Vaccine Trial Centre. Established in1984 Funded by WHO on Control of Diarrhea Diseases Full operation in1986

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Lesley Newman
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1 Vaccine Trial Centre Established in1984 Funded by WHO on Control of Diarrhea Diseases Full operation in1986

2 Past 29 Years of Research Experiences Cholera Vaccine Killed whole cell and B sub-unit oral vaccine CVD103-Hg resistant oral vaccine Rotavirus Vaccine- Rotashield (tetravalent oral vaccine) Poliomyelitis Vaccine (OPV & IPV) Malaria Vaccine Varicella Vaccine Measles Vaccine Cholera challenge-o1, O139 WRSS1 Shigella Vaccine HPV quadri-valent vaccine, nona- valent vaccine H1N1 LAIV vaccine (WHO) H5N2 LAIV Vaccine (WHO)

3 HIV Vaccine rgp 120 B, rgp 120 B/E ALVAC HIV Vaccine & rgp 120 B/E (Phase I/ II and III (RV144) RV305 RV306 Collaboration AFRIMS US, Thai MHRP Military HIV Research Program MOPH Chulalongkorn University Chiangmai University

4 VTC Project Timeline Projects Phase I/II trials Phase III trials Surveillance Elderly flu vaccine RV306 GPO Avian Flu Vaccine-V02 RV305 Dengue CYD14 Dengue CYD34 V Nonavalent HPV vaccine in Preadolescents and Adolescents live attenuated influenza vaccine (PLAIV) V Nonavalent HPV vaccine Safety, Immunogenicity and Efficacy Studies of WRSS1 Measurement of Anogenital Wart Burden and Cost of Illnesses Herpes Zoster and Post-Herpetic Neuralgia Associated Establishment of a Shigella sonnei Challenge Model for Evaluation HIV-1 CM235 env/cm240 gag/pol vaccine HIV-1 gag DNA with or without IL-12 DNA Assessing the psychosocial burden in woman with abnormal pap Efficacy of GARDASIL in mid adults, HPV vaccine MRKAd5 HIV-1 vaccine ALVAC-HIV vaccine + gp 120 B/E vaccine boost Immunogenicity and Safety of Quadrivalent, HPV vaccine in young adults ALVAC-HIV vaccine + oligo gp 160 or gp 120 B/E vaccine boost ALVAC-HIV vaccine + gp 120 B/E vaccine boost Cholera Challenge in volunteers using frozen V.cholera 0139 bacteria AIDSVAX B/E gp 120 alum subtype B/E (AIDSVAX B/E) gp 120 MF 59 subtype B alone or with subtype E gp 120 alum subtype B Total-27

5 Number of publications Publications during Total = year

6 79 Vaccine 2010; 28(4): Most Cited Publications (Publications during ) 104 J Infect Dis 2004; 190: Clin Infect Dis 2006; 42(12): J Antimicrob Chemother 2005; 56: PLoS Med 2005; 2(10): J Virol 2009; 83(14): Lancet 2009; 373(9679): N Engl J Med 2012;366(14): J Infect Dis 2006; 194(12): Science 2009; 326(5950): N Engl J Med 2009; 361(23):

7 HIV-1 Vaccine Clinical Trials in Thailand

8 1) Injecting Drug users (IVDUs) A Phase I/II AIDSVAX TM monovalent vaccine B Phase I/II AIDSVAX TM B/E bivalent vaccine C Phase III AIDSVAX TM B/E vaccine

9 2) Healthy, Community participation A Phase I/II Chiron gp120/mf59 subtype E antigen alone or combined with B antigen B Phase I/II ALVAC vaccine(vcp1521) prime AIDSVAX TM vaccine boost C Phase III of AlVAC priming and AIDSVAX boosting (RV144) D Phase I MRK HIV-I Vaccine E RV305 F RV306

10 AIDSVACCINE Trial IN THAILAND HIV-1 CM235 env/cm240 gag/pol vaccine HIV-1 gag DNA with or without IL-12 DNA phis-hiv-ae (DNA) and rfpy-hiv-ae MRKAd5 HIV-1 vaccine ALVAC-HIV vaccine + gp 120 B/E vaccine boost RV305 RV306 ALVAC-HIV vaccine + oligo gp 160 or gp 120 B/E vaccine boost ALVAC-HIV vaccine + gp 120 B/E vaccine boost AIDSVAX B/E gp 120 alum subtype B/E (AIDSVAX B/E) gp 120 MF 59 subtype B alone or with subtype E gp 120 alum subtype B gp 120 MF 59subtype B Peptide V3-MAPS

11 PREVENT ESTABLISHED INFECTION? *****

12 Immune responses against HIV Jhonston M and Fauci A. NEJM,2007,May17;356(20):

13 Scientific and Non-scientific Obstacles to the Development of an HIV Vaccine Clearance of HIV in an HIV-infected individual has not been demonstrated, suggesting that the innate and adaptive immune defense system cannot overcome the virus. Extensive viral subtype and sequence diversity limits the efficacy of current vaccine approaches to specific subtypes. Rapid changes in HIV genetic sequences as well as phenotypic features allow HIV to escape from immune suppression. Source: Adapted from Barouch (2008)

14 Super infection suggests that immune responses induced by one virus have no protective activity against the subsequent infection. There is a narrow window of opportunity for the immune system to clear initial infection before establishment of latent viral reservoirs. Immune correlates of protection remain poorly understood. Viral escape from humeral and cellular immune responses may limit sustained efficacy. Source: Adapted from Barouch (2008)

15 Obstacles to the Development of an HIV Vaccine Conserved antibody targets on the outer envelope protein are hidden. Appropriate animal models that can truly predict efficacy in humans are lacking. The interest of the pharmaceutical industry is limited. Long-term sustained commitment from governments and donors is limited. Source: Adapted from Barouch (2008)

16 Recombinant protein (gp120) AIDSVAX B/B or B/E DNA Live-recombinant vectors Using Ad5 Virus MRKAd5 Or ALVAC virus (bird pox virus) ALVAC HIV vaccine

17 Efficacy studies thus far Study Year Population Vaccine Vaccine Efficacy VAX 003, IDUs(Thailand) MSM(North America) AIDSVAX Vax % (95% CI:30.8%-23.8%) STEP Seronegative high risk voulnteers, US MRKAd5 24/741 V became HIV-1 infected VS 21/762 P Hazard ratio 1.2 (95% CI ) RV Community risk HVTN Thailand HIV-negative men and transgender women who have sex with men, US ALVAC, AIDSVAX DNA, MRKAD5 31.2% (95% CI: p-value: 0.04) 41 HIV infection in volunteers receiving vaccine and 30 cases in those receiving placebo. Pitisuttithum, et al. JID 2006 M Robertson, et al. Available at Supachai Rerks-Ngarm, et al. N Engl J Med 2009 HVTN505: SOURCE:

18 RV144: Prime - Boost strategy using two different vaccines:for inducing both humeral and cell mediated immunity Prime Vaccine: ALVAC-HIV (vcp1521) from Sanofi Pasteur Recombinant canarypox virus expressing the product of HIV-1 env, gag and protease genes gp120 env from Thai subtype E (92TH023) gp41, gag, and protease from LAI (subtype B) Booster vaccine: AIDSVAX B/E from VaxGen Inc. Recombinant gp120 from MN(subtype B)and A244 (subtype E)

16,402 HIV-negative men and women were enrolled. 13,978 participants had completed full series of vaccinations HIV test, risk assessment and counseling 0.

19 16,402 HIV-negative men and women were enrolled. 13,978 participants had completed full series of vaccinations HIV test, risk assessment and counseling (time in years) 6-month vaccination schedule 3 years of follow-up (every 6 mo.) ALVAC -HIV (vcp1521) priming at week 0, 4, 12, 24 AIDSVAX B/E gp120 boosting at week 12, 24

Challenges in site preparation Require massive infrastructure strengthening, capacity building (8 clinical sites at the district level) Personnel and staffing : training of

20 Challenges in site preparation Require massive infrastructure strengthening, capacity building (8 clinical sites at the district level) Personnel and staffing : training of various level of staffs on GCP, Protocol, SOP etc. (120 full time and 200 part time ) Establishing Trial Registry and Repository Center at MOPH (>100,000 specimens were collected)

21 HIV ELISA with electronic reporting system with VALIDITY system at AFRIMS Vaccine depository center (approx.109,000 vaccine vials delivered and kept in batches) Data management with Data fax,validating system at Mahidol U.( millions pages of case report forms)

22 Role of VTC staffs & CRC(s) Enrollment Vaccination Reactogenicity, AE(s), SAE(s), documentation, reporting and follow up

23 Clinical Team VTC SI MD Supervisor - 5 VTC CRC - 5 CRC - CRC 5/site - Pharmacist 2/site - RA 2/site MD Director-MOPH Nurse (6-10/site) Total 150 full time staff and 200 part times

24 Clinic Activities Inform consent process Video presentation, Group discussion Individual discussion Mini exam T/F and need to get 80% marks before signing consent form

25 RA Registry VDO informed consent

26 Group informed consent Individual Informed Consent

27 Urine Pregnancy Test (Only Female) Vital Signs

28 Medical History and Eligibility Check Blood Draw

29 VACCINE STORAGE VACCINE CODE

30 PHARMACIST DOCUMENTATION &preparation

31 Training CRC, RA, Pharmacist

32 Screening all sites (N = 26,658) Male 15,973 (60%) Female 10,685 (40%) Enrollment all sites (N = 16,402) Male 10,068 (61%) Female 6,334 (39%) Participants with age under 20 yrs (N =2,540) Male 1,658 (65%) Female 882 (35%) 13,977 volunteers received all 4 vaccinations 90% follow up at three years

Retention and clinical activities at the sites ( started from 2005) Provider based system 16,402 volunteers Enrolled 24-hour phone access Mailing and phone reminders Edutainment campaigns/

33 Retention and clinical activities at the sites ( started from 2005) Provider based system 16,402 volunteers Enrolled 24-hour phone access Mailing and phone reminders Edutainment campaigns/ interactive games Extend Service Hours on Sunday and one evening clinic per week 90% interval Retention Mobile unit activities Tracking activities (Home visit) Volunteer Relation, Club activities Cultural activities Quarterly exhibition with educational boards

34 Provider based system: The volunteers are entitled for receiving care and follow up continuously by the same staff. This was aimed to establish closed relation between the volunteers and clinical staff and to increase volunteers satisfaction of services. Volunteer satisfaction survey was conducted in 1,523 volunteers at clinical sites ( from 13/09/06 to 27/09/06). 1,141 volunteers (93%) expressed their satisfaction in provider based system.

Reminders : letter and phone call: This was carried out continuously since the beginning of the trial 71,583 reminder phone calls were made (average 3,974 calls per month).

35 Reminders : letter and phone call: This was carried out continuously since the beginning of the trial 71,583 reminder phone calls were made (average 3,974 calls per month). Among these phone calls, 69% of those contacted by phone said they will come to the clinics on the scheduled visits. 30% postponed visits For letter: average 1,973 letters per month were sent out (data collected from June 2006-December 2007).

36 Twenty-four hours access by phone: Every volunteer could call CRC/RA 24 hours when needed (only 7 month data were collected) 5,646 incoming calls were made from the volunteers after working hours. 56% wanted to confirm or change appointments. 6 % consulted about medical problems. 5% notified the changes of contact information. (data collected only after working hours from December 2006 to June 2007)

37 Educational campaigns / interactive games: Aim to increase knowledge, social value of vaccine research,participating and develop interpersonal relation between volunteers and clinic staff Exhibit educational boards every 1-3 months Provide games for the volunteers with questions and answers about the vaccine trial &important of follow up 1,437 volunteers participating in Question & Answer activities (arranged periodically), 93% of the volunteers answer correctly on their roles and responsibilities. (data collected from June 2006-December 2007)

38 Volunteer Relation Activities to create sense of ownership of the trial among the volunteers to establish communication channels and closer relationships among the volunteers and trial staff to strengthen the relationship among the trial volunteers from different sites and link them togethe They were facilitated by the district health office, MOPH,VTC-CRC, and NGOs

39 Cultural activities: Arrange cultural activities and seasonal activities such as New Year festival, Valentines day, Thai New Year, World AIDS day (data collected from June 2006-December 2007). Volunteer relation activities: 38 volunteer clubs were established in 2006 They were facilitated by VTC staff. the district health office, MOPH, and NGOs. Included voluntary community services such as Beach cleaning day, Traffic accident reduction campaigns, sport days, green campaigns etc.

40 Volunteer relation activities Cultural activities and Educational campaigns Buddhist ceremony Mother s day

41 Activities outside Clinical site: Mobile activites (Home visit): Home visit were done for missed appointment volunteers both within and outside study area for those volunteers consented for home visit. Aim to visit and encourage the volunteers to come for activities at clinical site 2,116 visits performed by mobile units. 55% were done in the other provinces. 45% were done within the study area ( data collected from July 2006 to December 2007)

42 Mobile unit activities Home visit activities

43 Community Engagement Activities Pre screening and Screening period Follow up phase Pre and post announcement of the interim analysis Pre and post announcement of the final results 43

the trial, need to follow up Community engagement implements in routine health campaigns

44 Community Activities Community health forum ( approximately 400 community Health Fora) for disseminating trial information and the understanding of HIV vaccine, update the status of the trial, need to follow up Community engagement implements in routine health campaigns Health fairs, campaigns Mobile unit health check up Community Advisory Board - meeting bimonthly

45 Together with recent results of community trial 2009,Nov19

47 Although protective efficacy was 31.2% 42 months after first vaccination, the highest efficacy was observed at ~12 MO. Proportional Hazard Model Calculations 12 months: 60% (Cox PH, 95% CI = 22, 80) 42 months: 31.2% (Cox PH, 95% CI = 1.1, 52.1) Kaplan Meier (KM) Efficacy Estimate (Vaccine/Placebo) at 6 Month Intervals

48 First Sign of Success for HIV VAccine R&D: The Thai HIV Vaccine Study (RV144) First HIV vaccine to show modest effectiveness in preventing HIV in humans. Demonstrated 31.2% efficacy at end of study (3.5 years)

49 RV144 Summary resutls( ) C1 V1 V2 C2 V3 C3 V4 C4 V5 C5 GP41 Modest efficacy No impact on post- 50 infection VL or CD4 32% -CTL:CD4 > CD % of breakthrough viruses CRF01_AE Early effect wanes responses 90% -Mainly bab detected and decreases rapidly Binding AB was directed to V2 Weak neutralizing antibody responses RV 144 RV September 2012

50 ADCC stimulated by RV144 vaccines Qualitatively similar to anti-hiv-1 responses observed during chronic HIV-1 infections May have been partly responsible for the modest degree of protection observed. Bonsignori M, Pollara J,--, Haynes BF. J Virol Nov;86(21): Confidential not for distribution 27 June 2011

51 gp70 V1-V2 Antibody Levels Inversely Correlated with the Rate of HIV Infection Vaccine Group Low/Medium V2 Response High V2 Response (Lesser the HIV infection risk) 51 Logistic regression model accounting for the sampling design: Estimated relative risk = 0.57 per sd increment in V2 response (p=0.015) 43% lower infection rate per sd increase 10 September 2012

52 Summary for Correlates of Risk and Sieve analysis IgG to gp70v1v2 (43% decrease in infection risk) IgA to Env panel (54% increase in infection risk).

53 Future HIV VACCINE clinical R&D Developing vaccines that induce both CD4 and CD8 responses (and different subsets of these responses), together with broad neutralizing antibodies Getting a better sense of what s happening at the mucosal sites of exposure the T-cell responses were measured mainly in the blood, which may or may not be indicative of the quality and magnitude of responses at the mucosal sites of sexual exposure.

Building on RV144: A Regional Vaccine Strategy RV305: Secondary Boost RV306: 1 year boost Phase IIb/III Efficacy: Phase III: Thai community risk or MSM highrisk Trials are

54 Building on RV144: A Regional Vaccine Strategy RV305: Secondary Boost RV306: 1 year boost Phase IIb/III Efficacy: Phase III: Thai community risk or MSM highrisk Trials are primeboost regimens with secondar y boost HIV test, risk assessment and counseling ALVAC prime (0, 4, 12, 24, 52 wk) AIDSVAX boost (12, 24, 52 wk) 54

55 Complete vaccination, FOLLOW up continue

56 RV306 Schedules ALVAC -HIV (vcp1521) or placebo AIDSVAX B/E gp120 or placebo 27/3 Group 1 100/10 Group 2 100/10 Group 3 0 months /10 Group 4 MHRP

57 Bridging to the Next Efficacy Study RV144 Next Efficacy trial Immunogenicity Boosting regimen at one year with adjuvanted vaccines CohortsM SM Bridging Phase 1 Phase 2

58 AVEC What are the steps from RV144 to a licensed vaccine? Licensure (?) Two trials: southern Africa (clade C) and Thailand Higher incidence (risk) hetero-sexual populations and MSM Better immunogens + new adjuvant + extra boost = higher VE 58 Antibody against V1V2 reduces infection risk RV144: 31% efficacy at 42 months, 60% at 12 months, low risk population

59 AVEC seeks to develop Thai vaccine production (or biologics) capability in general and HIV vaccine production specifically AVEC reduces risk through Thai government support leveraged by other funding support

60 Opportunities &Challenges for Future Vaccine Trials Target population at risk : MSM Vaccine : improve the constructs able to induce broad neutralizing antibodies Multiple doses AND COMPLEX regimen / delivery methods-retention, compliance Issues of HIV induced positivity- rate and duration of positivity Available of diagnostic test kits for true infection in setting of host countries

61 Community education and engagement on social value and scientific validity is very critical Funding supports Political commitment

62 C T V VTC Vitality Team Excellence Creativity

HIV Vaccine. 15 September 2016 นพ.นคร เปรมศร ผ อ านวยการส าน กงาน โครงการศ กษาว คซ นเอดส ทดลอง

HIV Vaccine. 15 September 2016 นพ.นคร เปรมศร ผ อ านวยการส าน กงาน โครงการศ กษาว คซ นเอดส ทดลอง HIV Vaccine 15 September 2016 นพ.นคร เปรมศร ผ อ านวยการส าน กงาน โครงการศ กษาว คซ นเอดส ทดลอง GLOBAL STATISTICS 2015 17 million people were accessing antiretroviral therapy 36.7 million people globally