1

RSV Nanoparticle Vaccine in the Elderly Day 56 Results of NVX757.102

15 October 2013

2

Clinical Applications for an RSV Vaccine

• RSV infects all children by age 2 years

• RSV is the leading cause of infant hospitalization

75,000 to 125,000 hospitalizations annually (in US)

• RSV is a leading cause of pneumonia in older adults

In some seasons, disease burden can be similar to flu Major impact in elders with pre-existing cardio-pulmonary disease

14,000 deaths and 175,000 hospitalizations annually

• 40+ years, no licensed vaccine

Note worried face; she’s thinking that she really ought to have an RSV vaccine.

3

Background

• The Novavax RSV F protein vaccine elicits: ‒ serum IgG responses to F protein, including antigenic site II linear

peptides, ‒ antibodies that compete with palivizumab for binding to RSV F, ‒ increases of 3 to 4-fold in neutralizing titers of young adult sera, over 6-

fold in in those young adults with baseline titers ≤ log2 7, ‒ protection against virus shedding and pulmonary pathology, with no

enhanced disease, in cotton rats. • In young adults, we have observed:

‒ doses of 60-90µg are approaching a plateau in immunogenicity, ‒ adsorption to aluminum is moderately beneficial, especially in those with

the lowest background titers • The current human trial was undertaken to evaluate the feasibility of

potentially useful immune responses in elderly subjects.

4 4

Study Objectives

• To describe the safety in subjects ≥ 60 y.o. of the RSV F protein vaccine, at 60 or 90µg doses, with or without AlPO4, and co-administered with standard dose, licensed trivalent inactivated influenza vaccine (TIV).

• To describe the immunogenicity of the RSV F vaccine, at 60 or 90µg doses, with or without AlPO4, based on anti-F IgG ELISA units, palivizumab-competitive antibody titers, IgG titers specific for RSV F antigenic peptide II, & microneutralization titers. ‒ To evaluate the utility of aluminum,

‒ To assess whether 90µg provided a signficant immunogenicity advantage over 60µg

• To determine whether the RSV vaccine interferes with the immunogenicity of co-administered TIV,

• To assess duration of responses.

5 5

Treatment Assignments

Treatment Group

Subjects Per Group

Study Day 0[1] Study Day 28 ± 2[2]

RSV-F Antigen Content

Aluminum Adjuvant [3]

Saline Placebo

Influenza Vaccine

Saline Placebo

Influenza Vaccine

A 40 60µg Yes -- Yes -- Yes

B 40 60µg -- -- Yes -- Yes

C 40 90µg Yes -- Yes -- Yes

D 40 90µg -- -- Yes -- Yes

E 60 -- -- Yes Yes Yes --

Note: All treatments will be administered by IM injection in a 0.5mL dose volume. [1] Day 0 vaccinations: Groups A through E - The assigned RSV-F test article or placebo will be administered into the RIGHT arm and TIV into the LEFT arm. [2] Day 28 vaccinations: All groups - The LEFT deltoid will be used for all injections. [3] Each adjuvanted RSV-F vaccine contains a 1.2mg dose of aluminum.

6 6

Safety Monitoring

• Standardized local and systemic AEs solicited according to defined grading scale x 7 days after the investigational dose ‒ Injection site pain, bruising, redness and swelling ‒ Fever, chills, arthralgia, myalgia, headache, fatigue, nausea, vomiting,

diarrhea

• Unsolicited AEs at each visit and at any time for 1 year. ‒ Severity and causality ‒ Medically-attended events ‒ Significant new medical conditions ‒ SAEs

• Clinical labs at baseline and 7 days after each dose ‒ CBC with platelet count and differential ‒ ALT, AST, alkaline phosphatase, total bilirubin, creatinine, BUN

7 7

Immunologic Monitoring

• Serum IgG antibody levels specific for the RSV F protein ‒ Readout in ELISA units (EU) anchored to a standard reference pool

• Serum titers of antibodies competitive with palivizumab for binding to RSV F protein ‒ Readout is serum titer yielding 50% inhibition of labeled palivizumab

reporter to immobilized RSV F ‒ Antibody readout in palivizumab-equivalent µg/mL (standardized based

on 50% inhibitory concentration of 2µg/mL for palivizumab itself)

• Serum titers of IgG binding to the antigenic site II peptide (a.a. 254-278)

• Serum RSV/A and B microneutralization (MN) titers ‒ Performed by Dr. P.A. Piedra, Baylor College of Medicine

• Serum HAI titers specific for Influenza A and B strains included in the TIV

8 8

Study Population and Disposition

Treatment Groups, Counts (%)

Placebo 60µg + Al 60µg - Al 90µg + Al 90µg - Al

Enrolled 60 40 40 40 40

Completed Day 56 59 (98)* 40 (100) 39 (98)* 40 (100) 40 (100)

Discontinued 0 0 0 0 0

Due to AE 0 0 0 0 0

Voluntary, non-AE 0 0 0 0 0

Lost to f/u 0 0 0 0 0

Investigator decision 0 0 0 0 0

Per-protocol 56 (93) 38 (95) 36 (90) 38 (95) 37 (93)

* Subject missed Day 56 visit

9 9

Demography

Treatment Groups Placebo 60µg + Al 60µg - Al 90µg + Al 90µg - Al

Gender

Female (%) 38 (63) 22 (55) 24 (60) 19 (48) 23 (58)

Male (%) 22 (37) 18 (45) 16 (40) 21 (52) 17 (42)

Mean age (SD) yrs 69.1 (5.5) 69.1 (5.8) 67.7 (5.6) 68 (5.8) 68.7 (5.7)

60 - <75 yrs (%) 51 (85) 34 (85) 34 (85) 34 (85) 34 (85)

≥75 yrs (%) 9 (15) 6 (15) 6 (15) 6 (15) 6 (15

Race (%)

White 58 (96) 40 (100) 39 (98) 37 (93) 40 (100)

Black 1 (2) - - 3 (7) -

All other 1 (2) - 1 (2) - -

Mean (SD) BMI in kg/m2 27.4 (4.9) 28.5 (4.6) 27.7 (4.9) 29.6 (5.0) 27.6 (4.1)

10 10

Safety Summary

Treatment Groups, Counts of Subjects with Events (%)

Placebo 60µg + Al 60µg - Al 90µg + Al 90µg – Al

Safety N 60 40 40 40 40

Any AE 42 (70) 30 (75) 25 (63) 27 (68) 23 (58)

Any solicited AE 28 (47) 22 (55) 12 (30) 21 (53) 19 (48)

Local 14 (23) 17 (43) 9 (23) 17 (43) 15 (38)

Systemic 22 (38) 12 (30) 6 (15) 16 (40) 10 (25)

Severe 1 (2) 1 (3) 0 0 1 (3)

Any unsolicited AE 31 (52) 18 (45) 21 (53) 16 (40) 16 (40)

Severe 2 (3) 0 1 (3) 0 0

Severe & Related 0 0 0 0 0

Serious 1 (2) 0 0 0 0

11 11

Anti-F IgG – Geometric Mean EU

12 12

Formulation-finding and dosing using Anti-F fold-increase metric

• Q: Is there a positive effect of AlPO4? A: Yes ‒ Effect of aluminum is only 1.1-fold at day 28 (p = 0.432), but ‒ Effect of aluminum is 1.4-fold at day 56 (p = 0.004) ‒ Similar to effect of aluminum in young adults.

• Q: Is 90µg better than 60µg? A: Yes ‒ Effect of increased antigen content is 1.3-fold at day 28 (p = 0.036) ‒ Effect of increased antigen content is 1.4-fold at day 56 (p = 0.001) ‒ Impact of increasing antigen is more apparent in the elderly than young

adults.

13 13

Immune Responses to Antigenic Site II Linear Peptide

14

Palivizumab-Competitive ELISA: Assay Methodology

Biotin-palivizumab

15 15

Induction of Palivizumab-competitive Antibodies

16 16

RSV A Microneutralization Titers – Geometric Mean Titers

Treatment Groups

Placebo 60µg + Al 60µg – Al 90µg + Al 90µg – Al

Day 0 (Baseline) 326 (251, 422)

258 (193, 345)

247 (190, 321)

269 (199, 366)

347 (245, 491)

Day 7 334 (259, 430)

305 (225, 413)

258 (202, 331)

305 (230, 403)

416 (306, 566)

Day 28 322 (252, 411)

431 (329, 564)

365 (271, 492)

412 (322, 528)

521 (380, 715)

Day 56 315 (248, 400)

388 (295, 512)

340 (259, 446)

470 (357, 617)

512 (383, 684)

*values cited are point estimates, parenthetic values are upper and lower 95% confidence

• Fold increases in microneutralization GMTs of 1.5 to 1.7-fold • Baseline GMTs, however, are already > 8.0 log2 • Adding 60-120µg of palivizumab to adult sera with 8.0-9.0 log2

baseline titers experimentally yields 1.3-1.7-fold increases in titer.

17 17

HAI – Geometric Mean Titers

Treatment Groups

HA Strain Placebo 60µg + Al 60µg – Al 90µg + Al 90µg – Al

A/California/07/2009

Day 0 35.6 (24.4, 51.9)

42.2 (28.1, 63.5)

40.0 (24.3, 65.9)

27.3 (15.9, 46.6)

41.9 (27.0, 65.1)

Day 28 154.1 (103.7, 229.0)

183.5 (121, 278.3)

195.8 (120.7, 317.8)

154.2 (100.6, 236.4)

157 (106.0, 232.6)

Day 56 122.6 (84.7, 177.5)

202.8 (141.5, 290.8)

192.1 (120.7, 305.6)

158.6 (105.2, 238.9)

193.0 (137.1, 271.6)

A/Victoria/361/11

Day 0 70.3 (45.8, 107.7)

73.7 (41.3, 131.3)

44.5 (27.5, 71.9)

61.4 (36.6, 102.9)

71.5 (44.0, 116.2)

Day 28 275.8 (196.4, 387.3))

305.7 (193.1, 484.1)

339.0 (218.5, 526.0)

341.1 (240.3, 484.1)

286.0 (203.5, 401.9)

Day 56 269.1 (191.6, 377.9)

380.6 (252.1, 574.5)

335.8 (228.1, 494.2)

384.0 (274.8, 536.7)

323.0 (225.9, 461.9)

B/Wisconsin/1/2010

Day 0 44.2 (34.1, 57.2)

46.7 (31.6, 69.1)

32.4 (21.3, 49.2)

39.3 (27.5, 56.2)

46.9 (32.7, 67.4)

Day 28 175.5 (126.1, 244.4)

199.2 (144.2, 275.0)

226.3 (162.8, 314.5)

193.8 (134.0, 280.2)

174.1 (116.6, 259.9)

Day 56 147.6 (107.5, 202.7)

214.2 (156.3, 293.6)

207.5 (151.0, 285.1)

212.3 (152.7, 295.1)

163.0 (117.3, 226.6)

*values cited are point estimates, parenthetic values are upper and lower 95% confidence

18 18

Conclusions: It’s Feasible

• Safety ‒ Primary finding is increase local reactogenicity concentrated in subjects

receiving aluminum compared to placebo. ‒ No severe-related events

• Immunogenicity ‒ No negative effects on trivalent influenza HAI responses ‒ By Anti-F IgG, aluminum and higher dose improve the anti-F responses:

• At 90µg, the added advantage of aluminum appears modest • Longer term sera will show whether aluminum improves persistence

‒ Subjects have almost no palivizumab-competitive antibodies at day 0, but: • Develop strong palivizumab-competitive responses and antigenic site

II antibodies • palivizumab-competitive antibodies attain levels that are protective in

preclinical studies (either by active or passive immunization) ‒ Microneutalization titers rise 1.5 to 1.7 fold, with greatest increases in

subjects with lowest titers at baseline.

19 19

An Intriguing Option for the Elderly (or Anyone): RSV F and Influenza VLP Combination Vaccine

Some immediate questions: • Can a formulation be developed that will accommodate both antigens? • Will they impair each other’s immune responses if co-injected?

20 20

An Initial Combination Vaccine Study in Balb/C Mice

Group Antigen Mice (N) Tri- Flu *Dose in µg

RSV F Antigen

Dose in µg

Immunization Days

1 Trivalent Flu + RSV 8 3 3 0, 21 2 Trivalent Flu + RSV 8 9 9 0, 21

3 Flu + Buffer (Flu) 8 3 ----- 0, 21

4 Flu + Buffer (Flu) 8 9 ----- 0, 21

5 RSV + Buffer (RSV) 8 -------- 3 0, 21

6 RSV + Buffer (RSV) 8 -------- 9 0, 21

7 Flu + Buffer (RSV) 8 3 -------- 0, 21

8 Flu + Buffer (RSV) 8 9 -------- 0, 21

9 RSV + Buffer (Flu) 8 ------- 3 0, 21

10 RSV + Buffer (Flu) 8 ------- 9 0, 21

21 21

Anti-F IgG Responses in the Presence of VLP Influenza Vaccine

• Background day 0 anti-F IgG levels < 100 • Superscript 1 = Influenza vaccine buffer, 2 = RSV vaccine buffer • RSV microneutralization titers and palivizumab-competitive titers show

the same pattern

22 22

B/Wisconsin Immunogenicity in the Presence of RSV F

• Background day 0 B/Wisconsin HAI < 20 • Superscript 1 = Influenza vaccine buffer, 2 = RSV vaccine buffer • A/California and A/Victoria HAI titers show the same pattern

23 23

The Impact of Adding Palivizumab (or Palivizumab-equivalent) to Serum MN Titers Depends on Where You Start

24 24

Why Doesn’t a Large Amount of Palivizumab-like Activity Lead to Big Fold-Rises in MN Titer

Starting MN titer (log2)

Starting MN titer

Added antibody (µg/mL)

Final MN titer

Final MN titer (log2)

Fold-rise in Titer

nil “0” 40 64 6 Infinite 2 4 40 68 6.09 17.0 4 16 40 80 6.32 5.0 6 64 40 128 7 2.0 7 128 40 192 7.59 1.5 8 256 40 320 8.32 1.3 9 512 40 576 9.17 1.13

Let 40µg/mL of palivizumab give a MN titer of 64 (about right) Now add it to sera of increasing base MN tier: