Safety of quadrivalent live attenuated influenza vaccine in subjects aged 2–49 years

BackgroundQuadrivalent live attenuated influenza vaccine (Q/LAIV) was licensed in 2012 and replaced trivalent live attenuated influenza vaccine in the United States during the 2013–2014 influenza season. This study assessed the safety of Q/LAIV in children and adults aged 2–49 years.MethodsThis was a prospective observational cohort study using data collected from Kaiser Permanente Northern California. Post-vaccination events of interest were any hospitalization, hospitalization for lower respiratory tract infection, and the following medically attended events: hypersensitivity, seizures/convulsions, lower respiratory tract infection, wheezing, Guillain-Barré syndrome, Bell’s palsy, encephalitis, neuritis, vasculitis, and narcolepsy/cataplexy. The rates of these events during the risk interval post-vaccination were compared with rates observed during reference periods later in the follow-up (within-cohort analysis) and with rates observed in frequency-matched unvaccinated controls and inactivated influenza vaccine (IIV) recipients.ResultsA total of 62,040 eligible Q/LAIV recipients were identified during the 2013–2014 influenza season. Within-cohort comparisons of all Q/LAIV recipients as well as comparisons between Q/LAIV recipients and unvaccinated controls or IIV recipients did not show any significantly higher risk of hospitalizations or medically attended events following administration of Q/LAIV. Additional analyses by setting (clinic visits, emergency department visits, and hospital admissions) and age group (2–4, 5–8, 9–17, and 18–49 years) also did not reveal clinically consistent findings that suggested any increased risk after administration of Q/LAIV.ConclusionIn this large population study of individuals aged 2–49 years, no safety signals associated with the administration of Q/LAIV were observed. A much larger study population would be needed to confidently reject any association between Q/LAIV and very rare events, specifically those with an incidence of <1 event/10,000 person-years.Trial registration: ClinicalTrials.gov NCT01985997     

Increasing uptake of live attenuated influenza vaccine among children in the United States, 2008–2014

The Advisory Committee on Immunization Practices (ACIP) recommends annual influenza vaccination for all persons in the United States aged ≥6 months. On June 25, 2014, ACIP preferentially recommended live attenuated influenza vaccine (LAIV) for healthy children aged 2–8 years [1]. Little is known about national LAIV uptake. To determine uptake of LAIV relative to inactivated influenza vaccine, we analyzed vaccination records from six immunization information system sentinel sites (approximately 10% of US population). LAIV usage increased over time in all sites. Among children 2–8 years of age vaccinated for influenza, exclusive LAIV usage in the collective sentinel site area increased from 20.1% (2008–09 season) to 38.0% (2013–14). During 2013–14, at least half of vaccinated children received LAIV in Minnesota (50.0%) and North Dakota (55.5%). Increasing LAIV usage suggests formulation acceptability, and this preexisting trend offers a favorable context for implementation of ACIP's preferential recommendation.     

Haemagglutinin stability was not the primary cause of the reduced effectiveness of live attenuated influenza vaccine against A/H1N1pdm09 viruses in the 2013–2014 and 2015–2016 seasons

During the 2013–2014 influenza season, the quadrivalent live attenuated influenza vaccine (QLAIV), had lower than expected vaccine effectiveness (VE) against circulating A/H1N1pdm09 viruses in the USA. The underlying reason proposed for this was that the A/H1N1pdm09 vaccine strain, A/California/07/2009 (A/CA09), had a thermally unstable haemagglutinin (HA) protein. Consequently, a new A/H1N1pdm09 candidate strain, A/Bolivia/559/2013 (A/BOL13), was developed for inclusion in the 2015–2016 QLAIV. A key parameter for selection of A/BOL13 was its more thermostable HA phenotype compared with A/CA09. During the 2015–2016 season, QLAIV containing A/BOL13 was found in some studies to have improved, but still with suboptimal, VE against circulating A/H1N1pdm09 viruses and was not recommended for use by the CDC in the US market in the 2016–2017 influenza season. This suggested that improved HA thermostability had not entirely resolved the reduced VE observed. One hypothesis for this was that, by improving thermostability, the A/BOL13 HA protein had been over-stabilised, compromising its activation at the low endosomal pH required for successful viral entry. Here we demonstrate that, while the A/BOL13 HA protein is more stable than that of A/CA09, its thermal and pH stability were comparable with historically efficacious LAIV strains, suggesting that the HA had not been over-stabilised. Furthermore, studies simulating potential heat exposure during distribution by exposing QLAIV nasal sprayers to 33 °C for 4 h showed that, while remaining within product specification, A/CA09 viral potency was statistically decreased after 12 weeks at 2–8 °C. These data suggest that although unfavourable HA protein stability may have contributed to the reduced VE of A/CA09 in 2013–2014, it was unlikely to have affected A/BOL13 in 2015–2016. We conclude that HA stability was not the primary cause of the reduced effectiveness of LAIV against A/H1N1pdm09 viruses in the 2013–2014 and 2015–2016 seasons.     

A postlicensure evaluation of the safety of Ann Arbor strain live attenuated influenza vaccine in children 24–59 months of age

Background

In the United States, live attenuated influenza vaccine (LAIV) was initially approved for use in individuals aged 5–49 years in 2003, which was extended to individuals aged 2–49 years in 2007. At that time, a postlicensure commitment was made to describe the safety of LAIV within a cohort of eligible children aged 2–5 years.

Methods

A prospective observational postmarketing study was conducted to evaluate the safety of LAIV. Rates of medically attended events (MAEs) and serious adverse events (SAEs) in eligible children aged 24–59 months receiving LAIV as part of routine care from October 2007 to March 2010 were compared with rates in a within-cohort self-control, as well as matched unvaccinated and matched trivalent inactivated influenza vaccine (TIV)-vaccinated controls. Children with asthma and other high-risk medical conditions before vaccination were excluded. All MAEs and SAEs through 42 days postvaccination and all hospitalizations and deaths through 6 months postvaccination were analyzed. Statistical significance was declared without multiplicity adjustment.

Results

A total of 28,226 unique LAIV recipients were matched with similar numbers of TIV-vaccinated and unvaccinated children. Of 4696 MAE incidence rate comparisons, 83 (1.8%) were statistically significantly higher and 221 (4.7%) were statistically significantly lower in LAIV recipients versus controls. No pattern of MAE rate differences suggested a safety signal with LAIV. Asthma/wheezing MAEs were not statistically increased in LAIV recipients. No anaphylaxis events occurred within 3 days postvaccination. Rates of SAEs were similar between LAIV and control groups.

Conclusions

Results of this postlicensure evaluation of LAIV safety in US children are consistent with preapproval clinical studies and Vaccine Adverse Event Reporting System reports, both of which demonstrated no significant increase in asthma/wheezing events or other adverse outcomes among eligible children aged 24–59 months who received LAIV.     

A study to evaluate the immunogenicity and shedding of live attenuated influenza vaccine strains in children 24–<48 months of age

BackgroundQuadrivalent live attenuated influenza vaccine (LAIV4) showed reduced effectiveness against the A/H1N1 component in the 2013–2014 and 2015–2016 influenza seasons. The most likely cause of reduced LAIV effectiveness against A(H1N1)pdm09 strains was poor intranasal replication.ObjectivesTo compare the immunogenicity and shedding of a new A/H1N1 strain (A/Slovenia), to a A/H1N1 strain known to have reduced effectiveness (A/Bolivia).Patients/methodsThis was a randomized, double-blind, multicenter study. Children aged 24–<48 months of age were randomized 1:1:1 to receive two doses of LAIV4 2017–2018 (LAIV4_A/Slovenia), or LAIV4 2015–2016 or trivalent LAIV (LAIV3) 2015–2016 formulations (LAIV4_A/Bolivia or LAIV3_A/Bolivia, respectively) on days 1 and 28. The primary endpoint was strain-specific hemagglutination inhibition (HAI) antibody seroresponse at 28 days post each dose, and secondary endpoints included immunogenicity, shedding, and safety. Solicited symptoms, adverse events (AEs), and serious AEs (SAEs) were recorded. Pre-specified statistical testing was limited to the primary endpoint of HAI antibody responses.ResultsA total of 200 children were randomized (median age 35.3 months; 53% male; 57% had previously received influenza vaccine). Significantly higher HAI antibody responses for the A/Slovenia strain were observed after Dose 1 and Dose 2. Neutralizing antibodies and nasal immunoglobulin A antibody responses were higher for A/Slovenia versus A/Bolivia. More children shed the A/Slovenia vaccine strain than the A/Bolivia strain on Days 4–7 after Dose 1. No deaths, SAEs, or discontinuations from vaccine occurred.ConclusionsThe new A(H1N1)pdm09 A/Slovenia LAIV strain demonstrated improved immunogenicity compared with a previous strain with reduced effectiveness and induced immune responses comparable to a highly efficacious pre-pandemic H1N1 LAIV strain. These results support the use of LAIV4 containing A/Slovenia as a vaccine option in clinical practice.     

Three-season effectiveness of inactivated influenza vaccine in preventing influenza illness and hospitalization in children in Japan, 2013–2016

ObjectivesWe assessed the vaccine effectiveness (VE) of inactivated influenza vaccine (IIV) in children 6 months to 15 years of age in 2015/16 season. In addition, based on the data obtained during the three seasons from 2013 to 2016, we estimated the three-season VE in preventing influenza illness and hospitalization.MethodsOur study was conducted according to a test-negative case-control design (TNCC) and as a case-control study based on influenza rapid diagnostic test results.ResultsDuring 2015/16 season, the quadrivalent IIV was first used in Japan. The adjusted VE in preventing influenza illness was 49% (95% confidence interval [CI]: 42–55%) against any type of influenza, 57% (95% CI: 50–63%) against influenza A and 34% (95% CI: 23–44%) against influenza B. The 3-season adjusted VE was 45% (95% CI: 41–49%) against influenza virus infection overall (N = 12,888), 51% (95% CI: 47–55%) against influenza A (N = 10,410), and 32% (95% CI: 24–38%) against influenza B (N = 9232). An analysis by age groups showed low or no significant VE in infants or adolescents. By contrast, VE was highest in the young group (1–5 years old) and declined with age thereafter. The 3-season adjusted VE in preventing hospitalization as determined in a case-control study was 52% (95% CI: 42–60%) for influenza A and 28% (95% CI: 4–46%) for influenza B, and by TNCC design, it was 54% (95% CI: 41–65%) for influenza A and 34% (95% CI: 6–54%) for influenza B.ConclusionWe demonstrated not only VE in preventing illness, but also VE in preventing hospitalization based on much larger numbers of children than previous studies.     

Hospitalizations within 14 days of vaccination among pediatric recipients of the live attenuated influenza vaccine,United States 2010–2012

BackgroundLive attenuated influenza vaccine (LAIV) is safe in healthy children ⩾2 years. The original clinical trials excluded individuals with underlying conditions; however, post-marketing data suggest LAIV may be safe for these populations.MethodsWe analyzed MarketScan Commercial Claims Databases from 2010 to 2012 to describe hospitalizations within 14 days of vaccination among LAIV recipients. We evaluated LAIV recipients aged 2–18 years and defined underlying conditions by presence of inpatient or outpatient ICD-9 code during the previous calendar year. We excluded asthma and immunocompromising conditions. We defined risk windows as 1–7 days and 8–14 days after vaccination; the control period was 12–4 days prior to and 15–23 days after vaccination. We conducted a self-controlled case series analysis using a conditional Poisson regression model to estimate incidence-rate ratios (IRR).Results1,216,123 children aged 2–18 years received LAIV from 2010 to 2012. 634 children met our inclusion criteria and were hospitalized during the observation period (12 days prior to vaccination to 23 days after vaccination). Of those hospitalized, 72 (11.4%) had non-asthma, non-immunocompromising underlying conditions. Children with non-asthma, non-immunocompromising underlying conditions had an all-cause hospitalization IRR of 1.1 (95% CI 0.6–2.0, p = 0.83) in the 1–7 day risk period and 0.9 (95% CI 0.4–1.7, p = 0.67) in the 8–14 day risk period. Children with no underlying conditions had an all-cause hospitalization IRR of 0.9 (0.8–1.2, p = 0.60) in the 1–7 day risk period and 1.1 (95% CI 0.9–1.3, p = 0.53) in the 8–14 day risk period. There were no differences in all-cause hospitalization risk in individuals with non-asthma, non-immunocompromising underlying conditions compared to those without underlying conditions in the 1–7 day (p = 0.88) or 8–14 day (p = 0.24) risk period.ConclusionsWe found no evidence of differences in post-LAIV hospitalization risk among children with non-asthma, non-immunocompromising underlying conditions compared to healthy children.     

Usage of quadrivalent influenza vaccine among children in the United States, 2013–14

Annual influenza vaccination is recommended for everyone ≥6 months in the U.S. During the 2013–14 influenza season, in addition to trivalent influenza vaccines, quadrivalent vaccines were available, protecting against two influenza A and two influenza B viruses. We analyzed 1,976,443 immunization records from six sentinel sites to compare influenza vaccine usage among children age 6 months–18 years. A total of 983,401 (49.8%) influenza vaccine doses administered were trivalent and 920,333 (46.6%) were quadrivalent (unknown type: 72,709). Quadrivalent vaccine administration varied by age and was least frequent among those <2 years of age.     

Post-licensure surveillance of quadrivalent live attenuated influenza vaccine United States,Vaccine Adverse Event Reporting System (VAERS), July 2013–June 2014

BackgroundQuadrivalent live attenuated influenza vaccine (LAIV4) was approved in 2012 for healthy persons aged 2–49 years. Beginning with the 2013–2014 influenza season, LAIV4 replaced trivalent live attenuated influenza vaccine (LAIV3).MethodsWe analyzed LAIV4 reports to VAERS, a national spontaneous reporting system. LAIV4 reports in 2013–2014 were compared to LAIV3 reports from the previous three influenza seasons. Medical records were reviewed for non-manufacturer serious reports (i.e., death, hospitalization, prolonged hospitalization, life-threatening illness, permanent disability) and reports of selected conditions of interest. We conducted Empirical Bayesian data mining to identify disproportional reporting for LAIV4.ResultsIn 2013–2014, 12.7 million doses of LAIV4 were distributed and VAERS received 779 reports in individuals aged 2–49 years; 95% were non-serious. Expired drug administered (42%), fever (13%) and cough (8%) were most commonly reported in children aged 2–17 years when LAIV4 was administered alone, while headache (18%), expired drug administered (15%) and exposure during pregnancy (12%) were most common in adults aged 18–49 years. We identified one death report in a child who died from complications of cerebellar vascular tumors. Among non-death serious reports, neurologic conditions were common in children and adults. In children, seizures (3) and Guillain-Barré syndrome (2) were the most common serious neurologic outcomes. We identified three serious reports of asthma/wheezing following LAIV4 in children. Data mining detected disproportional reporting for vaccine administration errors and for influenza illness in children.ConclusionsOur analysis of VAERS reports for LAIV4 did not identify any concerning patterns. The data mining finding for reports of influenza illness is consistent with low LAIV4 vaccine effectiveness observed for influenza A disease in children in 2013–2014. Reports of LAIV4 administration to persons in whom the vaccine is not recommended (e.g., pregnant women) indicate the need for education, training and screening regarding indications.     

Concurrent and cross-season protection of inactivated influenza vaccine against A(H1N1)pdm09 illness among young children: 2012–2013 case–control evaluation of influenza vaccine effectiveness

In 2012–2013, we examined 1729 laboratory-confirmed A(H1N1)pdm09 influenza cases matched 1:1 with healthy controls and estimated influenza vaccine effectiveness (VE) for trivalent inactivated influenza vaccine (IIV3) to be 67% (95% confidence interval = 58–74%) for ages 8 months to 6 years old. Among children aged 8–35 months old, VE for fully vaccinated children (73%, 60–81%) was significantly higher than VE for partially vaccinated children (55%, 33–70%). Significant cross-season protection from prior IIV3 was noted, including VE of 31% (8–48%) from IIV3 received in 2010–2011 against influenza illness in 2012––2013 without subsequent boosting doses.     

Inactivated influenza vaccine and spontaneous abortion in the Vaccine Safety Datalink in 2012–13, 2013–14, and 2014–15

IntroductionA recent study reported an association between inactivated influenza vaccine (IIV) and spontaneous abortion (SAB), but only among women who had also been vaccinated in the previous influenza season. We sought to estimate the association between IIV administered in three recent influenza seasons and SAB among women who were and were not vaccinated in the previous influenza season.MethodsWe conducted a case-control study over three influenza seasons (2012–13, 2013–14, 2014–15) in the Vaccine Safety Datalink (VSD). Cases (women with SAB) and controls (women with live births) were matched on VSD site, date of last menstrual period, age group, and influenza vaccination status in the previous influenza season. Of 1908 presumptive cases identified from the electronic record, 1236 were included in the main analysis. Administration of IIV was documented in several risk windows, including 1–28, 29–56, and >56 days before the SAB date.ResultsAmong 627 matched pairs vaccinated in the previous season, no association was found between vaccination in the 1–28 day risk window and SAB (adjusted odds ratio (aOR) 0.9; 95% confidence interval (CI) 0.6–1.5). The season-specific aOR ranged from 0.5 to 1.7 with all CIs including the null value of 1.0. Similarly, no association was found among women who were not vaccinated in the previous season; the season-specific aOR in the 1–28 day risk window ranged from 0.6 to 0.7 and the 95% CI included 1.0 in each season. There was no association found between SAB and influenza vaccination in the other risk windows, or when vaccine receipt was analyzed relative to date of conception.ConclusionDuring these seasons we found no association between IIV and SAB, including among women vaccinated in the previous season. These findings lend support to current recommendations for influenza vaccination at any time during pregnancy, including the first trimester.     

Immunogenicity and safety of AS03-adjuvanted 2009 influenza A H1N1 vaccine in children 6–35 months

We report on the evaluation of the immunogenicity and reactogenicity/safety of AS03-adjuvanted vaccine against pandemic influenza A/H1N1/2009 in young children. In this open-label, randomized study, 157 healthy children aged 6–35 months received two doses (21 days apart) of split-virion inactivated A/California/7/2009 H1N1 vaccine containing either (i) 1.9 μg hemagglutinin (HA) and AS03_B (5.93 mg tocopherol) (N = 104) or (ii) 3.75 μg HA and AS03_A (11.86 mg tocopherol) (N = 53). At 21 days following the first dose of AS03_B-adjuvanted vaccine (1.9 μg HA) the percentage of children with hemagglutination-inhibition titers of ≥40 against the vaccine strain rose from 3.0% before vaccination to 100%. The seroconversion rate was 99% and the geometric mean titer (GMT) increased from 6 to 313. After the second dose the GMT increased further to 2008. The higher dose AS03_A-adjuvanted 3.75 μg HA vaccine did not further increase the immune response. Solicited symptoms reported within 7 days following vaccination were mainly mild to moderate. After the first dose of AS03_B-adjuvanted vaccine (1.9 μg HA) the most common solicited symptoms were pain at the injection site (35.6%) and irritability (31.7%). Fever (axillary ≥37.5 °C) was reported with an incidence of 20.2%. After the second dose reactogenicity tended to increase (injection site pain: 41.3%; irritability: 46.2%; fever ≥37.5 °C: 67.3%). Spontaneously reported adverse events with an intensity that prevented normal activities were documented for 2.9–6.7% of doses with only one event (vomiting) considered related to vaccination. There was one serious adverse event reported in the AS03_A-adjuvanted 3.75 μg HA vaccine group (traumatic brain injury) which was not considered as related to vaccination. In conclusion, these data suggest that a first dose of AS03_B-adjuvanted A/H1N1/2009 vaccine containing 1.9 μg HA in children 6–35 months old is highly immunogenic and that the overall reactogenicity profile is acceptable although reactions including fever tend to increase after a second dose.     

Association of spontaneous abortion with receipt of inactivated influenza vaccine containing H1N1pdm09 in 2010–11 and 2011–12

IntroductionInactivated influenza vaccine is recommended in any stage of pregnancy, but evidence of safety in early pregnancy is limited, including for vaccines containing A/H1N1pdm2009 (pH1N1) antigen. We sought to determine if receipt of vaccine containing pH1N1 was associated with spontaneous abortion (SAB).MethodsWe conducted a case-control study over two influenza seasons (2010–11, 2011–12) in the Vaccine Safety Datalink. Cases had SAB and controls had live births or stillbirths and were matched on site, date of last menstrual period, and age. Of 919 potential cases identified using diagnosis codes, 485 were eligible and confirmed by medical record review. Exposure was defined as vaccination with inactivated influenza vaccine before the SAB date; the primary exposure window was the 1–28 days before the SAB.ResultsThe overall adjusted odds ratio (aOR) was 2.0 (95% CI, 1.1–3.6) for vaccine receipt in the 28-day exposure window; there was no association in other exposure windows. In season-specific analyses, the aOR in the 1–28 days was 3.7 (95% CI 1.4–9.4) in 2010–11 and 1.4 (95% CI 0.6–3.3) in 2011–12. The association was modified by influenza vaccination in the prior season (post hoc analysis). Among women who received pH1N1-containing vaccine in the previous influenza season, the aOR in the 1–28 days was 7.7 (95% CI 2.2–27.3); the aOR was 1.3 (95% CI 0.7–2.7) among women not vaccinated in the previous season. This effect modification was observed in each season.ConclusionSAB was associated with influenza vaccination in the preceding 28 days. The association was significant only among women vaccinated in the previous influenza season with pH1N1-containing vaccine. This study does not and cannot establish a causal relationship between repeated influenza vaccination and SAB, but further research is warranted.     

A randomized controlled trial of antibody response to 2019–20 cell-based inactivated and egg-based live attenuated influenza vaccines in children and young adults

BackgroundHemagglutination inhibition (HAI) titers to the live-attenuated influenza vaccine (LAIV4) are typically lower than its counterpart egg-based inactivated influenza vaccines (IIV). Similar comparisons have not been made between LAIV4 and the 4-strain, cell-culture inactivated influenza vaccine (ccIIV4). We compared healthy children’s and young adults’ HAI titers against the 2019–2020 LAIV4 and ccIIV4.MethodsParticipants aged 4–21 years were randomized 1:1 to receive ccIIV4 (n = 100) or LAIV4 (n = 98). Blood was drawn prevaccination and on day 28 (21–35) post vaccination. HAI assays against egg-grown A/H1N1, A/H3N2, both vaccine B strains and cell-grown A/H3N2 antigens were conducted. Primary outcomes were geometric mean titers (GMT) and geometric mean fold rise (GMFR) in titers.ResultsGMTs to A/H1N1, A/H3N2 and B/Victoria increased following both ccIIV and LAIV and to B/Yamagata following ccIIV (p < 0.05). The GMFR range was 2.4–3.0 times higher for ccIIV4 than for LAIV4 (p < 0.001). Within vaccine types, egg-grown A/H3N2 GMTs were higher (p < 0.05) than cell-grown GMTs [ccIIV4 day 28: egg = 205 (95% CI: 178–237); cell = 136 (95% CI:113–165); LAIV4 day 28: egg = 96 (95% CI: 83–112); cell = 63 (95% CI: 58–74)]. The GMFR to A/H3N2 cell-grown and egg-grown antigens were similar. Pre-vaccination titers inversely predicted GMFR.ConclusionThe HAI response to ccIIV4 was greater than LAIV4 in this study of mostly older children, and day 0 HAI titers inversely predicted GMFR for both vaccines. Lower prevaccination titers were associated with greater GMFR in both vaccine groups.     

Assessment of the immunogenicity and safety of varying doses of an MF59®-adjuvanted cell culture-derived A/H1N1 pandemic influenza vaccine in Japanese paediatric, adult and elderly subjects

Introduction

Effective vaccination strategies are required to combat future influenza pandemics. Here we report the results of three independent clinical trials performed in Japan to assess the immunogenicity, tolerability and safety of varying doses of a cell culture-derived MF59^®-adjuvanted A/H1N1 pandemic vaccine in healthy Japanese paediatric, adult and elderly subjects.

Methods

One hundred and twenty-three children (6 months–18 years), and 200 adults (19–60 years) were randomly assigned in a 1:1 ratio to receive two doses of vaccine containing either 7.5 μg antigen with a full (9.75 mg) adjuvant dose, or 3.75 μg antigen with a half (4.875 mg) adjuvant dose. One hundred elderly (≥61 years) subjects received only the low antigen/adjuvant vaccine formulation. Immunogenicity was assessed by haemagglutination inhibition assay at baseline and three weeks after the first and second vaccine doses on Days 22 and 43, respectively. Solicited and unsolicited adverse reactions were recorded for seven and 21 days post-immunization, respectively.

Results

In adult and elderly subjects, a single low antigen/adjuvant dose vaccination was sufficient to meet all of the three European licensure criteria established for influenza vaccines. One high, or two low antigen/adjuvant dose vaccinations were required to meet the licensure criteria in paediatric subjects. Both vaccine formulations were well tolerated, with the majority of adverse reactions mild to moderate in severity. None of the five serious adverse events reported throughout the three trials were considered to be vaccine-related by the investigators.

Conclusion

The use of MF59 adjuvant allows for much reduced vaccine antigen content, and a single dose administration schedule in adults and the elderly. The production of pandemic vaccine using modern cell culture techniques is highly advantageous in terms of the quantity, quality, and rapidity of antigen production; these benefits, in combination with the use of MF59, maximize manufacturing capacity and global vaccine supply. These data support the suitability of the investigational vaccine for use in the Japanese paediatric, adult, and elderly populations.