Tetravalent Dengue Purified Inactivated Vaccine (DPIV)

Status of the GSK / FIOCRUZ / U.S. Army Dengue Vaccine Candidate

Romulo Colindres, GSKNovember 2015

A Three Party Effort

• GSK, Fiocruz and the U.S. Army collaborate to develop DPIV

• All three parties contribute to preclinical and clinical R&D

• Technology transfer is an important component of our collaborations

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GSK Dengue Candidate Vaccine in Development

• Whole virus, purified and inactivated

• One dengue strain per serotype (DENV-1, 2, 3 & 4)

• Manufactured in Vero cells

• Combined with GSK Adjuvant System or with Alum

• 2 doses 4 weeks apart (booster dose to be confirmed)

• Projected characteristics:

• Can be administered in broad age range and in immuno-compromised

• Immunogenic in flavivirus-naïve and –primed

• Suitable for co-administration with other vaccines

• No risk of transmission, reversion or viral interference due to virus

inactivation

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Phase 1 Study DPIV-001NCT01666652, WRAIR manufactured antigen, U.S. Army as Sponsor

4ASTMH 2015

5ASTMH 2013

Pain Redness Swelling

Per

cen

tage

of

dos

es (

%)

0

20

40

60

80

100

1 g+Alum

4 g+Alum

1 g+AS01E

1 g+AS03B

Placebo

A

DPIV-001 Solicited Local Adverse EventsNCT01666652, WRAIR manufactured antigen, U.S. Army as Sponsor

Grade 3 or higher local solicited AEs were not reported.

6ASTMH 2013

DPIV-001 Solicited General Adverse EventsNCT01666652, WRAIR manufactured antigen, U.S. Army as Sponsor

Fatigue

GI S

ympto

ms

Hea

dache

Joint P

ain

Musc

le A

ches

Temper

ature

Per

cen

tage

of

dos

es (

%)

0

20

40

60

80

100

1 g+Alum

4 g+Alum

1 g+AS01E

1 g+AS03B

Placebo

B

• No SAE through Day 56

• Four SAEs were observed through M13

• All four SAEs were assessed by the investigator as not related to vaccination

• No potential immune-mediated diseases were reported through M13

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DPIV-001 Severe Adverse EventsNCT01666652, WRAIR manufactured antigen, U.S. Army as Sponsor

ASTMH 2015

DPIV-001 Day 56 seroconversion rates (MN50)

ATP immuno, dengue naïve subjects only

8Schmidt AC et al., ASTMH 2013, poster LB-2454

DPIV-001 GMTs and 95%CIs of neutralizing antibody titers

(MN50) in dengue naïve subjects up to Month 13

9ASTMH 2015

DPIV-001 Dengue type-specific B cell memory is maintained in

dengue naïve subjects at 1 year post vaccination

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SLIPE presentation, 24 June 2015, San Juan, Puerto Rico

DPIV-001 Per-subject neutralizing antibody titers

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Subset of 9 subjects who received a booster between M15 and M22

ASTMH 2015

Phase 1 Study DPIV-002NCT01702857, WRAIR manufactured antigen, US Army as Sponsor

12ASTMH 2015

DPIV-002 Demographic characteristicsPer-protocol cohort for immunogenicity Month 13

13ASTMH 2015

All participants were American hispanic or latino; N, number of subjects; n (%), number (percentage) of primed subjects in a given category;

SD, standard deviation; DENV, dengue virus.

Characteristic

1µg+Alum

(N=17)

4µg+Alum

(N=17)

1µg+AS01E

(N=15)

1µg+AS03B

(N=17)

Placebo

(N=17)

Mean age at first

vaccination ± SD,

years

27.2 ± 5.0 28.2 ± 5.9 30.2 ± 6.5 29.5 ± 6.5 29.1 ± 6.1

Seropositive for ≥1 DENV type at baseline

(primed subjects), N

15 15 14 17 17

Tetravalent-positive

primed subjects at

baseline, n (%)

13 (86.7) 14 (93.3) 12 (85.7) 16 (94.1) 14 (82.4)

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DPIV-002 Solicited Local Adverse Events (Any Grade)NCT01666652, WRAIR manufactured antigen, U.S. Army as Sponsor

ASTMH 2015

15

DPIV-002 Solicited General Adverse Events (Any Grade)NCT01666652, WRAIR manufactured antigen, U.S. Army as Sponsor

ASTMH 2015

1µg+Alum 4µg+Alum 1µg+AS01E 1µg+AS03B Placebo

DPIV-002: Geometric mean neutralizing antibody titers

(MN50) in primed subjects

16ASTMH 2015

10000

1000

100

1µg+Alum 4µg+Alum 1µg+AS01E 1µg+AS03B Placebo

DE

NV

-1D

EN

V-2

DE

NV

-3D

EN

V-4

DE

NV

GM

Ts

GMT 95% CI LL 95% CI UL

10000

1000

100

10000

1000

100

10000

1000

100

Confidential

Persistence of neutralizing antibody responsesPer-protocol cohort for immunogenicity Month 13, primed subjects

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GMT (95%CI)

AntibodyTime

point

1µg+Alum

(N=17)

4µg+Alum

(N=17)

1µg+AS01E

(N=15)

1µg+AS03B

(N=17)

Placebo

(N=17)

DENV-1 PRE 622 (172; 2247) 1152 (361; 3677) 590 (187; 1861) 599 (195; 1845) 758 (217; 2650)

D56 1421 (641; 3149) 2359 (1378; 4038) 2148 (1162; 3971) 2503 (1405; 4458) 822 (251; 2692)

M13 1122 (494; 2548) 2291 (1352; 3883) 1309 (662, 2590) 2051 (1156, 3641) 983 (305; 3165)

DENV-2PRE 523 (163; 1679) 610 (220; 1686) 741 (271; 2028) 500 (210; 1191) 457 (123; 1698)

D56 1207 (489; 2982) 1558 (820; 2960) 2451 (1229; 4887) 2355 (1357; 4085) 420 (130; 1356)

M13 793 (312; 2017) 1272 (628; 2575) 1566 (668; 3675) 1847 (945; 3609) 603 (157; 2316)

DENV-3PRE 390 (128; 1192) 722 (249; 2090) 681 (297; 1563) 387 (140; 1073) 401 (113; 1417)

D56 745 (356; 1560) 1869 (903; 3871) 2496 (1497; 4163) 2373 (1422; 3958) 369 (110; 1234)

M13 447 (190; 1050) 1092 (551; 2162) 1139 (580; 2239) 1389 (640; 3011) 348 (110; 1099)

DENV-4PRE 804 (284; 2273) 1766 (855; 3646) 539 (152; 1911) 1015 (621; 1657) 1461 (637; 3352)

D56 1770 (1045; 2997) 4332 (2755; 6812) 2842 (1242; 6503) 4786 (3551; 6452) 1467 (620; 3471)

M13 1142 (515; 2535) 3133 (1755; 5593) 1751 (622; 4929) 3267 (1703; 6268) 1441 (659; 3148)

GMT, geometric mean antibody titer; DENV, dengue virus; PRE, pre-vaccination; M13, 12 months post-dose 2

ASTMH 2015

DPIV Safety Profile as of November 2015

160 subjects exposed to 1 of 4 DPIV formulations

• No SAEs during the first 56 days in DPIV-001 and DPIV-002

• No withdrawals due to adverse events

• No safety signals identified to date

18Fourth Pan-American Dengue Research Network Meeting, Belém, Brazil

Poster Session Vaccines/Modeling, HP27, 21 October 2014 from 5:50 PM (DPIV-002)

ASTMH 2013, Abstract LB-2454, presented 16 November 2013 (DPIV-001)

Conclusions & Outlook

• DPIV plus adjuvant induces a balanced and high titered tetravalent

neutralizing antibody response in flavivirus naïve subjects within 2

months

• DPIV effectively boosts / induces a balanced and high titered

tetravalent neutralizing antibody response in dengue virus primed

subjects

• DPIV induces a lasting B memory response in humans

• We have lots of work to do …

• Select final formulation

• Age de-escalation down to infants

• Generate efficacy data in primed subjects

• Generate efficacy studies in naïve subjects

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Thank you!