Relative Vaccine Efficacy Research Articles

Modelling the Relative Vaccine Efficacy of ARCT-154, a Self-Amplifying mRNA COVID-19 Vaccine, versus BNT162b2 Using Immunogenicity Data.

Background: Self-amplifying mRNA vaccines have the potential to increase the magnitude and duration of protection against COVID-19 by boosting neutralizing antibody titers and cellular responses. Methods: In this study, we used the immunogenicity data from a phase 3 randomized trial comparing the immunogenicity of ARCT-154, a self-amplifying mRNA COVID-19 vaccine, with BNT162b2 mRNA COVID-19 vaccine to estimate the relative vaccine efficacy (rVE) of the two vaccines over time in younger (<60 years) and older (≥60 years) adults. Results: By day 181 post-vaccination, the rVE against symptomatic and severe Wuhan-Hu-1 disease was 9.2-11.0% and 1.2-1.5%, respectively, across age groups whereas the rVE against symptomatic and severe Omicron BA.4/5 disease was 26.8-48.0% and 5.2-9.3%, respectively, across age groups. Sensitivity analysis showed that varying the threshold titer for 50% protection against severe disease up to 10% of convalescent sera revealed incremental benefits of ARCT-154 over BNT162b2, with an rVE of up to 28.0% against Omicron BA.4/5 in adults aged ≥60 year. Conclusions: Overall, the results of this study indicate that ARCT-154 elicits broader and more durable immunogenicity against SARS-CoV-2, translating to enhanced disease protection, particularly for older adults against Omicron BA.4/5.

Antibody Persistence and Risk of COVID-19 Infection: Insights from Modeling.

In this post hoc exploratory study of the APHP-COVIBOOST trial (NCT05124171), we used statistical modeling to describe the evolution of neutralizing antibody (nAb) titers over time, asses its impact on SARS-CoV-2 infection, and explore potential differences between three booster vaccine formulations (D614, B.1.351, and BNT162b2). Antibody titers were measured for 208 adult participants at day 28, 3 months, and 6 months using a microneutralization assay against different Omicron subvariants. We developed four specific Bayesian statistical models based on a core model, accounting for vaccine-specific antibody decline, boosting of nAb for breakthrough infection, and risk of infection according to nAb levels. The model findings were cross-verified using another validated microneutralization assay. The decrease in nAb titers was significantly lower for the B.1.351 vaccine than for the other booster formulations. An inverse relationship was found between risk of infection upon exposure and nAb levels. With Omicron BA.1 data, these results translated into a positive relative vaccine efficacy against any infection over 6 months for the B.1.351 vaccine compared to the BNT162b2 (31%) and D614 (21%) vaccines. Risk of infection decreased with increasing nAb titers for all vaccines. Statistical models predicted significantly better antibody persistence for the B.1.351 booster formulation compared to the other evaluated vaccines.

The safety, immunogenicity, and efficacy of heterologous boosting with a SARS-CoV-2 mRNA vaccine (SYS6006) in Chinese participants aged 18 years or more: a randomized, open-label, active-controlled phase 3 trial

ABSTRACT Continuous emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), enhanced transmissibility, significant immune escape, and waning immunity call for booster vaccination. We evaluated the safety, immunogenicity, and efficacy of heterologous booster with a SARS-CoV-2 mRNA vaccine SYS6006 versus an active control vaccine in a randomized, open-label, active-controlled phase 3 trial in healthy adults aged 18 years or more who had received two or three doses of SARS-CoV-2 inactivated vaccine in China. The trial started in December 2022 and lasted for 6 months. The participants were randomized (overall ratio: 3:1) to receive one dose of SYS6006 (N = 2999) or an ancestral receptor binding region-based, alum-adjuvanted recombinant protein SARS-CoV-2 vaccine (N = 1000), including 520 participants in an immunogenicity subgroup. SYS6006 boosting showed good safety profiles with most AEs being grade 1 or 2, and induced robust wild-type and Omicron BA.5 neutralizing antibody response on Days 14 and 28, demonstrating immunogenicity superiority versus the control vaccine and meeting the primary objective. The relative vaccine efficacy against COVID-19 of any severity was 51.6% (95% CI, 35.5–63.7) for any variant, 66.8% (48.6–78.5) for BA.5, and 37.7% (2.4–60.3) for XBB, from Day 7 through Month 6. In the vaccinated and infected hybrid immune participants, the relative vaccine efficacy was 68.4% (31.1–85.5) against COVID-19 of any severity caused by a second infection. All COVID-19 cases were mild. SYS6006 heterologous boosting demonstrated good safety, superior immunogenicity and high efficacy against BA.5-associated COVID-19, and protected against XBB-associated COVID-19, particularly in the hybrid immune population. Trial registration: Chinese Clinical Trial Registry: ChiCTR2200066941

Safety, immunogenicity, and efficacy of a modified COVID-19 mRNA vaccine, SW-BIC-213, in healthy people aged 18 years and above: a phase 3 double-blinded, randomized, parallel controlled clinical trial in Lao PDR (Laos)

The mRNA vaccine has demonstrated significant effectiveness in protecting against SARS-CoV-2 during the pandemic, including against severe forms of the disease caused by emerging variants. In this study, we examined safety, immunogenicity, and relative efficacy of a heterologous booster of the lipopolyplex (LPP)-based mRNA vaccine (SW-BIC-213) versus a homologous booster of an inactivated vaccine (BBIBP) in Laos. In this phase 3 clinical trial, which was randomized, parallel controlled and double-blinded, healthy adults aged 18 years and above were recruited from the Southern Savannakhet Provincial Hospital and Champhone District Hospital. The primary outcomes were safety and immunogenicity, with efficacy as an exploratory endpoint. Participants who were fully immunized with a two-dose inactivated vaccine for more than 6 months were assigned equally to either the SW-BIC-213 group (25μg) or BBIBP group. The primary safety endpoint was to describe the safety profile of all participants in each group up to 6 months post-booster immunization. The primary immunogenic outcome was to demonstrate the superiority of the neutralizing antibody response, in terms of geometric mean titers (GMTs) of SW-BIC-213, compared with BBIBP 28 days after the booster dose. The exploratory efficacy endpoint aimed to assess the relative efficacy of SW-BIC-213 compared to BBIBP against virologically confirmed symptomatic COVID-19 over a 6-month period. The trial was registered with ClinicalTrials.gov (NCT05580159). Between October 10, 2022, and January 13, 2023, 1200 participants were assigned to SW-BIC-213 group and 1203 participants in the BBIBP group. All adverse reactions observed during the study were tolerable, transient, and resolved spontaneously. Solicited local reactions were the main adverse reactions in both the SW-BIC-213 group (43.8%) and BBIBP group (14.8%) (p<0.001). Heterologous boosting with SW-BIC-213 induced higher live virus neutralizing antibodies to SARS-CoV-2 wildtype and BA.5 strains with GMTs reaching 750.1 and 192.9 than homologous boosting with BBIBP with GMTs of 131.5 (p<0.001) and 47.5 (p<0.001) on day 29. The statistical findings revealed that, following a period of 14-day to 6-month after booster vaccination, the SW-BIC-213 group exhibited a relative vaccine efficacy (VE) of 70.1% (95% CI: 34.2-86.4) against symptomatic COVID-19 when compared to the BBIBP group. A heterologous booster with the COVID-19 mRNA vaccine SW-BIC-213 manifests a favorable safety profile and proves highly immunogenic and efficacious in preventing symptomatic COVID-19 in individuals who have previously received two doses of inactivated vaccine. Shanghai Strategic Emerging Industries Development Special Fund, Biomedical Technology Support Special Project of Shanghai "Science and Technology Innovation Action Plan", Shanghai Municipal Science and Technology Commission.

Cost-effectiveness of influenza vaccination with a high dose quadrivalent vaccine of the elderly population in Belgium, Finland, and Portugal

BackgroundSeasonal influenza may result in severe outcomes, resulting in a significant increase of hospitalizations during the winter. To improve the protection provided by the standard dose influenza quadrivalent vaccine (SDQIV), a high-dose vaccine (HDQIV) has been developed specifically for adults aged 60 and older who are at higher risk of life-threatening complications,ObjectivesThe aim of this study was to determine the cost-effectiveness of HD QIV vs. SD-QIV in the recommended population of three European countries: Belgium, Finland and Portugal.MethodsA cost-utility analysis comparing HDQIV vs. SDQIV was conducted using a decision tree estimating health outcomes conditional on influenza: cases, general practitioner and emergency department visits, hospitalizations and deaths. To account for the full benefit of the vaccine, an additional outcome—hospitalizations attributable to influenza—was also evaluated. Demographic, epidemiological and economic inputs were based on the respective local data. HDQIV relative vaccine efficacy vs. SDQIV was obtained from a phase IV efficacy randomized clinical trial. The incremental cost-effectiveness ratios (ICER) were computed for each country, and a probabilistic sensitivity analysis (1,000 simulations per country) was performed to assess the robustness of the results.ResultsIn the base case analysis, HDQIV resulted in improved health outcomes (visits, hospitalizations, and deaths) compared to SDQIV. The ICERs computed were 1,397, 9,581, and 15,267 €/QALY, whereas the PSA yielded 100, 100, and 84% of simulations being cost-effective at their respective willingness-to-pay thresholds, for Belgium, Finland, and Portugal, respectively.ConclusionIn three European countries with different healthcare systems, HD-QIV would contribute to a significant improvement in the prevention of influenza health outcomes while being cost-effective.

Efficacy, effectiveness, and safety of herpes zoster vaccine in the immunocompetent and immunocompromised subjects: A systematic review and network meta-analysis.

ObjectiveTo investigate the efficacy, effectiveness and safety of recombinant zoster vaccine (RZV) and zoster vaccine live (ZVL) in immunocompetent and immunocompromised subjects.MethodsData sources: PubMed, EMBASE, Cochrane Library, and Web of Science databases (up to Jan 2022) were searched to identify English articles. Search terms included randomized controlled trials (RCTs), observational studies, herpes zoster, RZV, ZVL. Study Selection: Only randomized controlled trials (RCTs) evaluating vaccine efficacy and safety and observational studies assessing vaccine effectiveness (after a vaccine was approved for marketing) were included. Data Extraction: Two researchers independently screened the literature, extracted the data, and checked the each other results.ResultsSeventeen RCTs and 19 cohort studies were included. Among immunocompetent subjects, RZV was superior to ZVL at wide intervals (relative vaccine efficacy: 84%, 95% CI: 53%–95%; relative vaccine effectiveness: 49%, 95% CI: 21%–67%), across genders and subjects aged ≥ 60 years. Among immunocompromised subjects, RZV was superior to placebo in terms of vaccine efficacy (60%, 95% CI: 49%–69%). There was no difference between ZVL and placebo in those with selected immunosuppressive conditions. RZV was 45% (95% CI: 30%–59%) superior to ZVL in real-world practice. Compared with placebo, adverse events related to RZV were primarily related to injection-site and systemic, and RZV did not increase the risk of serious adverse events (SAEs) or death. There was no difference in the incidence of adverse events between groups with and without immunosuppression.ConclusionsBoth RZV and ZVL can reduce the risk of herpes zoster in both immunocompetent and immunocompromised subjects. RZV was well-tolerated in the study population and demonstrated stronger protection than ZVL.Systematic review registrationProspero CRD42022310495.

Safety and Efficacy of a Third Dose of BNT162b2 Covid-19 Vaccine

BackgroundActive immunization with the BNT162b2 vaccine (Pfizer–BioNTech) has been a critical mitigation tool against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the coronavirus disease 2019 (Covid-19) pandemic. In light of reports of waning protection occurring 6 months after the primary two-dose vaccine series, data are needed on the safety and efficacy of offering a third (booster) dose in persons 16 years of age or older.MethodsIn this ongoing, placebo-controlled, randomized, phase 3 trial, we assigned participants who had received two 30-μg doses of the BNT162b2 vaccine at least 6 months earlier to be injected with a third dose of the BNT162b2 vaccine or with placebo. We assessed vaccine safety and efficacy against Covid-19 starting 7 days after the third dose.ResultsA total of 5081 participants received a third BNT162b2 dose and 5044 received placebo. The median interval between dose 2 and dose 3 was 10.8 months in the vaccine group and 10.7 months in the placebo group; the median follow-up was 2.5 months. Local and systemic reactogenicity events from the third dose were generally of low grade. No new safety signals were identified, and no cases of myocarditis or pericarditis were reported. Among the participants without evidence of previous SARS-CoV-2 infection who could be evaluated, Covid-19 with onset at least 7 days after dose 3 was observed in 6 participants in the vaccine group and in 123 participants in the placebo group, which corresponded to a relative vaccine efficacy of 95.3% (95% confidence interval, 89.5 to 98.3).ConclusionsA third dose of the BNT162b2 vaccine administered a median of 10.8 months after the second dose provided 95.3% efficacy against Covid-19 as compared with two doses of the BNT162b2 vaccine during a median follow-up of 2.5 months. (Funded by BioNTech and Pfizer; C4591031 ClinicalTrials.gov number, NCT04955626.)

Systematic review of the efficacy, effectiveness and safety ofhigh-dose seasonal influenza vaccines for the preventionof laboratory-confirmed influenza in individuals ≥18years of age.

This review sought to assess the efficacy, effectiveness and safety of high-dose inactivated influenza vaccines (HD-IIV) for the prevention of laboratory-confirmed influenza in individuals aged 18years or older. A systematic literature search was conducted in electronic databases and grey literature sources up to 7 February 2020. Randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSIs) were included. The search returned 28,846 records, of which 36 studies were included. HD-IIV was shown to have higher relative vaccine efficacy in preventing influenza compared with standard-dose influenza vaccines (SD-IIV3) in older adults (Vaccine effectiveness (VE)=24%, 95% CI 10-37, one RCT). One NRSI demonstrated significant effect for HD-IIV3 against influenza B (VE=89%, 95% CI 47-100), but not for influenza A(H3N2) (VE=22%, 95% CI -82 to 66) when compared with no vaccination in older adults. HD-IIV3 showed significant relative effect compared with SD-IIV3 for influenza-related hospitalisation (VE=11.8%, 95% CI 6.4-17.0, two NRSIs), influenza- or pneumonia-related hospitalisation (VE=13.7%, 95% CI 9.5-17.7, three NRSIs), influenza-related hospital encounters (VE=13.1%, 95% CI 8.4-17.7, five NRSIs), and influenza-related office visits (VE=3.5%, 95% CI 1.5-5.5, two NRSIs). For safety, HD-IIV were associated with significantly higher rates of local and systemic adverse events compared with SD-IIV (combined local reactions, pain at injection site, swelling, induration, headache, chills and malaise). From limited data, compared with SD-IIV, HD-IIV were found to be more effective in the prevention of laboratory-confirmed influenza, for a range of proxy outcome measures, and associated with more adverse events.

Vaccination and herd immunity thresholds in heterogeneous populations.

It has been suggested, without rigorous mathematical analysis, that the classical vaccine-induced herd immunity threshold (HIT) assuming a homogeneous population can be substantially higher than the minimum HIT obtained when considering population heterogeneities. We investigated this claim by developing, and rigorously analyzing, a vaccination model that incorporates various forms of heterogeneity and compared it with a model that considers a homogeneous population. By employing a two-group vaccination model in heterogeneous populations, we theoretically established conditions under which heterogeneity leads to different HIT values, depending on the relative values of the contact rates for each group, the type of mixing between the groups, the relative vaccine efficacy, and the relative population size of each group. For example, under biased random mixing assumption and when vaccinating a given group results in disproportionate prevention of higher transmission per capita, we show that it is optimal to vaccinate that group before vaccinating the other groups. We also found situations, under biased assortative mixing assumption, where it is optimal to vaccinate more than one group. We show that regardless of the form of mixing between the groups, the HIT values assuming a heterogeneous population are always lower than the HIT values obtained from a corresponding model with a homogeneous population. Using realistic numerical examples and parametrization (e.g., assuming assortative mixing together with vaccine efficacy of 95% and the value of the basic reproduction number, {mathcal{R}}_{0}, of the model set at {mathcal{R}}_{0}= 2.5), we demonstrate that the HIT value generated from a model that considers population heterogeneity (e.g., biased assortative mixing) is significantly lower (40%) compared with a HIT value of 63% obtained if the model uses homogeneous population.

Estimating public health and economic benefits along 10 years of Fluzone® High Dose in the United States

ObjectiveThe objective of this study was to estimate the public health and economic benefits (from a Medicare perspective) of Fluzone High-Dose® in the US elderly population, since its introduction in 2010. MethodsA budget impact model was developed using a decision tree framework and applied over 9 influenza seasons (2010/11 to 2018/19). The decision tree model was designed to capture influenza cases, hospitalizations possibly related to influenza or laboratory confirmed influenza, and influenza-related deaths. The analysis included influenza vaccines recommended by ACIP since 2010: SD TIV (trivalent), SD QIV (quadrivalent), HD TIV, aTIV (adjuvanted), ccQIV (cell-cultured). Two strategies were compared to evaluate the impact of HD TIV: a ‘with HD TIV’ strategy representative of the US vaccine landscape, and a ‘without HD TIV’ where the absence of HD TIV was modelled. Clinical and economic inputs were based on public US data from the CDC and national databases, while data on vaccine effectiveness were extracted from published literature and clinical trials. The impact of HD TIV was further explored in five scenario analyses and deterministic sensitivity analyses (DSA). ResultsOver 10 years, it is estimated that HD TIV resulted in an averted 1,333,479 influenza cases, 769,476 medical visits, 40,004 ED presentations, 520,342 cardiorespiratory hospitalizations and 73,689 deaths and generated an absolute $4.6 billion in savings, translating into a return on investment of 214.4%. Hospitalizations costs represented 98.4% and 98.3% of the management costs in the ‘with HD TIV’ strategy and ‘without HD TIV’ strategy respectively. Hospitalizations and HD TIV relative vaccine efficacy vs SD TIV as a major cost driver were further confirmed in scenario analysis and DSA. HD TIV remained cost saving under all the scenarios. ConclusionThe model showed that HD TIV higher efficacy translated into increased averted health and economic outcomes. HD TIV represented a cost saving intervention from a payer perspective since its introduction.

PIN60 Cost-Effectiveness of Quadrivalent Influenza Vaccine High Dose Versus Adjuvanted Standard Dose Trivalent Influenza Vaccine in England

Influenza is recognised as an important cause of morbidity and mortality in human populations, resulting in an average of over 21,000 influenza-associated deaths each year in England alone, with 85% of influenza-associated deaths in those over the age of 65. Quadrivalent Influenza Vaccine High-Dose (QIV-HD) has been specifically developed for the over 65 population, containing 4-times more antigen than current standard dose (SD) vaccines. The objective of this study is to estimate the cost-effectiveness of QIV-HD compared to adjuvant Trivalent Influenza Vaccine (aTIV) using clinically relevant endpoints. A static decision tree model was used to compare influenza cases, GP consultations, hospitalisations, and deaths resulting from influenza complications. Due to a sparsity of trial-based evidence and heterogeneous findings from observational studies for aTIV, three different relative vaccine efficacy scenarios were investigated for QIV-HD versus aTIV. In addition, cost-effectiveness was assessed for QIV-HD versus aTIV for a base case analysis in which hospitalisations were defined as due to influenza/pneumonia. Discounted QALY losses were included for hospitalisations and in-hospital deaths. Analyses were conducted from a UK healthcare system perspective over a one-year time horizon. Base case results, with hospitalisation defined as influenza/pneumonia events, indicate that QIV-HD would be considered a cost-neutral vaccination strategy (ICER: £824/QALY), considerably below the £20,000 willingness to pay threshold, delivering superior health outcomes in the over 65 population compared with the current approach using aTIV. When broader definitions of hospitalisations were considered, QIV-HD was shown to be the dominant vaccination strategy compared to aTIV across most scenarios assuming various vaccine efficacy inputs for aTIV for both lab-confirmed influenza cases and hospitalisations. QIV-HD could be a highly cost-effective, and in some cases dominant, alternative to aTIV in England and could reduce the annual public health burden of influenza-related complications.

Efficacy, immunogenicity, and safety of a plant-derived, quadrivalent, virus-like particle influenza vaccine in adults (18–64 years) and older adults (≥65 years): two multicentre, randomised phase 3 trials

Seasonal influenza remains a substantial public health threat despite the availability of egg-derived and other vaccines. Plant-based manufacturing might address some of the limitations of current vaccines. We describe two phase 3 efficacy studies of a recombinant quadrivalent virus-like particle (QVLP) influenza vaccine manufactured in plants, one in adults aged 18-64 years (the 18-64 study) and one in older people aged 65 years and older (the 65-plus study). We did two randomised, observer-blind, multinational studies in the northern hemisphere in the 2017-18 (the 18-64 study) and 2018-19 (the 65-plus study) influenza seasons. The 18-64 study was done at 73 sites and the 65-plus study was done at 104 sites, both across Asia, Europe, and North America. In the 18-64 study, inclusion criteria were body-mass index less than 40 kg/m2; age 18-64 years at screening visit; and good health. In the 65-plus study, inclusion criteria were body-mass index of maximum 35 kg/m2; aged 65 years or older at screening visit; not living in a rehabilitation centre or care home; and no acute or evolving medical problems. Participants in the 18-64 study were randomly assigned (1:1) to receive either QVLP vaccine (30 μg haemagglutinin per strain) or placebo. Participants in the 65-plus study were randomly assigned (1:1) to receive QVLP vaccine (30 μg haemagglutinin per strain) or quadrivalent inactivated vaccine (QIV; 15 μg haemagglutinin per strain). The primary outcome in the 18-64 study was absolute vaccine efficacy to prevent laboratory-confirmed, respiratory illness caused by antigenically matched influenza strains. The primary outcome in the 65-plus study was relative vaccine efficacy to prevent laboratory-confirmed influenza-like illness caused by any influenza strain. The primary analyses were done in the per-protocol population and safety was assessed in all participants who received the assigned treatment. These studies are registered with ClinicalTrials.gov (18-64 study NCT03301051; 65-plus study NCT03739112). In the 18-64 study, between Aug 30, 2017, and Jan 15, 2018, 10 160 participants were randomly assigned to receive either QVLP vaccine (5077 participants) or placebo (5083 participants). The per-protocol population consisted of 4814 participants in the QVLP group and 4812 in the placebo group. The study did not meet its primary endpoint of 70% absolute vaccine efficacy for the QVLP vaccine (35·1% [95% CI 17·9 to 48·7]) against respiratory illness caused by matched strains. 55 (1·1%) of 5064 participants in the QVLP group versus 51 (1·0%) of 5072 in the placebo group had a serious adverse event. Four (0·1%) and six [0·1%] participants had severe treatment-related treatment-emergent adverse events. In the 65-plus study, between Sept 18, 2018, and Feb 22, 2019, 12 794 participants were randomly assigned to receive either QVLP vaccine (6396 participants) or QIV (6398 participants). The per-protocol population consisted of 5996 participants in the QVLP group and 6026 in the QIV group. The study met its primary non-inferiority endpoint with a relative vaccine efficacy of the QVLP vaccine for the prevention of influenza-like illness caused by any strain of 8·8% (-16·7 to 28·7). 263 (4·1%) of 6352 participants in the QVLP group versus 266 (4·2%) of 6366 in the QIV group had serious adverse events (one [<0·1%] vs two [<0·1%] were considered treatment-related); one (<0·1%) versus three (<0·1%) participants had severe treatment-related treatment-emergent adverse events. These efficacy studies are the first large-scale studies of any plant-derived human vaccine. Together, they show that the plant-derived QVLP vaccine can provide substantial protection against respiratory illness and influenza-like illness caused by influenza viruses in adults. QVLP vaccine was well tolerated and no major safety signal arose in participants who received QVLP vaccine across the two studies. Medicago.

PIN30 - AN ECONOMIC MODEL TO ESTIMATE THE COST-EFFECTIVENESS OF TRIVALENT INFLUENZA VACCINE HIGH DOSE FOR THE ELDERLY POPULATION IN ENGLAND AND WALES

A large RCT (FIM12) and several real world studies have shown trivalent influenza vaccine high dose (TIV HD) to be more effective than standard dose trivalent influenza vaccine (SD) in terms of reducing influenza cases and hospitalisations, including serious cardio-respiratory events (CREs), in the elderly population. The aim of this study was to estimate the public health and economic impact of switching from SD to TIV HD for adults aged ≥65 years in England and Wales using econometric modelling. An age-structured decision tree model comparing multiple vaccination strategies was designed in Microsoft Excel. Model outcomes included influenza cases, influenza-related GP consultations, hospitalisations, and deaths. Two alternative hospitalisation definitions were used; respiratory hospitalisations attributable to influenza, and CREs (possibly attributable to influenza). All analyses were conducted from the UK healthcare system perspective. The model was populated with FIM12 clinical trial data and demographic, epidemiological, and economic inputs appropriate to the UK setting. Deterministic sensitivity analysis (DSA) was performed to assess the robustness of results. In England and Wales, switching from SD to TIV HD (in adults aged ≥65 years) was associated with a reduction of 75,000 cases of confirmed influenza, 19,000 influenza-related hospitalisations, and 4,000 deaths, in an average influenza season. Using thresholds of £20,000 and £30,000/QALY, TIV HD was estimated to be cost-effective at £23.75 and £30.70 per dose, respectively. The cost-effective price at £20,000/QALY increased to £115.15 when accounting for the vaccination effect in reducing CREs. DSA showed that these results were most sensitive to relative vaccine efficacy against influenza hospitalisations whereas the remaining parameters had a low impact on model outcomes. The results suggest that the inclusion of TIV HD on the influenza vaccination schedule has the potential to be a highly cost-effective intervention for the UK healthcare system and would contribute positively to improving public health goals.

Efficacy and effectiveness of high-dose versus standard-dose influenza vaccination for older adults: a systematic review and meta-analysis

ABSTRACTBackground: Influenza is responsible for a significant disease burden annually, especially in older adults. This study reviews the relative vaccine efficacy or effectiveness (rVE) of high-dose inactivated trivalent influenza vaccine (HD-IIV3) compared to standard-dose influenza vaccines (SD-IIV3) in adults ≥65 against influenza-associated outcomes to inform evidence-based decision-making to shift clinical practice and standard of care in this population.Methods: A systematic review was conducted for studies assessing the rVE of HD-IIV3 against probable/laboratory-confirmed influenza-like illness (ILI), hospital admissions, and death in adults ≥65. Results from individual seasons were meta-analyzed and a random-effects model was used to estimate pooled rVEs.Results: After screening 992 studies, seven studies were meta-analyzed. HD-IIV3 demonstrated better protection against ILI compared to SD-IIV3 (rVE = 19.5%; 95% CI: 8.6–29.0%). HD-IIV3 was also more effective at preventing hospital admissions from all-causes (rVE = 9.1%; 95% CI: 2.4–15.3%), as well as from influenza (rVE = 17.8%; 95% CI: 8.1–26.5%), pneumonia (rVE = 24.3%, 95% CI: 13.9–33.4%), and cardiorespiratory events (rVE = 18.2%; 95% CI: 6.8–28.1%). rVE against post-influenza mortality was 22.2% (95% CI: -18.2–48.8%) and 2.5% (95% CI: -5.2–9.5%) against all-cause mortality.Conclusions: Available evidence suggests HD-IIV3 is more effective than SD-IIV3 at reducing the clinical outcomes associated with influenza infection in older adults and should be considered for routine use in the 65+ population.

Efficacy, immunogenicity, and safety evaluation of an MF59-adjuvanted quadrivalent influenza virus vaccine compared with non-adjuvanted influenza vaccine in children: a multicentre, randomised controlled, observer-blinded, phase 3 trial

Young children have immature immune systems and respond poorly to standard influenza vaccines. The oil-in-water emulsion adjuvant MF59 can increase antigen uptake, macrophage recruitment, lymph node migration, and avidity to influenza virus. Therefore, we aimed to assess the relative efficacy, immunogenicity, and safety of an MF59-adjuvanted, quadrivalent, inactivated (subunit) influenza vaccine (aIIV4) compared with a US-licensed non-adjuvanted influenza vaccine in children. We did a multicentre, randomised controlled, observer-blinded, phase 3 trial of 146 sites including hospitals, clinics, and clinician offices in nine countries over two influenza seasons. We included children of either sex aged 6 months through 5 years. We stratified eligible participants and randomly assigned them (1:1), using a block size of four, to receive either aIIV4 or non-adjuvanted inactivated influenza vaccine (ie, trivalent inactivated influenza vaccine [IIV3] or quadrivalent inactivated influenza vaccine [IIV4]). We masked participants, parents or guardians, and outcome assessors to the administered vaccine. Designated personnel who were not masked administered aIIV4 in both seasons, or IIV3 in season one and IIV4 in season two. All vaccinations were administered intramuscularly. Children aged 6 through 35 months received one or two 0·25 mL doses, whereas those aged 3 through 5 years received one or two doses of 0·5 mL. The number of doses was dependent on previous vaccination status: vaccine-naive participants received a total of two doses of study vaccine, the first on day 1 and the second on day 29, whereas non-naive participants received only one dose on day 1. The primary outcome was relative vaccine efficacy assessed by RT-PCR-confirmed influenza due to any influenza strain in the overall study population and in prespecified age and dose subgroups. Immunogenicity against homologous and heterologous strains of influenza and safety were also measured. This study is registered with ClinicalTrials.gov, number NCT01964989. Between Nov 3, 2013, and March 5, 2014 (season one), and between Sept 30, 2014, and March 29, 2015 (season two), 10 644 participants were enrolled in this study. Of these participants, 10 612 were vaccinated (n=5338 with aIIV4 and n=5274 with comparator). Relative vaccine efficacy was not different between aIIV4 and the comparator vaccines in the overall study population (relative vaccine efficacy -0·67, 95% CI -19·81 to 15·41). The relative vaccine efficacy in the 6 through 23-month subgroup was significantly greater for aIIV4 than for the comparator vaccine (relative vaccine efficacy 31·37, 95% CI 3·14-51·38). aIIV4 elicited superior immunogenic response compared with the comparator for all four vaccine strains (geometric mean titre ratios 1·91 [95% CI 1·8-2·0] for A/H1N1, 1·71 [1·6-1·8] for A/H3N2, 2·19 [2·0-2·4] for B/Yamagata, and 2·27 [2·0-2·6] for B/Victoria) and three heterologous strains (1·94 [1·6-2·3] for A/H3N2, 2·17 [1·8-2·6] for B/Yamagata, and 2·12 [1·6-2·7] for B/Victoria) in participants aged 6 months through 5 years. The highest geometric mean titre ratios were observed in participants aged 6 through 23 months. Safety profiles were similar but more frequent solicited adverse events were reported with aIIV4 than with the comparator (3748 [73%] of 5138 vs 3242 [64%] of 5056). Although there was no additional benefit of aIIV4 compared with the US-licensed non-adjuvanted influenza vaccines in the overall study population, in the youngest and most vulnerable population of children in this trial, aIIV4 provided greater protection against influenza than a non-adjuvanted vaccine when assessed in this prespecified age group of 6 through 23 months. Additional clinical benefit was also apparent early after first vaccination in vaccine-naive participants aged 6 months through 5 years. Finally, aIIV4 and comparator had similar efficacy and vaccine safety profiles in children aged 6 months through 5 years. Seqirus UK Ltd.

Influenza vaccine efficacy trials: a simulation approach to understand failures from the past.

The success of a seasonal influenza vaccine efficacy trial depends not only upon the design but also upon the annual epidemic characteristics. In this context, simulation methods are an essential tool in evaluating the performances of study designs under various circumstances. However, traditional methods for simulating time-to-event data are not suitable for the simulation of influenza vaccine efficacy trials because of the seasonality and heterogeneity of influenza epidemics. Instead, we propose a mathematical model parameterized with historical surveillance data, heterogeneous frailty among the subjects, survey-based heterogeneous number of daily contact, and a mixed vaccine protection mechanism. We illustrate our methodology by generating multiple-trial data similar to a large phase III trial that failed to show additional relative vaccine efficacy of an experimental adjuvanted vaccine compared with the reference vaccine. We show that small departures from the designing assumptions, such as a smaller range of strain protection for the experimental vaccine or the chosen endpoint, could lead to smaller probabilities of success in showing significant relative vaccine efficacy.

Cost-effectiveness of seasonal influenza vaccination in pregnant women, health care workers and persons with underlying illnesses in Belgium

Risk groups with increased vulnerability for influenza complications such as pregnant women, persons with underlying illnesses as well as persons who come into contact with them, such as health care workers, are currently given priority (along with other classic target groups) to receive seasonal influenza vaccination in Belgium. We aimed to evaluate this policy from a health care payer perspective by cost-effectiveness analysis in the three specific target groups above, while accounting for effects beyond the target group. Increasing the coverage of influenza vaccination is likely to be cost-effective for pregnant women (median €6589 per quality-adjusted life-year (QALY) gained [€4073–€10,249]) and health care workers (median €24,096/QALY gained [€16,442–€36,342]), if this can be achieved without incurring additional administration costs. Assuming an additional physician's consult is charged to administer each additional vaccine dose, the cost-effectiveness of vaccinating pregnant women depends strongly on the extent of its impact on the neonate's health. For health care workers, the assumed number of preventable secondary infections has a strong influence on the cost-effectiveness. Vaccinating people with underlying illnesses is likely highly cost-effective above 50 years of age and borderline cost-effective for younger persons, depending on relative life expectancy and vaccine efficacy in this risk group compared to the general population. The case-fatality ratios of the target group, of the secondary affected groups and vaccine efficacy are key sources of uncertainty.

Influenza symptoms and their impact on elderly adults: randomised trial of AS03‐adjuvanted or non‐adjuvanted inactivated trivalent seasonal influenza vaccines

BackgroundPatient-reported outcomes (PROs) are particularly relevant in influenza vaccine trials in the elderly where reduction in symptom severity could prevent illness-related functional impairment.ObjectivesTo evaluate PROs in people aged ≥65 years receiving two different vaccines.MethodsThis was a phase III, randomised, observer-blind study (NCT00753272) of the AS03-adjuvanted inactivated trivalent split-virion influenza vaccine (AS03-TIV) versus non-adjuvanted vaccine (TIV). Using the FluiiQ questionnaire, symptom (systemic, respiratory, total) and life impact (activities, emotions, relationships) scores were computed as exploratory endpoints, with minimal important difference (MID) in influenza severity between vaccines considered post-hoc as >7%. Vaccine efficacy of AS03-TIV relative to TIV in severe influenza (hospitalisation, complication, most severe one-third of episodes based on the area under the curve for systemic symptom score) was calculated post-hoc. The main analyses (descriptive) were conducted in the according-to-protocol cohort (n = 280 AS03-TIV, n = 315 TIV) for influenza confirmed by culture or reverse transcriptase polymerase chain reaction.ResultsMean systemic symptom, total symptom and impact on activities scores were lower with AS03-TIV versus TIV. Mean respiratory symptom, impact on emotions and impact on relationships scores were similar. Influenza tended to be less severe with AS03-TIV, but the MID was reached only for impact on activities (mean 9·0%). Relative vaccine efficacy in severe influenza was 29·38% (95% CI: 7·60–46·02).ConclusionsAS03-TIV had advantages over TIV in impact on systemic symptoms and activities as measured by the FluiiQ in elderly people. Higher efficacy of AS03-TIV relative to TIV was shown for prevention of severe illness.

Cost-effectiveness of live attenuated influenza vaccine versus inactivated influenza vaccine among children aged 24–59 months in the United States

Background The US Advisory Committee on Immunization Practices (ACIP) recently expanded the influenza vaccine recommendation to include children 24–59 months of age. In a large head-to-head randomized controlled trial, live attenuated influenza vaccine, trivalent (LAIV) demonstrated a 54% relative reduction in culture-confirmed influenza illness compared with trivalent inactivated influenza vaccine (TIV) among children aged 24–59 months. Objective To evaluate the relative cost and benefit between two influenza vaccines (LAIV and TIV) for healthy children 24–59 months of age. Methods Using patient-level data from the clinical trial supplemented with cost data from published literature, we modeled the cost-effectiveness of these two vaccines. Effectiveness was measured in quality-adjusted life years (QALY) and cases of influenza avoided. The analysis used the societal perspective. Results Due to its higher acquisition cost, LAIV increased vaccination costs by $7.72 per child compared with TIV. However, compared with TIV, LAIV reduced the number of influenza illness cases and lowered the subsequent healthcare use of children and productivity losses of parents. The estimated offsets in direct and indirect costs saved $15.80 and $37.72 per vaccinated child, respectively. LAIV had a net total cost savings of $45.80 per child relative to TIV. One-way and probabilistic sensitivity analyses indicated that the model was robust across a wide range of relative vaccine efficacy and cost estimates. Conclusions Due to its increased relative vaccine efficacy over TIV, LAIV reduced the burden of influenza and lowered both direct health care and societal costs among children 24–59 months of age.

Capture-recapture method for estimating misclassification errors: application to the measurement of vaccine efficacy in randomized controlled trials.

The measure of efficacy is optimally performed by randomized controlled trials. However, low specificity of the judgement criteria is known to bias toward lower estimation, while low sensitivity increases the required sample size. A common technique for ensuring good specificity without a drop in sensitivity is to use several diagnostic tests in parallel, with each of them being specific. This approach is similar to the more general situation of case-counting from multiple data sources, and this paper explores the application of the capture-recapture method for the analysis of the estimates of efficacy. An illustration of this application is derived from a study on the efficacy of pertussis vaccines where the outcome was based on > or =21 days of cough confirmed by at least one of three criteria performed independently for each subject: bacteriology, serology, or epidemiological link. Log-linear methods were applied to these data considered as three sources of information. The best model considered the three simple effects and an interaction term between bacteriology and epidemiological linkage. Among the 801 children experiencing > or =21 days of cough, it was estimated that 93 cases were missed, leading to a corrected total of 413 confirmed cases. The relative vaccine efficacy estimated from the same model was 1.50 (95% confidence interval: 1.24-1.82), similar to the crude estimate of 1.59 and confirming better protection afforded by one of the two vaccines. This method allows supporting analysis to interpret primary estimates of vaccine efficacy.