 influenza season in the total (10.7; 95% confidence interval [CI], 2.72 to 18.1; P = .03) and propensity-matched cohorts (11.8; 95% CI, 0.85 to 21.5; P = .04), and was less than effect from TIV (TIV vs LAIV, 19.8; 95% CI, 13.6 to 25.5; P < .001). Among vaccine-naive service members, however, estimates for LAIV effect were more robust for both the 2005-2006 and 2006-2007 seasons (P = .01) and were comparable with TIV (eg, LAIV, 30.2; 95% CI, 11.2 to 45.2; vs TIV, 35.3; 95% CI, 25.9 to 43.6; in 2005-2006). Vaccination with TIV was associated with fewer medical encounters related to pneumonia and influenza compared with LAIV or no immunization. In this annually immunized population, this effect was less apparent in those vaccinated with LAIV.

Please cite this paper as: Belshe et al. (2010). Efficacy of live attenuated influenza vaccine in children 6 months to 17 years of age. Influenza and Other Respiratory Viruses 4(3), 141–145.Background It has been suggested that live attenuated influenza vaccine (LAIV) may be less effective in older individuals because of prior wild‐type influenza infections. LAIV is currently approved in the United States, South Korea and Hong Kong for individuals 2–49 years of age.Objective To examine data from previously published pediatric studies to determine the efficacy of LAIV in various age groups.Methods Four studies in which the subject age range exceeded 36 months were identified: one 2‐year study comparing LAIV with placebo and three 1‐year studies comparing LAIV with trivalent inactivated influenza vaccine (TIV). Efficacy against any strain regardless of antigenic similarity to vaccine was analyzed by age; age groups were based on the study design and sample size. A logistic regression model was used to assess whether age, as a continuous variable, was an effect modifier on LAIV efficacy.Results The efficacy of LAIV did not vary with age in children aged 15–84 months compared with placebo or in children aged 6 months to 17 years compared with TIV.Conclusions The available data from prospective, randomized studies in children does not support the concept that prior repeated exposure to influenza, either through wild‐type infection or vaccination with live, attenuated or inactivated vaccines, reduces the efficacy of LAIV compared with placebo or TIV. The decreased immunologic responses to LAIV reported in older individuals or those with pre‐existing immunity do not appear to translate into reduced protection from influenza in children.

To the editor: In the editorial by Penttinen and Friede, the authors summarised data from 2015 to 2016 on live attenuated influenza vaccine (LAIV) effectiveness in a Table and used the data in the Table to make several conclusions [1]. Unfortunately, the Table has several errors and, therefore, misrepresents the available data and studies. On 26 June 2016, the United States (US) Advisory Committee for Immunization Practices (ACIP) recommended that LAIV not be used during the 2016/17 season in the US [2]. Among all studies using a test-negative case–control design (TNCCD), the study from the US Centers for Disease Control and Prevention (CDC) (US Influenza Vaccine Effectiveness (VE) network) and the US Department of Defence (DoD) study (US Air Force School of Aerospace Medicine (USAFSAM) Sentinel Provider network) had the largest number of influenza A(H1N1)pdm09-infected children aged 2–17 years and larger or comparable numbers of children who received LAIV; these numbers were not correctly shown in the Table in the editorial. The US CDC study included 133 children aged 2–17 years who received LAIV (23 LAIV-vaccinated children had influenza A(H1N1)pdm09 infection) and 1,078 children who were unvaccinated. The US DoD study included 93 children vaccinated with LAIV (23 LAIV-vaccinated children had influenza A(H1N1)pdm09 infection) and 338 unvaccinated children (personal communication September 2016, Susan Federinko, USAFSAM). The youngest age for which LAIV is licensed for use in the US is two years; the US CDC VE estimates refer to children aged 2–17 years. The sample sizes for the other studies in the Table should also be consistently reported so that the same numerical comparisons are available for each study.

Recent observational studies report conflicting results regarding the effectiveness of live attenuated influenza vaccine (LAIV), particularly against influenza A(H1N1)pdm09. To compare the effectiveness of LAIV and inactivated influenza vaccine (IIV) against laboratory-confirmed influenza. A test-negative study to estimate influenza vaccine effectiveness (VE) using population-based, linked, individual-level laboratory, health administrative, and immunization data. Data were obtained from 10 169 children and adolescents aged 2 to 17 years (children) who were tested for influenza in inpatient or outpatient settings during periods when influenza was circulating based on a threshold level of 5% weekly test positivity for the province during the 4 influenza seasons spanning from November 11, 2012, to April 30, 2016, in Alberta, Canada. Logistic regression was used to estimate VE by vaccine type, influenza season, and influenza type and subtype. The relative effectiveness of each vaccine type was assessed by comparing the odds of laboratory-confirmed influenza infection for LAIV recipients with that for IIV recipients. The primary exposure was receipt of LAIV or IIV before testing for influenza. The primary outcome was influenza case status as determined by reverse-transcriptase polymerase chain reaction testing. A total of 10 779 respiratory specimens (from 10 169 children) collected and tested for influenza during the 4 influenza seasons were included, with 53.4% from males; the mean (SD) age was 7.0 (4.6) years. Across the 4 influenza seasons, 3161 children tested positive for influenza. Combining the 4 influenza seasons, the adjusted VE against influenza A(H1N1)pdm09 was 69% (95% CI, 56%-78%) for LAIV compared with 79% (95% CI, 70%-86%) for IIV. Vaccine effectiveness against influenza A(H3N2) was 36% (95% CI, 14%-53%) for LAIV and 43% (95% CI, 22%-59%) for IIV. Against influenza B, VE was 74% (95% CI, 62%-82%) for LAIV and 56% (95% CI, 41%-66%) for IIV. There were no significant differences in the odds of influenza infection for LAIV recipients compared with IIV recipients except for influenza B during the 2015-2016 season, when LAIV recipients had lower odds of infection than IIV recipients (odds ratio, 0.36; 95% CI, 0.17-0.76). There was no evidence to support the lack of effectiveness of LAIV against influenza A(H1N1)pdm09. These results support administration of either vaccine type in this age group.

Please cite this paper as: Ambrose CS et al. (2011) The relative efficacy of trivalent live attenuated and inactivated influenza vaccines in children and adults. Influenza and Other Respiratory Viruses 5(2), 67–75.In the United States, two types of vaccines are recommended for the prevention of influenza: an intranasal live attenuated influenza vaccine (LAIV) for eligible individuals aged 2–49 years and unadjuvanted injectable trivalent inactivated vaccines (TIV) for eligible individuals aged ≥6 months. Several recent studies have compared the efficacy of the 2 vaccines in children and adults. In children 6 months to 18 years of age, each of the four comparative studies of LAIV and TIV demonstrated that LAIV was more protective. In individuals 17–49 years of age, most comparative studies have demonstrated that LAIV and TIV were similarly efficacious or that TIV was more efficacious. However, LAIV was shown to be more protective than TIV in new military recruits of all ages, and placebo‐controlled studies in adults in 1997–1998 suggested that LAIV was more protective against the mismatched A/H3N2 strain. The relative efficacy of LAIV and TIV among young adults may vary depending on the specific population and the antigenic match between the vaccines and circulating strains. In adults 60 years of age and older, limited data suggest that the two vaccines are similarly effective. In children and adults, studies also suggest that the relative efficacy of LAIV versus TIV may increase when measured against more severe illness. Additional research comparing LAIV and TIV is needed in adults and would also be valuable in older children and adolescents. Studies should examine the role of pre‐existing immunity as well as vaccine impact on influenza illness of varying severity.

This Policy Statement was retired April 2025. This statement updates the recommendations of the American Academy of Pediatrics for the routine use of influenza vaccine and antiviral medications in the prevention and treatment of influenza in children during the 2021–2022 influenza season. A detailed review of the evidence supporting these recommendations is published in the accompanying technical report.1 The American Academy of Pediatrics recommends annual influenza immunization of all children without medical contraindications, starting at 6 months of age. Influenza vaccination is an important intervention to protect vulnerable populations and reduce the burden of respiratory illnesses during circulation of severe acute respiratory syndrome coronavirus 2, which is expected to continue during the 2021–2022 influenza season. Any licensed, recommended, age-appropriate vaccine available can be administered, without preference for one product or formulation over another. Antiviral treatment of influenza with any licensed, recommended, age-appropriate influenza antiviral medication is recommended for children with suspected or confirmed influenza who are hospitalized, have severe or progressive disease, or have underlying conditions that increase their risk of complications of influenza. Antiviral treatment may be considered for any previously healthy, symptomatic outpatient not at high risk for influenza complications, in whom an influenza diagnosis is confirmed or suspected, if treatment can be initiated within 48 hours of illness onset and for children whose siblings or household contacts either are younger than 6 months or have a high-risk condition that predisposes them to complications of influenza.

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.

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