Safety, immunogenicity, and lot-to-lot consistency of a quadrivalent inactivated influenza vaccine in children, adolescents, and adults: A randomized, controlled, phase III trial

Background: Inactivated quadrivalent influenza vaccine (IIV4) containing two influenza A strains and one strain from each B lineage (Yamagata and Victoria) may offer broader protection against seasonal influenza than inactivated trivalent influenza vaccine (IIV3), containing a single B strain. This study examined the safety, immunogenicity, and lot consistency of an IIV4 candidate. Methods: This phase III, randomized, controlled, multicenter trial in children/adolescents (9 through 17 years) and adults (18 through 60 years) was conducted in Australia and in the Philippines in 2012. The study was double-blind for IIV4 lots and open-label for IIV4 vs IIV3. Children/adolescents were randomized 2:2:2:1 and adults 10:10:10:1 to receive one of three lots of IIV4 or licensed IIV3. Safety data were collected for up to 6 months post-vaccination. Hemagglutination inhibition and seroneutralization antibody titers were assessed pre-vaccination and 21 days post-vaccination. Results: 1648 adults and 329 children/adolescents received IIV4, and 56 adults and 55 children/adolescents received IIV3. Solicited reactions, unsolicited adverse events, and serious adverse events were similar for IIV3 and IIV4 recipients in both age groups. Injection-site pain, headache, malaise, and myalgia were the most frequently reported solicited reactions, most of which were mild and resolved within 3 days. No vaccine-related serious adverse events or deaths were reported. Post-vaccination antibody responses, seroconversion rates, and seroprotection rates for the 3 strains common to both vaccines were comparable for IIV3 and IIV4 in both age groups. Antibody responses to IIV4 were equivalent among vaccine lots and comparable between age groups for each of the 4 strains. IIV4 met all European Medicines Agency immunogenicity criteria for adults for all 4 strains. Conclusions: In both age groups, IIV4 was well tolerated and caused no safety concerns, induced robust antibody responses to all 4 influenza strains, and met all EMA immunogenicity criteria for adults. Clinical trial registry number: NCT01481454

Dengue and Other Common Causes of Acute Febrile Illness in Asia: An Active Surveillance Study in Children

<div><p>Background</p><p>Common causes of acute febrile illness in tropical countries have similar symptoms, which often mimic those of dengue. Accurate clinical diagnosis can be difficult without laboratory confirmation and disease burden is generally under-reported. Accurate, population-based, laboratory-confirmed incidence data on dengue and other causes of acute fever in dengue-endemic Asian countries are needed.</p><p>Methods and principal findings</p><p>This prospective, multicenter, active fever surveillance, cohort study was conducted in selected centers in Indonesia, Malaysia, Philippines, Thailand and Vietnam to determine the incidence density of acute febrile episodes (≥38°C for ≥2 days) in 1,500 healthy children aged 2–14 years, followed for a mean 237 days. Causes of fever were assessed by testing acute and convalescent sera from febrile participants for dengue, chikungunya, hepatitis A, influenza A, leptospirosis, rickettsia, and <i>Salmonella</i> Typhi. Overall, 289 participants had acute fever, an incidence density of 33.6 per 100 person-years (95% CI: 30.0; 37.8); 57% were IgM-positive for at least one of these diseases. The most common causes of fever by IgM ELISA were chikungunya (in 35.0% of in febrile participants) and <i>S.</i> Typhi (in 29.4%). The overall incidence density of dengue per 100 person-years was 3.4 by nonstructural protein 1 (NS1) antigen positivity (95% CI: 2.4; 4.8) and 7.3 (95% CI: 5.7; 9.2) by serology. Dengue was diagnosed in 11.4% (95% CI: 8.0; 15.7) and 23.9% (95% CI: 19.1; 29.2) of febrile participants by NS1 positivity and serology, respectively. Of the febrile episodes not clinically diagnosed as dengue, 5.3% were dengue-positive by NS1 antigen testing and 16.0% were dengue-positive by serology.</p><p>Conclusions</p><p>During the study period, the most common identified causes of pediatric acute febrile illness among the seven tested for were chikungunya, <i>S.</i> Typhi and dengue. Not all dengue cases were clinically diagnosed; laboratory confirmation is essential to refine disease burden estimates.</p></div

Baseline demographic characteristics of the study cohort.

†<p>Where a participant was enrolled the day before his/her birthday, the age was rounded to 15.0 years. N is the number of participants present at Visit 1.</p

Incidence density of dengue in febrile participants.

†<p>For each participant, only the first occurrence of a dengue-positive acute febrile episode was used to calculate incidence density.</p>‡<p>Incidence density per 100 person-years of study follow-up. Laboratory-confirmed dengue: NS1 positive; Probable dengue: IgM positive and/or fourfold rise in IgG.</p

Incidence density of non-dengue infections in febrile participants.

<p>Acute infections were determined by IgM positivity.</p>†<p>For each participant, only the first occurrence of an infection was used to calculate incidence density.</p>‡<p>Incidence density per 100 person-years of follow-up. NC: not calculated.</p

Frequency of most commonly detected non-dengue infections in febrile participants.

<p>Data are the percentage of participants who had at least one acute febrile episode during the study, for whom IgM antibodies to these pre-specified infections were detected in acute or convalescent sera.</p

Percentage of virologically and serologically diagnosed dengue cases amongst participants who had at least one acute febrile episode during the study.

<p>Laboratory-confirmed dengue: NS1 antigen positive; Probable dengue: IgM positive and/or fourfold rise in IgG.</p

Proportion and incidence density of acute febrile episodes in the study cohort.

†<p>For each participant, only the first occurrence of an acute febrile episode was used to calculate the incidence density.</p