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CHIKV VLP vaccine
Bavarian Nordic’s chikungunya vaccine candidate
October 2024
Victoria Jenkins, PhD, MBA
VP Regulatory Affairs & CHIKV Program LeadBavarian Nordic
vije@bavarian -nordic.com
2E protein
Membrane
Capsid shell
RNA
CHIKV VLP vaccine
Chikungunya virus3CHIKV virus -like particle vaccine (CHIKV VLP)1
CHIKV, chikungunya virus; VLP, virus -like particle ; BLA, Biologics License Application; PDUFA, Prescription Drug User Free Act
1. Bennett SR, et al. Lancet Infect Dis. 2022;22(9):1343−1355. 2. Basore K et al. Cell. 2019 Jun 13;177(7):1725- 1737. 3. Sun S, et al. ELife. 2013;2:e00435
•Comprised of 3 recombinant chikungunya virus (CHIKV)
structural proteins that assemble into virus- like particles, which
mimic the CHIKV but cannot replicate
•Adjuvanted with aluminum hydroxide; single 40 µg VLP dose (0.8
mL) in a pre -filled syringe; administered IM
•Priority Review for the BLA granted by FDA (PDUFA target action date: 14th Feb 2025)
•Proposed indication: prevention of disease caused by
CHIKV infection in individuals 12 years of age and older
•Proposed contraindications: hypersensitivity, including
severe allergic reaction (anaphylaxis), to any component
•It was agreed with regulators to use a defined threshold of serum neutralizing antibodies as a surrogate endpoint of efficacy
in phase 3 clinical trials
Cryo-electron microscopy reconstruction of CHIKV VLP2
CHIKV- luciferase assay developed to evaluate v accine efficacy
measures cross- neutralization
Vaccine strain
Assay strainPhylogenetic analysis of CHIKV isolates based on a 1kb fragment in the E1 gene1
Asian
West AfricanECSA
3
1. Parola P, de Lamballerie X, Jourdan J, Rovery C, Vaillant V, Minodier P, et al. Emerg Infect Dis. 2006;12(10):1493- 1499. •CHIK181/25 live -attenuated virus (Asian
lineage AF15561) engineered to express
luciferase transgene (CHIKV -luc assay
reporter)
•Neutralization assay based on 80% (NT80)
reduction of luciferase activity following Vero cell infection with CHIKV -luc
•CHIKV -luc virus used in the assay is
heterologous to the CHIKV VLP (Asian vs West African)
ECSA, East-Central -South -African * CHIKV strain that was used as a challenge in nonhuman primate serum transfer study (next slide) *
Conservative serum neutralizing antibody (SNA) threshold chosen for phase 3
study immunogenicity endpoints based on NHP data & regulatory agency recommendations
CHIKV, chikungunya virus; NHPs, nonhuman primate; SNA, serum neutralizing antibodies; CI, confidence interval
Data presented at ESCMID Global 2024 (not yet published in a peer- reviewed article)
*FDA and EMASerum passive transfer and challenge
study in NHP
•NHPs received pooled sera from human
participants vaccinated with CHIKV VLP at
various dilutions i ntravenously and were
challenged with CHIKV 24 hours later
•Logistic regression model:
•SNA titer of 50 results in 99.97% [81-100]
probability of protection against viremia
•Regulatory agencies* proposed and agreed a
more conservative SNA titer threshold of 100
to be an acceptable surrogate endpoint
PredictedObserved
95%-CI
Pre-challenge SNA Titer (Day 0)Probability of protection against viremia
4
1. Bennett et al. Safety and immunogenicity of PXVX0317, an aluminium hydroxide -adjuvanted chikungunya virus -like particle vaccine: a randomized, double- blind, parallel -group, phase 2 trial. Lancet Infect Dis. 2022;22(9):1343- 55.
2. ClinicalTrials.gov ID: NCT05065983; 3. ClinicalTrials.gov ID: NCT03992872; 4. ClinicalTrials.gov ID: NCT05072080; 5. Clini calTrials.gov ID: NCT05349617. 6. Chang et al. Safety and tolerability of chikungunya virus- like particle vaccine in healthy adults: a phase 1 dose- escalation trial. Lancet, vol. 384,9959 (2014):2046-
52. 7. Goo et al. A virus -like particle vaccine elicits broad neutralizing antibody responses in humans to all chikungunya virus genotypes. J In fect Dis, vol. 214,10 (2016):1487- 1491. 8. Chen et al . Effect of a chikungunya virus -like particle vaccine on safety and tolerability outcomes: A randomized clinical trial. JAMA, vo l.
323,14 (2020):1369- 1377. 9. McCarty et al . Chikungunya virus virus -like particle vaccine is well tolerated and immunogenic in chikungunya seropositive individuals. Vaccine, vol. 41,42 (2023):6146- 6149. 9
BLA, Biologics license application 5CHIKV VLP vaccine clinical program
Study description Study designStudy phase
and numberAge range
(years)Number of participants
(vaccine recipients)
•Dose- and dose -schedule finding randomized, double -blind,
parallel- groupPhase 21
PXVX- CV-317-
00118 - 45 445 (441)
•Immunogenicity & Safety and tolerability of 40ug dose open labelPhase 22
EBSI-CV-317-01018 - 45 25 (25)
•Immunogenicity and safety in prior alphavirus vaccine
recipientsopen label, parallel -group Phase 23
EBSI-CV-317-00218 - 65 60 (60)
•Immunogenicity & Safety and tolerability
•Lot-to-lot consistencyrandomized, double -blind,
placebo -controlledPhase 34 (pivotal)
EBSI-CV-317-00412 - <65 3254 (2790)
•Immunogenicity & Safety and tolerabilityrandomized, double -blind,
placebo -controlledPhase 35 (pivotal)
EBSI-CV-317-005≥65 413 (206)
Immune response according to dose and dosing schedule
PXVX- CV-317-001
Phase 2
6
7•At year 1, Group 8 had significantly
higher GMTs vs Group 1 (491.7 vs
243.4; p -value=0.0019); this was
maintained at year 2 (279.7 vs 169.8;
p-value=0.0369)
•AEs mostly mild to moderate; no serious treatment -related unsolicited
AEs
•Local AEs more frequent in 40 ug adjuvanted CHIKV VLP group (40%) than in unadjuvanted group (23%)Single 40 µg CHIKV VLP adjuvanted dose had superior immunogenicity after
first vaccination, showed a rapid and durable response, and was well -tolerated
Primary Endpoint: GMT of anti -CHIKV SNA level on Day 57 (28 days after last vaccination); adjuvant = aluminum hydroxide
Vertical bars denote 95% confidence interval. GMT = geometric mean titer; NT80 = Neutralization Titer showing 80% neutralization
Bennett et al. Lancet Infect Dis. 2022;22(9):1343- 55.
(n=42)(n=46)
(n=42)(n=40)(n=38)(n=39)
Pivotal phase 3 studies
EBSI-CV-317-004 in individuals 12 to <65 years
EBSI-CV-317-005 in individuals ≥65 years
8
Richardson et al. Safety and Immunogenicity of an Adjuvanted Chikungunya Virus (CHIKV) Virus -like Particle (VLP) Based Vaccine in Two Pivotal Ph ase 3 Trials, ≥12 Years of Age. IDWeek oral presentation, 14 October 2023, Boston, MA.
AE = adverse event; AESI = adverse event of special interest; MAAE = medically attended adverse event; SAE = serious adverse event9Design of the two pivotal phase 3 studies
End of study
Placebo
(n=464)Adolescents
and Adults
12 to <65 years CHIKV VLP
(n=2790)
CHIKV VLP
(n=206)
Placebo
(n=207)Adults ≥65 yearsEBSI-CV-317-004
EBSI-CV-317-0051 15 22 29 phone 92 phone 183 Day:
IP administrationScreening visit
(within 30 days of Day 1)Treatment and observation Follow -up
Solicited AEs
Unsolicited AEs
SAEs/AESI/MAAEs1 8 15 22 29 phone 92 phone 183 Day:Primary Immunogenicity Endpoint
10Primary and key secondary objectives in phase 3 studies
EBSI-CV-317-004
12 to <65 years of age
Coprimary :
•SNA GMT at Day 22 versus placebo
•Difference in seroresponse rate1 versus
placebo at Day 22
•Safety
•Lot consistency of anti- CHIKV SNA GMT at
Day 22 (18 to 45 years)
Key Secondary:
•Seroresponse rates at Day 8, Day 15, Day
183 versus placeboEBSI-CV-317-005
≥65 years of age
Coprimary :
•SNA GMT at Day 22 versus placebo
•Difference in seroresponse rate1 versus
placebo at Day 22
•Safety
Key Secondary:
•Seroresponse rates at Day 15 and Day 183
versus placebo
1 Seroresponse rate (considered the presumptive seroprotection rate) was defined as the percentage of participants who achieve a CHIKV -luc neutralization titer (NT80) ≥100
GMT = geometric mean titer; SNA = serum neutralizing antibody
Balanced demographic characteristics in study including adolescents
and adults 12 to <65 years of age
1 Demographic characteristics of the IEP are displayed. 2 Percentages are based on the number of participants in each study arm.
BMI, body mass index; CHIKV, chikungunya virus; IEP, immunogenicity -evaluable population; LLOQ, lower limit of quantitation; SD, standard deviation; VLP, virus -like particle; B avarian Nordic data on file. Characteristic1 CHIKV VLP (n=2794) Placebo (n=464) Total (N=3258)
Age (years)
Mean (SD) 39 (14.3) 39 (14.4) 39 (14.3)
Age group, n (%)2
12 to 17 years 217 (7.8) 37 (8.0) 254 (7.8)
18 to 45 years 1636 (58.6) 270 (58.2) 1906 (58.5)
46 to 64 years 941 (33.7) 157 (33.8) 1098 (33.7)
Sex, n (%)2
Male 1358 (48.6) 233 (50.2) 1591 (48.8)
Female 1436 (51.4) 231 (49.8) 1667 (51.2)
Race, n (%)2
White 2043 (73.1) 341 (73.5) 2384 (73.2)
American Indian or Alaska Native 30 (1.1) 2 (0.4) 32 (1.0)
Asian 79 (2.8) 16 (3.4) 95 (2.9)
Black or African American 534 (19.1) 89 (19.2) 623 (19.1)
Native Hawaiian or Other Pacific Islander 6 (0.2) 4 (0.9) 10 (0.3)
Multiracial 78 (2.8) 8 (1.7) 86 (2.6)
Not reported 24 (0.9) 4 (0.9) 28 (0.9)
Ethnicity – n(%)2
Hispanic or Latino 506 (18.1) 71 (15.3) 577 (17.7)
Not Hispanic or Latino 2226 (79.7) 379 (81.7) 2605 (80.0)
Not reported 61 (2.2) 14 (3.0) 75 (2.3)
Unknown 1 (<0.1) 0 1 (<0.1)
BMI (kg/m2)
Mean (SD) 26.79 (4.53) 26.46 (4.61) 26.74 (4.54)
Balanced demographic characteristics in study including adults ≥65
years of age
1 Demographic characteristics of the IEP are displayed. 2 Percentages are based on the number of participants in each study arm.
BMI, body mass index; CHIKV, chikungunya virus; IEP, immunogenicity -evaluable population; LLOQ, lower limit of quantitation; SD, standard deviation; VLP, virus -like particle; B avarian Nordic data on file. Characteristic1CHIKV VLP (n=206) Placebo (n=207) Total (N=413)
Age (years)
Mean (SD) 71 (5.3) 71 (4.5) 71 (4.9)
Age group, n (%)2
65 to 74 years 159 (77.2%) 159 (76.8%) 318 (77.0%)
≥75 years 47 (22.8%) 48 (23.2%) 95 (23.0%)
Sex, n (%)2
Male 81 (39.3%) 90 (43.5%) 171 (41.4%)
Female 125 (60.7%) 117 (56.5%) 242 (58.6%)
Race, n (%)2
White 176 (85.4%) 168 (81.2%) 344 (83.3%)
American Indian or Alaska Native 1 (0.5%) 1 (0.5%) 2 (0.5%)
Asian 4 (1.9%) 1 (0.5%) 5 (1.2%)
Black or African American 20 (9.7%) 29 (14.0%) 49 (11.9%)
Multiracial 4 (1.9%) 5 (2.4%) 9 (2.2%)
Not reported 1 (0.5%) 3 (1.4%) 4 (1.0%)
Ethnicity – n(%)2
Hispanic or Latino 93 (45.1%) 90 (43.5%) 183 (44.3%)
Not Hispanic or Latino 112 (54.4%) 116 (56.0%) 228 (55.2%)
Not reported 1 (0.5%) 1 (0.5%) 2 (0.5%)
BMI (kg/m2)
Mean (SD) 27.3 (3.98) 27.6 (3.90) 27.5 (3.94)
13Rapid induction of robust anti -CHIKV seroresponse rates and GMT in
adolescents and adults 12 to <65 years of age
(immunogenicity evaluable population)
* Seroresponse rate (considered the presumptive seroprotection rate) was defined as the percentage of participants who achieved an anti -CHIK SNA NT80 titer ≥100
** Success criterion met: lower bound of the two -sided 95% CI on the difference in seroresponse rates between CHIKV VLP vaccine and placebo groups ≥70%;
Vertical bars denote 95% confidence interval; CI = confidence interval; GMT = geometric mean titer; IEP = immunogenicity evaluable population; SNA = serum neutralizing antibody; LLOQ =
Note: 15 was the lower limit of quantitation (LLOQ) for the human SNA assay, so results <LLOQ were set to a titer of LLOQ/2 o r 7.5 for analysis
Data presented at IDWeek 2023, Data not yet published in a peer -reviewed article.Anti-CHIKV SNA GMT Anti-CHIKV SNA seroresponse rate
P < 0.0001 for all time
points beyond Day 1P < 0.0001 for all time points beyond Day 1
115 183 228931,0961,618
338
788 8
1101001,00010,000
CHIKV VLP (N=2,559)
Placebo (N=424)SNA GMT (NT80)
Study day115 183 228479798
86
020406080100
CHIKV VLP (n=2,559)
Placebo (N=424)Seroresponse rate* (%)
Study day
•All co -primary endpoints were met:
•At Day 22, the seroresponse rate difference between vaccine and placebo group was 96.6% (95% CI: 95.0%, 97.5%)**
•At Day 22, the vaccine group GMT was significantly higher than that for placebo (1618 vs. 8; P<0.0001, ANOVA)
•The pairwise lot comparison of SNA response to CHIKV VLP vaccine in adults aged 18 to 45 years demonstrated equivalence
•All key secondary endpoints were metSeroresponse threshold
14Rapid induction of robust anti -CHIKV seroresponse rates and GMT
in adults ≥65 years of age
(immunogenicity evaluable population)
Anti-CHIKV SNA GMT
378724
233
898 8
1101001,00010,000
CHIKV VLP (n=189)
Placebo (n=183)SNA GMT (NT80)Seroresponse rate* (%)
Study day Study dayAnti-CHIKV SNA seroresponse rate
P < 0.0001 for all time
points beyond Day 1
P < 0.0001 for all time points beyond Day 1
115 183 22 115 183 228287
76
020406080100
CHIKV VLP (n=189)
Placebo (n=183)
* Seroresponse rate (considered the presumptive seroprotection rate) was defined as the percentage of participants who achieved an anti -CHIK SNA NT80 titer ≥100
Vertical bars denote 95% confidence interval; CI = confidence interval; GMT = geometric mean titer; IEP = immunogenicity evaluable population; SNA = serum neutralizing antibody; LLOQ = lower limit of quantitation
Note: 15 was the LLOQ for the human SNA assay, so results <LLOQ were set to a titer of LLOQ/2 or 7.5 for analysis
Data presented at IDWeek 2023, Data not yet published in a peer -reviewed article.Seroresponse threshold
•All co -primary endpoints were met
•At Day 22, the seroresponse rate difference between vaccine and placebo group was 86.2% (95% CI: 72.3%, 84.6%) **
•At Day 22, the vaccine group GMT was significantly higher than that for placebo (724 vs. 8; P<0.0001, ANOVA)
•All key secondary endpoints were met
CHIKV VLP vaccine was well -tolerated in individuals 12 to <65 years of age
Placebo CHIKV VLP Placebo CHIKV VLP Placebo CHIKV VLP21.9 10.0 0.3 0.0 0.3 0.01.7 0.7 0.1 0.10.1 0.0 0.04 0.0
020406080100
Injection site redness Injection site pain Injection site swellingIncidence (%)
10.8 10.7 11.9 10.5 13.16.3 6.4 2.2 5.4 4.4 4.8 4.60.4 0.28.4 6.1 5.8 5.74.1 2.8 2.1 1.1 2.1 2.6 2.3 2.0 0.2 0.00.7 0.2 0.3 0.4 0.4 0.4 0.1 0.0 0.3 0.2 0.4 0.0 0.2 0.0
020406080100
Fatigue Headache Myalgia Chills Arthralgia Nausea FeverLocal solicited AEs Days 1 -8 (safety population)
Systemic solicited AEs Days 1 -8 (safety population)
•Grade 3 (severe) local solicited AEs occurred in 5 (0.2%) CHIKV VLP vaccine recipients (4 injection site pain and 1 injection site redness);
no placebo recipients reported ≥Grade 3 events.
•Grade 3 (severe) systemic solicited AEs occurred in 41 (1.5%) CHIKV VLP vaccine recipients and in 2 (0.4%) placebo recipients.
15
Incidence (%)
AEs = adverse events
Note: One grade 4 (potentially life- threatening) systemic solicited AE of 105ºF fever was recorded in the electronic diary by a CHIKV VLP vaccine recipient, but the site deemed this entry an error.
16Incidence of AESI and MAAE did not differ between the CHIKV VLP vaccine
group and the placebo group in individuals 12 to <65 years of age
AE = adverse event; AESI = adverse event of special interest; MAAE = medically attended adverse event; SAE = serious adverse eve nt; SMC = safety monitoring committee; PT = preferred term.
Data presented at IDWeek 2023, Data not yet published in a peer -reviewed article.Unsolicited AEs Day 1 -29, and AESI, MAAEs and SAEs Day 1 -183 (safety population)
15.8
1.1 0.28.9
0.813.4
0.2 0.29.1
0.2
020406080100
Unsolicited AE Unsolicited AE
≥ Grade 3 AESI MAAE SAEIncidence (%)
•AESI defined as defined as new onset or worsening arthralgia that was medically attended
•One participant in the CHIKV VLP vaccine group had a severe (Grade 3) treatment-related unsolicited AE of dehydration, which
resolved without medical intervention
•There was one investigator assessed possibly related SAE (PT: retinal detachment) in the CHIKV VLP vaccine group that was assessed by the sponsor and independent SMC Chair as unrelated due to prior medical history of seeing ‘black spots’ in the right eye ( the
same eye with the retinal detachment) 1 month pre -study CHIKV VLP (n=2790)
Placebo (n=464)
17CHIKV VLP vaccine was well -tolerated in individuals ≥65 years of age
AEs = adverse events5.4 1.00.5 0.0 0.00.50.0
020406080100
Placebo CHIKV VLP Placebo CHIKV VLP Placebo CHIKV VLP Injection site pain Injection site redness Injection site swellingIncidence (%)
3.9 5.0 2.4 5.0 2.9 7.0 1.5 2.0 2.4 3.0 2.0 1.5 0.0 0.52.4 1.5 3.4 1.0 1.0 0.5 1.5 2.0 0.5 1.0 0.50.5 0.5
020406080100
Myalgia Fatigue Headache Arthralgia Chills Nausea Fever
•No participants experienced a grade 3 (severe) or higher local solicited AE
•Solicited AEs occurred at similar rates between groups and were of grade 1 (mild) or 2 (moderate) intensity, except for one
participant in the vaccine group who experienced two grade 3 (severe) systemic solicited AEs (headache and fatigue)Solicited local AEs Days 1 -8 (safety population)
Solicited systemic AEs Days 1 -8 (safety population)Incidence (%)
18Incidence of AESI and MAAE did not differ between the CHIKV VLP vaccine
group and the placebo group in individuals ≥65 years of age
Unsolicited AEs Days 1 -29, and AESI, MAAEs and SAEs Days 1 -183 (safety population)
12.6
1.9 0.09.2
1.916.4
1.4 0.511.1
1.4
020406080100
Unsolicited AE Unsolicited AE
≥ Grade 3 AESI MAAE SAEIncidence (%)
•AESI defined as defined as new onset or worsening arthralgia that was medically attended
•Fatigue and myalgia were the only treatment -related unsolicited AEs that each occurred in more than one participant
•No SAE was considered treatment -related
AE = adverse event; AESI = adverse event of special interest; MAAE = medically attended adverse event; SAE = serious adverse event; SMC = safety monitoring committee
Data presented at IDWeek 2023, Data not yet published in a peer -reviewed article.CHIKV VLP vaccine (n=206)
Placebo (n=207)
19Analysis of serious adverse events, arthralgia, arthritis and osteoarthritis
across clinical trials1 reveals no safety signal
1 Study PXVX- CV-317-001 Groups 8 and 10: 40 μg dose with 300 μg adjuvant single dose; studies EBSI -CV-317-002, EBSI -CV-317-010, EBSI -CV-317-004, and EBSI -CV-317-005. 2 There was 1 SAE (PT: retinal detachment) in the
CHIKV VLP vaccine group that was considered possibly treatment -related by the study investigator but was assessed by the sponsor and independent SMC Chair as unrelated due to prior medical historyEventCHIKV VLP vaccine
40/300 µg (N=3141)
n (%)Placebo
(N=675)
n (%)
Any Serious AEs 31/3141 (0.99) 4/675 (0.59)
Related Serious AEs2 0 0
Solicited AE of arthralgia 230/3114 (7.39) 41/661 (6.20)
Arthralgia Grade 3 7/3114 (0.22) 1/661 (0.15)
Arthralgia duration >15 days 0 0
Unsolicited Arthritis 1 (0.03) 0
Related arthritis 0 0
Unsolicited osteoarthritis 1 (0.03) 0
Related osteoarthritis 0 0
Summary: CHIKV VLP vaccine
20
•Single dose vaccine based on VLP technology, suitable for broad populations
•PDUFA target action date: Feb 14th, 2025
•Proposed indication: prevention of disease caused by CHIKV infection in individuals 12 years of age and older
PDUFA, FDA Prescription Drug User Free Act •Well-tolerated
•No treatment related SAEs as determined by sponsor
•Most solicited and unsolicited adverse events mild or moderate in intensity•Phase 3 trials demonstrated rapid and robust immune response in individuals 12 years of age and older
•Durable and boostable immune response in a phase 2 trial