Abstract
The global spread of the chikungunya virus (CHIKV) increases the exposure risk for individuals travelling to or living in endemic areas. This Phase 3 study was designed to demonstrate manufacturing consistency between three lots of the single shot live-attenuated CHIKV vaccine VLA1553, and to confirm the promising immunogenicity and safety data obtained in previous trials.
This randomized, double-blinded, lot-to-lot consistency, Phase 3 study, assessed immunogenicity and safety of VLA1553 in 408 healthy adults (18–45 years) in 12 sites across the USA. The primary endpoint was a comparison of the geometric mean titre (GMT) ratios of CHIKV-specific neutralizing antibodies between three VLA1553 lots at 28 days post-vaccination. Secondary endpoints included immunogenicity and safety over 6 months post-vaccination.
GMTs were comparable between the lots meeting the acceptance criteria for equivalence. The average GMT (measured by 50% CHIKV micro plaque neutralization test; μPRNT50) peaked with 2643 at 28 days post-vaccination and decreased to 709 at 6 months post-vaccination. An excellent seroresponse rate (defined as μPRNT50 titre ≥ 150 considered protective) was achieved in 97.8% of participants at 28 days post-vaccination and still persisted in 96% at 6 months after vaccination. Upon VLA1553 immunization, 72.5% of participants experienced adverse events (AEs), without significant differences between lots (related solicited systemic AE: 53.9% of participants; related solicited local AE: 19.4%). Overall, AEs were mostly mild or moderate and resolved without sequela, usually within 3 days. With 3.9% of participants experiencing severe AEs, 2.7% were classified as related, whereas none of the six reported serious adverse events was related to the administration of VLA1553.
All three lots of VLA1553 recapitulated the safety and immunogenicity profiles of a preceding Phase 3 study, fulfilling pre-defined consistency requirements. These results highlight the manufacturability of VLA1553, a promising vaccine for the prevention of CHIKV disease for those living in or travelling to endemic areas.
Introduction
VLA1553 is a live-attenuated chikungunya virus (CHIKV) vaccine candidate designed for active immunization to prevent the disease caused by the CHIKV. The vaccine is intended to benefit populations living in endemic regions as well as to serve as a prophylactic measure for travellers to areas at risk. The CHIKV vaccine is based on the La Reunion CHIKV strain (LR2006-OPY1) of the East Central South African genotype with a 183 nucleotide deletion in the nsP3 gene encoding the non-structural replicase complex protein nsP3, which attenuates virus replication in vivo.1 VLA1553 has been tested in healthy adults in a Phase 12 and Phase 3 studies3 both reporting a strong, sustained immune response without safety concerns.
CHIKV is vectored by the daytime-biting Aedes aegypti mosquito, which also transmits yellow fever, Zika and dengue viruses.4 CHIKV can also be transmitted by the more cold-tolerant Aedes albopictus mosquitoes spreading CHIKV to more temperate areas of the world such as Spain,5 Italy6 and France.7,8 The impact of global warming and increased international travel is aggravating this trend.9–13
To date, there have been >3.2 million CHIKV cases reported in the Americas with numbers sharply increasing between 2021 and 2023.14 As one of the viruses most likely to spread globally, efficient prophylaxis is an unmet medical need for CHIKV for a variety of reasons.15–17 CHIKV epidemics are explosive, rapidly moving, self-limiting and unpredictable.15,18,19 An acute CHIKV infection can last up to 3 months and initially begins with high fever followed by joint pain, typically 3–7 days after the infected mosquito bite.20,21 Other symptoms may include headache, myalgia, arthritis, maculopapular rash, conjunctivitis, ocular findings, oral manifestations, nausea or vomiting.20 A CHIKV infection can advance to a chronic phase characterized by arthralgia or arthritis and/or fatigue affecting all genders and age groups. The potential debilitating impact can last from months to years22–24 with persistent musculoskeletal symptoms25 or disabling polyarthritis.26 After CHIKV infection, even travellers without co-morbidities may develop septic shock requiring inotropic support and intensive care in rare occasions.27
CHIKV can infect anyone; however, the risk for severe disease or progression to chronicity has been highlighted in adults > 45 years of age, people with chronic medical conditions (e.g. cardiovascular diseases, obesity, diabetes or asthma) and newborns infected around the time of birth.21,28,29 So far, the only protective measures against infection were to use insecticides and restrict exposure to vector mosquitoes, which has fundamentally changed with the very recent marketing authorization of VLA1553 under the brand name IXCHIQ®.
In this Phase 3 study, three lots of VLA1553 were evaluated for immunogenicity and safety, to demonstrate manufacturing consistency, to extend the immunogenicity database obtained in study VLA1553-301, and to confirm the safety profile of VLA1553 administered as a single vaccination.3
Methods
Study design
This was a prospective, randomized, double-blinded, multicenter Phase 3 clinical study investigating the immunogenicity and safety of three lots of VLA1553 (target dose: 1 × 10E4, 50% Tissue Culture Infectious Dose (TCID50) per 0.5 ml). The study was performed at 12 study sites in the USA in compliance with the current International Council on Harmonization/Good Clinical Practice guidelines, the Food and Drug Administration (FDA) Code of Federal Regulations and the principles set forth in the Declaration of Helsinki. Ethics approval was obtained on 17 December 2020 from a central Institutional Review Board (Advarra IRB, Columbia, MD, USA) before any study related assessment. Enrolment occurred between 22 February 2021 and 3 June 2021.
The study is registered with ClinicalTrials.gov (NCT04786444).
Participants
Eligible participants were healthy adults aged 18–45 years. Female participants of childbearing potential must have started practicing an adequate method of contraception 30 days before screening and agreed to continue contraception for the first 3 months after vaccination. The main exclusion criteria included a history of prior CHIKV infection, immune-mediated or chronic arthritis/arthralgia or clinically relevant immune system disorders. Moreover, the participant must not have received any inactivated vaccine within 2 weeks, or any other live vaccine within 4 weeks prior to vaccination with VLA1553 (full list of selection criteria in Supplementary Table 1, available as Supplementary data at JTM online). All participants provided written informed consent prior to initiating any study-related procedure.
Randomization and masking
At Day 1, 409 healthy adults were block-randomized in a 1:1:1 ratio into one of the three study arms using a unique identification code obtained from the interactive voice/web response system (IXRS) at the screening visit. Participants, investigators and sponsor staff were blinded to the assignment into study arms. The vaccine was prepared by unblinded study staff in accordance with the IXRS information with the syringe content masked prior to administration to conceal content.
Procedures and outcomes
Participants received a single intramuscular vaccination with VLA1553 at Day 1 and were evaluated at study sites for safety and immunogenicity 7 days, 28 days, 3 months and 6 months post-vaccination. Blood samples were collected for safety (clinical chemistry, haematology and coagulation) and immunogenicity assessments at all study visits. Safety laboratory parameters were assessed using the FDA’s toxicity grading scale30 and captured as unsolicited AEs if considered clinically relevant by the investigator.
The safety measures taken for this study were identical to those of the large Phase 3 pivotal trial VLA1553-301.3 For the first 10 days post-vaccination, safety data were collected via an electronic diary to document daily oral body temperature along with solicited injection site and systemic AEs. In addition, participants were asked to record any other AEs and new concomitant medication or changes in medication along with information on travel to CHIKV endemic areas, which was continued with an electronic memory aid from Day 11 post-vaccination until study end including data on ongoing solicited AEs. Safety data were assessed at every visit by the investigator using the FDA’s toxicity grading scale for solicited AEs and laboratory values30 and subsequently entered into the electronic case report form. Safety monitoring focused on adverse events of special interest (AESI), which are events potentially indicative of an acute stage of a CHIKV-associated event. In this study, an AESI is defined as fever (≥38.0°C/100.4°F) in combination with one or more of any of the following: arthralgia, back pain, neurological symptoms, cardiac symptoms, or macular to maculopapular rash and/or polyadenopathies occurring between 2 and 21 days post-vaccination with one or all symptoms lasting for 3 days or more. Adverse events that met the seriousness criteria were reported as serious adverse event (SAE). Furthermore, an independent Data Safety Monitoring Board (DSMB) reviewed accruing safety information on a regular basis until the last participant had completed the end-of-study visit at Month 6.
The immune response after vaccination, i.e. CHIKV-specific neutralizing antibodies, was assessed using a validated μPRNT, which evaluates the levels of antibodies in human serum samples by neutralizing CHIKV infection of Vero cells as described previously.3 The serum neutralizing antibody titre (μPRNT50) was defined as the reciprocal of the serum dilution which induces a 50% reduction of virus plaques compared to the virus control.
The primary study objective was to demonstrate manufacturing consistency of VLA1553 in healthy adults aged 18–45 years 28 days after a single immunization. Secondary objectives included additional immunogenicity parameters and safety monitoring of VLA1553 up to Month 6. These included the frequency and severity of solicited injection site and systemic AEs within 10 days after vaccination, of unsolicited AEs within 28 days post-vaccination, and of AESIs, SAEs and any AEs during the entire study period.
Statistical analysis
All analyses of immunogenicity data were performed primarily on the per-protocol (PP) analysis set. The PP analysis set contains all participants who were baseline negative for CHIKV antibodies (measured by an IgG CHIKV-specific ELISA, Euroimmun), have received the vaccination and have evaluable immunogenicity data at baseline and the time point for the primary endpoint (28 days post-vaccination), without a major protocol deviation that could impact the immune response. The primary immunogenicity analysis was a comparison of the GMTs in the PP analysis set between the VLA1553 lots 1, 2 and 3 at 28 days post-vaccination by analysis of covariance (ANCOVA), using factor lot and study site as covariate. The ANCOVA model was applied to the log-transformed (natural log base e) μPRNT50 values of the three lots. If the three pair-wise 95% CIs for GMT ratios (obtained by taking the anti-log of the resulting 95% CIs for the least square means differences) were within the acceptance margins of 0.67 and 1.5, equivalence between the three commercial batches was postulated.
In total, 402 randomized participants (i.e. 134 per batch) were calculated to ensure that the three pair-wise comparisons had an overall power of ~90% based on a two-sided significance level of 5%, an assumed standard deviation of 0.32 (on a log10 scale), and acceptance margins of 0.67 and 1.5 for the GMT ratios, while correcting for an assumed trial drop-out rate of 10%, another 5% of participants with major protocol deviations and 2% of participants expected to be baseline positive for CHIKV.
Secondary immunogenicity analysis included the comparison of the GMTs between the three lots at 7 days, 28 days, 3 months, and 6 months post-vaccination by ANCOVA. Two-sided 95% CIs were calculated for the GMT and geometric mean fold increases of titers. In addition, seroresponse defined as a titre μPRNT50 ≥ 150, as a surrogate of protection deemed reasonably likely to predict clinical benefit, was compared over time between the study arms by Fisher’s Exact test with 95% CIs calculated.
All participants who received the single vaccination were included in the safety analysis. Safety tabulations were provided for solicited and unsolicited AEs by descriptive statistics. The 95% CIs according to Altman were generally provided for AE frequencies, assessing differences between the lots using Fisher’s Exact test.
Results
The 409 participants enrolled in this study were allocated to be vaccinated with one of three different lots (lot 1: 136, lot 2: 137 and lot 3: 136) of VLA1553. The first participant visit was on the 22 February 2021 with the last visit occurring on the 26 January 2022. As one participant did not receive VLA1553, 408 participants entered the study and 394 participants completed the visit at 28 days post-vaccination (primary study endpoint). Overall, 364 participants attended the end of study visit at Month 6 (Figure 1), whereas 44 participants discontinued from the study (lost to follow-up: 30, withdrawing consent: 13, other reasons: 1).
Disposition of study participants. There were 409 participants randomized. One participant (vaccination not received) was excluded resulting in a safety population of 408 participants. The total participant count for the PP set was 362. A total of 409 randomized participants—12 (participants who were baseline seropositive)—35 participants with major PDs. (There was one participant as described above who was not vaccinated, which is a major PD, and an additional 34 participants who had other major PDs.) In total 364 participants completed the study. n = number of subjects; ‘Discontinued the study’ includes all subjects who discontinued early, prior to Visit 5 (Month 6); ‘Completed Day 29’ refers to the primary study endpoint at 28 days post-vaccination
From 408 vaccinated participants tested at baseline by CHIKV specific ELISA, 12/408 tested seropositive or borderline for CHIKV antibodies and were excluded from the PP population. Additionally, 34 participants with other major protocol deviations (PDs) (visit window violations: 22; endpoint data violations: 9; prohibited medication: 2; exclusion criteria: 1) were excluded, leaving 362 participants in the PP analysis set.
More female subjects (54.7%; 223/408) than male subjects participated in the study; the majority of subjects were white (77.2%; 315/408). Mean age of the subjects was 33.2 years, mean height was 171.2 cm and mean body mass index was 29.4 kg/m2 without notable differences between arms in demographic or baseline characteristics (Supplementary Table 2, available as Supplementary data at JTM online). Likewise, demographics were well balanced in the PP analysis set.
After a single administration of VLA1553, CHIKV neutralizing antibody levels were consistent between the three investigated lots meeting the acceptance criteria for equivalence specified in the study protocol. The 95% CIs of the GMT were within the defined equivalence margins of 0.67 and 1.5 for all three lots at 28 days post-vaccination (Figure 2 and Supplementary Table 3, available as Supplementary data at JTM online). After adjusting for multiplicity of testing, the statistical significance level p was invariably > 0.95 when comparing the GMT ratios, indicating no differences between the titers. After a single dose, the GMT peaked with a titre of 2643 at 28 days post-vaccination with a seroresponse rate of 97.8% of participants achieving a titre likely expected to predict a clinical benefit (μPRNT50 ≥ 150).31 GMTs subsequently decreased similarly for all investigational lots to 846 at Month 3 and to 709 at Month 6 (Figure 2). At Month 6, 96.0% of participants were still above the seroresponse threshold of μPRNT50 ≥ 150.
CHIKV-neutralizing antibody titre over time (per protocol population). Neutralizing antibodies to the vaccine were evaluated from clinical specimen (human serum) using a micro plaque reduction neutralization test (μPRNT). A μPRNT50 titre was defined as the serum dilution with 50% plaque reduction in the μPRNT. Line plot of CHIKV-specific neutralizing antibodies geometric mean titers by study day and VLA1553 lot with Day 1 = day of vaccination
Upon immunization with VLA1553, 72.5% of participants (296/408) experienced any type of AE up to Month 6 (Table 1). Similar to the immunogenicity data, there were no significant differences in the overall AE type and frequency between the three lots. Among the safety population of 408 participants, the majority of AEs were solicited AEs reported by 249 participants (61.0%), mostly classified as related to VLA1553 by the investigators (57.8% of participants). Again, there were no significant differences in solicited AE frequency between the lots.
Summary of adverse events up to Month 6 (safety population)
| Adverse event category | Statistics | VLA1553 Lot 1 (N = 136) | VLA1553 Lot 2 (N = 137) | VLA1553 Lot 3 (N = 135) | Total (N = 408) |
|---|---|---|---|---|---|
| Any AE | n (%) | 98 (72.1) | 97 (70.8) | 101 (74.8) | 296 (72.5) |
| 95% CI P-value | 63.7, 79.4 | 62.4, 78.3 | 66.6, 81.9 | 67.9, 76.8 0.7533 | |
| Any related AE | n (%) | 82 (60.3) | 82 (59.9) | 83 (61.5) | 247 (60.5) |
| 95% CI P-value | 51.6, 68.6 | 51.1, 68.1 | 52.7, 69.7 | 55.6, 65.3 0.9668 | |
| Any related severe AE | n (%) | 5 (3.7) | 3 (2.2) | 3 (2.2) | 11 (2.7) |
| 95% CI P-value | 1.2, 8.4 | 0.5, 6.3 | 0.5, 6.4 | 1.4, 4.8 0.7457 | |
| Any SAE | n (%) | 3 (2.2) | 2 (1.5) | 0 | 5 (1.2) |
| 95% CI P-value | 0.5, 6.3 | 0.2, 5.2 | 0.0, 2.7 | 0.4, 2.8 0.3366 | |
| Any related SAE | n (%) | 0 | 0 | 0 | 0 |
| 95% CI P-value | 0.0, 2.7 | 0.0, 2.7 | 0.0, 2.7 | 0.0, 0.9 NC | |
| Any AESI as assessed by the investigator/DSMB | n (%) | 0 | 1 (0.7) | 0 | 1 (0.2) |
| 95% CI P-value | 0.0, 2.7 | 0.0, 4.0 | 0.0, 2.7 | 0.0, 1.4 >0.9999 | |
| Any related solicited AE | n (%) | 76 (55.9) | 79 (57.7) | 81 (60.0) | 236 (57.8) |
| 95% CI P-value | 47.1, 64.4 | 48.9, 66.1 | 51.2, 68.3 | 52.9, 62.7 0.7933 | |
| Any related solicited systemic AE | n (%) | 70 (51.5) | 72 (52.6) | 78 (57.8) | 220 (53.9) |
| 95% CI P-value | 42.8, 60.1 | 43.9, 61.1 | 49.0, 66.2 | 48.9, 58.8 0.5394 | |
| Any related solicited injection site AE | n (%) | 23 (16.9) | 30 (21.9) | 26 (19.3) | 79 (19.4) |
| 95% CI P-value | 11.0, 24.3 | 15.3, 29.8 | 13.0, 26.9 | 15.6, 23.5 0.5742 | |
| Any related unsolicited AE | n (%) | 22 (16.2) | 15 (10.9) | 30 (22.2) | 67 (16.4) |
| 95% CI P-value | 10.4, 23.5 | 6.3, 17.4 | 15.5, 30.2 | 13.0, 20.4 0.0413 | |
| Any related medically attended AE | n (%) | 7 (5.1) | 1 (0.7) | 5 (3.7) | 13 (3.2) |
| 95% CI P-value | 2.1, 10.3 | 0.0, 4.0 | 1.2, 8.4 | 1.7, 5.4 0.0689 |
| Adverse event category | Statistics | VLA1553 Lot 1 (N = 136) | VLA1553 Lot 2 (N = 137) | VLA1553 Lot 3 (N = 135) | Total (N = 408) |
|---|---|---|---|---|---|
| Any AE | n (%) | 98 (72.1) | 97 (70.8) | 101 (74.8) | 296 (72.5) |
| 95% CI P-value | 63.7, 79.4 | 62.4, 78.3 | 66.6, 81.9 | 67.9, 76.8 0.7533 | |
| Any related AE | n (%) | 82 (60.3) | 82 (59.9) | 83 (61.5) | 247 (60.5) |
| 95% CI P-value | 51.6, 68.6 | 51.1, 68.1 | 52.7, 69.7 | 55.6, 65.3 0.9668 | |
| Any related severe AE | n (%) | 5 (3.7) | 3 (2.2) | 3 (2.2) | 11 (2.7) |
| 95% CI P-value | 1.2, 8.4 | 0.5, 6.3 | 0.5, 6.4 | 1.4, 4.8 0.7457 | |
| Any SAE | n (%) | 3 (2.2) | 2 (1.5) | 0 | 5 (1.2) |
| 95% CI P-value | 0.5, 6.3 | 0.2, 5.2 | 0.0, 2.7 | 0.4, 2.8 0.3366 | |
| Any related SAE | n (%) | 0 | 0 | 0 | 0 |
| 95% CI P-value | 0.0, 2.7 | 0.0, 2.7 | 0.0, 2.7 | 0.0, 0.9 NC | |
| Any AESI as assessed by the investigator/DSMB | n (%) | 0 | 1 (0.7) | 0 | 1 (0.2) |
| 95% CI P-value | 0.0, 2.7 | 0.0, 4.0 | 0.0, 2.7 | 0.0, 1.4 >0.9999 | |
| Any related solicited AE | n (%) | 76 (55.9) | 79 (57.7) | 81 (60.0) | 236 (57.8) |
| 95% CI P-value | 47.1, 64.4 | 48.9, 66.1 | 51.2, 68.3 | 52.9, 62.7 0.7933 | |
| Any related solicited systemic AE | n (%) | 70 (51.5) | 72 (52.6) | 78 (57.8) | 220 (53.9) |
| 95% CI P-value | 42.8, 60.1 | 43.9, 61.1 | 49.0, 66.2 | 48.9, 58.8 0.5394 | |
| Any related solicited injection site AE | n (%) | 23 (16.9) | 30 (21.9) | 26 (19.3) | 79 (19.4) |
| 95% CI P-value | 11.0, 24.3 | 15.3, 29.8 | 13.0, 26.9 | 15.6, 23.5 0.5742 | |
| Any related unsolicited AE | n (%) | 22 (16.2) | 15 (10.9) | 30 (22.2) | 67 (16.4) |
| 95% CI P-value | 10.4, 23.5 | 6.3, 17.4 | 15.5, 30.2 | 13.0, 20.4 0.0413 | |
| Any related medically attended AE | n (%) | 7 (5.1) | 1 (0.7) | 5 (3.7) | 13 (3.2) |
| 95% CI P-value | 2.1, 10.3 | 0.0, 4.0 | 1.2, 8.4 | 1.7, 5.4 0.0689 |
n = number of participants; CI = confidence interval; DSMB=Data Safety Monitoring Board; NC = not calculated. Note: For each category, participants are included only once, even if they experienced multiple events in that category; related AE are those documented as ‘probably related’ or ‘possibly related’; AEs with missing causality were considered related; P-value calculated from Fisher’s exact test for difference between the treatment arms.
Summary of adverse events up to Month 6 (safety population)
| Adverse event category | Statistics | VLA1553 Lot 1 (N = 136) | VLA1553 Lot 2 (N = 137) | VLA1553 Lot 3 (N = 135) | Total (N = 408) |
|---|---|---|---|---|---|
| Any AE | n (%) | 98 (72.1) | 97 (70.8) | 101 (74.8) | 296 (72.5) |
| 95% CI P-value | 63.7, 79.4 | 62.4, 78.3 | 66.6, 81.9 | 67.9, 76.8 0.7533 | |
| Any related AE | n (%) | 82 (60.3) | 82 (59.9) | 83 (61.5) | 247 (60.5) |
| 95% CI P-value | 51.6, 68.6 | 51.1, 68.1 | 52.7, 69.7 | 55.6, 65.3 0.9668 | |
| Any related severe AE | n (%) | 5 (3.7) | 3 (2.2) | 3 (2.2) | 11 (2.7) |
| 95% CI P-value | 1.2, 8.4 | 0.5, 6.3 | 0.5, 6.4 | 1.4, 4.8 0.7457 | |
| Any SAE | n (%) | 3 (2.2) | 2 (1.5) | 0 | 5 (1.2) |
| 95% CI P-value | 0.5, 6.3 | 0.2, 5.2 | 0.0, 2.7 | 0.4, 2.8 0.3366 | |
| Any related SAE | n (%) | 0 | 0 | 0 | 0 |
| 95% CI P-value | 0.0, 2.7 | 0.0, 2.7 | 0.0, 2.7 | 0.0, 0.9 NC | |
| Any AESI as assessed by the investigator/DSMB | n (%) | 0 | 1 (0.7) | 0 | 1 (0.2) |
| 95% CI P-value | 0.0, 2.7 | 0.0, 4.0 | 0.0, 2.7 | 0.0, 1.4 >0.9999 | |
| Any related solicited AE | n (%) | 76 (55.9) | 79 (57.7) | 81 (60.0) | 236 (57.8) |
| 95% CI P-value | 47.1, 64.4 | 48.9, 66.1 | 51.2, 68.3 | 52.9, 62.7 0.7933 | |
| Any related solicited systemic AE | n (%) | 70 (51.5) | 72 (52.6) | 78 (57.8) | 220 (53.9) |
| 95% CI P-value | 42.8, 60.1 | 43.9, 61.1 | 49.0, 66.2 | 48.9, 58.8 0.5394 | |
| Any related solicited injection site AE | n (%) | 23 (16.9) | 30 (21.9) | 26 (19.3) | 79 (19.4) |
| 95% CI P-value | 11.0, 24.3 | 15.3, 29.8 | 13.0, 26.9 | 15.6, 23.5 0.5742 | |
| Any related unsolicited AE | n (%) | 22 (16.2) | 15 (10.9) | 30 (22.2) | 67 (16.4) |
| 95% CI P-value | 10.4, 23.5 | 6.3, 17.4 | 15.5, 30.2 | 13.0, 20.4 0.0413 | |
| Any related medically attended AE | n (%) | 7 (5.1) | 1 (0.7) | 5 (3.7) | 13 (3.2) |
| 95% CI P-value | 2.1, 10.3 | 0.0, 4.0 | 1.2, 8.4 | 1.7, 5.4 0.0689 |
| Adverse event category | Statistics | VLA1553 Lot 1 (N = 136) | VLA1553 Lot 2 (N = 137) | VLA1553 Lot 3 (N = 135) | Total (N = 408) |
|---|---|---|---|---|---|
| Any AE | n (%) | 98 (72.1) | 97 (70.8) | 101 (74.8) | 296 (72.5) |
| 95% CI P-value | 63.7, 79.4 | 62.4, 78.3 | 66.6, 81.9 | 67.9, 76.8 0.7533 | |
| Any related AE | n (%) | 82 (60.3) | 82 (59.9) | 83 (61.5) | 247 (60.5) |
| 95% CI P-value | 51.6, 68.6 | 51.1, 68.1 | 52.7, 69.7 | 55.6, 65.3 0.9668 | |
| Any related severe AE | n (%) | 5 (3.7) | 3 (2.2) | 3 (2.2) | 11 (2.7) |
| 95% CI P-value | 1.2, 8.4 | 0.5, 6.3 | 0.5, 6.4 | 1.4, 4.8 0.7457 | |
| Any SAE | n (%) | 3 (2.2) | 2 (1.5) | 0 | 5 (1.2) |
| 95% CI P-value | 0.5, 6.3 | 0.2, 5.2 | 0.0, 2.7 | 0.4, 2.8 0.3366 | |
| Any related SAE | n (%) | 0 | 0 | 0 | 0 |
| 95% CI P-value | 0.0, 2.7 | 0.0, 2.7 | 0.0, 2.7 | 0.0, 0.9 NC | |
| Any AESI as assessed by the investigator/DSMB | n (%) | 0 | 1 (0.7) | 0 | 1 (0.2) |
| 95% CI P-value | 0.0, 2.7 | 0.0, 4.0 | 0.0, 2.7 | 0.0, 1.4 >0.9999 | |
| Any related solicited AE | n (%) | 76 (55.9) | 79 (57.7) | 81 (60.0) | 236 (57.8) |
| 95% CI P-value | 47.1, 64.4 | 48.9, 66.1 | 51.2, 68.3 | 52.9, 62.7 0.7933 | |
| Any related solicited systemic AE | n (%) | 70 (51.5) | 72 (52.6) | 78 (57.8) | 220 (53.9) |
| 95% CI P-value | 42.8, 60.1 | 43.9, 61.1 | 49.0, 66.2 | 48.9, 58.8 0.5394 | |
| Any related solicited injection site AE | n (%) | 23 (16.9) | 30 (21.9) | 26 (19.3) | 79 (19.4) |
| 95% CI P-value | 11.0, 24.3 | 15.3, 29.8 | 13.0, 26.9 | 15.6, 23.5 0.5742 | |
| Any related unsolicited AE | n (%) | 22 (16.2) | 15 (10.9) | 30 (22.2) | 67 (16.4) |
| 95% CI P-value | 10.4, 23.5 | 6.3, 17.4 | 15.5, 30.2 | 13.0, 20.4 0.0413 | |
| Any related medically attended AE | n (%) | 7 (5.1) | 1 (0.7) | 5 (3.7) | 13 (3.2) |
| 95% CI P-value | 2.1, 10.3 | 0.0, 4.0 | 1.2, 8.4 | 1.7, 5.4 0.0689 |
n = number of participants; CI = confidence interval; DSMB=Data Safety Monitoring Board; NC = not calculated. Note: For each category, participants are included only once, even if they experienced multiple events in that category; related AE are those documented as ‘probably related’ or ‘possibly related’; AEs with missing causality were considered related; P-value calculated from Fisher’s exact test for difference between the treatment arms.
Solicited injection site AEs were reported by 19.4% (79/408) of participants vaccinated with VLA1553; they were exclusively of mild or moderate severity (Figure 3). Per definition, all solicited injection site AEs were classified as related to VLA1553 exposure. The most common solicited injection site AE was tenderness (14.2%; 58/408). Besides injection site pain with 6.4% of participants, all other local reactions were sporadically observed without significant differences between lots (Supplementary Table 4, available as Supplementary data at JTM online). The median duration of most injection site AEs was 2 days, except for rash with 4 days.
Solicited injection site adverse events by severity (safety population). Safety and tolerability of the vaccine were assessed in the safety population. Participant eDiaries were used for the collection of solicited injection site adverse events up to 10 days post-vaccination. Bars show the frequency of participants with solicited AEs after vaccination with VLA1553 (data pooled from all lots) by maximum severity
As the main AE category, solicited systemic AEs were reported by 57.1% of participants (233/408) vaccinated with VLA1553 (Figure 4). Although the vast majority of solicited systemic AEs were mild or moderate, 11 participants (2.7%) experienced related severe solicited AEs: these were fever (nine participants, maximum temperature was 40.5°C lasting 1 day; maximum duration of fever: 5 days), fatigue (1 participant, duration 2 days) as well as arthralgia, myalgia and headache (1 participant each, duration 1 day). However, no statistically significant differences were observed between lots (Supplementary Table 5, available as Supplementary data at JTM online). All related severe solicited AEs resolved within a maximum of three days. Overall, the most common related solicited systemic AEs (≥20%) were fatigue (36.3%; 148/408), headache (33.6%; 137/408) and myalgia (22.3%; 91/408).
Solicited systemic adverse events by severity (safety population). Safety and tolerability of the vaccine were assessed in the safety population. Participant eDiaries were used for the collection of daily oral body temperature and solicited systemic adverse events up to 10 days post-vaccination. Bars show the frequency of participants with solicited AEs after vaccination with VLA1553 (data pooled from all lots) by maximum severity
Approximately one third of participants reported unsolicited AEs (34.1%; 139/408), of which approximately half (67 participants) experienced related unsolicited AEs. Over the duration of the study, the most frequently reported related unsolicited AEs (≥1%) were neutropenia (2.9%; 12/408), lymphadenopathy (1.5%; 6/408), chills (1.5%; 6/408) and arthralgia (1%; 4/408). A total of 1.5% of participants (6/408) reported a severe unsolicited AE. However, no significant differences with regard to severe related unsolicited AEs were observed between lots (Table 1).
Up to Month 6, five unrelated SAEs were reported; they included acute appendicitis (2), spontaneous abortion (2) and acute cholecystitis (1). A single participant met the criteria of AESI experiencing mild arthralgia (duration: 6 days) and severe fever (duration: 3 days), but both AEs were self-limiting. None of the documented AEs led to study withdrawal. An independent DSMB regularly reviewed accruing safety information until the last participant had completed the visit at 6 months. This included three pregnancies reported during the study: two pregnancies ended with spontaneous abortion (no reasons for miscarriage identified) and one progressed well up to vaginal birth. The DSMB reviewed and discussed all reported miscarriages in detail and did not raise any safety concerns.
Discussion
Study VLA1553-302 met its primary endpoint demonstrating lot-to-lot consistency at 28 days post-vaccination. Moreover, this study confirmed the high seroresponse rate observed in the pivotal trial for the VLA1553 vaccine candidate with a seroresponse in 97.8% of participants 28 days after vaccination, which persisted throughout the study resulting in 96% of participants with a titre well above μPRNT50 ≥ 150 at Month 6.3 This serological surrogate of protection was agreed as an endpoint with regulators to allow evaluation of vaccine effectiveness against CHIKV during the licensure pathway, because a typical vaccine efficacy trial is not considered feasible for chikungunya as discussed previously.3
The vaccine candidate VLA1553 was generally well tolerated independent of the administered lot. An independent DSMB continuously evaluated safety data during the study including two reported miscarriages and did not identify any safety concern. In contrast to infection with the Zika virus, CHIKV infection during pregnancy does not appear to increase the risk of fetal complications.32–36
The reported trial VLA1553-302 was designed independently from the previous pivotal Phase 3 trial VLA1553-301.3 Without overlap in trial participants, several endpoints were carried forward to this lot-to-lot exercise to augment the safety and immunogenicity database established so far. A comparison of the trial outcomes showed consistent immunogenicity outcomes with almost all vaccinated participants achieving seroresponse and titers considered protective against chikungunya disease. With regard to the safety profile, the frequencies of AEs were close to or slightly higher than those observed in the pivotal Phase 3 trial (any related AE: 60.5% vs 51.1%; any AESI: 0.2% vs 0.3%; any related severe AE: 2.7% vs 2.0%; any related injection site AE: 19.4% vs 15.0%; any related solicited systemic AE: 53.9% vs 49.1%).
A comparison of the safety profile to three other marketed vaccines suggests that VLA1553 has similar or even lower rates of reported solicited local and systemic AEs. For VLA1553, the reported solicited local AEs were mostly tenderness (14.2%) and pain at the injection site (6.4%) For the mRNA vaccine COMIRNATY®, a substantially higher rate of pain at the injection site has been reported (88.6%),37 which also applied to BEXSERO® (≥83%)38 and SHINGRIX® with higher rates of pain (78%), redness and swelling.39 Likewise, the most frequent solicited systemic AEs of VLA1553, such as fatigue, headache, myalgia and arthralgia compared favourably to COMIRNATY®,37 BEXSERO®38 and SHINGRIX®.39 The live-attenuated yellow fever vaccine YF-VAX® reported similar rates of headache, fatigue, myalgia, fever and nausea.40 Taken together, VLA1553 induced AEs to a comparable or even lesser level when compared with the marketed vaccines outlined above.
This study has several limitations. Designed as lot-to-lot study, the evaluation of short-term outcomes does not provide sufficient information about long-term vaccine efficacy and safety. As lot-to-lot studies are better performed in a uniform population, the age group selected for the study were adults aged 18–45, which may have different immunogenicity and safety responses to vaccines compared to other age groups and may not be fully representative for the broad traveller’s population. However, it was shown in the pivotal Phase 3 trial that older age did not have an impact on the safety or immunogenicity, with identical study outcomes in older participants.3 To close another gap, we are currently performing a long-term follow-up study in a subset of participants from the aforementioned pivotal trial assessing immunogenicity and safety for at least 5 years.
Conclusions
Our study confirmed that VLA1553 was manufactured consistently, with all three lots exhibiting comparably high neutralizing antibody titers and safety profiles. The trial corroborates that VLA1553 is able to induce a robust and durable immune response. With a high seroresponse rate of 97.8% at 28 days post-vaccination and persisting in 96.0% of participants at Month 6, this trial readily confirms the seroresponse rates observed in an earlier pivotal trial for VLA1553.3 The immunogenicity readout demonstrated again that nearly every vaccine developed titers above the threshold defined for seroresponse, i.e. μPRNT50 ≥ 150, which is considered reasonably likely to predict protection. Moreover, the data extend our current knowledge base by confirming the favourable safety profile described in study VLA1553-301. Taken together, this recommends VLA1553 as an excellent candidate for the prevention of disease caused by the CHIKV for travellers and people in endemic areas alike.
Funding
The study was designed and funded by Valneva Austria. In addition, we acknowledge the Coalition for Epidemic Preparedness Innovation (CEPI) and EU Horizon 2020 for partially funding the VLA1553 development program. Employees of Valneva were responsible for study design, data collection, data analysis, data interpretation and writing of the report. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication.
Acknowledgements
Valneva acknowledges the independent data safety monitoring board and its members (Herwig Kollaritsch, Lin Chen, Eva-Maria Poellabauer) for their active role in this study. We also want to acknowledge the highly relevant contributions to our VLA1553 program by the late Prof. Fabrice Simon and Prof. Frank von Sonnenburg, whose valuable input we will miss greatly. Valneva acknowledges all investigators, site staff and participants for contributing to this study.
Author contributions
Robert McMahon, Martina Schneider, Sandra Hadl, Romana Hochreiter, Michael Koren, Robert Mader, Katrin Dubischar, Susanne Eder-Lingelbach, Nina Wressnigg (Study concept and design), Robert McMahon, Ulrike Fuchs, Oliver Zoihsl, Vera Buerger, Susanne Eder-Lingelbach (Supervised the study), Romana Hochreiter, Annegret Bitzer, Karin Kosulin (Supervised the serological analyses), and Robert McMahon, Ulrike Fuchs, Martina Schneider, Romana Hochreiter, Karin Kosulin Robert Mader, Katrin Dubischar, Oliver Zoihsl, Vera Buerger, Susanne Eder-Lingelbach, Sandra Hadl (Analysed and interpreted data). All authors contributed to the drafting and revision of the manuscript, reviewed and approved the final version
Conflict of interest
R.Mc.M., M.S., U.F., S.H., R.H., A.B., K.K., O.Z., N.W., V.B., K.D., S.E. and J.J. are Valneva employees and own stock and share options in Valneva. M.K. is director, clinical trials centre at Walter Reed Army Institute of Research, Bethesda, MD, USA. R.M. is a scientific consultant for Valneva and has received payments.
Data availability
All data that underlie the results reported in this article (including study protocol) on individual participants will be made available to researchers who provide a methodologically sound proposal.
Footnotes
†Data from this study until 28 days of post-vaccination have been presented at the 32nd European Congress of Clinical Microbiology & Infectious Diseases (ECCMID 2022) and study data up to Month 6 at the 33rd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2023).
