Trivalent and quadrivalent MF59(®)-adjuvanted influenza vaccine in young children: a dose- and schedule-finding study

Young children are at increased risk for influenza infections and related complications. The protection offered to children by conventional trivalent inactivated influenza vaccines (TIV) is suboptimal, due to poor immunogenicity and a higher exposure to infection and complications in this age group, particularly from influenza B strains. In this dose-ranging, factorial design trial, we report the safety and immunogenicity of different combinations of adjuvanted (ATIV) and non-adjuvanted trivalent (TIV) and quadrivalent (QIV) influenza vaccines in 480 healthy children 6 to <36 months of age.The results show that the second B strain added to TIV was immunogenic and did not affect immunogenicity of the other strains. The addition of the MF59^® adjuvant promoted robust immune responses with notable elevations in antibodies observed even after one dose. A dose-response relationship was observed between the antibody response and MF59 adjuvant. No patterns in safety and tolerability emerged with different adjuvant and antigen doses nor with the addition of a second B strain. MF59-adjuvanted QIV offers potential advantages to young children.     

A randomized controlled trial of antibody response to 2018–19 cell-based vs. egg-based quadrivalent inactivated influenza vaccine in children

BackgroundCurrent influenza vaccine effectiveness (VE) improvement efforts focus on minimizing egg adaptation mutations during manufacture. This study compared immune response of two FDA-approved quadrivalent inactivated influenza vaccines in an unblinded randomized controlled trial.MethodsParticipants were 144 community dwelling, healthy children/adolescents aged 4–20 years, randomized 1:1 in blocks of 4 to a vaccine grown in cell culture (ccIIV4 [Flucelvax®]; n = 85); or in egg medium (IIV4 [Fluzone ®]; n = 83). Blood was drawn at day 0 prevaccination and at day 28 (19–35 days) post vaccination. Hemagglutination inhibition (HI) assays against A/H1N1 and both B strains and microneutralization (MN) assays against egg-based and cell-based A/H3N2 strains were conducted. The primary outcome measure was seroconversion (day 28/day 0 titer ratio ≥ 4 with day 28 titer ≥ 40). Secondary outcomes were elevated titers (day 28 HI titer ≥ 1:110), geometric mean titers (GMTs) and mean fold rise (MFR) in titers. Outcomes were compared for 74 ccIIV4 recipients and 70 IIV4 recipients, and for those vaccinated and unvaccinated the previous year. Only the HI and MN laboratory analysis team was blinded to group assignment.ResultsIn this racially diverse (81% non-white) group of children with a median age of 14 years, baseline demographics did not differ between vaccine groups. At day 0, half or more in each vaccine group had elevated HI or MN titers. Low seroconversion rates (14%-35%) were found; they did not differ between groups. Among 2018–19 ccIIV4 recipients, those unvaccinated in the previous season showed significantly higher MFR against A/H1N1 and A/H3N2 cell-grown virus than the previously vaccinated. Similar results were found for MFR against B/Victoria among 2018–2019 IIV4 recipients.ConclusionIn mostly older children with high baseline titers, no differences in seroconversion or other measures of antibody titers were found between ccIIV4 and IIV4 recipients against egg- and cell-grown influenza vaccine viruses.Clinical Trials NoNCT03614975.     

The faces of influenza vaccine recommendation: A Literature review of the determinants and barriers to health providers’ recommendation of influenza vaccine in pregnancy

IntroductionWHO recommends influenza vaccination for pregnant women and health providers (HPs), yet global uptake for both is persistently low. Research suggests that HPs greatly influence uptake of influenza vaccine in pregnant women. Our review studies HPs’ recommendation of influenza vaccine to pregnant women, determinants and barriers to recommendation, and the role that HPs may play in global influenza vaccine coverage.MethodsWe undertook a comprehensive global review of literature relating to HPs’ recommendation of seasonal influenza vaccines to pregnant women and the determinants and barriers to recommendation and how this may vary by country and context. We evaluated data from each study including frequency of HP recommendation, vaccine coverage, determinants and barriers to recommendation, and the odds of recommending. We tracked the frequency of determinants and barriers to recommendation in heat maps and organized data by world regions and income classifications.ResultsFrom 32 studies in 15 countries, we identified 68 determinants or barriers to HPs’ recommendation. Recommendation rates were highest (77%) in the Americas and lowest in South East Asia (18%). A HP’s own influenza vaccine status was a main determinant of recommendation in multiple country contexts and from different provider types. Financial barriers to recommendation were present in higher-income countries and policy-related barriers were highlighted in lower-income countries. HP perceptions of safety, efficacy, and the utility of vaccine were the most frequently cited barriers, relevant in almost every context.ConclusionsHP recommendation is important to influenza vaccine implementation in pregnant women. A HP’s own status is an important recommendation determinant in multiple contexts. Vaccine program implementation plans should consider the impact of HPs' knowledge, awareness and vaccine confidence on their own uptake and recommendation practices, as well as on the uptake among pregnant women. Addressing safety and efficacy concerns is relevant in all contexts for HPs and pregnant women.     

Is the adjuvanted influenza vaccine more effective than the trivalent inactivated vaccine in the elderly population? Results of a case–control study

Introduction

Influenza illness is an important public health problem and annual vaccination is globally recommended for high risk populations.

Objective

The aim was to evaluate and compare the effectiveness of influenza vaccines in reducing hospitalizations for influenza or pneumonia during two influenza seasons in the elderly.

Methods

A case–control study was performed, using administrative database of the Local Health Unit Roma-A (LHU RM-A). The included subjects were at least 65 years old and residing in one of the four districts of the LHU. The cases were hospitalized for influenza or pneumonia during influenza season in the years 2010–2011 and 2011–2012. The controls were hospitalized in the same period, but not for influenza or pneumonia. The subjects were immunized with the trivalent inactivated influenza vaccine (TIV) in the first influenza season (2010–2011) and with the adjuvanted influenza vaccine MF59 (ATIV) in the second season (2011–2012).

Results

A total of 269 cases and 1247 controls were included for the 2010–2011 influenza season, and 365 cases and 1227 controls were selected for the 2011–2012 season. Up to 63.6% cases and 53.5% controls in the 2010–2011 season and 78.6% of cases and 64.1% of controls in the 2011–2012 season have not been vaccinated. Female gender and high educational level were protective factors for hospitalization. Subjects over 75 years were at high risk of hospitalization compared to 65–74 years olds. Influenza vaccination reduced significantly hospitalization in both seasons. In subjects with 65–74 years TIV was more effective than ATIV; vice versa for those over 75 years old.

Discussion and conclusion

TIV and ATIV reduce hospitalization for influenza or pneumonia with a variable degree of protection in different age groups. In particular, ATIV is more effective in individuals over 75 years old.     

Monitoring the safety of high-dose,trivalent inactivated influenza vaccine in the vaccine adverse event reporting system (VAERS), 2011 – 2019

BackgroundOn 12/23/2009 a new high-dose trivalent inactivated influenza vaccine (IIV3-HD) was licensed for adults aged ≥65 years. We assessed the post-licensure safety data for IIV3-HD in the Vaccine Adverse Event Reporting System (VAERS) during 2011–2019.MethodsWe searched VAERS for reports after IIV3-HD during 1/1/2011–06/30/2019 in persons aged ≥65 years. Medical records were reviewed for all death reports and for certain pre-specified conditions (e.g. Guillain Barré Syndrome [GBS], anaphylaxis). We also reviewed certain groups who received IIV3-HD erroneously (e.g. pregnant women, children). Empirical Bayesian data mining was used to identify disproportional reporting.ResultsVAERS received 12,320 reports after IIV3-HD;723 reports (5.9%) were serious. The most common adverse events (AEs) among serious reports were pyrexia (30.2%), asthenia (28.9%), and dyspnea (24.9%), and among non-serious reports were injection site erythema (16.8%), pain in extremity (15.8%), and injection site pain (14.2%). Among 55 death reports, the most common causes of death were diseases of the circulatory system (n = 23;41.8%). Based on medical record review, there were 61 reports of GBS and 13 of anaphylaxis. There were 13 reports of pregnant-women who inadvertently received IIV3-HD; three reports described arm pain or local reactions, and 10 did not report any AE. Among 59 reports of children who erroneously received IIV3-HD, 31 experienced an AE (most commonly injection site or constitutional reactions) and the remaining 28 reports did not describe any AE.ConclusionsPost-licensure safety data of IIV3-HD during 9 influenza seasons revealed no new or unexpected safety concerns among individuals ≥65 years. Inadvertent administration of IIV3-HD to children or pregnant women was observed, although with no serious AEs reported. Training and education of providers in vaccine recommendations and groups for whom the vaccine is indicated may help in preventing these vaccine administration errors. This review provides baseline information for future monitoring of the quadrivalent-high-dose influenza vaccine.     

On the bias of estimates of influenza vaccine effectiveness from test–negative studies

Estimates of the effectiveness of influenza vaccines are commonly obtained from a test-negative design (TND) study, where cases and controls are patients seeking care for an acute respiratory illness who test positive and negative, respectively, for influenza infection. Vaccine effectiveness (VE) estimates from TND studies are usually interpreted as vaccine effectiveness against medically-attended influenza (MAI). However, it is also important to estimate VE against any influenza illness (symptomatic influenza (SI)) as individuals with SI are still a public health burden even if they do not seek medical care. We present a numerical method to evaluate the bias of TND-based estimates of influenza VE with respect to MAI and SI. We consider two sources of bias: (a) confounding bias due to a (possibly unobserved) covariate that is associated with both vaccination and the probability of the outcome of interest and (b) bias resulting from the effect of vaccination on the probability of seeking care. Our results indicate that (a) VE estimates may suffer from substantial confounding bias when a confounder has a different effect on the probabilities of influenza and non-influenza ARI, and (b) when vaccination reduces the probability of seeking care against influenza ARI, then estimates of VE against MAI may be unbiased while estimates of VE against SI may be have a substantial positive bias.     

Does pneumococcal vaccine reduce influenza morbidity in humans?

A retrospective study was conducted to verify the possibility that people immunized with pneumococcal vaccine (PV) show lower morbidity not only for pneumonia but also for influenza. A total of 450 individuals were enrolled between 1999 and 2003 and allocated to one of the following groups: (A) not vaccinated; (B) immunized with PV during 1999; (C) immunized with anti-influenza vaccine (Flu-V) each year; and (D) immunized with PV once in 1999 and Flu-V every consecutive year. People from group B showed significantly lower percentage of influenza-related diseases during the year 2000 in comparison with those from group A (p<0.01), whereas in the course of 2001 the morbidity of patients from group B was lower compared with the other groups (p<0.01). The results point to a way to decrease the morbidity of influenza-related diseases by immunization with PV only, at least for 2-3 years, avoiding Flu-V administration and permitting considerable saving for health care providers. Therefore, it is concluded that PV can reduce the morbidity of influenza at a greater rate than the Flu-V.     

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.     

Effectiveness of inactivated influenza vaccine in children by vaccine dose, 2013–18

ObjectivesWe assessed the vaccine effectiveness (VE) of inactivated influenza vaccine (IIV) by vaccine dose in children aged 6 months to 12 years for whom two doses are recommended in Japan to ascertain the appropriate vaccine doses.MethodsVE was assessed according to a test-negative case-control design based on rapid influenza diagnostic test (RIDT) results. Children aged 6 months to 12 years with a fever ≥38 °C who had received an RIDT in outpatient clinics of 24 hospitals were enrolled for all five seasons since 2013/14. VE by vaccine dose (none vs. once or twice, and once vs. twice) was analyzed.ResultsIn the dose analysis, 20,033 children were enrolled. Both one- and two-dose regimens significantly reduced cases in preventing any influenza, influenza A, and influenza B, but there was no significant difference in adjusted VE between one- and two-dose regimens overall (adjusted OR, 0.560 [95% CI, 0.505–0.621], 0.550 [95% CI, 0.516–0.586]), 0.549 [95% CI, 0.517–0.583], and 1.014 [95% CI, 0.907–1.135], for none vs. once, none vs. twice, none vs. once or twice, and once vs. twice for any influenza, respectively). Both one- and two-dose regimens significantly reduced cases with any influenza and influenza A every season. Also, both regimens significantly reduced cases of any influenza, influenza A, and influenza B among children aged 1–12 years, especially among those aged 1–5 years. In the 2013/14, 2015/16, and 2016/17 seasons, however, only the two-dose regimen was significantly effective in preventing influenza B. Both one- and two-dose regimens significantly reduced cases involving hospitalization due to any influenza and influenza A.ConclusionsBoth one- and two-doses regimens of IIV were effective in preventing influenza for children aged 6 months to 12 years. The two-dose regimen was more effective against influenza B in some seasons.     

Safety and immunogenicity of a 9-valent HPV vaccine in females 12–26 years of age who previously received the quadrivalent HPV vaccine

ObjectivesTo assess the safety and immunogenicity of the investigational 9-valent (6/11/16/18/31/33/45/52/58) HPV (9vHPV) vaccine in prior recipients of a 3-dose regimen of quadrivalent (6/11/16/18) HPV (qHPV) vaccine.MethodsV503-006 was a randomized, double-blinded, safety/tolerability and immunogenicity study of the 9vHPV vaccine in females 12–26 years of age who were previously vaccinated with qHPV vaccine. Subjects were randomized in a 2:1 ratio to receive 3 doses of 9vHPV vaccine (n = 618) or saline placebo (n = 306) at day 1, month 2, and month 6. Systemic, injection-site and serious adverse experiences (AEs) were monitored. Serum samples were collected at day 1, month 2, and month 7. Anti-HPV 6/11/16/18/31/33/45/52/58 titers were measured using the 9-valent HPV competitive Luminex Immunoassay (cLIA).ResultsThe frequency of injection-site AEs (days 1–5 following any vaccination) was higher in the 9vHPV vaccine group than in the placebo group (91.1% and 43.9%, respectively). The frequencies of vaccine-related systemic AEs (days 1–15 following any vaccination) were generally comparable between the 2 groups (30.6% in the 9vHPV vaccine group, and 25.9% in the placebo group). One vaccine-related serious AE was reported in each of the 9vHPV vaccine and placebo groups. Few subjects (9vHPV = 0.5%; placebo = 0%) discontinued due to an AE. At 4 weeks post-dose 3, over 98% of subjects in the 9vHPV vaccine group were seropositive for HPV types 31/33/45/52/58, with marked elevations in cLIA geometric mean titers (GMTs) to these HPV types. Anti-HPV 31/33/45/52/58 GMTs were lower than in subjects administered 9vHPV vaccine who had not previously received qHPV vaccine (based on cross-study analyses); the clinical significance of this difference is unknown.ConclusionsAdministration of a 3-dose regimen of 9vHPV vaccine to adolescent girls and young women 12–26 years of age who are prior qHPV vaccine recipients is highly immunogenic with respect to HPV types 31/33/45/52/58 and generally well tolerated.     

Do antibody responses to the influenza vaccine persist year-round in the elderly? A systematic review and meta-analysis

IntroductionThe influenza vaccine is less immunogenic in older than younger adults, and the duration of protection is unclear. Determining if protection persists beyond a typical seasonal epidemic is important for climates where influenza virus activity is year-round.MethodsA systematic review protocol was developed and registered with PROSPERO [CRD42015023847]. Electronic databases were searched systematically for studies reporting haemagglutination-inhibition (HI) titres 180–360 days following vaccination with inactivated trivalent seasonal influenza vaccine, in adults aged ⩾65 years. Geometric mean titre (GMT) and seroprotection (HI titre ⩾1:40) at each time point was extracted. A Bayesian model was developed of titre trajectories from pre-vaccination to Day 360. In the meta-analysis, studies were aggregated using a random-effects model to compare pre-vaccination with post-vaccination HI titres at Day 21–42 (‘seroconversion’), Day 180 and Day 360. Potential sources of bias were systematically assessed, and heterogeneity explored.Results2864 articles were identified in the literature search, of which nineteen met study inclusion/exclusion criteria. Sixteen studies contained analysable data from 2565 subjects. In the Bayesian model, the proportion of subjects seroprotected increased from 41–51% pre-vaccination to 75–78% at seroconversion. Seroprotection subsequently fell below 60% for all serotypes by Day 360: A/H1 42% (95% CI 38–46), A/H3 59% (54–63), B 47% (42–52). The Bayesian model of GMT trajectories revealed a similar pattern. By Day 360, titres were similar to pre-vaccination levels. In the meta-analysis, no significant difference in proportion of subjects seroprotected, 0 (−0.11, 0.11) or in log₂ GMT 0.30 (−0.02, 0.63) was identified by Day 360 compared with pre-vaccination. The quality of this evidence was limited to moderate on account of significant participant dropout.ConclusionsThe review found consistent evidence that HI antibody responses following influenza vaccination do not reliably persist year-round in older adults. Alternative vaccination strategies could provide clinical benefits in regions where year-round protection is important.     

Safety and immunogenicity of a seasonal quadrivalent influenza vaccine (GC3110A) in healthy participants aged ≥ 65 years

BackgroundSeasonal Influenza is still considered associated with seasonal morbidity and hospitalization in the elderly population. The World Health Organization (WHO) recommended seasonal quadrivalent influenza vaccine (QIV) to reduce burden of two currently circulating influenza B lineages. Until 2019 Korean National Immunization Program (NIP) recommended trivalent influenza vaccine (TIV) after ongoing debates on cost effectiveness of QIV for elderly population. Although influenza vaccine only showed modest effect on reducing influenza in elderly, this study aimed to evaluate the immunogenicity and safety of inactivated QIV in healthy participants ≥ 65 years of age.MethodsA total of 274 healthy participants aged ≥ 65 years received a QIV. Seroconversion-based vaccine efficacy of 4 strains of seasonal influenza was assessed 21 days after vaccination and adverse events were monitored until 180 days after vaccination.ResultsThe percentages of participants seroconverted after vaccination on HI antibody against each strain were 36.5% (99/271) to A/H1N1, 47.6% (129/271) to A/H3N2, 40.6% (110/271) to B Yamagata, and 49.1% (133/271) to B Victoria. The percentages of participants seroprotected after vaccination on HI antibody against each strain were 81.2% (220/271) to A/H1N1, 98.5% (267/271) to A/H3N2, 95.2% (258/271) to B Yamagata, and 93.7% (254/271) to B Victoria. There was no serious adverse event (SAE) related with the study vaccine.ConclusionThe quadrivalent split influenza vaccine is expected to offer seroprotection against influenza A and both influenza B lineages even in the elderly population.     

High-dose influenza vaccine use among patients receiving hemodialysis in the United States, 2010–2013

BackgroundStandard influenza vaccines may be of limited benefit to patients with end-stage renal disease (ESRD). These patients may benefit from high-dose influenza vaccine, currently indicated for patients aged ≥65 years. Studies in other populations have demonstrated that high-dose vaccine elicits a stronger immunological response. We compared vaccine uptake in the United States and predictors of receipt for high-dose and standard influenza vaccines.MethodsUsing data from the United States Renal Data System (2010–2013), we conducted a cohort study of 421,482 adult patients on hemodialysis. We examined temporal trends in uptake of high-dose or standard trivalent influenza vaccine each influenza season, and used multivariate logistic regression to assess the association between individual-level variables (e.g., demographics, comorbidities) and facility-level variables (e.g., facility size and type) with vaccine receipt.ResultsThe proportion of patients with ESRD who were vaccinated with any influenza vaccine increased from 68.3% in 2010 to 72.4% in 2013. High-dose vaccines were administered to 0.9% of patients during the study period, and 16.7% of high-dose vaccines were administered to patients <65 years of age. Among patients aged ≥65 years, older patients (>79 vs. 65–69 years: OR, 1.29; 95% CI, 1.19–1.41) and patients at hospital-based versus free-standing dialysis facilities (OR, 2.31; 95% CI, 2.13–2.45) were more likely to receive high-dose vaccine, while blacks (vs. whites [OR, 0.66; 95% CI, 0.61–0.71]) and patients with longer duration of ESRD (>9 vs. 0 years: OR, 0.66; 95% CI, 0.55–0.78) were less likely to receive the high-dose vaccine.ConclusionsWhile the overall influenza vaccination rate has increased, use of high-dose vaccine among patients with ESRD was very low. Being an older patient, living in the Midwest, and receiving care at hospital-based facilities were the strongest predictors of receiving high-dose vaccine.     

Stability of influenza sub-unit vaccine. Does a couple of days outside the refrigerator matter?

In this study 27 full scale production batches of influenza sub-unit vaccine were evaluated on their stability. The batches varied with respect to the strains they contained and regarding the presence of the preservative thiomersal in the solution. The stability study showed that haemagglutinin content was the most sensitive parameter. An increase in the storage temperature strongly increased the degradation rate of haemagglutinin. The degradation rate of the haemagglutinin differed for the different strains tested. However, statistical evaluation of the data obtained for the most sensitive strain tested showed that even exposure during a 2 week period of the vaccine to room temperature would not adversely affect the shelf life claim of the influenza subunit vaccine of 1 year in the refrigerator. Moreover, this study showed that the presence of thiomersal in the solution has no effect on the stability of the vaccine.