Novel Vaccine Products for Planned Phase I Immunogenicity Studies in Infants

Office of AIDS Research Novel Vaccine Products for Planned Phase I Immunogenicity Studies in Infants L. Jean Patterson, PhD Office of AIDS Research, NIH February 7, 2017

Office of AIDS Research OAR Responsibilities -Coordinate the scientific, budgetary, legislative, and policy elements of NIH HIV/AIDS research. -Develop a strategic plan as a roadmap for allocation of funds -Receive and disperse across NIH all funds for HIV/AIDS research -Ensure that research dollars are invested in the highest priority areas of scientific opportunity in the global fight against HIV/AIDS

Office of AIDS Research Overarching High Priority Areas Reduce the Incidence of HIV/AIDS Next Generation HIV Therapies Research Toward a Cure HIV-Associated Comorbidities, Complications, & Coinfections Less Toxic and Longer Lasting Treatment Basic Research, Health Disparities, Behavioral & Social Sciences, and Training Optimize Engagement and Retention

Office of AIDS Research IMPAACT Network Vaccine Task Force Outcomes -Immune responses to candidate vaccines have been shown to be of higher magnitude and durability in infants compared to adults. -Immune modulation in infancy and childhood may enhance the efficacy of products administered later in life. Gaps exist in our understanding of infant immunity.

Office of AIDS Research IMPAACT Vaccine Task Force Outcomes-cont. 3 recommendations: -Known surrogates of immune protection in pediatric cohorts could and should be studied using existing samples. -Efficacy studies are not feasible at this time within IMPAACT. -However, a Vaccine Working Group soon will be established to develop and implement a rolling protocol design within a 3-year timeframe to evaluate safety and immunogenicity of multiple candidate HIV vaccine products and other agents/products to prevent HIV transmission.

Office of AIDS Research Criteria for selection of candidate vaccine products Must be: Unencumbered by Industry/Pharma partners Already tested or soon to enter Phase I clinical trial in adults GMP product on the shelf or ready in the next 6-12 months Enough available product for infant studies

Overall Summary of Available Products 1. DNA/Protein: PDPHV-201401 (HVTN protocol 124) Shan Lu, UMass 2. CH505 Envelope Clade C Gp120 lineage design proteins; T/F, Wk 53, 78, 100 envelopes (HVTN 115 enrolling soon) Bart Haynes, Duke 3. Env proteins: -BG505 SOSIP Gp140 trimer, developed from a Clade A, infant T/F virus (planned as part of an HVTN adjuvants trial) John Moore, Cornell -Gp145 trimeric Clade C envelope, DAIDS/MHRP -Gp140 fold-on trimer, Clade C envelope, MHRP

Office of AIDS Research A. DNA/Protein prime-boost or co-immunization DNA prime/protein boost using multigene polyvalent HIV vaccine (DP6-001 clinical trial) Shan Lu, UMass -6 DNA plasmids encoding gp120 genes from primary HIV envelopes; clades A, B(2), C, E, and gag gene from clade C subtype -5 Gp120 proteins matching same clades as DNA formulated in QS21 -Healthy volunteers were enrolled in Phase I trial at UMMS -DNA (ID or IM) at Wk 0, 4, 12; protein boosts (IM) at Wk 20, 28, IM

High level Env-Specific Serum IgG Responses in DP6-001 Vaccinees (quickly rising to the level of 10 4-10 5 level following a single protein boost) gp120 specific IgG titers 10000000 gp120 specific IgG titers (log 10 ) 1000000 100000 10000 1000 100 10 7 6 5 4 3 2 1 Group A (DNA-ID x 3 + protein x 2) Group B (DNA-IM x 3 + protein x 2) gp120 specific IgG titers 0 10 20 30 40 50 60 10000000 002 1000000 005 007 100000 009 013 017 10000 021 022 1000 030 034 035100 Weeks g p 1 2 0 -s p e c ific a n tib o d y r e s p o n s e in D P 6-0 0 1 v a c cweeks in e e 10 7 6 5 4 3 2 1 0 10 20 30 40 50 60 001 003 010 012 015 016 020 023 024 029 031 033 g p 1 2 0 -s p e c ific Ig G tite r s 1 0 6 G ro u p A 1 0 5 G ro u p B 1 0 4 1 0 3 1 0 2 1 0 1 0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0 5 5 W e e k Long lasting IgG titers for the study period Wang, S., et. al. Vaccine, 2008

A panel of human mabs with potent and cross reactive (against 3-4 subtypes) ADCC and ADCP activities from DP6-001 volunteers Matthew R. Costa et al. J. Virol. 2016;90:10362-10378

PDPHV-201401 (HVTN protocol 124) PD-201401 (DNA vaccines produced from E coli) gp120-a, gp120-b, gp120-c, gp120-ae, Gag-C 0.4 mg each for a total of 2 mg at each immunization IM injection PP-201401 (protein vaccines produced from CHO) gp120-a, gp120-b, gp120-c, gp120-ae 100 mcg each for a total of 400 mcg at each immunization Adjuvant GLA-SE (from IDRI) Two possible immunization schedules Sequential: DNA: months 0, 2, 4 and protein months 6, 8 Simultaneous: DNA + protein: months 0, 2, 4, 6, 8 Shan Lu, UMass

Infant versus adults rhesus macaques immunized with DNA prime-rad5 VRC vaccine more evidence that DNA priming elicits high titered antibodies VRC DNA prime-rad5 boost regimes in HVTN505 adult macaques infant macaques Vincent Han, Sallie Permar, Koen Von Rompay, Bart Haynes

Study Summary When using DNA as a priming immunogen, infant rhesus macaques responded better than adult rhesus macaques with regard to binding and neutralizing antibody induction.

Office of AIDS Research B. Envelope proteins lineage design CH505 Envelope Clade C Gp120 proteins; T/F, Wk 53, 78, 100 envelopes (HVTN 115 enrolling soon) Bart Haynes, Duke -Isolated over time in an individual who went on develop broadly neutralizing antibodies - Liao, et. al., Nature, 2013 -Envs selected coincided with emergence of lineages able to develop into bnabs -Need to re-purify Wk 53 protein before use as immunogen -May see accelerated development of bnabs in infants -Plan to use GLA-SE adjuvant (IDRI) in adult trial -Sallie Permar proposal to IMPAACT (CAP523)

Office of AIDS Research C. Envelope proteins as part of a boosting strategy or alone BG505 SOSIP Gp140 trimer, developed from a Clade A, infant T/F virus (planned as part of an HVTN adjuvants trial) John Moore, Cornell -In rabbits and NHPs, elicits high titered homologous Tier 2 neutralizing antibodies, but unfortunately not Tier 2 heterologous neuts, which are desired -Later, more stabilized versions of this trimer have been developed in the laboratory, known to elicit fewer anti-v3 antibodies and presumably better Tier 2 neutralizing antibodies - Use as a boosting immunogen in future strategies Sanders, et. al., J. Virol. 2002; Sanders, et. al., Plos Pathogens 2013; de Taeye, et. al., Cell 2015

Vaccination of neonates with soluble CH505 near-native SOSIP trimers Study goal: To determine whether the neonate antibody repertoire can recognize bnab epitopes on HIV-1 Env with trimer vaccination. Env TF TF TF w53 w78 w100 Timept (week) 0 7 12 18 24 30 Adults N=4 Neonates Infants **Some data after week 20 are still pending for adults N=3

Summary CH505 chimeric trimer vaccination of infants elicited higher binding, CD4 blocking, as well as tier 1 neutralizing antibodies. Studies are underway with stabilized chimeric CH505 sequential trimers with the V3 loop and the gp41 unexposed to compare immunogenicity of closed trimers versus open trimers in infants.

Office of AIDS Research C. Envelope proteins as part of a boosting strategy or alone cont. Gp145 trimeric Clade C envelope DAIDS/MHRP -Was intended as a boost protein for the replicating Tian Tian vaccine in China, but unsure of status of this trial Gp140 fold-on trimer, Clade C envelope MHRP -Not native-like, but has been in adults as a boost for the APPROACH study

Office of AIDS Research D. Longer shot candidates -CE p24 DNA prime/p55 Gag DNA IL-12 boost and/or boost with available Envelope protein (Mullins) Q1 2017 -Clade B Gp120 envelope protein (BG3521 11) (Haynes) Q3 2017 -Chimp AdC6/C7 Clade C Gp120 (Ertl) - TBD -ChAdOx1 + HIV consv6 (Hanke) TBD -mrna - TBD

Office of AIDS Research Acknowledgements OAR, OD IMPAACT BioQual Maureen Goodenow Sharon Nachman Mark Lewis Peter Kim John Sleasman Bonnie Mathieson Duke UC Davis DAIDS, NIAID Barton Haynes Koen Von Rompay Mary Marovich Sallie Permar Kevin Ryan Vincent Han Michael Pensiero Kevin Saunders Sheryl Zwerski David Montefiori Carl Dieffenbach Rob Parks UMass Shan Lu Beth Israel Deaconess Medical Center Sampa Santra

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