Vaccine Trial Centre

Established in1984 Funded by WHO on Control of Diarrhea Diseases Full operation in1986 Past 29 Years of Research Experiences • Cholera Killed whole cell and B sub-unit oral vaccine CVD103-Hg resistant oral vaccine • - Rotashield (tetravalent oral vaccine) • Poliomyelitis Vaccine (OPV & IPV) • • Cholera challenge-O1, O139 • WRSS1 Shigella Vaccine • HPV quadri-valent vaccine, nona- valent vaccine • H1N1 LAIV vaccine (WHO) H5N2 LAIV Vaccine (WHO) 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 VTC Project Timeline 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13 14 Projects Elderly flu vaccine RV306 GPO Avian Flu Vaccine-V02 RV305 Dengue CYD14 Dengue CYD34 V503-002 Nonavalent HPV vaccine in Preadolescents and Adolescents live attenuated (PLAIV) V503-001 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 ™ 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 Phase I/II trials Phase III trials Surveillance Publications during 2004-2013

16 14 Total = 75 12 10 8

6 Number of publications of Number 4 2 0 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 year Most Cited Publications (Publications during 2004-2013) 79 Vaccine 2010; 28(4):950-7. 104 J Infect Dis 2004; 190:702-6. 137 Clin Infect Dis 2006; 42(12):1726-34.

143 J Antimicrob Chemother 2005; 56:745-755.

185 PLoS Med 2005; 2(10):390. 185 J Virol 2009; 83(14):7337-48. 266 Lancet 2009; 373(9679):1949-57. 294 N Engl J Med 2012;366(14):1275-86. 416 J Infect Dis 2006; 194(12):1661-1671. 663 Science 2009; 326(5950):285-9. 1274 N Engl J Med 2009; 361(23):2209-20. HIV-1 Vaccine Clinical Trials in Thailand 1) Injecting Drug users (IVDUs)

A. 1995 Phase I/II AIDSVAXTM monovalent vaccine B. 1998 Phase I/II AIDSVAXTM B/E bivalent vaccine C. 1999 -2003 Phase III AIDSVAXTM B/E vaccine 2) Healthy, Community participation A. 1998 Phase I/II Chiron gp120/MF59 subtype E antigen alone or combined with B antigen B. 2000 Phase I/II ALVAC vaccine(vCP1521) prime AIDSVAXTM vaccine boost C. 2003- 2009 Phase III of AlVAC priming and AIDSVAX boosting (RV144) D. 2003- 2009 Phase I MRK HIV-I Vaccine E. 2012-2014 RV305 F. 2013- RV306 AIDSVACCINE Trial IN THAILAND

94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13 RV306 RV305 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

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 PREVENT ESTABLISHED ? ***** Immune responses against HIV Jhonston M and Fauci A. NEJM,2007,May17;356(20):2073-81 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 . • 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) • 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) Obstacles to the Development of an HIV Vaccine

• Conserved 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) 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 Efficacy studies thus far

Study Year Population Vaccine Vaccine Efficacy

IDUs(Thailand) VAX Vax003-0.1% 1997-02 MSM(North AIDSVAX 003,004 (95% CI:30.8%-23.8%) America) 24/741 V became HIV-1 infected VS Seronegative high STEP 2005-07 MRKAd5 21/762 P risk voulnteers, Hazard ratio 1.2 US (95% CI 0.6-2.2)

ALVAC, 31.2% RV144 2003-09 Community risk (95% CI: 1.1-51.2 AIDSVAX Thailand p-value: 0.04) HIV-negative men 41 HIV infection in volunteers HVTN and transgender DNA, 2009-13 receiving vaccine and 30 cases 505 women who have MRKAD5 in those receiving placebo. Pitisuttithum, et al. JID 2006 sex with men, US M Robertson, et al. Available at http://www.hvtn.org/science/step_buch.html Supachai Rerks-Ngarm, et al. N Engl J Med 2009 HVTN505: SOURCE: http://www.aidsmap.com/Researchers-stop-the-only-current-HIV-vaccine-efficacy-trial/page/2640732/ RV144: Prime - Boost strategy using two different :for inducing both humeral and cell mediated Prime Vaccine: ALVAC-HIV (vCP1521) from

• 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

HIV test, risk assessment and counseling

0.5 1 2 3 (time in years) 6-month 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 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) • 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) Role of VTC staffs & CRC(s)

• Enrollment • Vaccination • Reactogenicity, AE(s), SAE(s), documentation, reporting and follow up Clinical Team

VTC MD Director-MOPH • SI • MD Supervisor - 5 • Nurse (6 - 10/site) • VTC CRC - 5 • CRC - CRC 5/site - Pharmacist 2/site Total 150 full time - RA 2/site staff and 200 part times 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 RA Registry VDO informed consent Group informed consent

Individual Informed Consent Vital Signs

Urine Pregnancy Test (Only Female) Medical History and Blood Draw Eligibility Check VACCINE CODE PHARMACIST DOCUMENTATION &preparation Training CRC, RA, Pharmacist 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) Extend Service Hours on Sunday 24-hour Mailing Edutainment and one evening phone and campaigns/ Provider clinic per week access phone interactive based games system reminders

16,402 90% volunteers interval Enrolled Retention

Mobile Tracking Volunteer Cultural Quarterly unit activities Relation, activities exhibition activities (Home Club visit) activities with educational boards 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). • 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). 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) 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 &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)

– 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 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. Volunteer relation activities Cultural activities and Educational campaigns Buddhist ceremony

Mother’s day 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) Mobile unit activities Home visit activities 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 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 • Together with recent results of community trial

2009,Nov19

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 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) RV144 Summary resutls(2009-2013)

• Modest efficacy

• Early effect wanes • No impact on post- 50

infection VL or CD4 • 4032% -CTL:CD4 > CD8

30 responses RV 144 RV152 20 • 90% of 10 0

C1 C2 C3 C4 C5 GP41 breakthrough V1 V2 V3 V4 V5 CRF01_AE • 90% -Mainly bAb detected and decreases rapidly • Binding AB was directed to V2 • Weak neutralizing antibody responses

49 9 September 2012 ADCC stimulated by RV144 vaccines

• Qualitatively similar to anti-HIV-1 responses observed during chronic HIV-1

• May have been partly responsible for  the modest degree of protection observed. Bonsignori M, Pollara J,--, Haynes BF. J Virol. 2012 Nov;86(21):11521-32.

50 Confidential – not for distribution 27 June 2011 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)

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

51 10 September 2012 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)

. 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 . 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

Phase IIb/III Trials are Efficacy: RV305: prime- boost Secondary Boost •Phase III: Thai regimens community risk with secondar RV306: or MSM high- y 1 year boost risk boost

2011 2012 2013 2014 2015 2016 2017

HIV test, risk assessment and counseling

ALVAC prime (0, 4, 12, 24, 52 wk)

AIDSVAX boost (12, 24, 52 wk)

54 Complete vaccination , FOLLOW up continue 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 3 6 9 100/10 Group 4 months 12

MHRP Bridging to the Next Efficacy Study

Next Efficacy RV144 trial

Bridging Immunogenicity CohortsM Phase 1 Boosting regimen at one year SM with adjuvanted vaccines Phase 2 AVEC to a licensed vaccine? What are the steps from RV144 58 lowriskpopulation RV144:efficacy31% atat60% months,months, 12 42 Better extra “boost” = higherVE extra= “boost” populationsMSM and hetero(risk) Higherincidence immunogens and Thailand and TwoAfrica C) trials:southern(clade reducesinfection risk Antibodyagainst V1V2 + new adjuvant+ new + Licensure (?) - sexual  . 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 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 • Community education and engagement on social value and scientific validity is very critical

• Funding supports • Political commitment VTC

V Vitality T Team Excellence C Creativity