Safety and immunogenicity of a quadrivalent inactivated influenza vaccine in adults

Background and aims

Although two antigenically distinct B strain lineages of influenza have co-circulated globally since the mid-1980s, trivalent influenza vaccines (TIVs) contain only one, resulting in frequent mismatches. This study examined the safety and immunogenicity of an inactivated quadrivalent influenza vaccine (QIV) candidate.

Methods

This was a phase III, randomized, active-controlled, multicenter trial in adults during the 2011/2012 influenza season. Enrollment was stratified to include equal numbers of subjects 18–60 and >60 years of age. Subjects were randomized 5:1:1 to be vaccinated with the QIV, the licensed TIV, or an investigational TIV containing the alternate B strain lineage. Hemagglutinin inhibition antibody titers were assessed pre-vaccination and 21 days post-vaccination.

Results

1116 subjects were vaccinated with QIV, 226 with the licensed TIV, and 223 with the investigational TIV. For all four vaccine strains, antibody responses to the QIV were non-inferior to the response to the TIV for the matched strains. For both B strains, post-vaccination antibody responses to the QIV were superior to the responses to the TIVs lacking the corresponding B strain. The QIV met all European Medicines Agency criteria for all four vaccine strains. Solicited reactions, unsolicited adverse events, and serious adverse events were similar for the QIV and pooled TIV groups. The most commonly reported solicited reactions were injection-site pain, headache, and myalgia, and most solicited reactions were mild or moderate and appeared and resolved within 3 days of vaccination. No treatment-related serious adverse events or deaths were reported.

Conclusions

The inactivated QIV was well tolerated without any safety concerns. For all four vaccine strains, antibody responses to the QIV were superior to the responses to TIV for the unmatched strains and non-inferior for the matched strains. QIV could therefore help address an unmet need due to mismatched B strains in previous influenza vaccines.

Clinical trial registry number

EudraCT: 2011-001976-21.     

Immunogenicity,reactogenicity, and safety of inactivated quadrivalent influenza vaccine candidate versus inactivated trivalent influenza vaccine in healthy adults aged ≥18 years: A phase III,randomized trial

Background

Two influenza B lineages have been co-circulating since the 1980s, and because inactivated trivalent influenza vaccine (TIV) contains only one B strain, it provides little/no protection against the alternate B-lineage. We assessed a candidate inactivated quadrivalent influenza vaccine (QIV) containing both B lineages versus TIV in healthy adults.

Methods

Subjects received one dose of QIV (lot 1, 2, or 3) or one of two TIVs (B strain from Victoria or Yamagata lineage); randomization was 2:2:2:1:1. Hemagglutination-inhibition assays were performed 21-days post-vaccination; superiority of QIV versus TIV for the alternate B-lineage was demonstrated if the 95% confidence interval (CI) lower limit for the GMT ratio was ≥1.5, and non-inferiority against the shared strains was demonstrated if the 95% CI upper limit for the GMT ratio was ≤1.5. Reactogenicity and safety were assessed during the post-vaccination period. NCT01196975.

Results

Immunogenicity of QIV lots was consistent, QIV was superior to TIV for the alternate B-lineage strain, and QIV was non-inferior versus TIVs for shared strains (A/H1N1, A/H3N2, B-strain). Reactogenicity and safety profile of the QIV was consistent with seasonal influenza vaccines.

Conclusion

QIV provided superior immunogenicity for the added B strain without affecting the antibody response to the TIV strains, and without compromising safety.     

Immunogenicity and safety of inactivated quadrivalent influenza vaccine in adults: A systematic review and meta-analysis of randomised controlled trials

BackgroundA quadrivalent influenza vaccine (QIV) includes two A strains (A/H1N1, A/H3N2) and two B lineages (B/Victoria, B/Yamagata). The presence of both B lineages eliminate potential B lineage mismatch of trivalent influenza vaccine (TIV) with the circulating strain.MethodsElectronic database searches of Medline, Embase, Cochrane Central Register of Controlled Trials (CCRCT), Scopus and Web of Science were conducted for articles published until June 30, 2015 inclusive. Articles were limited to randomised controlled trials (RCTs) in adults using inactivated intramuscular vaccine and published in English language only. Summary estimates of immunogenicity (by seroprotection and seroconversion rates) and adverse events outcomes were compared between QIV and TIV, using a risk ratio (RR). Studies were pooled using inverse variance weights with a random effect model and the I² statistic was used to estimate heterogeneity.ResultsA total of five RCTs were included in the meta-analysis. For immunogenicity outcomes, QIV had similar efficacy for the three common strains; A/H1N1, A/H3N2 and the B lineage included in the TIV. QIV also showed superior efficacy for the B lineage not included in the TIV; pooled seroprotection RR of 1.14 (95%CI: 1.03–1.25, p = 0.008) and seroconversion RR of 1.78 (95%CI: 1.24–2.55, p = 0.002) for B/Victoria, and pooled seroprotection RR of 1.12 (95%CI: 1.02–1.22, p = 0.01) and seroconversion RR of 2.11 (95%CI: 1.51–2.95, p < 0.001) for B/Yamagata, respectively. No significant differences were found between QIV and TIV for aggregated local and systemic adverse events within 7 days post-vaccination. There were no vaccine-related serious adverse events reported for either QIV or TIV. Compared to TIV, injection-site pain was more common for QIV, with a pooled RR of 1.18 (95%CI: 1.03–1.35, p = 0.02).ConclusionIn adults, inactivated QIV was as immunogenic as seasonal TIV, with equivalent efficacy against the shared three strains included in TIV, and a superior immunogenicity against the non-TIV B lineage.     

General practice encounters following seasonal influenza vaccination as a proxy measure of early-onset adverse events

Background

In 2010, use of seasonal trivalent influenza vaccine (TIV) in children <5 years of age was suspended in Australia following reports of vaccine-related febrile convulsions. We investigated the utility of data on primary care [general practice (GP)] consultations for any reason within three days of receipt of influenza vaccine as recorded on the Australian Childhood Immunisation Register (ACIR) as a means of signal detection.

Methods

Data on GP consultations were obtained from Medicare Australia (Australian Government Department of Human Services) for children recorded on the ACIR as receiving either TIV or monovalent influenza vaccine. Rates of GP consultation by day following ACIR-recorded receipt of influenza vaccine were compared by year (2008–2010), vaccine type, age and region.

Results

In 2010, GP encounter rates on the day after receipt of the TIV manufactured by bioCSL (formerly CSL Biotherapies (Fluvax^®) were significantly higher than both bioCSL TIVs in the previous two years [rate ratio (RR) 1.9; 95% CI: 1.7–2.2] and Sanofi Pasteur TIV, Vaxigrip^® [RR 1.6, 95% CI 1.4–1.7] in 2009–2010. Encounter rates were also higher than for CSL Monovalent influenza vaccine, Panvax^® [RR 1.9, 95% CI 1.7–2.2] in 2009–2010. These findings were robust to adjustment for age group (≤2, >2 years) and region (Western Australia vs other Australian states/territories).

Conclusions

A primary care consultation on the day after vaccine receipt is a reasonable proxy for early reactogenicity and has potential for use in various settings.     

The economic value of a quadrivalent versus trivalent influenza vaccine

The recently licensed quadrivalent seasonal influenza vaccine (QIV) may provide better protection than the traditional trivalent influenza vaccine (TIV) as it includes one more influenza B strain. We developed a Monte Carlo simulation model to determine the economic value of a QIV compared to the TIV for 10 influenza seasons (1999–2009). The addition of the influenza B strain to convert the TIV into a QIV could result in substantial cost-savings to society (median of $3.1 billion) and third party payers (median of $292 million), even when the cost of QIV is significantly higher.     

Evaluating the safety of influenza vaccine using a claims-based health system

Introduction

As part of the Centers for Disease Control and Prevention's monitoring and evaluation activities for influenza vaccines, we examined relationships between influenza vaccination and selected outcomes in the 2009–2010 and 2010–2011 influenza seasons in a claims-based data environment.

Methods

We included patients with claims for trivalent influenza vaccine (TIV) and/or 2009 pandemic influenza A H1N1 vaccine (H1N1) during the 2009–2010 and 2010–2011 influenza seasons. Patients were followed for several pre-specified outcomes identified in claims. Seizures and Guillain–Barré Syndrome were selected a priori for medical record confirmation. We estimated incidence rate ratios (IRR) using a self-controlled risk interval (SCRI) or a historical comparison design. Outcomes with elevated IRRs, not selected a priori for medical record review, were further investigated with review of claims histories surrounding the outcome date to determine whether the potential event could be ruled-out or attributed to other causes based on the pattern of medical care.

Results

In the 2009–2010 season, no significant increased risks for outcomes following H1N1 vaccination were observed. Following TIV administration, the IRR for peripheral nervous system disorders and neuropathy was slightly elevated (1.07, 95% CI: 1.01–1.13). The IRR for anaphylaxis following TIV was 28.55 (95% CI: 3.57–228.44). After further investigation of claims histories, the majority of potential anaphylaxis cases had additional claims around the time of the event indicating alternate explanatory factors or diagnoses. In the 2010–2011 season following TIV administration, a non-significant elevated IRR for anaphylaxis was observed with no other significant outcome findings.

Conclusion

After claims history review, we ultimately found no increased outcome risk following administration of 998,881 TIV and 538,257 H1N1 vaccine doses in the 2009–2010 season, and 1,158,932 TIV doses in the 2010–2011 season.     

A prospective observational safety study on MF59 adjuvanted cell culture-derived vaccine,Celtura during the A/H1N1 (2009) influenza pandemic

Background

The present study was a prospective observational study to evaluate the safety profile of Celtura^®, a monovalent, cell culture-derived, inactivated subunit influenza vaccine prepared from A/California/07/2009(H1N1) with the adjuvant MF59^®. Subjects were enrolled prospectively during the H1N1 2009 influenza pandemic at medical centres in Colombia, Chile, Switzerland, and Germany during the period December 2009 to June 2010.

Methods

Subjects ages 18 and older were followed for the occurrence of adverse events (AEs) for six months after vaccination. Adverse events of special interest (AESIs) were neuritis, convulsion (seizure), anaphylaxis, encephalitis, vasculitis, Guillain-Barre syndrome, demyelinating conditions, Bell's palsy, and laboratory-confirmed vaccination failure.

Results

Overall, 7348 AEs were reported in 2296 of 3989 enrolled subjects (57.6%). Only two AEs were considered related to injection site reactions. No laboratory-confirmed cases of influenza were reported. There were 108 medically confirmed serious adverse events (SAEs) reported among 73 subjects with 6 such SAEs described as possibly or probably related to vaccination. Three fatal cases were reported and assessed as not related to vaccination. Two AESIs classified as convulsion were reported and assessed as not related to vaccination. Both AESIs occurred well outside the pre-specified 7 day risk window representing the likely timeframe of the occurrence of seizure following vaccination.

Conclusions

The results of this study support the overall good safety profile of MF59 adjuvanted cell culture-derived influenza vaccine as administered in adults during the 2009–2010 H1N1 influenza pandemic. No concern is raised regarding the occurrence of AESIs.     

The cost-effectiveness of trivalent and quadrivalent influenza vaccination in communities in South Africa,Vietnam and Australia

BackgroundTo inform national healthcare authorities whether quadrivalent influenza vaccines (QIVs) provide better value for money than trivalent influenza vaccines (TIVs), we assessed the cost-effectiveness of TIV and QIV in low-and-middle income communities based in South Africa and Vietnam and contrasted these findings with those from a high-income community in Australia.MethodsIndividual based dynamic simulation models were interfaced with a health economic analysis model to estimate the cost-effectiveness of vaccinating 15% of the population with QIV or TIV in each community over the period 2003–2013. Vaccination was prioritized for HIV-infected individuals, before elderly aged 65+ years and young children. Country or region-specific data on influenza-strain circulation, clinical outcomes and costs were obtained from published sources. The societal perspective was used and outcomes were expressed in International$ (I$) per quality-adjusted life-year (QALY) gained.ResultsWhen compared with TIV, we found that QIV would provide a greater reduction in influenza-related morbidity in communities in South Africa and Vietnam as compared with Australia. The incremental cost-effectiveness ratio of QIV versus TIV was estimated at I$4183/QALY in South Africa, I$1505/QALY in Vietnam and I$80,966/QALY in Australia.ConclusionsThe cost-effectiveness of QIV varied between communities due to differences in influenza epidemiology, comorbidities, and unit costs. Whether TIV or QIV is the most cost-effective alternative heavily depends on influenza B burden among subpopulations targeted for vaccination in addition to country-specific willingness-to-pay thresholds and budgetary impact.     

Safety, tolerability, and immunogenicity of inactivated trivalent seasonal influenza vaccine administered with a needle-free disposable-syringe jet injector

Background

Jet injectors (JIs) avoid safety drawbacks of needle-syringe (N-S) while generating similar immune responses. A new generation of disposable-syringe jet injectors (DSJIs) overcomes the cross-contamination risk of multi-use-nozzle devices used in 20th-century campaigns. In the first study in humans, the newly-US-licensed LectraJet^® model M3 RA DSJI was compared to N-S.

Methods

Sixty healthy adults received one 0.5 mL intramuscular dose of the 2009-2010 seasonal, trivalent, inactivated influenza vaccine (TIV) in randomized, double-masked fashion by either DSJI (n = 30) or N-S (n = 30). Adverse reactions were monitored for 90 days after injection, and serologic responses assayed by hemagglutination inhibition (HI) at days 28 and 90.

Results

There were no related serious adverse events (SAEs), nor differing rates of unsolicited AEs between DSJI and N-S. Solicited erythema and induration occurred more often after DSJI, but were transient and well-tolerated; a trend was noted for fewer systemic reactions by DSJI. Pre-vaccination HI geometric mean titers (GMT) increased by 28 days for H1N1, H3N2, and B antigens by 13-, 14-, and 8-fold via DSJI, and by 7-, 10-, and 7-fold for N-S, respectively. No trending differences in GMT, seroconversion, or seroprotection were noted; sample sizes precluded non-inferiority assessment.

Conclusions

DSJI delivery of TIV is well-tolerated and immunogenic.     

A Phase III randomised trial of the immunogenicity and safety of quadrivalent versus trivalent inactivated subunit influenza vaccine in adult and elderly subjects,assessing both anti-haemagglutinin and virus neutralisation antibody responses

BackgroundTrivalent influenza vaccines (TIVs) offer substantial protection against matching B-strains, however, protection against alternate-lineage B-strains may be enhanced by adding a second B-strain in quadrivalent influenza vaccines (QIVs). In this Phase III, double-blind, multicentre, randomised study, the immunogenicity and safety of subunit inactivated QIV versus TIV was assessed in adult (aged ≥18 to ≤60 years) and elderly (aged ≥61 years) subjects by analysing a combination of haemagglutinin inhibition (HI) and virus neutralisation (VN).MethodsSubjects (n = 1980) were recruited off season (2015/2016) from 20 centres in five European countries and randomised to receive either QIV (n = 1538), TIV with B-strain of the Victoria lineage (n = 221) or TIV with B-strain of the Yamagata lineage (n = 221). The primary aim was to demonstrate non-inferiority of QIV to TIV for immunogenicity against matched influenza strains based on post-vaccination HI titres. Secondary aims were to show superiority of QIV to TIV for immunogenicity against alternate-lineage B-strains and to characterise the immune response by reverse cumulative distribution (RCD) curves of antibody titres and derived serological parameters for HI and VN. Reactogenicity and occurrence of adverse events were assessed post-vaccination.ResultsQIV elicited a non-inferior immune response for matched strains (upper limit of 95% CI for HI geometric mean ratios [GMRs] <1.5) and a superior response for alternate-lineage B-strains (HI GMRs < 1; p < 0.0001) versus TIV. RCD curves demonstrated that post-vaccination HI and VN titres were higher for QIV versus TIV for both alternate-lineage B-strains. Seroconversion rates and geometric mean fold increases of the VN assay were consistent with the HI assay for all strains in QIV. Reporting rates of local and systemic reactions were similar in both vaccine groups.ConclusionsQIV was non-inferior in immunogenicity to TIV for matched strains and superior to the alternate-lineage B-strains in TIV. Safety and tolerability profiles of QIV and TIV were comparable.     

The effectiveness of trivalent inactivated influenza vaccine in children over six consecutive influenza seasons

Objective

To estimate the effectiveness of two doses of trivalent inactivated influenza vaccine (TIV) over six consecutive influenza seasons in a small community in Japan.

Patients and methods

A prospective, non-randomized, observational study of TIV effectiveness was performed involving children aged 6 months to 6 years accessing pediatric services in Soma and Shinchi, Japan. The total number of children under observation was 14,788. Each fall from 2002 to 2007 TIV was offered to all children with an average uptake of 52.9%. Influenza rapid diagnostic tests were performed to all children with respiratory symptoms and a temperature >38 °C during each surveillance period. The efficacy of two doses of TIV was estimated by the relative risk of influenza illness and influenza associated hospitalizations and effectiveness by reduction in all respiratory illness in vaccinated and unvaccinated children.

Results

Influenza A occurred each year resulting in approximately one in five children in the unvaccinated group having an influenza A related clinic visit. For influenza A, two doses of TIV showed yearly efficacies that ranged from 42% to 69% with the highest efficacy during the 2002/2003 influenza season when the vaccine strains were well matched with the circulating viruses. The overall efficacy of two doses of TIV against influenza A and B associated illness was 52% and 59%, respectively. TIV also reduced the rate of the influenza associated hospitalizations attributable to both influenza A and B.

Conclusions

Vaccination with two doses of TIV was consistently effective in preventing influenza-associated clinic visits and hospitalizations.     

Active-controlled phase III study of an egg-cultivated quadrivalent inactivated split-virion influenza vaccine (GC3110A) in healthy Korean children aged 6–35 months

The inactivated trivalent influenza vaccine (TIV) offers limited protection when two influenza B lineages co-circulate or when there is a vaccine mismatch (i.e., discordance in the predominant circulating B strain and WHO-recommended B strain). Inactivated quadrivalent influenza vaccine (QIV) may reduce the burden of influenza. Here, we report the results of a phase 3 clinical trial that evaluated the immunogenicity and safety of a novel QIV, GC3110A, in Korean children aged 6–35 months, which has been approved and is currently in use in Korea. The study involved two parts. In Part 1, the safety of GC3110A was evaluated in 10 subjects. After none of the subjects reported grade 3 adverse events (AEs), we proceeded to Part 2. Part 2 was a randomized, double-blind, multicenter phase 3 trial wherein we compared the immunogenicity and safety of GC3110A with those of a licensed control TIV. Immunogenicity was evaluated by measuring hemagglutination inhibition titers. The 200 participants enrolled in Part 2 were randomized in a 4:1 ratio to receive GC3110A or control TIV. The study vaccine group met both primary (i.e., the lower limit of 95% confidence interval [CI] of the seroconversion rate exceeds 40% for four strains) and secondary (i.e., the lower limit of 95% CI of the seroprotection rate exceeds 70% for four strains) immunogenicity endpoints. There was no significant between-group difference in the seroconversion rate, seroprotection rate, and geometric mean titer for the shared strains. However, the study vaccine group demonstrated significantly higher immunity for the additional strain B/Yamagata. In the safety analysis, there was no significant between-group difference in the proportion of participants with solicited local AEs, solicited systemic AEs, and unsolicited AEs. In conclusion, the results indicate that GC3110A has comparable immunogenicity and safety to those of TIV.Clinical Trial Registry Number: NCT03285997.     

Lineage-matched versus mismatched influenza B vaccine effectiveness following seasons of marginal influenza B circulation

BackgroundSeveral countries have recently transitioned from the trivalent inactivated influenza vaccine (TIV) to the quadrivalent inactivated influenza vaccine (QIV) in order to outweigh influenza B vaccine-mismatch. However, few studies thus far evaluated its benefits versus the TIV in a systematic manner. Our objective was to compare the QIV VE with lineage-mismatched TIV VE.MethodsWe estimated the 2015–2016, 2017–2018, 2019–2020 end-of season influenza B VE against laboratory-confirmed influenza-like illness (ILI) among community patients, using the test-negative design. VE was estimated for pre-determined age groups and for moving age intervals of 15 years.ResultsSince 2011–2012 season, alternate seasons in Israel were dominated by influenza B circulation. Compared with the lineage-mismatched TIV used during the 2015–2016 and 2017–2018 seasons, the 2019–2020 QIV showed the highest all-ages VE, with VE estimates of 56.9 (95% CI 30.1 to 73.4), 16.5 (95% CI –22.5 to 43.1) and ?25.8 (95% CI ?85.3 to 14.6) for the 2019–2020, 2017–2018 and 2015–2016 seasons, respectively. The 2019–2020 VE point estimated were the highest for the 0.5–4, 5–17 and 18–44 years age groups and for more 15-year age intervals as compared to the other seasons.ConclusionsOur results support the rapid transition from the TIV to the QIV.     

Association of HLA class II genes with clinical hyporesponsiveness to trivalent inactivated influenza vaccine in children

Background

The primary prevention measure for influenza infection has been the use of influenza vaccines. However, even when the vaccine and circulating strains are well-matched, some healthy children do not respond to the vaccine, likely due to a genetic basis for immune hyporesponsiveness. The primary objective of this study was to identify HLA class II genes associated with clinical hyporesponsiveness after trivalent inactivated influenza vaccine (TIV) in children.

Methods

We conducted a case–control study nested within a retrospective cohort of children that were screened at birth for HLA-DR,DQ genotypes by the Diabetes Autoimmunity Study in the Young (DAISY) and were subsequently followed for up to 8 years by Kaiser Permanente, Colorado (KPCO). Hyporesponsiveness was clinically defined as the occurrence of influenza or influenza-like illness (ILI) in peak influenza weeks in children fully vaccinated with TIV. Each child with clinical hyporesponse (n = 252) was matched to 4 randomly selected controls (n = 1006) by age and season. Children with clinical hyporesponse to TIV were identified using the Kaiser electronic clinical and immunization databases. Fully vaccinated children within the KPCO-DAISY cohort who did not have a diagnosis of ILI during the entire influenza season were eligible to be controls for that season. Class II HLA-DRB1 and HLA-DQB1 genes were the primary exposure variables. We used conditional logistic regression to calculate the matched odds ratios.

Results

In non-Hispanic white children, HLA-DR7/4,DQB1*0302 genotype was significantly associated (OR = 5.15; 95% CI = 1.94, 13.67; p = 0.001), while in Hispanic children, HLA-DRB1*15 or 16 allele (OR = 0.31; 95% CI = 0.14, 0.69; p = 0.004) and HLA-DR7/Y (DRB1*11, DRB1*13 and DRB1*14) genotype (OR = 5.84; 95% CI = 1.68, 20.28; p = 0.006) were significantly associated with clinical hyporesponsiveness after TIV.

Conclusions

HLA class II genes are associated with clinical hyporesponsiveness to TIV. This finding is important as it may help identify a group of children who are not protected by the commonly used TIV and may require alternative preventive strategies.     

Cost-effectiveness analysis of switching from a trivalent to a quadrivalent inactivated influenza vaccine in the Peruvian immunisation programme

BackgroundSeasonal influenza is an acute respiratory infection mostly caused by type A and B influenza viruses. The severe form of the infection can be life-threatening and lead to a significant burden. Vaccination is the most efficient way of preventing influenza infections and limit this burden.ObjectivesTo assess the cost-effectiveness of switching from a trivalent influenza vaccine (TIV) to a quadrivalent influenza vaccine (QIV) in the vaccination programme in Peru, and to evaluate the health and economic impact of reaching the vaccination coverage rate targeted by the Ministry of Health.MethodsA decision-analytic static cost-effectiveness model, was adapted to the Peruvian setting under both payer and societal perspectives.ResultsA switch from TIV to QIV would prevent 29,126 additional cases (including 12,815 consultations), 54 hospitalisations, and 23 deaths related to influenza, mostly in the population <2 years-old and >60 years-old. This would lead to a saving of US $505,206 under the payer perspective, that would partially offset the investment necessary to introduce QIV into the immunisation programme. The resulting incremental cost-effectiveness ratio (ICER) is $16,649 per QALYs gained. The main drivers of the model results were vaccine efficacy against influenza B viruses, degree of match, vaccines prices and proportion of cases attributable to influenza B. The robustness of the results seems satisfactory as QIV has the probability of being a cost-effective strategy of 83.8% (considering a threshold of three GDP per capita). Reaching the coverage targeted by the Ministry of Health would result in health benefits and disease management savings, and lower ICERs.ConclusionIntroducing QIV instead of TIV in the Peruvian immunisation programme is expected to be a cost-effective strategy, especially in younger children and the elderly. The benefit of QIV would be even more important if the coverage targeted by the Ministry of Health would be reached in the most vulnerable groups.     

Safety and immunogenicity of a modified process hepatitis B vaccine in healthy neonates

Background

A manufacturing process using a modified adjuvant was developed to optimize the consistency and immunogenicity for recombinant hepatitis B vaccine (control: RECOMBIVAX-HB™). This modified process hepatitis B vaccine (mpHBV), which was previously shown to have an acceptable safety and immunogenicity profile in young adults, has now been studied in newborn infants.

Methods

Healthy 1–10-day-old neonates (N = 566) received 3 intramuscular doses (5 μg hepatitis B surface antigen [HBsAg] per dose) of either mpHBV or control at Day 1, and Months 1 and 6. Serum antibody to HBsAg (anti-HBs) was assayed at Month 7 (1 month Postdose 3). Anti-HBs geometric mean titers (GMTs) and seroprotection rates (SPRs) (% of subjects with an anti-HBs titer ≥10 mIU/mL) were compared at Month 7. After each dose, injection-site adverse experiences (AEs) and axillary temperatures were recorded for 5 days; systemic AEs were recorded for Days 1–14.

Results

Month 7 SPR was 97.9% for the mpHBV group and 98.9% for the control. The GMT was 843.7 mIU/mL for the mpHBV group and 670.1 mIU/mL for the control. The GMT ratio (mpHBV/control) was 1.26 (95% confidence interval [CI]: 0.94, 1.69), meeting the prespecified non-inferiority criteria. The percentages of subjects reporting any AE, injection-site AEs, or systemic AEs were similar across the 2 vaccination groups. There were no serious AEs.

Conclusions

The safety profile of mpHBV was comparable to that of the control vaccine. The geometric mean antibody titer for mpHBV was higher than control vaccine in this infant population, but the difference did not meet the predefined statistical criterion for superiority.     

Comparison of the immunogenicity and safety of quadrivalent and tetravalent influenza vaccines in children and adolescents

BackgroundChildren and adolescents are susceptible to influenza. Vaccination is the most important strategy for preventing influenza, yet there are few studies on the immunogenicity and safety of quadrivalent inactivated influenza vaccine (QIV) containing two A strains (H1N1 and H3N2) and two B lineages (Victoria and Yamagata). Therefore, to further clarify the immunogenicity and safety of QIV in children and adolescents, a meta-analysis was performed to provide a reference for the development of influenza prevention strategies.MethodsPubMed, EMBASE and Cochrane Library were searched for articles published as of February 12, 2019. Random clinical trials comparing the immunogenicity and safety of QIV and TIV among children and adolescents were selected. The main outcomes were comparisons of immunogenicity (seroprotection rate [SPR] and seroconversion rate [SCR] and adverse events using risk ratios (RRs). The meta-analysis was performed using random-effects models.ResultsAmong the 6 months up to 3 years group, QIV showed a higher SPR for B lineages than for TIV-B/Yamagata, with pooled RRs of 3.07 (95% CI: 2.58–3.66) and 1.06 (95% CI: 1.01–1.11), respectively. For the 3 years through 18 years, QIV had a higher SCR and SPR for the Yamagata lineage than for TIV-B/Victoria, with pooled RRs of 2.30 (95% CI: 1.83–2.88) and 1.16 (95% CI: 1.03–1.30), respectively. Compared to TIV-B/Yamagata, a higher SCR and SPR for the Victoria lineage was found for QIV, with RRs of 3.09 (95% CI: 1.99–4.78) and 1.72 (95% CI: 1.22–2.41), respectively. Regarding adverse events, only pain was more frequently reported for QIV than TIV ; the RR was 1.09 (95% CI: 1.02–1.17).ConclusionsThe immunogenicity of QIV for common ingredients was similar to that of TIV, but the former exhibited significantly higher immunogenicity for the unique lineage. QIV also had the same reliable safety as TIV.     

Factors that may explain observed associations between trivalent influenza vaccination and gastrointestinal illness in young children

Background

Previously published studies reported an increased risk of gastrointestinal illness in the 14 days following trivalent influenza vaccination (TIV) in young children. While gastrointestinal illness may be a true adverse effect of TIV, other factors may influence this observed association, such as seasonal illness patterns and children being exposed to gastrointestinal pathogens at medical visits. The objective of this study was to examine factors influencing the association between TIV and gastrointestinal illness. Specifically, using data from a previous influenza vaccine safety study, we examined the association between medical encounters without TIV and gastrointestinal illness.

Methods

Using electronic health record (EHR) data from 6 managed care organizations (MCOs), we identified medically attended gastrointestinal illness cases among children 24–59 months in the 2002–2006 influenza seasons. We matched each case to four controls on sex, birthdate (month/year), MCO, influenza season, and presence of a chronic condition. We then looked 1–14 days prior to the index date (gastrointestinal illness diagnosis date) to determine whether the child had a medical encounter. We excluded previous medical encounters with gastrointestinal-related diagnoses or TIV. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals.

Results

We identified 2062 gastrointestinal illness cases and matched them to 8248 controls. We observed increased odds of gastrointestinal illness within 14 days after a medical encounter (odds ratio = 1.9; 95% confidence interval [CI]: 1.7–2.2) among children without chronic conditions. Among children with chronic conditions, the odds ratio was 3.9 (95% CI: 2.5–6.2).

Conclusions

We demonstrated that another exposure related to vaccination, medical visits, is also associated with increased odds for gastrointestinal illness. This study highlights challenges of interpreting results from observational vaccine safety studies when there are co-occurring exposures, and the importance of investigating confounding in EHR data, which are an essential resource for vaccine safety research.     

Safety and immunogenicity of a tetravalent dengue vaccine in healthy children aged 2–11 years in Malaysia: A randomized,placebo-controlled,Phase III study

Background

Dengue disease is a major public health problem across the Asia-Pacific region for which there is no licensed vaccine or treatment. We evaluated the safety and immunogenicity of Phase III lots of a candidate vaccine (CYD-TDV) in children in Malaysia.

Methods

In this observer-blind, placebo-controlled, Phase III study, children aged 2–11 years were randomized (4:1) to receive CYD-TDV or placebo at 0, 6 and 12 months. Primary endpoints included assessment of reactogenicity following each dose, adverse events (AEs) and serious AEs (SAEs) reported throughout the study, and immunogenicity expressed as geometric mean titres (GMTs) and distribution of dengue virus (DENV) neutralizing antibody titres.

Results

250 participants enrolled in the study (CYD-TDV: n = 199; placebo: n = 51). There was a trend for reactogenicity to be higher with CYD-TDV than with placebo post-dose 1 (75.4% versus 68.6%) and post-dose 2 (71.6% versus 62.0%) and slightly lower post-dose 3 (57.9% versus 64.0%). Unsolicited AEs declined in frequency with each subsequent dose and were similar overall between groups (CYD-TDV: 53.8%; placebo: 49.0%). Most AEs were of Grade 1 intensity and were transient. SAEs were reported by 5.5% and 11.8% of participants in the CYD-TDV and placebo groups, respectively. No deaths were reported. Baseline seropositivity against each of the four DENV serotypes was similar between groups, ranging from 24.0% (DENV-4) to 36.7% (DENV-3). In the CYD-TDV group, GMTs increased post-dose 2 for all serotypes compared with baseline, ranging from 4.8 (DENV-1) to 8.1-fold (DENV-3). GMTs further increased post-dose 3 for DENV-1 and DENV-2. Compared with baseline, individual titre increases ranged from 6.1-fold (DENV-1) to 7.96-fold (DENV-3).

Conclusions

This study demonstrated a satisfactory safety profile and a balanced humoral immune response against all four DENV serotypes for CYD-TDV administered via a three-dose regimen to children in Malaysia.     

Immune response after one or two doses of pandemic influenza A (H1N1) monovalent,AS03-adjuvanted vaccine in HIV infected adults

Introduction

Continued research is needed to evaluate and improve the immunogenicity of influenza vaccines in HIV infected patients. We aimed to determine the antibody responses after one or two doses of the AS03-adjuvanted pandemic influenza A (H1N1) vaccine in HIV infected patients.

Method

Following the influenza season 2009/2010, 219 HIV infected patients were included and divided into three groups depending on whether they received none (n = 60), one (n = 31) or two (n = 128) doses of pandemic influenza A (H1N1) vaccine. At inclusion, antibody titers for all patients were analyzed and compared to pre-pandemic antibody titers analyzed from serum samples in a local storage facility.

Results

4–9 months after a single immunization, we found a seroprotection rate of 77.4% and seroconversion rate of 67.7%. After two immunizations the rates increased significantly to seroprotection rate of 97.7% and seroconversion rate of 86.7%.

Conclusion

A single dose of AS03-adjuvanted pandemic influenza A (H1N1) vaccine created an adequate immune response in HIV infected patients lasting as long as 4–9 months. Two doses improved the immunogenicity further.