Oil-in-Water Emulsion Adjuvant with Influenza Vaccine in Young Children

Vesikari, Timo; Knuf, Markus; Wutzler, Peter; Karvonen, Aino; Kieninger‐Baum, Dorothee; Schmitt, Heinz-Josef; Baehner, Frank; Borkowski, Astrid; Tsai, Theodore F.; Clemens, Ralf

doi:10.1056/nejmoa1010331

Cited by 292 publications

(229 citation statements)

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“…Of the 4,372 studies initially identified (Figure), 18 RCTs [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39], 14 non-randomised clinical trials [40][41][42][43][44][45][46][47][48][49][50][51][52][53], and six observational studies [54][55][56][57][58][59] were eligible for inclusion. The clinical trial registry search yielded 12 additional relevant studies (five RCTs and seven nonrandomised trials).…”

Section: Resultsmentioning

confidence: 99%

“…Multiple study designs were encountered in terms of comparison groups; for non-adjuvanted TIV, comparison with placebo was only found in one study [33]. Five studies examined adjuvanted vaccines (MF59 or virosomal adjuvant) in at least one study arm [30,31,34,35,39].…”

Section: Characteristics Of Randomised Controlled Trialsmentioning

confidence: 99%

“…We used these studies for meta-analysis of fever rate and one additional study [39], where we assumed a fever definition of ≥ 38 °C based on two similar studies by the same lead author [31,35].…”

Section: Characteristics Of Randomised Controlled Trialsmentioning

confidence: 99%

“…Five studies were assessed as being at low risk of bias [26,31,[33][34][35]. Ten studies had medium risk of bias [22,24,25,[27][28][29][30]32,38,39], and three studies had high risk [23,36,37]. Sensitivity analyses limited only to low-risk studies were not feasible; there were too few studies, and two did not use a fever definition of ≥ 38 °C.…”

Section: Characteristics Of Randomised Controlled Trialsmentioning

confidence: 99%

“…The pooled proportion estimate of fever was 6.7% (95% confidence interval (CI): 3.0-11.8) after first dose of TIV based on five eligible RCTs [22,29,31,38,39]. None of these RCTs had a high risk of bias.…”

Section: Non-adjuvanted Vaccines In Children Six To 35 Months Of Agementioning

confidence: 99%

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Systematic review of fever, febrile convulsions and serious adverse events following administration of inactivated trivalent influenza vaccines in children

et al. 2015

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In 2010, increased febrile convulsions (FC) occurred after administration of inactivated trivalent influenza vaccine (TIV) in Australia. We systematically reviewed the rates of fever, FC and serious adverse events (SAEs) after TIV, focussing on published and unpublished clinical trial data from 2005 to 2012, and performed meta-analysis of fever rates. From 4,372 records in electronic databases, 18 randomised controlled trials (RCTs), 14 non-randomised clinical trials, six observational studies and 12 registered trials (five RCTs and seven non-randomised) were identified. In published RCTs, fever ≥ 38 °C rates after first dose of non-adjuvanted TIV were 6.7% and 6.9% for children aged 6-35 months and ≥ 3 years, respectively. Analysis of RCTs by vaccine manufacturer showed pooled fever estimates up to 5.1% with Sanofi or GlaxoSmithKline vaccines; bioCSL vaccines were used in two non-randomised clinical trials and one unpublished RCT and were associated with fever in 22.5-37.1% for children aged 6-35 months. In RCTs, FCs occurred at a rate of 1.1 per 1,000 vaccinated children. While most TIVs induced acceptably low fever rates, bioCSL influenza vaccines were associated with much higher rates of fever in young children. Future standardised study methodology and access to individual level data would be illuminating.

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Section: Resultsmentioning

confidence: 99%

Section: Characteristics Of Randomised Controlled Trialsmentioning

confidence: 99%

Section: Characteristics Of Randomised Controlled Trialsmentioning

confidence: 99%

Section: Characteristics Of Randomised Controlled Trialsmentioning

confidence: 99%

Section: Non-adjuvanted Vaccines In Children Six To 35 Months Of Agementioning

confidence: 99%

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Systematic review of fever, febrile convulsions and serious adverse events following administration of inactivated trivalent influenza vaccines in children

et al. 2015

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Influenza Vaccination in 2013-2014

Neuzil

2013

JAMA

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Serological Responses to an Avian Influenza A/H7N9 Vaccine Mixed at the Point-of-Use With MF59 Adjuvant

Mulligan

Bernstein

Winokur

et al. 2014

JAMA

124

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for the DMID 13-0032 H7N9 Vaccine Study Group IMPORTANCE Human infections with avian influenza A/H7N9 have resulted in high morbidity and mortality in China.OBJECTIVE To compare safety and immunogenicity of different doses of influenza A/Shanghai/2/13 (H7N9) vaccine mixed with or without the MF59 adjuvant. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, phase 2 trial at 4 US sites enrolled 700 adults aged 19 to 64 years beginning in September 2013; 6-month follow-up was completed in May 2014.INTERVENTIONS The H7N9 inactivated virus vaccine was administered intramuscularly on days 0 and 21 at nominal doses of 3.75, 7.5, 15, or 45 μg of hemagglutinin (actual doses approximately 50% higher) with or without the MF59 adjuvant. A total 99, 100, or 101 participants were randomized to each group (7 groups; N = 700). MAIN OUTCOMES AND MEASURESProportions achieving day 42 antibody titer of 40 or greater or seroconversion (a minimum 4-fold increase to titer Ն40) with the hemagglutination inhibition assay; vaccine-related serious adverse events through month 13; and solicited postvaccination symptoms through day 7.RESULTS Hemagglutination inhibition antibodies were minimal after participants received an unadjuvanted vaccine. After receiving 2 doses of H7N9 vaccine at a dosage of 3.75 μg plus the MF59 adjuvant, day 42 seroconversion occurred in 58 participants (59%; 95% CI, 48%-68%). The peak seroconversion occurred at day 29 in 62 participants (62%; 95% CI, 52%-72%). The day 42 geometric mean titer was 33.0 (95% CI, 24.7-44.1). Higher antigen doses were not associated with increased response. For the neutralizing antibody assays, after receiving 3.75 μg of H7N9 vaccine plus the MF59 adjuvant, day 42 seroconversion occurred in 81 participants (82%; 95% CI, 73%-89%). The day 42 geometric mean titer was 81.4 (95% CI, 66.6-99.5). There was no statistically significant difference in day 42 hemagglutination inhibition seroconversion after mixing adjuvant with either the first or both 15 μg doses (n = 34 [35%; 95% CI, 25%-45%] vs n = 47 [47%; 95% CI, 37%-58%], respectively; P = .10). Recent receipt of seasonal influenza vaccination and older age were associated with attenuated response. No vaccine-related serious adverse events occurred. Solicited postvaccination symptoms were generally mild with more local symptoms seen in participants who received the adjuvant.CONCLUSIONS AND RELEVANCE Point-of-use mixing and administration of 2 doses of H7N9 vaccine at the lowest tested antigen dose with MF59 adjuvant produced seroconversion in 59% of participants. Although these findings indicate potential value in this approach, the study is limited by the absence of antibody data beyond 42 days and the absence of clinical outcomes.

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Oil-in-Water Emulsion Adjuvant with Influenza Vaccine in Young Children

Abstract: Influenza vaccine with the MF59 adjuvant is efficacious against PCR-confirmed influenza in infants and young children. (Funded by Novartis Vaccines and Diagnostics; ClinicalTrials.gov number, NCT00644059.).

Cited by 292 publications

References 36 publications

Systematic review of fever, febrile convulsions and serious adverse events following administration of inactivated trivalent influenza vaccines in children

Systematic review of fever, febrile convulsions and serious adverse events following administration of inactivated trivalent influenza vaccines in children

Influenza Vaccination in 2013-2014

Serological Responses to an Avian Influenza A/H7N9 Vaccine Mixed at the Point-of-Use With MF59 Adjuvant

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