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Barbara Ensoli, MD, PhDNational AIDS Center

Istituto Superiore di SanitàRome, Italy

Where we stand now and what we foresee

Symposium

Preventive and Therapeutic HIV Vaccines: Novel Candidates and Strategies in 2011

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Results from completed Phase IIb/III preventative trials

• AIDSVAX B/B and AIDSVAX B/E (rgp120 Env) – no protection in a high-risk population.

• STEP (Ad5-gag/pol/nef) – no protection in a high-risk population, increased HIV-infection risk in Ad5-seropositive vaccinees(?).

• ALVAC/AIDSVAX (Canaripox-gag/pro/env prime + rgp120 Env protein boost) – 30% protection in a low-risk population: immune correlates of protection unclear (polyfunctional cytolytic CD4 T cell responses & Ab response to V2 loop?).

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Number of preventative vaccine candidates in each phase of clinical development

(April 2011)

Number of unique vaccine candidates: 42

Of these 42, 8 candidates are being tested in multiple phases

Phase I: 40

Phase II: 8

Phase IIb: 2

Note: No candidates in development beyond Phase IIb.RV144 follow-on studies not included

Source: Bill & Melinda Gates Foundation

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Regimen types in Phases I, II, and IIb of clinical development

Source: Bill & Melinda Gates Foundation

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What is new in the pipeline

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Bomsel et al, Immunity 2011

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Key Results

• The gp41 (Rgp41 + P1/MPER) based mucosal vaccine delivered by virosomes (2 I.M. primings followed by 2 I.M. or I.N. boosters) protected only monkeys boosted intranasally from repeated (13) low-dose vaginal SHIVSF162P3 challenge.

• Protection correlated with: transcytosis blocking gp41-specific mucosal IgAs and gp41-MPER-specific mucosal IgGs with ADCC activities.

• Although anti-gp41 IgA and IgG were also present in serum, no antiviral activities were detected in blood, suggesting that circulating antiviral antibodies may not be required for protection, a concept to consider in the design of preventative HIV-1-AIDS vaccines.

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Is a replication competent vector needed?

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Vaccine: 3 RhCMV-SIV vectors encoding Gag, a Rev-Tat-Nef fusion protein, or Env

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Key features• A replication competent Rhesus CMV vector expressing several SIV

antigens (Gag, Env, a Rev-Tat-Nef fusion protein), elicits effector memory T cells (Tem), the predominant type of T cell in mucosal effector sites.

• Administered twice, 98 days apart, subcute. Half of the vaccinees (12) were boosted with and adenoviral vector (Ad5) instead of RhCMV

• Repeated (weekly), low dose, intrarectal, challenge with SIVmac239, 10 months after the boost

• Outcome: All 24 animals became infected, of which 13 rapidly (wk 3) controlled infection to undetectable levels (occasional blips up to week 30): no evidence of residual virus upon CD8 T cell depletion and at post-mortem analyses (4/4 monkeys, 1 yr after last challenge): eradication?

Control not observed in the parallel arm vaccinated with a DNA prime - Ad5 boost regimen, known to mainly elicit central memory T cells

• Planned to advance to clinical testing, provided that safety issues are solved: CMV provokes a persistent infection which is associated to premature aging but attenuation may also impact on immunogenicity

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Tat/Env/Gag/Nef

Tat/Env

Control Tat only

Tat/Env Tat/Env/Gag/Nef

CD4 after challenge

Weeks post-challenge

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Viral load after challenge

Tat/Env Tat/Env/Gag/Nef

Control Tat only

Weeks post-challenge Weeks post-challenge

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Key results

• Cynomolgus monkeys primed mucosally with replication-competent adenoviruses encoding HIV-1 Tat (Ad-HIV tat) and Env (Ad-HIV env), and boosted systemically with the Tat and Env proteins controlled infection upon intravenous challenge with 30 MID50 of SHIV89.6P.

• Containment (reduced chronic viremia) was stronger (4 logs for Tat/Env, P <0.0001) than that afforded by the multigenic group (Ad-HIV tat, Ad-HIV env, Ad-SIV gag, and Ad-SIV nef recombinants and Tat, Env, and Nef proteins) (3 logs, P = 0.0003).

• The strikingly greater reduction in the Tat/Env group than in the multigenic group (P = 0.014) correlated with Tat and Env binding antibodies and Env-specific ADCC activity (Florese et al J Immunol 2009).

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Conclusions

A multicentric phase I open-label preventative trial is starting with the Tat/DV2 Env protein combination versus single antigens in 50 high risk individuals in Italy (cooperation with Susan Barnett, Novartis)

P002:EudraCT number 2008-007224-26

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Therapeutic trials

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Arcelis™immunotherapy (AGS-004)

• ex vivo generation of autologous DCs, subsequently loaded by electroporation with in vitro transcribed RNA encoding 4 of the patient’s own HIV antigens together with RNA encoding CD40L, and reinjected into the patient intradermally, 4 times, 4 weeks apart,while on HAART and then HAART was interrupted.

• Results from the Phase IIa (n=22) study indicate delay of HAART resumption in treated subjects (no amelioration of CD4 T cell counts).

• A Phase IIb trial is ongoing.

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Vacc-4x

• The vaccine consists of 4 synthetic peptides (from 20 to 27 amino acids long) based on the HIV-1 p24 protein given multiple times intradermally together with GM-CSF

• At the end of treatment HAART was interrupted and time to resumption used as a surrogate markers of efficacy

• Efficacy was also assessed by retrospective comparison to similar patients from the Athena cohort that interrupted HAART without receiving the vaccine

• The Vacc-4x group showed a significantly slower decline in mean CD4+ T cell counts (p<0.0001) over time and remained HAART-free for a median of 70 weeks (17 months) compared to 16 weeks (4 months) for the Athena cohort at the time of analysis, suggesting a significant benefit of the Vacc-4x immunotherapy intervention in terms of CD4+ T cell decline following HAART interruption (Sommerfelt et al, AIDS 2006)

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Dermavir• A synthetic plasmid DNA encoding 15 HIV clade B protein, administered

topically with the dendritic cell-targeting DermaPrep medical device.

• When expressed in lymph node dendritic cells the15 HIV proteins can self assemble to form HIV VLPs.

• These HIV antigen presenting dendritic cells prime naïve T cells and expand the HIV-specific T cell pool to kill HIV-infected cells.

• In a randomized, placebo-controlled, dose-ranging Phase II study (GIEU006) 36 HIV-infected individuals not on HAART (HIV-RNA: 5,000 to 150,000 copies/mL and CD4: = 400 cells/mm3) were randomized to receive one of three DermaVir doses (0.2, 0.4 or 0.8 mg of pDNA) or placebo 4 times, six weeks apart.

• A statistically significant reduction of 0.5 log10 copies/mL was observed at the 0.4 mg dose.

• No change of CD4+ cell counts recorded

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GTU® MultiHIV

• The Multi‐HIV antigens/epitopes approach exploits a novel delivery system termed gene transport unit (GTU), a proprietary technology of FIT BIOTECH, which increases the immunogenicity of plasmid DNA vaccines thereby avoiding the need for an heterologous boosting.

• GTU® MultiHIV is a plasmid DNA comprising complete sequences of Rev, Nef, Tat, p17/p24 proteins + Pol and Env T cell epitopes of a subtype B-HIV-1 Han-2 isolate.

• The vaccine (clade B) has been tested in a phase II trial in South Africa and has been proven safe and well tolerated.

• IM vaccine delivery resulted in a significant increase (p = 0.006) in CD4 counts and a 0.5 log decrease in viraemia (p = 0.006) as compared to placebo (Vardas et al , AIDS Res. Human Retroviruses 2008).

• A new phase I trial (Clinicaltrials.gov: NCT01130376) is planned.

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TUTI-16

• TUTI-16 is a synthetic, self-adjuvanting, universal HIV-1 Tat epitope vaccine.

• A randomized, double-blind, placebo- controlled, dose escalating study was conducted in 22 asymptomatic, ART free HIV infected subjects (THYMON-08001).

• Subjects were immunized subcute 3 times over 12 weeks, and assessed monthly through 20 weeks.

• Highly statistically significant reduction in HIV viral load from baseline as compared to placebo (p = 0.008).

• CD4 T cell counts not decreased at the highest dose used (0.6 mg), as compared to the placebo group.

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Tat protein vaccine

A phase II multicentric clinical trial with Tat (ISS T-002, Clinicaltrials.gov: NCT00751595) was conducted in 160 individuals under effective HAART (B. Ensoli et al, PLoS ONE 2010).

Eighty-eight individuals enrolled with the same criteria in a parallel prospective observational study at the same clinical sites (ISS OBS T-002, Clinicaltrials.gov: NCT01024556) were examined as reference group.

Tat immunization increased T-reg, reduced immune activation (CD38+CD8+ T cells and biochemical markers), increased CD4+ T cells and B lymphocytes, increased CD4+ and CD8+ central memory and naïve T cells, reduced effector memory CD4+ and CD8+ T cells, and increased T cell responses against Env and recall antigens (Candida, CMV, EBV, Flu).

More immune-compromised individuals experienced greater therapeutic effects.

A double-blind placebo-controlled therapeutic phase II trial in HAART is starting in South Africa (200 patients).

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Track C Symposia Session – Preventive and Therapeutic HIV Vaccines: Novel Candidates

and Strategies in 2011Co-Chairs: Barbara Ensoli, Italy and Yiming Shao, China

Env-based vaccines – Susan Zolla-Pazner• Generic and conserved structure exists within the second and third sequence “variable region”.• Epitope-scaffold immunogens can be rationally designed, synthesized, and used in a DNA

prime/protein boost regimen to focus the immune response on specific epitopes.• Using this prime/boost approach, it is possible to:

- Use the epitopes recognized by neutralizing monoclonal antibodies as templates for vaccine design.

- Focus the immune response on the selected epitope(s)- Induce Abs in rabbits that mediate neutralization of diverse strains of HIV-1

Antibody-mediated vaccines protection against HIV – Susan Barnett• Results from RV144 & active immunization of NHP using prime-boost and adjuvanted protein

vaccines indicate that vaccine protection against HIV is achievable • Protection in these settings appears to be attributed to high titer, high avidity, Env binding &

virus neutralizing Abs• There is an urgent need to identify & produce Env proteins & adjuvants for the next series of

Phase 2b clinical trials- Envs must be immunogenic eliciting desired Ab responses- Envs must have properties that allow for large scale production and rapid

translation into effective preventions without delays- Safe adjuvants (MF59) can be employed to enhance immunogenicity of the Envs & vaccine efficacy

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DNA vaccines – David WeinerDNA vaccines have been well studied but poorly immunogenic as a stand alone platform in NHP and humans. We have focused on improving the immune responses induced by DNA vaccine technologies through multiple means including genetic optimization, inclusion of plasmid genetic adjuvants and new formulation and delivery technologies.  We will show that these combined approaches can induce strong levels of immunity in NHP and humans.  The use of this combined technology for the development of HIV vaccines and Therapies will be the focus of this presentation. 

Dendritic cell-based therapeutic vaccine approaches – Felipe García• Concept of functional cure• Basis for using dendritic cells as therapeutic vaccines• Clinical trial perfomed in the last few years• Perspectives of future

Conclusions: Yiming Shao

Track C Symposia Session – Preventive and Therapeutic HIV Vaccines: Novel Candidates

and Strategies in 2011Co-Chairs: Barbara Ensoli, Italy and Yiming Shao, China

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Preventative vaccine candidates being tested

Source: Bill & Melinda Gates Foundation

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Preventative vaccine candidates being tested

Source: Bill & Melinda Gates Foundation