Cervarix visar överlägset immunsvar i första jämförande studien mellan de två tillgängliga vaccinerna mot livmoderhalscancer

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1 Solna, Cervarix visar överlägset immunsvar i första jämförande studien mellan de två tillgängliga vaccinerna mot livmoderhalscancer GlaxoSmithKlines vaccin mot livmoderhalscancer, Cervarix, har visat signifikant kraftigare immunsvar jämfört med Gardasil i den första storskaliga jämförande studien på de två godkända vaccinerna mot humant papillomvirus (HPV). 1A Enligt vad som meddelats denna vecka på den 25:e internationella papillomviruskonferensen (IPV) i Malmö undersökte den jämförande studien två viktiga mått på immunsvar: neutraliserande antikroppar och B-minnesceller, vilka man anser spelar en viktig roll för hur bra ett vaccin skyddar kvinnor mot HPV-infektion och efterföljande livmoderhalscancer på lång sikt. 2A-7A I alla åldrar som studerats (kvinnor år) var nivåerna av neutraliserande antikroppar med Cervarix mer än två gånger högre än med Gardasil för HPV typ 16 och mer än sex gånger högre för HPV typ 18. Dessa resultat hade hög statistisk signifikans (p<0,0001). 1B Dessutom var andelen kvinnor med påvisbara neutraliserande antikroppar i sekret från livmoderhalsen högre i gruppen som fick Cervarix. 1C Jämfört med Gardasil gav Cervarix också nästan tre (2,7) gånger fler B-minnesceller mot HPV 16 och 18. 1D Hillar Kangro, medicinsk rådgivare vid GlaxoSmithKline: Närvaron av neutraliserande antikroppar på infektionsstället (livmoderhalsen) förefaller vara en viktig del av vaccininducerat skydd mot HPV. För första gången har vi robusta kliniska bevis för att dessa två vacciner inte framkallar samma immunsvar mot HPV typ 16 och 18, de två vanligaste cancerframkallande virustyperna. Vi är säkra på att dessa resultat, tillsammans med nya resultat från fler viktiga studier som presenteras denna vecka, visar potentialen hos Cervarix. Båda vaccinerna visade en kliniskt acceptabel säkerhetsprofil. Frekvensen av rapporterade symtom var högre med Cervarix. Reaktioner på injektionsstället var vanligast. 8A Följsamheten för att fullfölja vaccinationsprogrammet var dock jämförbar för båda vaccinerna, vilket indikerar att båda tolererades väl. 8B De fullständiga resultaten från denna jämförande studie kommer att publiceras i en vetenskapligt granskad tidskrift. Resultaten från slutanalysen av fas III-studien (HPV-008) kommer också att presenteras på konferensen och visar att Cervarix har stor och statistiskt signifikant effekt mot cellförändringar som är förstadier till cancer och som är orsakade av de HPV-typer som ingår i vaccinet (HPV 16 och 18). 9A

2 Dessutom visar data att Cervarix ger typspecifikt skydd mot förändringar förknippade med andra cancerframkallande HPV-typer utöver HPV 16 och A Därmed visades att den totala skyddseffekten mot cellförändringar var större än vad som kan förväntas av ett vaccin som endast skyddar mot HPV 16 och Frekvenserna av allvarliga biverkningar och medicinskt betydelsefulla tillstånd var likartade i studie- och kontrollgrupperna. 9B En tredje studie som kommer att presenteras i Malmö har visat att Cervarix ger höga och bestående nivåer av antikroppar mot HPV 16 och 18 under 7,3 års uppföljning efter vaccination. Detta är den längsta uppföljning som hittills rapporterats för något godkänt vaccin mot livmoderhalscancer. 12 Vacciner mot livmoderhalscancer ska ge långsiktigt skydd, eftersom kvinnor fortsätter att vara utsatta för risk för HPV-infektion och cellförändringar i livmoderhalsen under hela livet. Hillar Kangro, medicinsk rådgivare: Förebyggande av livmoderhalscancer är en folkhälsoprioritet i såväl industriländer som i utvecklingsländer. Vi är mycket nöjda med dessa resultat och hur de främjar förståelsen av den roll Cervarix har när det gäller att skydda kvinnor mot livmoderhalscancer. För mer information Jonas Vikman, informationschef, , jonas.vikman@gsk.com Hillar Kangro, medicinsk rådgivare, , hillar.o.kangro@gsk.com Kommentarer till redaktörer Om HPV 008 Effekt- och säkerhetsresultat från interimsanalysen av HPV-008-studien har tidigare publicerats i Lancet. 13 De data som presenterats på den 25:e internationella papillomviruskonferensen (IPV) i Malmö kommer från slutanalysen av studien. Ytterligare resultat blir tillgängliga när studieanalysen så småningom är avslutad. Om Cervarix Vaccinationens huvudsakliga roll är att skydda kvinnor mot livmoderhalscancer. Eftersom kvinnor är i riskzonen under den sexuellt aktiva perioden i livet krävs det av ett vaccin mot livmoderhalscancer att det ger ett långsiktigt skydd och framkallar ett starkt immunsvar mot de vanligaste cancerframkallande HPV-typerna. Page 2

3 Cervarix utvecklades specifikt med ett nytt adjuvans, AS04, för att ge höga och bestående antikroppsnivåer i syfte att ge långsiktigt skydd mot de vanligaste och aggressivaste HPV-typerna. 15 Det har visats att Cervarix i allmänhet tolereras väl. De vanligaste biverkningarna efter vaccination omfattar smärta, rodnad och svullnad vid injektionsstället. 16 Hittills har Cervarix godkänts i 95 länder, däribland de 27 medlemsstaterna i Europeiska unionen (EU), Australien, Brasilien, Sydkorea, Mexiko och Taiwan. Ansökningar om godkännande har inlämnats i ytterligare mer än 20 länder, däribland Japan, Kanada och USA. GSK inlämnade också vaccinet till Världshälsoorganisationen (WHO) för godkännande i september Om HPV och livmoderhalscancer Ungefär 100 typer av humant papillomvirus har hittills identifierats 17. Av dessa vet man att ungefär 15 virustyper orsakar livmoderhalscancer. 18 HPV typ 16 och 18 svarar globalt sett för ungefär 70 procent av livmoderhalscancerfallen. Typ 45, 31 och 33 tillhör de näst vanligaste cancerframkallande HPVtyperna. 14B,19 Persisterande infektion med cancerframkallande HPV-typer kan leda till onormala vaginalutstryk, förstadier till cancer i livmoderhalsen och livmoderhalscancer. Globalt sett kommer mer än kvinnor att nydiagnostiseras med livmoderhalscancer 20A och kvinnor kommer att dö av sjukdomen varje år. 20B GlaxoSmithKline Biologicals GlaxoSmithKlines vaccinenhet, är ett av världens ledande vaccinföretag och ledande inom innovation. Företaget är verksamt inom forskning, utveckling och tillverkning av vacciner med över 30 vacciner godkända för försäljning och ytterligare 20 vacciner under utveckling. GSK Biologicals har sitt huvudkontor i Belgien och 13 produktionsanläggningar strategiskt placerade runt jordklotet distribuerade GSK Biologicals 1,1 miljarder vaccindoser till 176 länder i både industri- och utvecklingsländer, vilket innebär i genomsnitt tre miljoner doser per dag. GlaxoSmithKline är ett av världens ledande forskningsbaserade läkemedels- och hälsoföretag och engagerar sig för att förbättra människors livskvalitet genom att göra det möjligt för dem att vara mer aktiva, må bättre och leva längre. Besök för mer information. Cervarix är ett registrerat varumärke som tillhör GlaxoSmithKline-koncernen. Gardasil är ett registrerat varumärke som tillhör Merck & Co., Inc. Page 3

4 Referenser 1. Einstein M et al. Comparative evaluation of immunogenicity of two prophylactic human papillomavirus vaccines. Abstract presented at the 25 th International Papillomavirus Conference (IPV) 8-14 May 2009; Malmo, Sweden 2. Stanley M et al. Chapter 12: Prophylactic HPV vaccines: Underlying mechanisms. Vaccine. 2006; 24 Suppl 3:S Giannini SL et al. Enhanced humoral and memory B-cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/aluminium salt combination (AS04) compared to aluminium salt only. Vaccine 2006; 24: Inglis S et al. Chapter 11: HPV vaccines: Commercial Research & amp; Development. Vaccine 2006;24 Suppl 3:S99-S Villa LL. Vaccines against papillomavirus infections and disease. Rev Chilena Infectol. 2006; 23: Banatvala J, Van Damme P, Oehen S. Lifelong protection against hepatitis B: the role of vaccine immunogenicity in immune memory. Vaccine 2000;19(7-8): Banatvala JE, Van Damme P. Hepatitis B vaccine - do we need boosters? J Viral Hepat 2003;10(1): Einstein M et al. Immune response after primary vaccination course: a comparative trial of two HPV prophylactic vaccines. Invited abstract presented at the 25 th International Papillomavirus Conference (IPV) 8-14 May 2009; Malmo, Sweden 9. Paavonen J et al. Final phase III efficacy analysis of Cervarix in young women. Abstract presented at the 25 th International Papillomavirus Conference (IPV) 8-14 May 2009; Malmo, Sweden 10. Skinner SR et al. Cross-protective efficacy of Cervarix against oncogenic HPV types beyond HPV-16/18. Abstract presented at the 25 th International Papillomavirus Conference (IPV) 8-14 May 2009; Malmo, Sweden 11. Smith J S et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: A meta-analysis update. Int J Cancer 2007; 121: De Carvalho N et al. Immunogenicity and safety of HPV-16/18 AS04-adjuvanted vaccine up to 7.3y. Abstract presented at the 25 th International Papillomavirus Conference (IPV) 8-14 May 2009; Malmo, Sweden 13. Paavonen J et al. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet 2007; 369: Bosch X et al. Epidemiology and Natural History of Human Papillomavirus Infections and Type-Specific Implications in Cervical Neoplasia. Vaccine 2008; 26S: K1 K Aguilar JC. Vaccine adjuvants revisited. Vaccine 2007; 25: Descamps D, Hardt K, Spiessens B et al. Safety of human papillomavirus (HPV)-16/18 AS04 adjuvanted vaccine for cervical cancer prevention: a pooled analysis of 11 clinical trials. Human Vaccine, 2009; 55: WHO. Expert Committee on Biological Standardization. Guidelines to assure the quality, safety and efficacy of recombinant Human Papillomavirus virus-like particle vaccines, accessed on 27/3/2009 at Muñoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003; 348: Cohen J. High Hopes and Dilemmas for a Cervical Cancer Vaccine. Science 2005; 308: World Health Organization. Initiative for Vaccine Research. Accessed on February 13, 2009 Page 4

5 Cervarix IPV LOC Press Release Reference Pack PAGE CLAIM SUPPORTING REFERENCE LOCATION OF CLAIM IN REFERENCE 1 GlaxoSmithKline s cervical cancer vaccine, Cervarix has demonstrated a significant higher immune response compared to Gardasil in the first largescale comparative study of the two licensed HPV vaccines 1A: Einstein M et al. Comparative evaluation of immunogenicity of two prophylactic human papillomavirus vaccines. Abstract presented at the 25 th International Papillomavirus Conference (IPV) 8-14 May 2009; Malmo, Sweden Higher immune response was observed with Cervarix than Gardasil 1A: Page 1; paragraph 5 conclusions ; line the comparative study looked at two key measures of immune response, neutralising antibodies and memory B cells, believed to play an important role in how well a vaccine will protect women from HPV infection and subsequent cervical cancer over the long term. 2A: Stanley M et al. Chapter 12: Prophylactic HPV vaccines: Underlying mechanisms. Vaccine. 2006; 24 Suppl 3:S Nonetheless, the overall data consistently show that L1 VLPs induce high levels of serum neutralising IgG, and the results of VLP vaccination both in animal infections and clinical trials support the notion that it is this activity that is critical for protection. 3A: Giannini SL et al. Enhanced humoral and memory B-cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/aluminium salt combination (AS04) compared to aluminium salt only. Vaccine.2006; 24: Based on studies in pre-clinical models, an effective L1 VLP based prophylactic vaccine designed to protect against HPV persistent infection and subsequent cervical lesion development will need to induce strong humoral immune responses. Preclinical models predict that induction of high levels of neutralising antibody following vaccination with L1 VLPs will be important for an efficacious prophylactic vaccine. 4A: Inglis S et al. Chapter 11: HPV vaccines: Commercial Research & Development. Vaccine. 2006;24 Suppl 3:S99-S105 The successful animal studies suggested that, at a minimum, a vigorous antibody response to the L1 protein of HPV would be required for a successful vaccine and that sustained detectable levels of antibody at the site of primary infection would be necessary for continued protection. 5A: Villa LL. Vaccines against papillomavirus infections and disease. Rev Chilena Infectol. 2006; 23: Vaccines to prevent HPV infection aim to induce neutralizing antibodies directed to conformational epitopes of capsid proteins, which most probably will be type specific. The protection against infection depends on the amount of antibodies produced by the host, its availability at the infection site and the persistence of the neutralizing antibodies along time. 6A: Banatvala J, Van Damme P, Oehen S. Lifelong protection against hepatitis B: the role of vaccine immunogenicity in immune memory. Vaccine 2000;19(7-8): Long-term protection against hepatitis B (HB) disease is dependent on persistence of a strong immune memory.the strength of immune memory and of subsequent secondary immune response can therefore be predicted by the antibody response 2A: Page S3/109; column 1, paragraph 1, lines A: Page 2; column 1; paragraph 3; lines 1-8 4A: Page S3/101; paragraph 2; lines 1-5 5A: Page 158; column 2, paragraph 2, lines 1-7 6A: Page 877, Abstract section Page 5

6 following primary vaccination. 7: Banatvala JE, Van Damme P. Hepatitis B vaccine -- do we need boosters? J Viral Hepat 2003;10(1):1 6 7: Page 1, Summary section protection is dependent on immune memory Page 6

7 1 Across all ages studied (women 18 45), neutralising antibody measures for Cervarix were more than two times higher than those for Gardasil forhuman papillomavirus (HPV ) type 16, and more than six times higher for HPV type 18. These results were highly statistically significant (p<0.0001). 1 In addition, the proportion of women with detectable levels of neutralising antibodies in cervical secretions was higher in the group that received Cervarix 1 Compared to Gardasil, Cervarix also produced nearly three (2.7) times more memory B cells for HPV 16 and Rates of solicited symptoms were higher for Cervarix with injection site reactions being most common. 2 Compliance with the full vaccination course was comparable for both vaccines which indicates that both were well tolerated. 2..Cervarix provides a high and statistically significant level of efficacy against pre-cancerous lesions associated with each of the HPV types included in the vaccine (HPV 16 and HPV 18). 2 Cervarix also provides type-specific protection against pre-cancerous lesions associated with some additional common cancer-causing HPV types other than HPV 16 and HPV 18. 1B: Einstein M et al. Comparative evaluation of immunogenicity of two prophylactic human papillomavirus vaccines. Abstract presented at the 25 th International Papillomavirus Conference (IPV) 8-14 May 2009; Malmo, Sweden In ATP cohort (seronegative/dna-negative before vaccination for HPV type analyzed), GMTs of serum neutralizing antibodies were fold higher for HPV-16 and fold higher for HPV-18 with Cervarix than Gardasil, across all age strata. 1C: Einstein M et al. Comparative evaluation of immunogenicity of two prophylactic human papillomavirus vaccines. Abstract presented at the 25 th International Papillomavirus Conference (IPV) 8-14 May 2009; Malmo, Sweden Positivity rates for neutralising antibodies (CVS) were higher with Cervarix than Gardasil across all age strata. 1D: Einstein M et al. Comparative evaluation of immunogenicity of two prophylactic human papillomavirus vaccines. Abstract presented at the 25 th International Papillomavirus Conference (IPV) 8-14 May 2009; Malmo, Sweden frequency of circulating antigen-specific memory B-cells in responders was 2.7 fold higher with Cervarix TM than Gardasil for HPV-16 and HPV-18 8A: Einstein M et al. Immune response after primary vaccination course: a ccomparative trial of two HPV prophylactic vaccines. Invited abstract presented at the 25 th International Papillomavirus Conference (IPV) 8-14 May 2009; Malmo, Sweden Both vaccines were generally well-tolerated. Rates of solicited symptoms were higher for Cervarix, injection site reactions being most common. Compliance was high ( 84%) for both vaccines. 8B: Einstein M et al. Immune response after primary vaccination course: a ccomparative trial of two HPV prophylactic vaccines. Invited abstract presented at the 25 th International Papillomavirus Conference (IPV) 8-14 May 2009; Malmo, Sweden Compliance was high ( 84%) for both vaccines. 9A: Paavonen J et al. Final phase III efficacy analysis of Cervarix in young women. Abstract presented at the 25 th International Papillomavirus Conference (IPV) 8-14 May 2009; Malmo, Sweden VE (96.1%CI) against HPV-16/18 CIN2+ in the ATP- E was 92.9% (79.9;98.3) in the pre-defined primary analysis 10A: Skinner SR et al. Cross-protective efficacy of Cervarix against oncogenic HPV types beyond HPV-16/18. Abstract presented at the 25 th International Papillomavirus Conference (IPV) 8-14 May 2009; Malmo, Sweden 1B: Page 1; results ; lines 1-3 1C: Page 1; results ; lines 6-7 1D: Page 1; results ; lines A: Page 1; results ; lines B: Page 1; results ; line 11 9A: Page 2; results ; lines A: Page 1; paragraph 3 results ; lines 7-9 Overall VE against CIN2+ associated with 14 oncogenic types, including vaccine types (HPV- 16/18/31/33/35/39/45/51/52/56/58/59/66/68) was 77.7% (63.5, 87.0; p <0.0001). Page 7

8 2 Rates of serious adverse events and medically significant conditions were similar between study and control groups. 2 The efficacy demonstrated against any lesion, regardless of HPV type in women with or without prior infection, was greater than would be expected for a vaccine targeting only HPV types 16 and Results from a third study also presented in Malmö show Cervarix provides high and sustained antibody levels against HPV 16 and HPV 18 through the 7.3 years of follow-up after vaccination. This is the longest follow up reported to date for any licensed cervical cancer vaccine. 2 Immune response and protection are closely linked 9B: Paavonen J et al. Final phase III efficacy analysis of Cervarix in young women. Abstract presented at the 25 th International Papillomavirus Conference (IPV) 8-14 May 2009; Malmo, Sweden Rates of adverse events (including serious adverse events and medically significant conditions) were generally similar between groups. 11: Smith J S et al. Human papillomavirus type distribution in invasive cervical cancer and highgrade cervical lesions: A meta-analysis update. Int J Cancer 2007; 121: In summary, this meta-analysis suggests that a prophylactic vaccine against HPV 16/18 has the potential to prevent more that two-thirds of worldwide invasive cervical cancer (ICC) and half of high-grade intraepithelial lesions (HSIL) 12: De Carvalho N et al. Immunogenicity and safety of HPV-16/18 AS04-adjuvanted vaccine up to 7.3y. Abstract presented at the 25 th International Papillomavirus Conference (IPV) 8-14 May 2009; Malmo, Sweden The HPV-16/18 AS04-adjuvanted vaccine offers high and sustained antibody levels and 100% seropositivity against both HPV-16 and HPV-18 up to 7.3 years after vaccination with a favourable safety profile. This is the longest follow-up reported for any licensed HPV vaccine. 2B: Stanley M et al. Chapter 12: Prophylactic HPV vaccines: Underlying mechanisms. Vaccine. 2006; 24 Suppl 3:S Nonetheless, the overall data consistently show that L1 VLPs induce high levels of serum neutralising IgG, and the results of VLP vaccination both in animal infections and clinical trials support the notion that it is this activity that is critical for protection. 3B: Giannini SL et al. Enhanced humoral and memory B-cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/aluminium salt combination (AS04) compared to aluminium salt only. Vaccine.2006; 24: Based on studies in pre-clinical models, an effective L1 VLP based prophylactic vaccine designed to protect against HPV persistent infection and subsequent cervical lesion development will need to induce strong humoral immune responses. Preclinical models predict that induction of high levels of neutralising antibody following vaccination with L1 VLPs will be important for an efficacious prophylactic vaccine. 4B: Inglis S et al. Chapter 11: HPV vaccines: Commercial Research & Development. Vaccine. 2006;24 Suppl 3:S99-S105 The successful animal studies suggested that, at a minimum, a vigorous antibody response to the L1 protein of HPV would be required for a successful vaccine and that sustained detectable levels of antibody at the site of primary infection would be necessary for continued protection. 5B: Villa LL. Vaccines against papillomavirus infections and disease. Rev Chilena Infectol. 2006; 23: Vaccines to prevent HPV infection aim to induce 9B: Page 2; results ; lines : Page 624; column 2;, lines : Page 2; conclusions ; lines 1-4 2B: Page S3/109; column 1, paragraph 1, lines B: Page 2; column 1; paragraph 3; lines 1-8 4B: Page S3/101; paragraph 2; lines 1-5 5B: Page 158; Page 8

9 neutralizing antibodies directed to conformational epitopes of capsid proteins, which most probably will be type specific. The protection against infection depends on the amount of antibodies produced by the host, its availability at the infection site and the persistence of the neutralizing antibodies along time. column 2, paragraph 2, lines 1-7 6B: Banatvala J, Van Damme P, Oehen S. Lifelong protection against hepatitis B: the role of vaccine immunogenicity in immune memory. Vaccine 2000;19(7-8): Long-term protection against hepatitis B (HB) disease is dependent on persistence of a strong immune memory.the strength of immune memory and of subsequent secondary immune response can therefore be predicted by the antibody response following primary vaccination. 7B: Banatvala JE, Van Damme P. Hepatitis B vaccine -- do we need boosters? J Viral Hepat 2003;10(1):1 6 6B: Page 877, Abstract section 7B:: Page 1, Summarpy section protection is dependent on immune memory Page 9

10 2 Cervarix provides protection against the most common cancer-causing virus types - HPV 16 and 18 2 [Cervarix] is the only vaccine to provide additional, type-specific protection against persistent infection caused by HPV 45 and HPV 31 3 The efficacy and safety results from the interim analysis of the HPV 008 study were previously published in the Lancet 3... HPV 45 and HPV 31, which, along with type 33, are the most common cancer causing HPV types after 16 and 18 worldwide 9B: Paavonen J et al. Final phase III efficacy analysis of Cervarix in young women. Abstract presented at the 25 th International Papillomavirus Conference (IPV) 8-14 May 2009; Malmo, Sweden VE (96.1%CI) against HPV-16/18 CIN2+ in the ATP- E was 92.9% (79.9;98.3) in the pre-defined primary analysis 10B: Skinner SR et al. Cross-protective efficacy of Cervarix against oncogenic HPV types beyond HPV-16/18. Abstract presented at the 25 th International Papillomavirus Conference (IPV) 8-14 May 2009; Malmo, Sweden VE (96.1% CI; p-value) against CIN2+ was: 100% (82.2, 100; p<0.0001) for HPV-31/45... Crossprotection was further substantiated by VE against individual HPV types including 31&45. 13: Paavonen J et al. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet 2007; 369: See full paper 14A: Bosch X et al. Epidemiology and Natural History of Human Papillomavirus Infections and Type-Specific Implications in Cervical Neoplasia. Vaccine 2008; 26S: K1 K16 Figure 4. Type-specific HPV prevalence across the spectrum of HPV related cervical diagnoses. Multiple infections counted several times. ADC: Adenocarcinoma; HSIL: High squamous intraepithelial lesions; SCC: Squamous cervical carcinoma 9B: Page 2; results ; lines B: Page 1; paragraph 3 results ; lines : See full paper 14A: Page 8; Figure 4 3 Cervarix was specifically designed with a novel adjuvant, AS04, to deliver high and sustained levels of antibodies aimed at providing long-term protection against the most common and aggressive HPV types 3 Cervarix has been shown to be generally well tolerated. The most common symptoms after vaccination included pain, redness and swelling at the injection site. 15. Aguilar JC. Vaccine adjuvants revisited. Vaccine 2007; 25: This vaccine develops more rapid, intense and long lasting immune response compared with control vaccine in these high-risk groups, showing safety and clinically acceptable local reactions similar to other licensed hepatitis B vaccines. The AS04 adjuvant formulation has been tested as part of a promising HPV vaccine development. 16: Descamps D, Hardt K, Spiessens B et al. Safety of human papillomavirus (HPV)-16/18 AS04 adjuvanted vaccine for cervical cancer prevention: a pooled analysis of 11 clinical trials. Human Vaccine, 2009; 55: 1-9. In conclusion, analysis of this large database shows the HPV-16/18 ASO4-adjuvanted cervical cancer 15: Page 3757; ; lines : Page 1; column 1; paragraph 1; Page 10

11 vaccine to have favourable safety profile in women of all ages. The incidence of solicited local symptoms (pain, redness and swelling at the injection site) reported during the 7-day period after each vaccine dose is shown in Table 1. lines Page 2; paragraph 4; lines 3-5 Page 11

12 3 Approximately 100 types of human papillomavirus have been identified to date 3 Approximately 100 types of human papillomavirus have been identified to date and, of these, approximately 15 virus types are known to cause cervical cancer 4 HPV types 16 and 18 are responsible for approximately 70 percent of cervical cancers globally, with types 45, 31 and 33 among the next most common cancercausing HPV strains. 12B, WHO. Expert Committee on Biological Standardization. Guidelines to assure the quality, safety and efficacy of recombinant Human Papillomavirus virus-like particle vaccines, accessed on 27/3/2009 at _2006.pdf Over 100 different types of HPV have been identified and molecularly characterized. 18: Muñoz N et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003; 348: Our epidemiologic classification, based on HPVtype specific odds ratios and HPV prevalence among patients and controls, identified 15 HPV types as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82). 14B: Bosch X et al. Epidemiology and Natural History of Human Papillomavirus Infections and Type-Specific Implications in Cervical Neoplasia. Vaccine 2008; 26S: K1 K16 Figure 4. Type-specific HPV prevalence across the spectrum of HPV related cervical diagnoses. Multiple infections counted several times. ADC: Adenocarcinoma; HSIL: High squamous intraepithelial lesions; SCC: Squamous cervical carcinoma 17: Page 3; ; lines : Page 524; column 2; ; lines B: Page 8; Figure 4 19: Cohen J. High Hopes and Dilemmas for a Cervical Cancer Vaccine. Science 2005; 308: Bosch helped conduct an IARC coordinated study published last year in the International Journal of Cancer that examined the HPV types detected in more than 3000 women from 25 countries who had cervical cancer. The researchers found relatively modest geographical differences, with two types, HPV 16 and 18, occurring in more than 70% of the cases. 19: Page 619 ; paragraph 3 ; lines 1-9 Page 12

13 4 Worldwide, more than 500,000 women will be newly diagnosed and more than 280,000 women will die. 20A 20B: World Health Organization. Initiative for Vaccine Research. Accessed on April 20, Disease burden: Human Papillomavirus (HPV) causes cervical cancer, and is the second biggest cause of female cancer mortality worldwide with 288,000 deaths yearly. About 510,000 cases of cervical cancer are reported each year with nearly 80% in developing countries: in Africa, in Latin America, and in Asia. 20A: Page 1, Disease burden, Lines B: Page 1, Disease burden, Lines 1-3 Page 13