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Background The safety and immunogenicity profile of COVID-19 vaccines when administered concomitantly with seasonal influenza vaccines have not yet been reported. We therefore aimed to report the results of a substudy within a phase 3 UK trial, by evaluating the safety, immunogenicity, and efficacy of NVX-CoV2373 when co-administered with licensed seasonal influenza vaccines. Methods We did a planned exploratory substudy as part of the randomised, observer-blinded, placebo-controlled, phase 3 trial of the safety and efficacy of the COVID-19 vaccine (NVX-CoV2373) by co-administrating the influenza vaccine at four study hospitals in the UK. Approximately, the first 400 participants meeting the main study entry criteria—with no contraindications to influenza vaccination—were invited to join the substudy. Participants of the main study were randomly assigned (1:1) to receive two intramuscular injections of either NVX-CoV2373 (5 μg) or placebo (normal saline) 21 days apart; participants enrolled into the substudy were co-vaccinated with a single (0·5 mL) intramuscular, age-appropriate (quadrivalent influenza cell-based vaccine [Flucelvax Quadrivalent; Seqirus UK, Maidenhead] for those aged 18–64 years and adjuvanted trivalent influenza vaccine [Fluad; Seqirus UK, Maidenhead] for those ≥65 years), licensed, influenza vaccine on the opposite deltoid to that of the first study vaccine dose or placebo. The influenza vaccine was administered in an open-label manner and at the same time as the first study injection. Reactogenicity was evaluated via an electronic diary for 7 days after vaccination in addition to monitoring for unsolicited adverse events, medically attended adverse events, and serious adverse events. Immunogenicity was assessed with influenza haemagglutination inhibition and SARS-CoV-2 anti-spike protein IgG assays. Vaccine efficacy against PCR-confirmed, symptomatic COVID-19 was assessed in participants who were seronegative at baseline, received both doses of study vaccine or placebo, had no major protocol deviations affecting the primary endpoint, and had no confirmed cases of symptomatic COVID-19 from the first dose until 6 days after the second dose (per-protocol efficacy population). Immunogenicity was assessed in participants who received scheduled two doses of study vaccine, had a baseline sample and at least one post-vaccination sample, and had no major protocol violations before unmasking (per-protocol immunogenicity population). Reactogenicity was analysed in all participants who received at least one dose of NVX-CoV2373 or placebo and had data collected for reactogenicity events. Safety was analysed in all participants who received at least one dose of NVX-CoV2373 or placebo. Comparisons were made between participants of the substudy and the main study (who were not co-vaccinated for influenza). This study is registered with ClinicalTrials.gov, number NCT04583995. Findings Between Sept 28, 2020, and Nov 28, 2020, a total of 15 187 participants were randomised into the main phase 3 trial, of whom 15 139 received treatment (7569 received dose one of NVX-CoV2373 and 7570 received dose one of placebo). 431 participants were co-vaccinated with a seasonal influenza vaccine in the substudy (217 received NVX-CoV2373 plus the influenza vaccine and 214 received placebo plus the influenza vaccine). In general, the substudy participants were younger, more racially diverse, and had fewer comorbid conditions than those in the main study. Reactogenicity events were more common in the co-administration group than in the NVX-CoV2373 alone group: tenderness (113 [64·9%] of 174 vs 592 [53·3%] of 1111) or pain (69 [39·7%] vs 325 [29·3%]) at injection site, fatigue (48 [27·7%] vs 215 [19·4%]), and muscle pain (49 [28·3%] vs 237 [21·4%]). Incidences of unsolicited adverse events, treatment-related medically attended adverse events, and serious adverse events were low and balanced between the co-administration group and the NVX-CoV2373 alone group. No episodes of anaphylaxis or deaths were reported within the substudy. Co-administration resulted in no change to influenza vaccine immune response although a reduction in antibody responses to the NVX-CoV2373 vaccine was noted. NVX-CoV2373 vaccine efficacy in the substudy (ie, participants aged 18 to

Introduction Influenza is associated with significant morbidity and mortality worldwide. Whilst vaccination is key for the prevention of influenza infection, there are many factors which may contribute to reduced vaccine effectiveness, including antigenic evolution via both antigenic drift and egg-adaptations. Due to the currently dissociated and indirect evidence supporting both the occurrence of these two phenomena in the egg-based manufacturing process and their effects on vaccine effectiveness, this topic remains a subject of debate. Objective To review the evidence and level of agreement in expert opinion supporting a mechanistic basis for reduced vaccine effectiveness due to egg-based manufacturing, using an expert consensus-based methodology and literature reviews. Methods Ten European influenza specialists were recruited to the expert panel. The overall research question was deconstructed into four component principles, which were examined in series using a novel, online, two-stage assessment of proportional group awareness and consensus. The first stage independently generated a list of supporting references for each component principle via literature searches and expert assessments. In the second stage, a summary of each reference was circulated amongst the experts, who rated their agreement that each reference supported the component principle on a 5-point Likert scale. Finally, the panel were asked if they agreed that, as a whole, the evidence supported a mechanistic basis for reduced vaccine effectiveness due to egg-based manufacturing. Results All component principles were reported to have a majority of strong or very strong supporting evidence (70–90%). Conclusions On reviewing the evidence for all component principles, experts unanimously agreed that there is a mechanistic basis for reduced vaccine effectiveness resulting from candidate influenza virus variation due to egg-based manufacturing, particularly in the influenza A/H3N2 strain. Experts pointed to surveillance, candidate vaccine virus selection and manufacturing stages involving eggs as the most likely to impact vaccine effectiveness.

SummaryBackgroundThe safety and immunogenicity profile of COVID-19 vaccines when administered concomitantly with seasonal influenza vaccines has not yet been reported.MethodsA sub-study on influenza vaccine co-administration was conducted as part of the phase 3 randomized trial of the safety and efficacy of NVX-CoV2373. The first ∼400 participants meeting main study entry criteria and with no contraindications to influenza vaccination were invited to join the sub-study. After randomization in a 1:1 ratio to receive NVX-CoV2373 (n=217) or placebo (n=214), sub-study participants received an age-appropriate, licensed, open-label influenza vaccine with dose 1 of NVX-CoV2373. Reactogenicity was evaluated via electronic diary for 7 days post-vaccination in addition to monitoring for unsolicited adverse events (AEs), medically-attended AEs (MAAEs), and serious AEs (SAEs). Influenza haemagglutination inhibition and SARS-CoV-2 anti-spike IgG assays were performed. Vaccine efficacy against PCR-confirmed, symptomatic COVID-19 was assessed. Comparisons were made between sub-study and main study participants.FindingsSub-study participants were younger, more racially diverse, and had fewer comorbid conditions than main study participants. Reactogenicity events more common in the co-administration group included tenderness (70.1% vs 57.6%) or pain (39.7% vs 29.3%) at injection site, fatigue (27.7% vs 19.4%), and muscle pain (28.3% vs 21.4%). Rates of unsolicited AEs, MAAEs, and SAEs were low and balanced between the two groups. Co-administration resulted in no change to influenza vaccine immune response, while a reduction in antibody responses to the NVX-CoV2373 vaccine was noted. Vaccine efficacy in the sub-study was 87.5% (95% CI: -0.2, 98.4) while efficacy in the main study was 89.8% (95% CI: 79.7, 95.5).InterpretationThis is the first study to demonstrate the safety, immunogenicity, and efficacy profile of a COVID-19 vaccine when co-administered with seasonal influenza vaccines. The results suggest concomitant vaccination may be a viable immunisation strategy.FundingThis study was funded by Novavax, Inc.Research in ContextEvidence before this studyWe searched PubMed for research articles published from December 2019 until 1 April 2021 with no language restrictions for the terms “SARS-CoV-2”, “COVID-19”, “vaccine”, “co-administration”, and “immunogenicity”. There were no peer-reviewed publications describing the simultaneous use of any SARS-CoV-2 vaccine and another vaccine. Several vaccine manufacturers had recent publications on phase 3 trials results (Pfizer/BioNTech, Moderna, AstraZeneca, Janssen, and the Gamaleya Research Institute of Epidemiology and Microbiology). Neither these publications nor their clinical trials’ protocols (when publicly available) described co-administration and they often had trial criteria specifically excluding those with recent or planned vaccination with any licenced vaccine near or at the time of any study injection.Added value of this studyImmune interference and safety are always a concern when two vaccines are administered at the same time. This is the first study to demonstrate the safety and immunogenicity profile and clinical vaccine efficacy of a COVID-19 vaccine when co-administered with a seasonal influenza vaccine.Implications of all the available evidenceThis study provides much needed information to help guide national immunisation policy decision making on the critical issue of concomitant use of COVID-19 vaccines with influenza vaccines.

Standard influenza vaccines are produced using egg-based manufacturing methods. Through the process, the resulting egg-adapted viral strains may differ from the selected vaccine strain. Cell-derived influenza vaccine manufacturing prevents egg-adaptation of the antigen which can improve vaccine effectiveness. We evaluated the cost-effectiveness of quadrivalent cell-derived influenza vaccine (QIVc) versus an egg-based quadrivalent influenza vaccine (QIVe) in preventing seasonal influenza from German societal and payer perspectives. Adapted version of the individual-based dynamic 4Flu transmission model was combined with a decision-tree to calculate the impact of QIVc versus QIVe on influenza over 20 seasons in Germany. Egg-adaptation, resulting in lower effectiveness of QIVe versus QIVc towards the H3N2 influenza strain, is sourced from a US retrospective study and assumed in 100% (base case) or 55% (conservative scenario) of years. Influenza-related probabilities of outpatient visits, hospitalizations, productivity loss, and mortality, with associated (dis)utilities/costs, were extracted from literature. Costs and outcomes were discounted 3.0%/year. Replacing QIVe with QIVc in subjects aged ≥ 9 years can annually prevent 167,265 symptomatic cases, 51,114 outpatient visits, 2,091 hospitalizations, and 103 deaths in Germany. The annual number of quality-adjusted life-years (QALYs) increased by 1,628 and healthcare costs decreased by €178 M from societal perspective. From payer perspective, the incremental cost-effectiveness ratio was €2,285 per QALY. Scenario analyses confirmed results robustness. The use of QIVc compared to QIVe, in the German Immunization Program, could significantly prevent outpatient visits and hospitalizations and would enable substantial savings from a societal perspective.

Suboptimal vaccine effectiveness against seasonal influenza is a significant public health concern, partly explained by antigenic differences between vaccine viruses and viruses circulating in the environment. Haemagglutinin mutations within vaccine viruses acquired during serial passage in eggs have been identified as a source of antigenic variation between vaccine and circulating viruses. This study retrospectively compared the antigenic similarity of circulating influenza isolates with egg- and cell-propagated reference viruses to assess any observable trends over a 16-year period. Using annual and interim reports published by the Worldwide Influenza Centre, London, for the 2002&ndash, 2003 to 2017&ndash, 2018 influenza seasons, we assessed the proportions of circulating viruses which showed antigenic similarity to reference viruses by season. Egg-propagated reference viruses were well matched against circulating viruses for A/H1N1 and B/Yamagata. However, A/H3N2 and B/Victoria cell-propagated reference viruses appeared to be more antigenically similar to circulating A/H3N2 and B/Victoria viruses than egg-propagated reference viruses. These data support the possibility that A/H3N2 and B/Victoria viruses are relatively more prone to egg-adaptive mutation. Cell-propagated A/H3N2 and B/Victoria reference viruses were more antigenically similar to circulating A/H3N2 and B/Victoria viruses over a 16-year period than were egg-propagated reference viruses.

This study set out to evaluate influenza- and respiratory-related illnesses recorded during primary care physician consultations in England following the H1N1 pandemic in 2009 and to enable the development of a dynamic disease model. Data were obtained from the Clinical Practice Research Datalink of primary care records over four influenza seasons (2010–2014). The primary outcome of the study was incidence of influenza- and respiratory-related diagnoses, calculated per practice and by season and age group. Upper respiratory tract infection diagnoses were most frequently recorded (mean seasonal practice level incidence; 3,762 consultations per 100,000 [SD = 1,989]), and influenza-related diagnoses were least frequently recorded across all seasons, except one. Incidence rates for the under 18 population were higher than those for the general population, in particular for upper respiratory tract infection (range of 8,024–9,950 versus 3,228–4,120, respectively) and otitis media diagnoses (2,668–3,652 versus 782–1,057, respectively). For influenza-related diagnoses, the 65+ age group, the 0 to

This study compared the economic value of pediatric immunisation programmes for influenza to those for rotavirus (RV), meningococcal disease (MD), pneumococcal disease (PD), human papillomavirus (HPV), hepatitis B (Hep B), and varicella reported in recent (2000 onwards) cost-effectiveness (CE) studies identified in a systematic review of PubMed, health technology, and vaccination databases. The systematic review yielded 51 economic evaluation studies of pediatric immunisation — 10 (20%) for influenza and 41 (80%) for the other selected diseases. The quality of the eligible articles was assessed using Drummond's checklist. Although inherent challenges and limitations exist when comparing economic evaluations of immunisation programmes, an overall comparison of the included studies demonstrated cost-effectiveness/cost saving for influenza from a European-Union-Five (EU5) and United States (US) perspective; point estimates for cost/quality-adjusted life-years (QALY) from dominance (cost-saving with more effect) to ≤45,444 were reported. The economic value of influenza programmes was comparable to the other vaccines of interest, with cost/QALY in general considerably lower than RV, Hep B, MD and PD. Independent of the perspective and type of analysis, the economic impact of a pediatric influenza immunisation program was influenced by vaccine efficacy, immunisation coverage, costs, and most significantly by herd immunity. This review suggests that pediatric influenza immunisation may offer a cost effective strategy when compared with HPV and varicella and possibly more value compared with other childhood vaccines (RV, Hep B, MD and PD).

Influenza continues to cause severe illness in millions and deaths in hundreds of thousands annually. Vaccines are used to prevent influenza outbreaks, however, the influenza virus mutates and annual vaccination is required for optimal protection. Vaccine effectiveness is also affected by other potential factors such as the human immune system, a mismatch with the chosen candidate virus, and egg adaptation associated with egg-based vaccine production. This article reviews the influenza vaccine development process and describes the implications of the changes to the cell-culture process and vaccine strain recommendations by the World Health Organization since the 2017 season. The traditional manufacturing process for influenza vaccines relies on fertilized chicken eggs that are used for vaccine production. Vaccines must be produced in large volumes and the complete process requires approximately 6 months for the egg-based process. In addition, egg adaptation of seed viruses occurs when viruses adapt to avian receptors found within eggs to allow for growth in eggs. These changes to key viral antigens may result in antigenic mismatch and thereby reduce vaccine effectiveness. By contrast, cell-derived seed viruses do not require fertilized eggs and eliminate the potential for egg-adapted changes. As a result, cell-culture technology improves the match between the vaccine virus strain and the vaccine selected strain, and has been associated with increased vaccine effectiveness during a predominantly H3N2 season. During the 2017–2018 influenza season, a small number of studies conducted in the United States compared the effectiveness of egg-based and cell-culture vaccines and are described here. These observational and retrospective studies demonstrate that inactivated cell-culture vaccines were more effective than egg-based vaccines. Adoption of cell-culture technology for influenza vaccine manufacturing has been reported to improve manufacturing efficiency and the additional benefit of improving vaccine effectiveness is a key factor for future policy making considerations.

Introduction During the 2013-2014 influenza season, Public Health England extended routine influenza vaccination to all 2- and 3-year-old children in England. To estimate the impact of this change in policy on influenza-related morbidity and mortality, we developed a disease transmission and surveillance model informed by real-world data. Methods We combined real-world and literature data sources to construct a model of influenza transmission and surveillance in England. Data were obtained for four influenza seasons, starting with the 2010-2011 season. Bayesian inference was used to estimate model parameters on a season-by-season basis to assess the impact of targeting 2- and 3-year-old children for influenza vaccination. This provided the basis for the construction of counterfactual scenarios comparing vaccination rates of ~2% and ~35% in the 2- and 3- year-old population to estimate reductions in general practitioner (GP) influenza-like-illness (ILI) consultations, respiratory hospitalizations and deaths in the overall population. Results Our model was able to replicate the main patterns of influenza across the four seasons as observed through laboratory surveillance data. Targeting 2- and 3-year-old children for influenza vaccination resulted in reductions in the general population of between 6.2-9.9% in influenza-attributable GP ILI consultations, 6.1-10.7% in influenza-attributable respiratory hospitalizations, and 5.7-9.4% in influenza-attributable deaths. The decrease in influenza-attributable ILI consultations represents a reduction of between 4.5% and 7.3% across all ILI consultations. The reduction in influenza-attributable respiratory hospitalizations represents a reduction of between 1.2% and 2.3% across all respiratory hospitalizations. Reductions in influenza-attributable respiratory deaths represent a reduction of between 0.9% and 2.4% in overall respiratory deaths. Conclusion This study has provided evidence that extending routine influenza vaccination to all healthy children aged 2 and 3 years old leads to benefits in terms of reduced utilization of healthcare resources and fewer respiratory health outcomes and deaths.

Background Lower influenza vaccine effectiveness (VE) against circulating H3N2 strains compared with other influenza viruses is partly explained by antigenic mismatch between circulating strains and the vaccine strain (Belongia 2016). This mismatch has recently been linked to a new glycosylation site introduced in the egg-adaptation step (Zost 2017) and HA L194P substitution (Wu 2017) for H3N2. Vaccine manufactured using seed virus wholly grown in mammalian (e.g., Madin–Darby Canine Kidney—MDCK) cells, as with the NH17-18 version of Flucelvax®, avoids these mutations. Preliminary reports suggest that this cell-based vaccine showed greater VE than did similar egg-based vaccines [FDA Statement]. This study aimed to compile existing data on antigenic similarity to measure the degree of match with circulating wild-type isolates of egg- and MDCK-propagated versions of the vaccine H3N2 virus over multiple seasons. Methods Using publicly available reports from the Worldwide Influenza Centre, London (Crick), we compiled data on antigenic similarity, defined as H3N2 circulating wild-type virus isolates showing no more than a 4-fold reduction in titer to antisera raised against wholly MDCK- or egg-propagated versions of the vaccine H3N2 viruses. Titers were compared using hemagglutination inhibition (HI) assays and/or plaque reduction neutralization assays (PRNA). Results Data from Northern Hemisphere influenza seasons of 2011–2012 to 2017–2018 show a substantially higher proportion of tested circulating influenza H3N2 viruses matched the MDCK-propagated reference viruses than did corresponding egg-propagated reference vaccine viruses (Figures 1 and 2). In half of the seasons evaluated, there was little to no antigenic similarity between circulating viruses and the egg-based vaccine viral seed. Conclusion These data suggest higher levels of mismatch have occurred consistently with egg-propagated H3N2 reference viruses compared with MDCK-propagated reference viruses when measured against circulating wild-type isolates and may further explain the potential for lower VE observed against H3N2 historically. Furthermore, these data point to the importance of continuing to utilize cell-derived seeds in creating seasonal influenza vaccines for this strain. Disclosures S. Rajaram, Seqirus: Employee, Salary. J. Van Boxmeer, Seqirus: Employee, Salary. B. Leav, Seqirus: Employee and Shareholder, Salary. P. Suphaphiphat, Seqirus: Employee, Salary. I. Iheanacho, Seqirus: Consultant, Research support. K. Kistler, Seqirus: Consultant, Research support.

Background : Influenza poses a significant burden on healthcare systems and society, with under-recognition in the paediatric population. Existing vaccination policies (largely) target the elderly and other risk groups where complications may arise. Objective : The goal of this study was to evaluate the cost-effectiveness of annual paediatric vaccination (in 2–17-year-olds) with live attenuated influenza vaccination (LAIV), as well as the protective effect on the wider population in England and Wales (base). The study aimed to demonstrate broad applications of the model in countries where epidemiological and transmission data is limited and that have sophisticated vaccination policies (Brazil, Spain, and Taiwan). Methods : The direct and indirect impact of LAIV in the paediatric cohort was simulated using an age-stratified dynamic transmission model over a 5-year time horizon of daily cycles and applying discounting of 3.5% in the base case. Pre-existing immunity structure was based on a 1-year model run. Sensitivity analyses were conducted. Results : In the base case for England and Wales, the annual paediatric strategy with LAIV was associated with improvements in influenza-related events and quality-adjusted life years (QALYs) lost, yielding an incremental cost per QALY of £6,208. The model was robust to change in the key input parameters. The probabilistic analysis demonstrated LAIV to be cost effective in more than 99% of iterations, assuming a willingness-to-pay threshold of £30,000. Incremental costs per QALY for Brazil were £2,817, and for the cases of Spain and Taiwan the proposed strategy was dominant over the current practice. Conclusion : In addition to existing policies, annual paediatric vaccination using LAIV provides a cost-effective strategy that offers direct and indirect protection in the wider community. Paediatric vaccination strategies using LAIV demonstrated clinical and economic benefits over alternative (current vaccination) strategies in England and Wales as well as Brazil, Spain, and Taiwan. Keywords: cost-effectiveness; dynamic transmission model; influenza; paediatric; LAIV; herd immunity; alternative country profiles (Published: 28 June 2016) Citation: Journal of Market Access & Health Policy 2016, 4: 31205 - http://dx.doi.org/10.3402/jmahp.v4.31205

In 2012, the Joint Committee on Vaccination and Immunisation recommended that the National Immunisation Programme for influenza be extended to include healthy children/adolescents aged 2–17 years. In the UK, extension of this new immunisation programme began in 2013–2014 and targeted children aged 2 years and 3 years in primary care. Several implementation pilots were undertaken in primary schools across England, Scotland, Wales and Northern Ireland, as well as a single pilot in a secondary school in England. This article shares lessons learnt from experiences in England and Scotland to provide guidance for other countries considering the addition of childhood influenza vaccination into their national immunisation programmes. Recommendations are provided to help ensure effective preparation and management of new childhood influenza vaccination programmes in other countries. This article describes the processes utilised in England and Scotland for programme setup, workforce management, identification and care of contraindicated patients, collection of data on vaccine uptake, communication strategies, and education of parents and children.

Objectives To evaluate changes in influenza vaccination rates in healthy and at-risk children following the implementation of the UK's childhood influenza immunisation programme.Design Observational cohort study before and after initiation of the UK's childhood influenza immunisation programme over three influenza seasons (2012–2013, 2013–2014 and 2014–2015) using data from the Clinical Practice Research Datalink (CPRD).Setting More than 500 primary care practices in the UK.Population All individuals aged 2–17 years on 1 September, with at least 12 months of medical history documented in CPRD were retained in the analysis.Intervention Starting in 2013–2014, all children aged 2 and 3 years were offered influenza vaccination through general practice, and primary school-aged children were offered influenza vaccination in selected counties in England (described as pilot regions). The vaccination programme was extended to all children aged 4 years in England in 2014–2015.Main outcome measure Cumulative vaccination rate from 1 September to 28 February of the next calendar year as assessed by a time-to-event statistical model (vaccination uptake). Age group, sex, region and type of high-risk medical condition were assessed as predictors.Results Vaccination uptake increased considerably from 2012–2013 to 2013–2014 in targeted children aged 2–3 years, both in children with a high-risk medical condition (from 40.7% to 61.1%) and those without (from 1.0% to 43.0%). Vaccination rates increased also, though less markedly, in older children. In 2014–2015, vaccination rates remained higher than 40% in healthy children aged 2–3 years, although they decreased slightly from 2013–2014 (from 43.0% to 41.8%). Vaccination rates in older healthy children continued to increase, driven primarily by an increase in children aged 4 years to 31.3% in 2014–2015.Conclusions The introduction of a universal childhood vaccination policy in the UK increased vaccination rates for targeted children, including those with high-risk conditions.