Industry perspective on pediatric HIV vaccine development. Marguerite Koutsoukos Director, Vaccine Development Leader, GSK

Transcription

1 Industry perspective on pediatric HIV vaccine development Marguerite Koutsoukos Director, Vaccine Development Leader, GSK 2 nd Workshop on Prevention Trials in Infants Born to HIV-Positive Mothers Maputo, Feb 7 th, 2017

2 Some insights from the pediatric Malaria vaccine development 2

3 Despite major efforts in malaria control over past decade, the malaria disease burden remains unacceptably high One child dies from malaria every 2 minutes WORLDWIDE 214 million malaria cases in ,000 deaths in 2014 Mostly in children <5y (70%) WHO African Region 188 million cases - 88% of total burden - Mainly P. falciparum 395,000 deaths - 90% of total burden - 74% in children <5y Significant cost and annual loss of economic growth Prevalence of P. falciparum in infants between 2-10 years of age in 2014 ( WHO World Malaria Report 2015 (data from 2014) 3

4 The age of peak incidence of malaria depends on the transmission intensity Maternal antibodies provide partial protection during the first 3 months of life. Natural immunity develops over time against clinical manifestations of malaria (blood stage) Development of natural immunity depends on frequency and duration of parasite exposure (intensity of malaria transmission) The age category with the highest malaria incidence depends on the speed of acquisition of natural immunity. Age distribution of hospitalised malaria in areas with different malaria transmission HIGH Peak Incidence in less than 1y Tanzania, Namawala/Michenga (1991-2) PfPR 2-10 = 87% MODERATE Peak Incidence between 1 and 3y The Gambia, Sukuta (1992-5) PfPR 2-10 = 42% 60 LOW Similar incidence throughout childhood Yemen, Hodeidahk(2002-4) PfPR 2-10 = 2% % Age (years) Snow RW et al. J Infect Dis 1998; 177: Mutabingwa TK et al. PLoS Med 2005; 2:e407 Okiro EA et al. Malar J 2009; 8:4 - Guinovart C et al. Malar J 2008; 7:36. 4

5 The RTS,S malaria vaccine development programme: A 30-year effort from GSK and successful partnerships 1984 GSK/WRAIR initiate collaboration 1995 First clinical tests begin in adults in US 1998 First trials in Africa begin in the Gambia (4) 2004 Key Proof-of- Concept study in children in Mozambique (1,8) 2009 Phase III efficacy study start 2011 First Phase III efficacy results in 5-17 months old over 12 months of follow-up (11) 2013 Third Phase III efficacy results over 18 months of followup and per study site (13) 2015 Final Phase III efficacy results including 3-4 years of follow-up and effect of 4 th dose of RTS,S (14) 1987 RTS,S first created by combining the malaria CS protein and hepatitis B surface antigen 1997 Key proof-ofconcept study shows 6 out of 7 volunteers in challenge trial are fully protected (3) 2001 GSK/MVI partnership initiated 2007 Phase II results in African children (5) and infants (2,10) 2011 Key Phase II efficacy results in African children (6) and infants (7,9) 2012 Second Phase III efficacy results in 6-12 weeks old over 12 months of follow-up (12) 2014 File submitted to the European Medicines Agency (EMA) 2015 EMA Positive Scientific Opinion granted (15) WHO recommends pilot introduction (16) (1) Alonso P et al. Lancet 2004; (2) Aponte J et al. Lancet 2007; (3) Stoute J et al. NEJM 1997; (4) Doherty J et al. AJTMH 1999; (5) Bejon P et al. NEJM 2008; (6) Olotu A et al. Lancet ID 2011; (7) Asante KP et al. Lancet ID 2011; (8) Sacarlal J et al. JID 2009; (9) Agnandji ST et al. JID 2010; (10) Abdulla S et al. NEJM 2008; (11) RTS,S Clinical Trials Partnership. NEJM 2011; (12) RTS,S Clinical Trials Partnership. NEJM 2012; (13) RTS,S Clinical Trials Partnership. PLoS Med 2014; (14) RTS,S Clinical Trials Partnership. Lancet 2015; (15) (16) 5

6 Mosquirix : the start of the next journey From vaccine to vaccination EMA Positive Scientific Opinion (July 2015) IM administration 3 doses at 1-month interval 4th dose months later WHO policy recommendation (January 2016) Pre-qualification procedure Marketing authorization applications NRA licensure in African countries Procurement by UN agencies Start Phase IV studies and pilots: benefit-risk in real-life settings (2018) 6

7 Some similarities but also major differences between HIV and Malaria vaccine development Malaria HIV Prevention of disease Availability of human challenge model Relatively easy to show efficacy in Phase II studies Major burden of disease in 6m- 1y old babies Efficacy level ~50 % Recommended malaria preventive interventions fully implemented in clinical trials Schedule aligned to EPI to improve coverage Prevention of infection Predictability of Non Human Primate challenge model still questionable Demonstration of efficacy requires large studies Major burden of infection in > aged 15+ Expected efficacy level ~ 50 % Use of recommended preventions in clinical trials Which vaccination platform depending on age and schedule 7

8 GSK prophylactic HIV vaccine development 8

9 HIV still a major challenge In 2015, There were 36.7 million [34.0 million 39.8 million] people living with HIV Africa Adult HIV prevalence Worldwide, 2.1 million [1.8 million 2.4 million] people became newly infected with HIV Eastern and southern Africa accounts for 46% of the global total of new HIV infections Around 46% [43 50%] of all people living with HIV had access to treatment 1.1 million [ million] people died from AIDS-related illnesses AFRIDEVINFO 2016 UNAIDS FACT SHEET NOVEMBER

10 GSK HIV vaccine program Some historical perspective Involvement in HIV vaccine development since the early days Both prophylactic and therapeutic approaches Several candidates in the clinics Requirement for specific of immune response and development of potential candidates = moving target PRO HIV-005 TH HIV-008 TH HIV-010 TH HIV-011 Challenging program Adjuvanted Proteins F4co/AS (p24, RT, Nef,p17) Public & private partnership CD4 (bn)ab gp120/neftat/as CD8 MV1-F4 Vectors HuAd35-GRIN HIV-001 HVTN-041 PRO-HIV-002 TH HIV-007 PRO HIV-011 PRO HIV

11 In the field, all vaccine efficacy trials have failed, except one Trial Vaccine Components Efficacy VAX 004 gp120 (B/B) / Alum No VAX 003 gp120 (B/E) / Alum No STEP RV144 HVTN 505 Ad5 (gag, pol, nef (B) ALVAC (gag, pol, env) (B/E) + gp120 (B/E) / Alum DNA (gag, pol, nef) (B) DNA (env)(a/b/c) + Ad5 (gag, pol) (B) Ad5 (env) (A/B/C) No Yes (31 %) No Adapted from Vaccine 2013; 31(35):

12 RV144: first efficacy results bring some hope 16,402 men and women between the ages of 18 and 30 years in Thailand VE 31.2% [1.1 to 52.1; p=0.04] at 3,5 y Post-hoc VE 60.5% at 1 year but rapidly thereafter High gp70-v1v2 binding IgG and low IgA antibodies binding to Env seem to correlate with risk reduction NEJM 2009;361(23): Lancet 2012;12(7): NEJM 2012;366(14): Lancet Infect Dis 2012;12:

13 Pox-Protein Public & Private Partnership P5 Established in 2010 to build on the success of RV144 results To advance and ultimately license HIV pox-protein vaccine candidates that have the potential to achieve a broad public health impact 14

14 P5 Strategy: focus on Southern Africa Construct Bivalent Subtype C gp120 / MF59 Construct ALVAC-HIV-C (vcp2438) Add Booster at 12 months Optimize regimen for regional relevance, increased potency, and durability 15

15 HVTN 702 efficacy launched 16

16 What about pediatric HIV vaccine development 17

17 Global / regional new HIV infection data New infections Region Total Aged 15+ Aged 0 14 Global 2,1 million (1,8 million 2,4 million) 1,9 million (1,7 million 2,2 million) ( ) Eastern and Southern Africa ( ,1 million ( ,1 million) ( ) Western and Central Africa ( ) ( ) ( ) Ø 6% of new infections in Eastern and Southern Africa are found in aged 0-14 Ø Situation in 10 years from now Nov

18 Regional antiretroviral therapy 2015 % of adults (aged 15+) living with HIV accessing antiretroviral therapy Global 46 % (43 50%) % of children (aged 0-14) living with HIV accessing antiretroviral therapy 49 % (42 55 %) % of pregnant women accessing antiretroviral medicines to prevent mother-tochild transmission of HIV 77 % (69 86 %) Eastern and Southern Africa 53 % (50 57 %) 63 % (56 71 %) 90 % (82 95 %) Western and Central Africa 29 % (24 35 %) 20 % (16 25 %) 48 % (40 58 %) Ø % of children aged 0-14 accessing therapy in Eastern and Southern Africa can still to be improved Nov

19 Mother-to-child HIV transmission Mother-to-child transmission (MTCT) accounts for over 90% of new HIV infections among children MTCT from HIV-infected mother to her child through: pregnancy, delivery, breastfeeding Probability of HIV transmission Without treatment With ART treatment % < 5% Prevention of Mother-to-child transmission (PMTCT) includes: Prevention of HIV transmission Prevention of infection in women of childbearing potential Prevention of unintended pregnancies Treatment of HIV infected mothers, their children, their family 20

20 Global plan for PMTCT: results depending on countries 21

21 Barriers to PMTCT Knowledge about HIV, MTCT and PMTCT Knowledge of HIV status Confusion over exclusive breastfeeding HIV stigma, discrimination and PMTCT, stigma in healthcare settings Country and clinic resources Early infant diagnosis; immediacy of treatment initiation Cultural beliefs and gender dynamics; male involvement Role of vaccination 22

22 GSK Target Product Profile adapted to MTCT: questions HIV Prophylactic Primary target indication Primary target population Efficacy endpoint Duration of protection Dosage, admin & schedule Interaction / Co-Ads Safety Target Product Profile Prevention of HIV infection (all clades) ENDEMIC REGION Minimum Product Profile Prevention of HIV infection (clade C or A) Pregnant women (seronegative / seropositive) New-borns from infected mothers Infants from infected mothers Toddlers Not inferior to standard of care 1 year IM (1-3 doses) Which schedule No interference with other vaccination (pregnant women ie. Boostrix, Flu; infants ie. BCG, EPI) Clinically acceptable safety profile + Safe in HIV seropositive Shelf-life/storage Thermostable, 3 years Storage at 2 C to 8 C; 3 years Presentation AD syringes + safety boxes Vials + safety boxes 23

23 Key points to consider Maturity of immune system in neonates and infants Interference with maternal antibodies Impact of different mode of HIV transmission (blood milk versus sexual): will a vaccine that protects from HIV infection though sexual contact also protect from mother-to-child transmission Difficulty to identify correlate of protection Different correlate of protection Different epitope-specificity Need for safety and efficacy data in adults population before Need for age de-escalation safety & immunogenicity studies Which efficacy trial 24

24 Key points to consider Efficacy trial design Groups /objectives Is it ethical to randomize to placebo recipients Is it ethical to test a vaccine on its own Non-inferiority as compared to ART treatment Add-on to ART-treatment à superiority to ART treatment à Impact on sample size Treatment 1 Placebo 2 Vaccine 3 ART + Control 4 ART + Vaccine à Feasibility to enroll enough subjects Screening Infection Maternal antibodies 25

25 Key points to consider Maturity of immune system in neonates and infants Interference with maternal antibodies Impact of different mode of HIV transmission (blood milk versus sexual): will a vaccine that protects from HIV infection though sexual contact also protect from mother-to-child transmission Difficulty to identify correlate of protection Different correlate of protection Different epitope-specificity Need for safety and efficacy data in adults population before Need for age de-escalation safety & immunogenicity studies Which efficacy trial Vaccine implementation 26

26 Key points to consider Vaccine implementation in low resources settings Vaccines considered as most inexpensive means of improving health and lowering mortality and morbidity caused by infectious diseases However wide implementation remains a challenge (vaccines licensed since 10 years, proven to be safe and effective, at low price and still not part of national immunization programs) Many obstacles and challenges remain Medical & scientific: lack of awareness, limited data on disease burden, malnutrition, multiple infections, altered immune status, appearance of emerging and new pathogens; new improved vaccine: technologically sophisticated, safety and acceptability Structural & demographic: rapid urbanization, overcrowding cities, poor sanitation, movement of migrants, missed immunization schedules, poor infrastructure, logistic problems, expanding populations Economic and political: limited resources, affordability of vaccines and maintenance of vaccine infrastructure, competing priorities, resistance to innovation Societal & cultural: poverty, illiteracy, religious taboos, superstition, irrational fears 27

27 Key points to consider Maturity of immune system in neonates and infants Interference with maternal antibodies Impact of different mode of HIV transmission (blood milk versus sexual): will a vaccine that protects from HIV infection though sexual contact also protect from mother-to-child transmission Difficulty to identify correlate of protection Different correlate of protection Different epitope-specificity Need for safety and efficacy data in adults population before Need for age de-escalation safety & immunogenicity studies Which efficacy trial Vaccine implementation Public health impact 28

28 Importance to complement Vaccine Efficacy estimates with estimates of potential Public Health Impact Vaccine efficacy needs to be translated into public health impact in order to understand the true absolute value of vaccination: Example: The effect of Human Rotavirus Vaccine on severe rotavirus gastroenteritis in the first year of life in Malawi and South Africa Malawi South Africa - Vaccine Efficacy 49 % 77 % - Baseline incidence (episodes/1,000 infants/year) - Number of severe rotavirus gastroenteritis cases averted (per 1,000 PYAR) Madhi S. et al. NEJM 2010;362:

29 Key points to consider Maturity of immune system in neonates and infants Impact of different mode of HIV transmission (blood milk versus sexual): will a vaccine that protects from HIV infection though sexual contact also protect from mother-to-child transmission Difficulty to identify correlate of protection Different correlate of protection Different epitope-specificity Need for safety and efficacy data in adults population before Need for age de-escalation safety & immunogenicity studies Which efficacy trial Vaccine implementation Public health impact Access and costs 30

30 Key points to consider Access and costs One in five children in Africa still does not receive basic life-saving vaccines GAVI support to developing countries focused on introduction and increase of access to vaccines to protect every child with a full package of WHO-recommended life-saving vaccines GAVI support, eligibility and transition policy: Eligibility support determined by the country s Gross National Income (GNI) per capita according to World Bank data (< threshold) Once threshold achieved, countries enter an accelerated transition process and start phasing out of GAVI support. During this period, GAVI will intensify its efforts to help transitioning countries be in a good position to financially sustain their immunisation programmes and new vaccines 31

31 Next steps Further define burden of disease and need for vaccination in different populations, age groups, countries à vaccination of adolescents/adults of childbearing potential, neonates, infants, maternal immunization Better understand immune responses required depending on the transmission route Better understand the immune response in neonates and infants Further explore correlate of protection Try and anticipate armamentarium availability in 10 years from now Maximize preventative antiretroviral treatment; improve access to treatment Consultations Regulatory authorities, WHO, GAVI 32

32 Conclusions The level of infection through mother-to-child transmission much lower than through sexual transmission Vaccine development path not clear, since many questions still to be answered Epidemiological situation and preventative armamentarium will further evolve until a vaccine could be ready for implementation Focus on vaccine development for adolescents / adult women with childbearing potential Should we consider maternal immunization Need to reflect on all these questions before launching a pediatric vaccination program 33

33 Acknowlegements HIV Bill & Melinda Gates Foundation Nina Russell, Pervin Anklesaria DAIDS, NIH HVTN IAVI Mary Marovitch, Mike Pensiero Larry Corey, Jim Kublin, Julie Mc Elrath, Glenda Gray Angela Lombardo, Fran Priddy, Jo Cox, Eddy Sayeed, Jim Ackland Duke University Barton Haynes, Georgia Tomaras Center for Vaccinology, Ghent University and Hospital Geert Leroux-Roels, Eva. Van Braeckel, Frédéric Clément Institut Pasteur FrédéricTangy Ragon Institute of Massachussetts General Hospital Bruce Walker, Mathias Lichterfeld, Marcus Altfeld Study staffs, study volunteers and families All investigators involved in the therapeutic program GSK & Novartis Vaccine Development Teams Malaria Study volunteers and families Study staff PATH Malaria Vaccine Initiative Malaria Clinical Trials Alliance Bill & Melinda Gates Foundation World Health Organization GSK Malaria Vaccine Development Teams 34

34 Thank you