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Punnee Pitisuttithum - MBBS, DTM&H,FRCPT Faculty of Tropical Medicine , Mahidol University

Clinical Evaluation of Pandemic Live Attenuated Influenza Vaccine (PLAIV) Candidate Strain A/17/CA/2009/38 (H1N1) in Healthy Thais. Punnee Pitisuttithum - MBBS, DTM&H,FRCPT Faculty of Tropical Medicine , Mahidol University August 17,2011, Salaya,MU.

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Punnee Pitisuttithum - MBBS, DTM&H,FRCPT Faculty of Tropical Medicine , Mahidol University

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  1. Clinical Evaluation of Pandemic Live Attenuated Influenza Vaccine (PLAIV) Candidate Strain A/17/CA/2009/38 (H1N1) in Healthy Thais PunneePitisuttithum - MBBS, DTM&H,FRCPT Faculty of Tropical Medicine , MahidolUniversity August 17,2011, Salaya,MU

  2. WHO-Major approaches to increasing supplies of pandemic influenza vaccine • Develop regional and national plans for seasonal influenza vaccination programmes • Build a new production facilities in developing and/or industrialized countries • Explore formulations of influenza vaccine other than those commonly used for seasonal vaccination

  3. Live Attenuated Influenza Virus Vaccine

  4. Russian Donor strain

  5. Potential advantages of LAIVs no down-stream processing required (harvested vaccine is simply packaged); high yield (20-50 doses of monovalent vaccine per an egg); needle-free delivery (administration is via an intra-nasal spray), which may facilitate administration in resource-poor settings; induction of a broad immune response including mucosal, systemic and cell-mediated responses (in contrast parenterally administered inactivated vaccines do not induce mucasal immunity); induction of cross-reactive immune responses;

  6. การพัฒนาวัคซีน ขึ้นทะเบียน -ข การทดสอบระยะที่ 3 ประสิทธิผล การทดสอบระยะที่ 2 ความปลอดภัยและภูมิคุ้มกัน การทดสอบระยะที่ 1 ความปลอดภัยในมนุษย์ การศึกษาในสัตว์ทดลอง (ความปลอดภัยและภูมิต้านทาน) การศึกษาในห้องปฏิบัติการ

  7. ในการที่ผ่านแต่ละระยะจะต้องผ่านเกณฑ์ที่กำหนดไว้ตั้งแต่เริ่มต้นในการที่ผ่านแต่ละระยะจะต้องผ่านเกณฑ์ที่กำหนดไว้ตั้งแต่เริ่มต้น -ข

  8. History of LAIV Development in Thailand • 2004 outbreak of H5N1 in Thailand • 2005 Indonesia stop sending flu viruses to WHO • 2006 Serious discussion on equitable sharing of benefits from sharing viruses • 2007 WHO/HQ started supporting developing countries to build up capacity to produce Flu vaccine in 6 countries, including Thailand • 2008 Thailand success in producing first seasonal IIV at 2 doses per egg

  9. May 2009 Sublicensing agreement on LAIV with WHO based on Russian Technology from IEM, St Petersberg • 16th July 2009 received the H1N1 (2009) pre-Master seeds from Russia, through WHO support and start MS, WS, vaccine viruses • August 12thfirst PLAIV vaccine concentrate was harvested • August 25thfirst PLAIV clinical lot filled and tested

  10. H1N1 2009 LAIV A/California/07/2009 (H1N1). X A/Leningrad/134/17/57 (H2N2) A/17/California/2009/38 (H1N1) vaccine Pre master seed

  11. Facility for GMP production of clinical trial lot certified by WHO

  12. Initial Obstracles For production • Less yield, low dose • than expected • SPF eggs-imported • -German, US • -not available in Thailand • -Stabilizer??

  13. PLAIV vaccine intranasal route • Nasal applicator-imported • Need to be available locally

  14. Characterization of candidate vaccines • Vaccine Production-identity(genotype, phenotype);toxicity (mice,guinea pig ferret) • Potency-immune response (mice , ferret) • Stability • Batch release and Independent Laboratory evaluation • Standards and Reference Materials

  15. H1N1 2009 GPO vaccine Pre master seed from Russia Each step required Identity- genotypic, phenotypic Toxicities-mice,guinea pig Immuninty and attenuation in animal model master seed Working seed Virus concentrates Bulk vaccine Vaccine product

  16. วัคซีนไข้หวัดใหญ่ชนิดเชื้อเป็นอ่อนฤทธิ์วัคซีนไข้หวัดใหญ่ชนิดเชื้อเป็นอ่อนฤทธิ์ • มีความไวต่ออุณหภูมิ • เจริญเติบโตได้ในที่เย็น • อ่อนฤทธิ์

  17. การศึกษาในสัตว์ทดลอง 1. ความปลอดภัย • เชื้อไม่ก่อให้เกิดโรค • เชื้อยังคงมีคุณสมบัติ • เติบโตได้ดีในที่เย็น ~ 33oC • ตายเมื่ออุณหภูมิ > 38oC • ยังคงอ่อนฤทธิ์ 2. ระดับภูมิต้านทาน

  18. PRE–CLINICAL STUDY (1) • INFECTIVITY: 7.5–8.5 lg EID50/0.2 ml • IDENTITY (CONFIRMATION OF GENOME FORMULA): 6:2 • GENETIC STABILITY (CONFIRMATION OF STABILITY OF MUTATIONS IN THE GENOME OF VACCINE STRAIN RESPONSIBLE FOR THE ATTENUATION): by Faculty of Science ,MU GMP facility for CLINICAL lot production is at Silapakorn U

  19. PRE–CLINICAL STUDY (2) • ATTENUATION (CONFIRMATION OF THE ts/ca/attPHENOTYPE): ts/ca (IN HENS’ EGG). att(IN MICE). • TOX STUDY: SAFE FOR MICE removal of adventitious agents by Faculty of Medicine, Siriraj,MU • GUENEA PIGS ( by GPO, Fac. Vet, MU) AND FERRETS STUDY (Amsterdam): for Safe & immunogenicity Immune response –at Fac.Medicine,SirirajHosp,MU

  20. WILD TYPE AND COLD–ADAPTED VIRUSES IN FERRETS 8 attenuated 6 non–attenuated 4 lg EID50/mL/gr 2 0 1 2 3 4 5 6 7 8 9 10 Wild type virus Vaccine strain Lungs Nasal turbinates

  21. การทดสอบระยะที่ 3 ประสิทธิผล การทดสอบระยะที่ 2 ความปลอดภัยและภูมิคุ้มกัน สำหรับวัคซีนหวัด การทดสอบระยะที่ 1 ความปลอดภัยในมนุษย์ การศึกษาในสัตว์ทดลอง (ความปลอดภัยและภูมิต้านทาน) การศึกษาในห้องปฏิบัติการ

  22. Phase I/II Safety and Immunogenicity of Pandemic Live Attenuated Influenza Vaccine (PLAIV) Candidate Strain A/17/CA/2009/38 (H1N1) in Healthy Thais PunneePitisuttithum - MBBS, DTM&H,FRCPT Faculty of Tropical Medicine , Mahidol University

  23. Objectives Overall Primary objectives (Part A, Part B) • To evaluate safety and reactogenicity of PLAIV manufactured by GPO, Thailand • To evaluate humoral immune response of the above vaccine after intranasal application by using HAI test, micro neutralization assays • To determine the vaccine induced local IgA response by ELISA Secondary objectives (Part A) • To assess shedding and stability of the viral strain by using PCR method.

  24. Part A: • The study is a double blind randomized study involving 24 participants with the main objective of assessing safety-tolerability and optimal immune response of the newly manufactured PLAIV candidate strain A/17/CA/2009/38 (H1N1). • It is study of two different inoculums sizes of candidate vaccines (5.0-6.5 log10 EID50 or 6.6-7.5 log10 EID50) and given two doses 21 days apart. Vaccine : Pandemic Live Attenuated Influenza Vaccine (PLAIV) Candidate Strain A/17/CA/2009/38 (H1N1) in 5% sucrose (0.5ml intranasally)

  25. Part A • 24 Volunteers • Divided into 2 groups,12 volunteers each group • Group 1 received 5.8 log 10 EID50 • Group 2 received 6.9 log 10 EID50 Vaccine : Placebo = 3:1

  26. Part B: • The study is a double blind randomized study involving 324 participants with the main objective of assessing immune responses and safety of the newly manufactured PLAIV candidate strain A/17/CA/2009/38 (H1N1). • Using the PLAIV of 6.5-7.5 log10 EID50 and given in intranasally two doses 21 days apart.

  27. Table 1.Number of participants in 3 stratified age groups Total =108 each arm

  28. Activities (Part A) Immunization D1,D21 (Two doses) Safety follow up for 7 days after each immunization and D21,D42,D60 Nasal swab D2,3,5,7 Nasal wash D1,21,42,D60 Blood drawn D1,D21,D42,D60

  29. Other systemic reactions will be assessed in 4 scales as follow: 0 - no No symptoms 1 -mild Ill-defined symptoms 2 –moderate Symptoms, affecting normal daily activity 3 -severe Symptoms markedly affecting normal daily activity and needed medication or clinic visit or activity limit

  30. Data & Safety Monitoring Board-Chair-MU (Advised by WHO regional office and TDR) • Monitoring by WHO-TDR • Audit-initial audited by WHO-TDR from Roch • Safety monitoring team appointed by sponsor-Chaired by Prof. Dr. Apornpirom

  31. Results 88 screen (14 re-screened) High titre HAI 16/78 (20.5%) Abnormal CxR 7/88 Other abnormalities 24 Low dose 5.8 (EID 50) High dose 6.9 (EID 50) 12 1st Immunization 12 Abnormal CXR (re-read) 2nd Immunization 11 12 (2) Delayed Immunization (URI)-PCR for seasonal and pandemic flu-negative

  32. Reactogenicity –Part A • One had fever from the high dose group(38 oc) • Few reported cough ,scratchy throat and myalgia from both groups and also the placebos. • Reactogenicity declined after second immunization

  33. Immunological Measurements (Siriraj Hospital) Specific antibodies analysis includes specific anti-influenza antibodies to the vaccine strain (HAI test, ELISA, micro-neutralization assay). HAI assay • Sera were pre-treated with receptor destroying enzyme and were tested for hemagglutinin-inhibition (HI) antibodies using standard procedures and whole influenza A and B viruses homologous to the vaccine strains in a standard micro-titer assay

  34. 40 Samples were sent to NSBC –WHO reference lab: different in HI titre, the NSBC results in relatively higher titer. Micro-neutralization assay mNT was performed in MDCK cell monolayer using the local isolate, A/Thailand/104/2009(H1N1) as well as A/CA/07/2009(H1N1) as the test viruses. sIgA in the nasal wash - Nasal wash specimens were tested for influenza virus specific IgA antibodies using an enzyme-linked immunosorbent assay (ELISA).

  35. Nasal swab samples were collected on D2, 3, 5 and 7after each vaccination. • Viral shedding in nasal swab samples was determined by real time RT-PCR for M geneusing CDC protocolfor the 2009 pandemic influenza virus. • Sensitivity of detection is limited to 10-100 copies/reaction. • RNP was used as the house keeping gene.

  36. Conclusion • LAIVCandidate Strain A/17/CA/2009/38 (H1N1) • appeared to be safe in small number of healthy • adults • Viral shedding rate was low since it was • found only in two cases at D2 afterfirst vaccination. • In term of immune responses , it is difficult to • conclude since the sample size was small and there • may be other immune responses that should be • measured other than HAI and MN for LAIV vaccine • for example local IgA or cell mediated immunity

  37. DSMB recommendation: • No safety concern • Continue as planned to children and middle age group

  38. Phase I/II Safety and Immunogenicity of Pandemic Live Attenuated Influenza Vaccine (PLAIV) Candidate Strain A/17/CA/2009/38 (H1N1) in Healthy Thais PunneePitisuttithum MB,BS, DTM&H,FRCP(T) Faculty of Tropical Medicine , Mahidol University 17-18 Feb 2011.Geneva Part B

  39. Study Design • It is a double blind randomized study using the 6.6-7.5 log10 EID50 dose (stabilizer is similar to Medimmune) • 324 participants (243 vaccines and 81 placebos) will be enrolled Vaccine: Placebo = 3:1 (108 each group)

  40. Activities • Immunization D1,D21 vaccine • using stabilizer which • is similar to Med Immune LAIV vac • Safety follow up for 7 days • after each immunization,D21,42,60 • Nasal wash D1.D21,42,60 • (ONLY 40 IN ADULT GROUP) • Blood drawn D1,21,42,60

  41. GPO FLU VACCINE -01 Part B Total Screen = 1048 cases Total enroll = 363 cases Not eligible = 685 cases Rescreen = 40 cases Group I (Age > 12-18) Total Screen = 404 cases(male= 195, female= 209) ; Rescreen = 6 cases Total enroll = 110 cases (male= 49, female= 61) Not eligible = 294 cases (HI Titer=234, *Others = 60) Group II (Age ≥ 18-49) Total Screen = 267 cases(male= 101, female= 166) Total enroll = 110 cases (male= 44, female= 66) Not eligible = 157 cases (HI Titer=82, *Others = 75) Screen Group II replace Group I Total Screen = 21 cases(male= 1, female= 20); Rescreen = 10 cases Total enroll = 10 cases (male= 0, female= 10) Not eligible = 11 cases (HI Titer=5, *Others = 6) Group III (Age ≥ 49) Total Screen = 356 cases(male= 63, female= 293) ; Rescreen = 24 cases Total enroll = 133 cases (male= 18, female= 115) Not eligible = 223 cases (HI Titer=56, *Others = 167) *(Others ; Abnormal CXR , Anemia, HBsAg +ve, HCV +ve, chronic disease, High AST, ALT, CPK , Abnormal urine, etc…)

  42. 40% reported AE suspected to be related to the vaccine and equally distributed in all three age groups Blinded data only those reported AEs are shown in the graph

  43. Common AE suspected to be related to the treatment were rhinorrhea (8%) • throat irritation (5%), • nasopharyngitis (8%) • cough(4%) • and upper respiratory tract infection (1%) • The majority were mild,19% reported as moderate and only 2% reported severe in intensity • There is no serious adverse event (SAE) reported in part B

  44. Comparison of Local Reaction Post Immunization (from total volunteers) majority were mild grade 29% 27.5% Subjects, % 21% 19% 16% 14% 11% 14% 13% 13% 10% 11% 6% 5.8% 5% 1% 1.8%

  45. Comparison of Maximum Grade of Local Reaction at Post Immunization separate by age group 1st immunization 2nd immunization Mild Subjects, % Subjects, %

  46. Comparison of Fever - Post Immunization (from total volunteers) Subjects, % N=6% N=2% N=0.6%

  47. Comparison of Systemic Reaction Post Immunization (from total volunteers) 19% Subjects, % 17% 13% 11% 9% 10% 9% 7% 7% 7% 7%0 6% 6% 0.03%

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