ONE STEP AHEAD OF THE FLU PREFLUCEL

Transcription

1 ONE STEP AHEAD OF THE FLU PREFLUCEL

2 Seasonal influenza is an acute contagious illness with systemic and respiratory symptoms. can range in severity from mild symptoms to life threatening pneumonia and encephalitis. 1,2 is caused by human influenza viruses type A or B and should not be confused with the common cold, which is caused by other viruses, including rhinovirus, coronaviruses or respiratory syncytial virus (RSV). 3 can affect all age groups, the risk being highest among the elderly, and people of any age with certain chronic diseases e.g. diabetes, cardiovascular diseases, or a weakened immune system. 1 kills an estimated 40,000 to 220,000 people annually in the European Union. 1,4 Influenza vaccination is the most effective way of preventing influenza, as recommended by WHO and EU national authorities. has to be repeated every autumn, because influenza virus strains are constantly changing due to antigenic drift of the virus genome. 5 should occur anytime between September and the end of the influenza season, i.e. into early spring. Influenza activity in the Northern Hemisphere usually peaks in January or February. 6 does not protect against the common cold caused by other viruses, which usually peaks in November or December. 6 Rhinoviruses, Respiratory Syncytial Virus and influenza virus, season 2008/2009 in Lyon, France. 7 Number of laboratory confirmed cases Rhinoviruses RSV Influenza August September October November December January February Week number, year 1

3 PREFLUCEL NEW SEASONAL SPLIT INFLUENZA VACCINE USING INNOVATIVE VERO CELL TECHNOLOGY New seasonal split influenza vaccine Manufactured by using innovative Vero cell technology Cutting-edge purity - free of egg protein, antibiotics and preservatives Very well tolerated in clinical studies Generates a strong immune response Provides demonstrated protection against culture-confirmed influenza Over the full influenza season Against matching strains* And against drifted strains** The natural virus, which is identical in protein composition to that circulating in nature, is used in the production of PREFLUCEL INNOVATIVE VERO CELL TECHNOLOGY A well-established, highly standardized, and closed manufacturing process Allows for a shorter and more flexible production cycle compared to traditional egg-based influenza vaccines Enables use of the natural virus instead of reassortants *Demonstrated reduction of influenza virus infection caused by vaccine matching strains by 78.5% in a Phase 3 clinical trial conducted in the US during the 2008/2009 influenza season (n=7236) **Demonstrated reduction of influenza virus infection caused by matching and mismatching strains by 71.5% in a Phase 3 clinical trial conducted in the US during the 2008/2009 influenza season (n=7236) 2

4 PREFLUCEL Very well tolerated in clinical studies involving more than 9,000 adults and elderly subjects. 8 Can be administered to people with hypersensitivity to eggs, egg products, or egg or chicken protein, because it is free of egg protein. Free of preservatives and antibiotics 8 In clinical studies with PREFLUCEL, the most frequently observed adverse reactions were malaise, mayalgia, injection-site pain, fatigue, and headache. 8 For more information on the safety profile of PREFLUCEL, please see prescribing information. PREFLUCEL - CONVENIENT FOR USE PREFLUCEL is supplied prefilled in a Readyject syringe, a patented syringe system developed by Baxter. Well established syringe system with attached needle Equipped with a multi-facet needle designed for smooth delivery Entirely latex-free Fitted with tamper-proof rigid needle shield to ensure product integrity 3

5 PREFLUCEL IS HIGHLY IMMUNOGENIC Influenza vaccine efficacy is assessed using a surrogate of protection defined as the antibody titers elicited by the vaccine. Measuring the immune response using the hemagglutinin inhibition (HI) assay provides information about the amount of antibodies formed against the virus strains contained in the vaccine. PREFLUCEL exceeded the three criteria for immunogenicity set by the European Medicines Agency (EMA) in all three Phase 3 clinical studies completed thus far, including an overall number of more than 8,000 adults and elderly subjects who received PREFLUCEL. Seroprotection rate of PREFLUCEL in adults and the elderly by strain 8 100% A/H1N1 A/H3N2 B 100% A/H1N1 A/H3N2 B 80% 60% CHMP criteria 80% 60% CHMP criteria 40% 40% 20% 20% 0 Seroprotection in Adults 0 Seroprotection in Elderly (n=3473) (n=1548) * Phase 3 clinical study conducted in 2008/2009 * Phase 3 clinical study conducted in 2008/2009 The EMA s Committee for Medicinal Products for Human Use (CHMP) has set up the following requirements, which must be achieved by an influenza vaccine in order to be considered efficacious. 9 Criteria for the assessment of immunogenicity defined by EMA 11 Defined from day 0 - day 21 CHMP Standard years 60 + Proportion of vaccine recipients with seroconversion 1 or a significant increase 2 in antibody titers (seroconversion rate) Geometric mean increase 3 in antibody titers (seroconversion factor) Proportion of vaccine recipients with protective antibody titers 4 (seroprotection rate) > 40 % > 2,5 > 70 % > 30 % > 2 > 60 % 1. HI: prevaccination titer < 1:10 and postvaccination titer of 1:40 2. HI: prevaccination titer 1:10 and postvaccination titer 4 times higher 3. Post-/prevaccination titers: day 21/day 0 or day 42/day 0 4. HI titer 1:40 4

6 PREFLUCEL: DEMONSTRATED PROTECTION AGAINST CULTURE CONFIRMED INFLUENZA The clinical benefit of seasonal influenza vaccination lies in the protection from influenza illness and thereby, the reduction of severe morbidity and mortality. This benefit can most accurately be demonstrated in a robust placebo controlled efficacy study confirming not only that the vaccine triggered antibody production, but also protected against influenza virus infections. Therefore, PREFLUCEL was assessed in a placebo controlled study with 7,236 individuals in the US during the 2008/2009 influenza season. PREFLUCEL PROTECTED AGAINST MATCHING STRAINS** PREFLUCEL demonstrated a reduction in influenza cases by 78.5% Reduction in influenza cases by 78.5% Cases Number of CCI*-cases in the unvaccinated group Number of CCI*-cases in the vaccinated group *CCI = Culture confirmed influenza; ** Matching strain= strain contained in the vaccine formulation recommended by the WHO for the respective influenza season. PREFLUCEL ALSO PROTECTS AGAINST DRIFTED STRAINS The influenza virus is constantly changing due to the continuous evolution of the virus under immune pressure (antigenic drift), including during the influenza season. Therefore, protection against drifted viruses is important. PREFLUCEL also protected against infection by both matching and mismatching influenza strains that were circulating during the influenza season, reducing influenza cases by 71.5%. 10* Reduction in influenza cases by 71.5% Cases Number of LCI*-cases in the unvaccinated group Number of LCI*-cases in the vaccinated group *LCI= Laboratory confirmed influenza 5

7 PREFLUCEL IS PROTECTIVE OVER THE FULL INFLUENZA SEASON Vaccination against seasonal influenza is usually given in September / October to cover the coming epidemic, which usually peaks in January or February of the following year. 11 PREFLUCEL s efficacy was followed up through the full season, starting with vaccination in October and lasting until the end of May. 10 Vaccine Efficacy (95% CI) by Study Week All Matching or Mismatching Strains 120 PREFLUCEL S efficacy remained stable over the full influenza season* 100 VE (95% CI) ,5 80,0 73,3 76,0 72,2 70,5 71,4 74,4 73,3 73,5 73,5 72,1 71,4 03 Jan 17 Jan 31 Jan 14 Feb 28 Feb 14 Mar 28 Mar 11 Apr End date of week *Vaccine efficacy (VE) against all matching or mismatching strains by week was calculated in order to detect if VE could have been affected by an epidemiological change during the influenza season. A CLINICAL STUDY OF PREFLUCEL CONFIRMED THE CORRELATION BETWEEN HI TITERS AND PROTECTION The correlate of protection established for egg-derived influenza vaccines (HI 1:40) also predicted Vero cell derived influenza vaccine-induced protection 10 An HI titer of 15 already correlated with protection, and there was no additional protection beyond an HI titer of 1: ,4 Youden index 0,2 0,203 0,198 0,259 0,270 0,262 0,242 0,250 0,068 0, HI titer cuttoff value The Youden s index (sensitivity + specificity 1) for the different reciprocal HI titer cut-off values is graphically displayed for the A/H1N1 strain. The Youden s index predicts the cut-off HI titer associated with seroprotection. 6

8 VERO CELL PRODUCTION OF PREFLUCEL ALLOWS FOR THE USE OF THE NATURAL VIRUS INSTEAD OF REASSORTANTS To ensure high growth in the egg matrix, the virus used in egg-based vaccine production has to be genetically modified by mixing the genes of the natural virus with those of a high-growth virus strain. This reassortment, which takes several weeks to complete, results in virus variants that are often antigenically distinct from the original viruses and may be clinically 12, suboptimal for inducing protective antibodies to the natural virus circulating in humans. In contrast, virus propagated in mammalian-derived tissue culture has been demonstrated to be representative of the natural virus. 12, 17 This allows production to begin as soon as the strains for the next influenza season have been selected. Reassortant virus Genetically modified virus adapted for production in eggs through combination of the natural virus with a different, high-growth virus strain. Hemagglutinin (HA) Neuroaminidase (NA) 7

9 PREFLUCEL PRODUCTION USES THE NATURAL VIRUS: POTENTIAL FOR A MORE COMPLETE IMMUNE RESPONSE Generally, influenza vaccine can activate two information channels that trigger the immune response: 1. The antigens on the surface of the virus: Hemagglutinin (HA) and Neuraminidase (NA) 2. The proteins inside the virus particle (mainly nucleo- and matrix proteins) While the surface antigens, especially the HA, drive the immune response by producing antibodies, the inner proteins contribute positively to the cell-mediated immune response that tend to be more cross-reactive among subtypes. 18 The inner proteins may be particularly important for protecting elderly from influenza illness. 19 As a split influenza vaccine, PREFLUCEL still contains both the surface and the inner proteins. 18 Additionally, in contrast to influenza vaccines produced in eggs, all proteins in PREFLUCEL originate from the virus circulating in nature, therefore PREFLUCEL offers the potential for a more complete immune response. NATURAL virus Original seasonal virus with all external and internal viral proteins circulating in nature. Hemagglutinin (HA) Neuroaminidase (NA) 8

10 BAXTER S VERO CELL TECHNOLOGY IS A WELL-ESTABLISHED, HIGHLY STANDARDIZED, CLOSED MANUFACTURING PROCESS Vero cells have been widely used in human vaccine production e.g. polio and rabies over the past three decades. 12,20 Baxter s proprietary Vero cell technology uses a well-established mammalian cell line that has been extensively tested 12,21 and is fully accepted by regulatory authorities in both Europe and the US in the production of human vaccines. 12,21 In contrast to the use of embryonated chicken eggs, Baxter s Vero cell-based manufacturing uses a highly standardized, closed production process, 12 ensuring freedom from interaction between the vaccine and its environment, and has high purity in the absence of antibiotics. Vero cell technology production process Another major advantage of the Vero cell line is that it can be grown and infected on microcarrier beads and cultivated in fermenters, allowing large-scale production of vaccines. Vero cells on microcarrier beads before infection with influenza virus. Vero cells grown on microcarrier beads. 2-3 days after infection: the replicating virus has exerted a cytopathic effect on the Vero host cells. 9

11 VERO CELL PRODUCTION ALLOWS FOR A SHORTER AND MORE FLEXIBLE PRODUCTION CYCLE Traditionally, influenza vaccines have been prepared from viruses grown in embryonated chicken eggs, typically requiring between one and two eggs per dose of vaccine.21 During egg- Egg-based based vaccine production, eggs must Start of Process first be sterilized, candled, inoculated with the virus, and incubated before Influenza production process: Egg-based vs. cell culture-based method (adapted from Wright 13 small volumes of allantoic fluid can be harvested from each egg. The entire production process takes about 22 weeks. 13 Secure raw material supply Because Vero cell production does not depend on the supply of eggs or reassortants, production of the vac- Cell-culture based Create and qualify reassortants Start of Process cine can start immediately after Use ampoule with seed virus from WHO receipt of the recommended WHO virus strains and safety testing. weeks.13 Preparation Production of seed virus QUALITY CONTROL Additionally, the Vero cell platform would allow for rapid changes that may be needed for new vaccine formulations. Inoculation with virus followed by period of incubation and virus growth Separation, Inactivation, Purification and Filtration Production of seed virus QUALITY CONTROL The entire process takes about 12 Formulation, Filling and Finishing Delivery 22 Weeks Total 12 Weeks Total 10

12 HEALTH ECONOMIC IMPACT OF INFLUENZA VACCINATION Influenza vaccination has substantial public health and economic benefits: 23 Cost-effective or even cost-saving in adults and elderly. 23* Associated with significant reductions in pneumonia, hospitalizations, and death. 4, 23,24 Vaccinating health care workers (HCW) protects not only the HCW themselves but also contributes to the indirect protection of their (high risk) patients. 25 Vaccinating healthy adults reduces work absenteeism and the negative impact on work productivity. 26 Vaccination not only reduces influenza in vaccinees, but also reduces disease transmission to others in the community. 27 *Results in health economic analyses are presented as net costs or savings per person vaccinated (i.e. as a cost benefit analysis) or as net costs or savings per year of life saved (i.e. as a cost effectiveness analysis)

13 This prescribing information is intended for international use only and is based on the SPC (summary of product characteristics) for Preflucel approved under decentralised procedure (DCP) in Austria and Czech Republic. The product is not yet approved in other countries. Please always consult your full country-specific SPC prior to using the product. PRESCRIBING INFORMATION PREFLUCEL Suspension for injection in a pre-filled syringe Influenza Vaccine (Split Virion, Inactivated, prepared in Vero Cell Cultures) 2010/2011 season Composition Vaccine composed of purified, inactivated split influenza virions, containing antigens of the following strains*: A/California/07/2009 (H1N1) A/Perth/16/2009 (H3N2) like strain (A/Victoria/210/2009) B/Brisbane/60/2008 (B) * propagated in Vero cells (continuous cell line of mammalian origin) ** haemagglutinin 15 micrograms HA** 15 micrograms HA** 15 micrograms HA** per 0.5 ml dose This vaccine complies with the WHO recommendation (Northern Hemisphere) and EU decision for the 2010/2011 season. Excipients: trometamol, sodium chloride, polysorbate 80, water for injections Indications Prophylaxis of influenza in adults and elderly. The use of PREFLUCEL should be based on official recommendations. Posology and method of administration Adults (18 years of age and older) and elderly (older than 60 years of age): 0.5 ml Immunization should be carried out by intramuscular injection (into the deltoid muscle). Contraindications Hypersensitivity to the active substances or to any of the excipients or residues (e.g. formaldehyde, benzonase or sucrose). Immunization shall be postponed in patients with febrile illness or acute infection. Warnings and precautions for use As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of an anaphylactic event following the administration of the vaccine. PREFLUCEL should under no circumstances be administered intravascularly. Antibody response in patients with endogenous or iatrogenic immunosuppression may be insufficient. Interactions PREFLUCEL may be given at the same time as other vaccines. Immunization should be carried out on separate limbs. It should be noted that adverse reactions may be intensified. The immunological response may be diminished if the patient is undergoing immunosuppressant treatment. Although not seen with PREFLUCEL, following influenza vaccination, false positive results in serology tests using the ELISA method to detect antibodies against HIV1, Hepatitis C and especially HTLV1 have been observed. The Western Blot technique disproves the falsepositive ELISA test results. The transient false positive reactions could be due to the IgM response to the vaccine. Pregnancy and lactation The safety of PREFLUCEL in pregnancy and lactation has not been assessed in clinical trials. In general, data from influenza vaccinations in pregnant women do not indicate adverse fetal and maternal outcomes attributable to the vaccine. For pregnant women with medical conditions that increase their risk of complications from influenza, the vaccine may be administered according to national recommendations. PREFLUCEL may be used during lactation. Undesirable effects In clinical studies with PREFLUCEL involving over 9000 adult and elderly subjects (7212 adults aged 18 59; 1789 elderly aged 60+), the following undesirable effects have been observed with the following frequencies: very common ( 1/10); common ( 1/100, <1/10); uncommon ( 1/1000, <1/100); rare ( 1/10000, <1/1000); very rare (< 1//10000), not known (cannot be estimated from the available data): Very common ( 1/10): headache*; myalgia; injection site reaction: pain*; systemic reactions: fatigue, malaise. Common ( 1/100, <1/10): ocular hyperemia; hyperhidrosis; arthralgia*; injection site reactions: swelling, erythema, ecchymosis, induration*; systemic reactions: chills, pyrexia. Uncommon ( 1/1000, <1/100): hypersensitivity/anaphylactic reaction; eye irritation; eye discharge; pharyngeal edema; pruritus; injection site reaction: pruritus, warmth; systemic reactions: chest discomfort. Rare ( 1/10000, <1/1000); very rare (< 1//10000): multiple sclerosis. There are no data from post-marketing experiences with PRE- FLUCEL. *These reactions usually disappear within 1-2 days without treatment. Incompatibilities PREFLUCEL must not be mixed with other medicinal products. Medicinal product subject to medical prescription. September

14 References 1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12) 13) 14) 15) 16) 17) 18) 19) 20) 21) 22) 23) 24) 25) 26) 27) 28) European Centre for Disease Prevention and Control (ECDC). Influenza - Fact sheet for citizens [ Accessed July 20, European Centre for Disease Prevention and Control (ECDC). Seasonal Influenza - Questions and Answers [ Accessed July 20, Eccles R. Understanding the symptoms of the common cold and influenza. Lancet Infect Dis 2005; 5: European Centre for Disease Prevention and Control (ECDC). Seasonal Human Influenza and Vaccination - The Facts [ Accessed July 20, World Health Organization (WHO). Global Influenza Surveillance Network [ Accessed July 20, EuroFlu - The WHO European Influenza Network. Continued pandemic H1N1 influenza detections in the European Region [ EuroFlu - Weekly Electronic Bulletin Accessed July 20, Casalegno JS, Bouscambert-Duchamp M, Morfin F, Lina B, Escuret V. Rhinoviruses, A(H1N1)v, RVS: The race for hivernal pandemics, France Euro Surveill. 2009;14(44):pii= Available online: aspx?articleid=19390 Summary of Product Characteristics of PREFLUCEL (dated xx-xxx-xx). EMA. Guidance on harmonisation of requirements for influenza vaccines (CPMP/BWP/214/96). [ Accessed July 20, Data on file, Baxter AG, Vienna, Austria. MMWR Weekly Report. Prevention and Control of Seasonal Influenza with Vaccines. July 31, Vol 58; No.RR-8 Barrett PN, Mundt W, Kistner O, Howard MK. Vero cell platform in vaccine production: moving towards cell culture-based viral vaccines. Expert Rev Vaccines 2009; 8: Wright PF. Vaccine preparedness--are we ready for the next influenza pandemic? N Engl J Med 2008; 358:2540-3: Schild GC, Oxford JS, de Jong JC, Webster RG. Evidence for host-cell selection of influenza virus antigenic variants. Nature 1983; 303: Robertson JS, Nicolson C, Major D, Robertson EW, Wood JM. The role of amniotic passage in the egg-adaptation of human influenza virus is revealed by haemagglutinin sequence analyses. J Gen Virol 1993; 74 (Pt 10): Hardy CT, Young SA, Webster RG, Naeve CW, Owens RJ. Egg fluids and cells of the chorioallantoic membrane of embryonated chicken eggs can select different variants of influenza A (H3N2) viruses. Virology 1995; 211: Robertson JS, Bootman JS, Newman R, et al. Structural changes in the haemagglutinin which accompany egg adaptation of an influenza A(H1N1) virus. Virology 1987; 160:31-7. Jameson J, Ennis FA. Human cytotoxic T-lymphocyte repertoire to Influenza A viruses. J Virol 1998; 72 (11): Mc Elhoney JE, Xie D, Hayer WD. T cell responses are better correlates of vaccine protection in elderly. J Immunol 2006; 176 (10): Montagnon BJ, Fanget B, Nicolas AJ. The large-scale cultivation of VERO cells in micro-carrier culture for virus vaccine production. Preliminary results for killed poliovirus vaccine. Dev Biol Stand 1981; 47: Barrett PN, Portsmouth D, Ehrlich H. Developing cell culture-derived pandemic vaccines. Current Opinion Molecular Therapeutics 2010; 12(1): Howard MK, Kistner O, Barrett PN. Pre-clinical development of cell culture (Vero)-derived H5N1 pandemic vaccines. Biol Chem 2008; 389: Nichol K. The efficacy, effectiveness and cost-effectiveness of inactiveated influenza virus vaccines. Vaccine 2003; 21: Nichol KL. Efficacy and effectiveness of influenza vaccination. Vaccine 2008; 26 Suppl 4:D Burls A, Jordan R, Barton P, Olowokure B, Wake B, Albon E, Hawker J. Vaccinating healthcare workers against influenza to protect the vulnerable Is it a good use of healthcare resources? A systematic review of the evidence and an economic evaluation. Vaccine 2006; 24: Nichol K, Heilly S, Greenberg M, Ehlinger E. Burden of Influenza-Like Illness and Effectiveness of Influenza Vaccination among Working Adults Aged Years. Clinical Infectious Diseases 2009;48: Weycker D, Edelsberg J, Halloran ME, Longini IM Jr, Nizam A, Ciuryla V, Oster G. Population-wide benefits of routine vaccination of children. Vaccine 2005; 23: Nichol K, Nordin J, Mullooly J. Influence of clinical outcome and outcome period definitions on estimates of absolute clinical and economic benefits of influenza vaccination in community dwelling elderly persons. Vaccine 2006; 24: Baxter and PREFLUCEL are trademarks of Baxter International Inc., its subsidiaries or affiliates. All other products or trademarks mentioned in this folder are the property of their respective owners. Project No: BS-VA-251 August

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