Efficacy, immunogenicity, and safety of a plant-derived, quadrivalent, virus-like particle influenza vaccine in adults (18–64 years) and older adults (≥65 years): two multicentre, randomised phase 3 trials

Ward, Brian J.; Makarkov, Alexander; Séguin, Annie; Pillet, Stéphane; Trépanier, Sonia; Dhaliwall, Jiwanjeet; Libman, Michael; Vesikari, Timo; Landry, Nathalie

doi:10.1016/s0140-6736(20)32014-6

Cited by 155 publications

(147 citation statements)

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“…Differences between unadjuvanted and adjuvanted formulations and between the two adjuvants were less pronounced in the IFN-γ ELISpot than for antibody responses, suggesting that CoVLP alone can stimulate a cellular response. The ability of CoVLP by itself to induce a degree of cellular immunity is consistent with extensive studies of T cell responses to plant-derived influenza vaccine candidates 29,31,32 . Nonetheless, the IFN-γ ELISpot responses to adjuvanted formulations were consistently higher at most CoVLP dose levels compared to CoVLP alone, particularly after the second dose.…”

Section: Discussionsupporting

confidence: 74%

“…This platform has also been used to produce hemagglutininbearing VLP vaccines for avian (monovalent) and seasonal (quadrivalent) influenza that induce balanced humoral and T cell responses [29][30][31][32] . The CoVLP vaccine was administered alone or with AS03 or CpG1018 adjuvants in healthy adults 18-55 years of age.…”

Section: Phase 1 Randomized Trial Of a Plant-derived Virus-like Particle Vaccine For Covid-19mentioning

confidence: 99%

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Phase 1 randomized trial of a plant-derived virus-like particle vaccine for COVID-19

Ward

Gobeil

Séguin

et al. 2021

Nat Med

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Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are being deployed, but the global need greatly exceeds the supply, and different formulations might be required for specific populations. Here we report Day 42 interim safety and immunogenicity data from an observer-blinded, dose escalation, randomized controlled study of a virus-like particle vaccine candidate produced in plants that displays the SARS-CoV-2 spike glycoprotein (CoVLP: NCT04450004). The co-primary outcomes were the short-term tolerability/safety and immunogenicity of CoVLP formulations assessed by neutralizing antibody (NAb) and cellular responses. Secondary outcomes in this ongoing study include safety and immunogenicity assessments up to 12 months after vaccination. Adults (18–55 years, n = 180) were randomized at two sites in Quebec, Canada, to receive two intramuscular doses of CoVLP (3.75 μg, 7.5 μg, and 15 μg) 21 d apart, alone or adjuvanted with AS03 or CpG1018. All formulations were well tolerated, and adverse events after vaccination were generally mild to moderate, transient and highest in the adjuvanted groups. There was no CoVLP dose effect on serum NAbs, but titers increased significantly with both adjuvants. After the second dose, NAbs in the CoVLP + AS03 groups were more than tenfold higher than titers in Coronavirus 2019 convalescent sera. Both spike protein-specific interferon-γ and interleukin-4 cellular responses were also induced. This pre-specified interim analysis supports further evaluation of the CoVLP vaccine candidate.

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Section: Discussionsupporting

confidence: 74%

Section: Phase 1 Randomized Trial Of a Plant-derived Virus-like Particle Vaccine For Covid-19mentioning

confidence: 99%

Phase 1 randomized trial of a plant-derived virus-like particle vaccine for COVID-19

Ward

Gobeil

Séguin

et al. 2021

Nat Med

Self Cite

255

276

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“…We report here the results of a Phase 1 study initiated in July 2020 evaluating the safety, tolerability and immunogenicity of two doses, 21-days apart of 3.75, 7.5 or 15 µg of a virus-like-particle vaccine candidate for Covid-19 produced in plants (hereafter called CoVLP). This recombinant platform has been used to produce hemagglutinin (HA)-bearing VLP vaccines for avian (monovalent) and seasonal (quadrivalent) influenza that induce balanced humoral and T cell responses 28-31 . The CoVLP vaccine was administered alone or with AS03 or CpG1018 adjuvants in healthy adults 18-55 years of age.…”

Section: Introductionmentioning

confidence: 99%

Phase 1 trial of a Candidate Recombinant Virus-Like Particle Vaccine for Covid-19 Disease Produced in Plants

Ward

Gobeil

Séguin

et al. 2020

Preprint

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Background: The stabilized prefusion form of the SARS-CoV-2 spike protein is produced by transient expression in Nicotiana benthamiana. The trimeric spike glycoproteins are displayed at the surface of self-assembling Virus-Like-Particles that mimic the shape and the size of the virus. The candidate vaccine (CoVLP) administered alone or with AS03 or CpG1018 adjuvants was evaluated in a Phase 1 trial in healthy adults. (ClinicalTrials.gov number NCT04450004) Methods: The study was a randomized, partially-blinded, prime-boost 21 days apart, dose-escalation Phase 1 study intended to assess the safety, tolerability, and immunogenicity of CoVLP at three dose levels (3.75 microgram, 7.5 microgram, and 15 microgram) unadjuvanted or adjuvanted with either CpG 1018 or AS03 in 180 SARS-CoV-2 seronegative healthy adults 18 to 55 years of age. Enrollment was staggered for dose-escalation. At each dose level, the vaccine was initially administered to a small number of subjects. Vaccination of the remaining subjects at the same dose level and the next higher vaccine dose level was administered with approval of an Independent Data Monitoring Committee (IDMC). The same procedure was followed for the second vaccine administration. Monitoring of safety signals was performed throughout the study with pre-determined pausing/stopping rules if there was clear evidence of harmful effects such as severe adverse events (AEs) related to the treatment. The primary endpoints were the safety and tolerability of the vaccine after each dose and the immunogenicity as assessed by neutralizing antibody responses assessed using a vesicular stomatitis virus (VSV) pseudovirion assay and interferon-gamma and interleukin-4 (IL-4) ELISpot assays at Days 0, 21 and 42. Secondary endpoints were anti-spike antibody responses by ELISA and neutralizing antibodies measured by live virus plaque reduction neutralization test (PRNT) assay at Days 0, 21 and 42 and immunogenicity with additional safety and immunogenicity endpoints planned for 6-months following the last vaccination. The anti-spike and neutralizing antibody responses were compared with 23 convalescent serum samples from symptomatic Covid-19 patients. We performed a primary analysis at day 42. Results: A total of 180 subjects (102 females: 78 males: average 34.3 years) were recruited to the study and interim safety and immunogenicity data up to day 42 after the first dose are reported here. There was no obvious CoVLP dose effect in safety outcomes for any of the formulations tested and all formulations were generally well-tolerated. Most solicited local and systemic AEs were mild-moderate and transient. Reactogenicity was increased in all adjuvanted formulations and was generally highest in the CoVLP+AS03 groups. Local and systemic adverse events were reported with similar frequency after the first and second doses in subjects who received either CoVLP alone or CoVLP+CpG1018 but increased in both frequency and severity after the second dose in the CoVLP+AS03 groups. CoVLP alone only elicited a weak total anti-spike IgG response at the highest dose level and little-to-no neutralization antibody response, even after the second dose. Cellular responses in the CoVLP alone groups (IFN-gamma and IL-4) were detectable after the second dose but were still only marginally above background levels. The addition of either adjuvant substantially increased both antibody and cellular responses at most CoVLP dose levels and changes were most pronounced after the second dose. However, a substantial neutralizing antibody response after the first dose was only seen in all CoVLP+AS03 groups. After the second dose, both total anti-spike IgG and neutralizing antibody titers in the CoVLP+AS03 groups were higher than those in the CoVLP+CpG1018 groups. The antibody titers achieved were either similar to (CoVLP+CpG1018) or at least 10-times higher (CoVLP+AS03) than those seen in convalescent plasma. Administration of CoVLP with either adjuvant also significantly increased the cellular responses. After 2 doses, both IFN-gamma and IL-4 responses were significantly increased in the CoVLP+CpG1018 groups. In the CoVLP+AS03 groups, significant increases in the cellular responses were observed after the first dose while IFN-gamma and IL-4 increased further in both magnitude and number of subjects responding after the second dose. Again, the cellular responses in the CoVLP+AS03 groups were higher than those seen in the CoVLP+CpG1018 groups. Conclusion: These data demonstrate that CoVLP administered with either CpG1018 or AS03 has a safety profile similar to other candidate vaccines for SARS-CoV-2. When administered with either AS03 or CpG1018, several of the CoVLP dose levels elicited strong humoral and T cell responses after the second dose. When administered with AS03, even the 3.75 microgram CoVLP dose elicited neutralizing antibody titers that were ~10-times higher than those observed in individuals recovering from Covid-19 as well as consistent and balanced IFN-gamma and IL-4 responses. Although many CoVLP formulations were immunogenic, in the absence of established correlates of protection and given the advantages of dose-sparing in the context of the on-going pandemic, these findings suggest that CoVLP (3.75 microgram)+AS03 has a good benefit/risk ratio and support the transition of this formulation to studies in expanded populations and to efficacy evaluations

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“…Quite recently, a new vaccine, the recombinant quadrivalent virus-like particle (QVLP) influenza vaccine containing influenza hemaggutinins expressed with the use of a plantbased platform, was demonstrated to be equally effective as the other quadrivalent vaccines in phase 3 clinical trials and is awaiting approval, allowing for a cheaper and faster influenza vaccine production [6].…”

Section: Types Of Influenza Vaccinesmentioning

confidence: 99%

Vaccines for Influenza

2021

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Efficacy, immunogenicity, and safety of a plant-derived, quadrivalent, virus-like particle influenza vaccine in adults (18–64 years) and older adults (≥65 years): two multicentre, randomised phase 3 trials

Cited by 155 publications

References 40 publications

Phase 1 randomized trial of a plant-derived virus-like particle vaccine for COVID-19

Phase 1 randomized trial of a plant-derived virus-like particle vaccine for COVID-19

Phase 1 trial of a Candidate Recombinant Virus-Like Particle Vaccine for Covid-19 Disease Produced in Plants

Vaccines for Influenza

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