RSV Nanoparticle Vaccine in the Elderly Day 56 Results of NVX October 2013

Transcription

1 RSV Nanoparticle Vaccine in the Elderly Day 56 Results of NVX October

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 Note worried face; she s thinking that she really ought to have an RSV vaccine years, no licensed 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 log 2 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. 3

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 AlPO 4, and coadministered 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 AlPO 4, 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. 4 4

5 Treatment Assignments Treatment Group Subjects Per Group RSV-F Antigen Content Study Day 0 [1] Study Day 28 ± 2 [2] 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 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. 5 5

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 6 6

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 ) 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 7 7

8 Study Population and Disposition Treatment Groups, Counts (%) Placebo 60µg + Al 60µg - Al 90µg + Al 90µg - Al Enrolled Completed Day (98)* 40 (100) 39 (98)* 40 (100) 40 (100) Discontinued Due to AE Voluntary, non-ae Lost to f/u Investigator decision Per-protocol 56 (93) 38 (95) 36 (90) 38 (95) 37 (93) * Subject missed Day 56 visit 8 8

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) (7) - All other 1 (2) - 1 (2) - - Mean (SD) BMI in kg/m (4.9) 28.5 (4.6) 27.7 (4.9) 29.6 (5.0) 27.6 (4.1) 9 9

10 Safety Summary Treatment Groups, Counts of Subjects with Events (%) Placebo 60µg + Al 60µg - Al 90µg + Al 90µg Al Safety N 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) (3) Any unsolicited AE 31 (52) 18 (45) 21 (53) 16 (40) 16 (40) Severe 2 (3) 0 1 (3) 0 0 Severe & Related Serious 1 (2)

11 11 11 Anti-F IgG Geometric Mean EU

12 Formulation-finding and dosing using Anti-F fold-increase metric Q: Is there a positive effect of AlPO 4? 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 13 Immune Responses to Antigenic Site II Linear Peptide

14 Palivizumab-Competitive ELISA: Assay Methodology Biotin-palivizumab 14

15 15 15 Induction of Palivizumab-competitive Antibodies

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 (259, 430) 305 (225, 413) 258 (202, 331) 305 (230, 403) 416 (306, 566) Day (252, 411) 431 (329, 564) 365 (271, 492) 412 (322, 528) 521 (380, 715) Day (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 log 2 Adding µg of palivizumab to adult sera with log 2 baseline titers experimentally yields fold increases in titer

17 HAI Geometric Mean Titers Treatment Groups HA Strain Placebo 60µg + Al 60µg Al 90µg + Al 90µg Al Day (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) A/California/07/200 9 Day (103.7, 229.0) (121, 278.3) (120.7, 317.8) (100.6, 236.4) 157 (106.0, 232.6) Day (84.7, 177.5) (141.5, 290.8) (120.7, 305.6) (105.2, 238.9) (137.1, 271.6) Day (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) A/Victoria/361/11 Day (196.4, 387.3)) (193.1, 484.1) (218.5, 526.0) (240.3, 484.1) (203.5, 401.9) Day (191.6, 377.9) (252.1, 574.5) (228.1, 494.2) (274.8, 536.7) (225.9, 461.9) Day (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) B/Wisconsin/1/2010 Day (126.1, 244.4) (144.2, 275.0) (162.8, 314.5) (134.0, 280.2) (116.6, 259.9) Day (107.5, 202.7) (156.3, 293.6) (151.0, 285.1) (152.7, 295.1) (117.3, 226.6) *values cited are point estimates, parenthetic values are upper and lower 95% confidence 17 17

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 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? 19 19

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 , 21 2 Trivalent Flu + RSV , 21 3 Flu + Buffer (Flu) , 21 4 Flu + Buffer (Flu) , 21 5 RSV + Buffer (RSV) , 21 6 RSV + Buffer (RSV) , 21 7 Flu + Buffer (RSV) , 21 8 Flu + Buffer (RSV) , 21 9 RSV + Buffer (Flu) , RSV + Buffer (Flu) ,

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 21 21

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 22 22

23 23 23 The Impact of Adding Palivizumab (or Palivizumab-equivalent) to Serum MN Titers Depends on Where You Start

24 Why Doesn t a Large Amount of Palivizumab-like Activity Lead to Big Fold-Rises in MN Titer Let 40µg/mL of palivizumab give a MN titer of 64 (about right) Now add it to sera of increasing base MN tier: Starting MN titer (log 2 ) Starting MN titer Added antibody (µg/ml) Final MN titer Final MN titer (log 2 ) Fold-rise in Titer nil Infinite