HIV and Challenges of Vaccine Development

Transcription

1 Dale and Betty Bumpers accine Research Center ational nstitute of Allergy and nfectious Diseases ational nstitutes of Health H and Challenges of accine Development Richard A. Koup, MD

2 What Mediates accine-induced Protection? RUS YPE OF ACCE ACCE-DUCED PROECO MMUE COROL Smallpox Live Antibodies, CL CL Rabies Killed virus Antibodies Antibodies, CD4, CL Polio Live or killed virus Antibodies Antibodies accine-induced antibodies (neutralizing) most commonly protect against viral infections. Measles Live Antibodies; CL Antibodies, CD4, CL Mumps Live Antibodies Antibodies Rubella Live Antibodies Antibodies aricella zoster Live Antibodies; CL Antibodies, CL Little evidence that cells actually mediate protection against viral challenge. nfluenza Protein Antibodies Antibodies, CD4, CL Hepatitis A Killed virus Antibodies Antibodies, CD4, CL Hepatitis B Protein Antibodies Antibodies, CD4, CL HP LP Antibodies CD4, CL However, once infected, cells are clearly involved in mediating viral control. Hepatitis C CD4, CL Cytomegalovirus CD4, CL Epstein-Barr virus CD4, CL HS types 1 and 2 CL H-1 and H-2 CD4, CL HH 6 Antibodies, cells

3 herefore Efforts should be directed towards developing immunogens that stimulate neutralizing antibodies t has been difficult to induce neutralizing antibodies to H ariable loops Envelope is heavily glycosylated Shielding of neutralization domains Multiple clades of H with only limited crossneutralization Early vaccines generated binding, but not neutralizing, antibodies

4 History of Efficacy rials axgen gp120 Canarypox/gp120 R 144 Merck 023/H 502 (SEP) rad5 gag/pol/nef H 503 (Phambili) DA/rAd5 env/gag/pol/nef H 505 Enrollment Follow-up Final analysis nterim analysis

5 History of Efficacy rials axgen gp120 Canarypox/gp120 R 144 Merck 023/H 502 (SEP) rad5 gag/pol/nef H 503 (Phambili) DA/rAd5 env/gag/pol/nef H 505 Enrollment Follow-up Final analysis nterim analysis

6 SEP/Phambili mmunogenicity Merck rad5 expressing H clade B Gag, Pol, and ef Strong ELSpot and CD8 responses to H Gag, Pol, and ef o Env, so no binding or neutralizing antibodies Expected result: o effect on acquisition Positive effect on lowering virus load

7 Lack of Efficacy in the SEP rial: Merck rad H accine rad5 vaccine expressing Clade B Gag, Pol, ef Cumulative umber of H nfections: M population (males) Cumulative number of H infections (events) o 20 Effect on iral 20 Load Ad accine 24 Placebo Cumulative number of H infections (events) Ad5 > accine 9 Placebo ime to event (weeks) ime to event (weeks) ncreased acquisition among Ad5 seropositive volunteers: 1) Unrelated to Ad-specific CD4 cells as targets for infection 2) Associated with lack of circumcision 3) Associated with HS-2 serostatus (but unrelated to vaccine)

8 History of Efficacy rials axgen gp120 Canarypox/gp120 R 144 Merck 023/H 502 (SEP) rad5 gag/pol/nef H 503 (Phambili) DA/rAd5 env/gag/pol/nef H 505 Enrollment Follow-up Final analysis nterim analysis

9 Modest Efficacy in R144: An Effect on Acquisition ALAC -H (vcp1521) Canarypox expressing H-1 subtype E gp120 and H-1 subtype B gag and protease ADSAX B/E H gp120 from subtype E and subtype B

10 accination and Follow-up Schedule H test, risk assessment and counseling (time in years) 6 month vaccination schedule 3 years of follow up (every 6 mo.) ALAC H (vcp1521) priming at week 0, 4, 12, 24 ADSAX B/E gp120 boosting at week 12, 24 accine:placebo = 1:1

11 Efficacy (m) 52,985 person-years 125 infections accine infections: 51 Placebo infections: 74 E: 31.2% p= % C: 1.1, 52.1 (O Brien-Flemingadjusted)

12 Summary of Analyses m PP (# subjects) 16,402 16,395 12,542 Person years 52,985 52,985 36,720 accine/placebo (event #) 56 / / / 50 accine efficacy 26.4% 31.2% 26.2% 2-sided p value % confidence interval -4.0, , , 51.9 ncludes 5 vaccine and 2 placebo recipients who were H positive at baseline Decreased event numbers, lower precision

13 F- /L-2 CS 6 months post-final vaccination Frequency (%) CD4 CD8 Antigen P P Env Only 45/142 (32) * 1/54 (2) 5/133 (4) 4/52 (8) Gag Only 0/144 0/56 3/136 (2) 1/53 (2) Env + Gag 2/142 (1) 0/54 0/131 0/51 Any H 47/142 (33)* 1/54 (2) 8/131 (6) 5/51 (10) *P < compared to placebo

14 Binding Antibody 2 weeks post-final vaccination Antigen Frequency (%) Reciprocal GM B gp /142 (99) ( ) E gp ( ) B p24 74/142 (52) 138 ( ) P< compared to placebo group all Antigens Only eutralize ier 1 iruses

15 Efficacy at 1 year appeared higher (Kaplan-Meier-based estimates) m PP month Events Efficacy Events Efficacy % n/a n/a % 21 68% % 41 41% % 53 27% % 62 31% Can we build on this early efficacy?

16 Pox Protein Development Plan (Draft) Ongoing R144 Follow up in hailand Studies: R144i immune correlates studies R305 protein boosting study R306 expanded immunogenicity study Objective: Determine correlate of protection for use in future trials; optimize the regimen Partners/Funders: US Army, hai Gov t, H, sanofi pasteur, BMGF Candidate selection Research ALAC is default vector prime Proteins boosts BD R144 immune correlates mmune grid Cost, product availability Population: Heterosexual, high risk Products: DA + YAC (sanofi) + gp140 (Polymun)/MF59 (D) vs. YAC (sanofi) + gp140 (Polymun)/MF59 (D) Objective: Extend results & accelerate evaluation of other products using adaptive trial design and first available protein Partners/Funders: H, H, sanofi pasteur, ovartis, BMGF Licensure S. Africa ph2b hailand ph2b Population: MSM, high risk Products: ALAC (sanofi) + gp120/mf59 (D) Objective: Confirm result & demonstrate efficacy in target population with potential for licensure Partners/Funders: US Army, hai Gov t, H, sanofi, BMGF? Africa ph2b Population: Heterosexual, high risk Products: ALAC (sanofi) + gp120/mf59 (D) Objective: Extend result & translate vaccine to Africa, other highrisk groups Partners/Funders: H, H, sanofi, ovartis, BMGF, RSA?

17 R 144 Correlates Discovery Effort mplications for future clinical development of this product Humoral & nnate mmunity Cellular mmunity Host Genetics Animal Models Scientific Advisory Groups ADSORY GROUPS Product Development Advisory Group Scientific Steering Committee mplications for future scientific inquiry into the result and evaluation/design of other candidates and studies PA H Steering Committee R144 Steering Committee MHRP - DADS Steering Committee

18 R144 Correlates Research: Collaborating nstitutions 35 investigators from 20 institutions working on 32 different assays (~150 total staff) Cornell, Duke, Harvard, UCSC, UC, Rush, U Mass, orthwestern, YU, U Wash, Oxford, Kings College, Mahidol, St. George s, U Melbourne, Scripps, H/UMD, G/OSHU, MHRP, Monogram Bio, H (AD, C)

19 wo Phases of Correlates Discovery Phase ( March 2011) Broad survey of innate, humoral, systems biology, genetic, and cellular assay evaluation/comparison. Multiple Bab, ab, ADCC, ADC approaches Statistical plan Phase (March July 2011) Case-control Evaluation of a broad range of assays but with downselection to optimize the statistical design specimens have been shipped to collaborating labs in the past few weeks.

20 R144 rial: Cellular mmune Analyses Cellular mmunity WG (McElrath) cells: Antigen-specific CD4+ & CD8+ cells Composite assay ntracellular cytokine staining Soluble mediators (Luminex) ranscriptional arrays (PBMC) Proliferation (CFSE) Epitope mapping Functional phenotypes B cells: gp140-binding ELSpot functional phenotypes K cells: polyfunctionality receptor expression Monocytes, mdcs: phagocytosis

21 he Antigen: A244 gd+ gp120 (component of ADSAX) A K L H L S R S 310 G P G E Q S 320 P K 3 S R R C F Y E C Y A K R E D G G R 4β7 bs D 340 E G 350 E A L S G L L L 200 F G 290 Q E K L D 280 P W 360 F Y A L K G 260 S 420 E D P S S 270 K A G Q C C A L H D K Q C H P C 2 4 K G K E K 250 C K P Y L H G 240 E A 210 A Y G K C Q D K 190 P L 370 H E K F S F L K G K P 410 R D R Y E S Q D 230 L R S P L K C L M C P P K S F 380 E 220 K P 430 L C F P P C C P K F L 130 S L G G S P P Q C 180 Y K 140 S F 170 D K Q C H Q 390 D C E R L D E 120 W H F C R G E F 400 G 440 M Q E Q D A E S L M H M S C W S 460 Q 1 G G 150 L M 110 G F E A K W M L S 450 G K L A Q A E A H W P L 100 L P A Y M R R 470 H A C P D G P D C1 G D Q E A 80 S C E D A P K Y A L A D F L 490 A E A K A 70 D K G S L D K G H A W R M A D R G E G 5 P G H L P G R F E R K 60 F E W A P 50 D L G R E K R COOH R F 510 L G E K P L L D Q L L E P Y L K Y K Q E P R A R R 500 HS gd A K 520 G L R A A A G G M H 2 Amino acid sequence inside circles represents A244 gp120 gd(+). (adapted from Leonard, et al.,j.biol. Chem. 265, 10373, 1990).

22 Linear 2 Peptide Binding 4 7 binding epitope Peptide umber H-infected R144 RC vaccine (DA/Ad5)

23 History of Efficacy rials axgen gp120 Canarypox/gp120 R 144 Merck 023/H 502 (SEP) rad5 gag/pol/nef H 503 (Phambili) DA/rAd5 env/gag/pol/nef H 505 Enrollment Follow-up Final analysis nterim analysis

24 H 505 Phase 2b, randomized, placebo-controlled trial to evaluate the safety and effect on post-h acquisition viremia of a multiclade H-1 DA plasmid vaccine followed by a multiclade H-1 recombinant adenoviral vector vaccine in H-uninfected, adenovirus type 5 neutralizing antibody negative, circumcised men who have sex with men

25 H 505: Schedule and Endpoints Prime Boost Study Groups Day 0 Wk 4 Wk 8 Wk 24 accine 675 DA DA DA rad5 Placebo 675 PBS PBS PBS FFB rial was powered for a viral load effect (SEP trial era) 45 H infection endpoints 90% power to detect 1.0 log 10 reduction in plasma L 80% power to detect 57% reduction in acquisition How do the antibody responses compare to R144? Should the trial size be increased to provide better power to detect an acquisition effect?

26 Study Design est sera from R144 and H204 by ELSA against five envelope proteins Sera: 50 vaccinees and 25 placebo recipients from R vaccinees from H204 (precursor to H 505) 5 clade B H infected donors ime points: 2-4 weeks post final vaccination and 6 months later Proteins: Env B-M Env E-A244 RC EnvA RC EnvB RC EnvC 25 placebo recipients were negative against all proteins. hose data are not included in the subsequent graphs.

27 Env Antibody iters: R144 and H204 R144 peak R144 6 months H204 peak H204 6 months H+ sera Conclusions: Both products induced predominantly type specific antibodies Similar peak titers Similar loss of titer over six months

28 eutralizing Antibodies: H204 Most vaccinees had no neutralizing antibodies A few had good neutralization against ier 1 viruses M and SF162 hese were tested at 1:10 dilution against ier 2 viruses D50 eutralization iter10000 M ier 1 SF162.LS % eutralization (1:10 serum dilution) ier 2 Clade A Clade B Clade C ML n= 2 n= 4 n= 4

29 Rationale for adding acquisition as a primary endpoint in H 505 R144 showed that a reduction in acquisition is possible with a vaccine regimen that does not induce broadly neutralizing antibodies. he H 505 vaccine regimen induces antibody responses of similar magnitude and function as those induced by the R144 regimen. he H 505 vaccine regimen induces equivalent CD4 cell responses and CD8 cell responses that are superior to those in R144. he Smac239 homologue of the H 505 vaccine regimen has been shown to reduce acquisition by ~50% in an S challenge model.

30 H 505: Schedule and Endpoints Prime Boost Study Groups Day 0 Wk 4 Wk 8 Wk 24 accine 1100 DA DA DA rad5 Placebo 1100 PBS PBS PBS FFB What will we learn at primary analysis? 66 total and 52 evaluable H infection endpoints 90% power to detect 1.0 log 10 reduction in plasma L 80% power to detect 50% reduction in acquisition

31 H 505 Accrual Opened - May 29, 2009 First enrollment - June 11, 2009 Original sites activated - September 2, 2009 Atlanta Bethesda Birmingham Boston Fenway Brigham Chicago Los Angeles ashville ew York Columbia Union Square Philadelphia San Francisco Rochester Seattle ew sites activated August 2010 Annandale Baylor Cleveland Dallas Denver East Midtown Orlando

32 ADS accine Clinical rials-works in Progress Michelangelo s Unfinished Atlas 2003: axgen - lack of protection by gp120 antibodies 2007: SEP - no viral load protection by rad5 Gag, Pol, ef (pure CD8 vaccine) 2009: R144-31% fewer infections from canarypox Gag, Pol, Env/gp120 boost 2011: H 505 DA/rAd5 expressing Gag, Pol, ef, and 3 Envs: powered for an acquisition effect n the battle between antibody and cell vaccines, antibodies appear to have won Questions: 1. Future of pure cell vaccines? 2. Response to Env important but 3. eutralizing vs non-neutralizing antibodies? 4. Can other platforms that include Env provide better protection, and if so, by what mechanism?

33 Results from H prevention trials Study Length Effect size of Study (C) H accine (hai R144) 3.5 y 31% (1, 51) 1% DF gel (Caprisa, Karim et al.) 2.5 y 39% (6, 60) DF/FC PrEP (iprex, Grant et al 2010) 1.2 y 44% (15, 63) 12 mo effect Circumcision (Orange Farm, Rakai, Kisumu) 0% % 57% (42, 68) Efficacy An H vaccine should be considered a component of a comprehensive approach to H prevention Prof. Glenda Gray, H Conference, ov 2010 Padian S, et al. Weighing the gold in the gold standard: challenges in H prevention research. ADS 2010, 24:

34 Dale and Betty Bumpers accine Research Center ational nstitute of Allergy and nfectious Diseases ational nstitutes of Health accine Research Center Gary abel Peter Kwong John Mascola Daniel Douek Robert Seder mmunology Core Bob Bailer & staff Laurie Lamoreaux Collaborators elson Michael Jerome Kim Larry Corey Julie McElrath Flow Cytometry Core Mario Roederer & staff Clinical rials Core Barney Graham Mary Enama & staff Brenda Larkin & staff Contractors ical Genec Community Advisory Board accine trial volunteers!

35 ACKOWLEDGEMES University of Washington And 16,402 hai men and women who participated in the trial