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

Abstract

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.

Producing Vaccines against Enveloped Viruses in Plants: Making the Impossible, Difficult

“…It is striking that the HBV VLP vaccine candidate trials, which consisted of feeding human volunteers HBsAg-producing lettuce [ 18 ] or uncooked potato [ 20 ], never progressed beyond early phase clinical testing. In contrast, the influenza [ 63 ] and SARS-CoV-2 [ 70 ] VLPs which are currently at late-stage clinical development are both purified products formulated for injection.…”

“…While examples of plant-produced enveloped virus vaccine candidates can be found from a wide variety of enveloped virus families, the only examples of products clinically tested in humans to date are hepatitis B virus [ 18 , 20 ], influenza virus [ 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ], and SARS-CoV-2 [ 70 ]. There have, however, been numerous pre-clinical trials in animal models, and some trials of potential veterinary vaccines in target animals [ 54 , 64 , 102 , 165 , 191 ].…”

“…The first report in the scientific literature of a plant-produced vaccine candidate against SARS-CoV-2 is from Medicago, who managed to use their experience with influenza VLPs (see above) to produce a VLP vaccine candidate against the new coronavirus threat. This VLP consists of the SARS-CoV-2 S protein with a number of modifications: a few stabilising point mutations, a plant signal peptide instead of the native sequence, and the transmembrane domain and cytoplasmic tail of S were replaced with the equivalent sequences from influenza H5 HA [ 70 ], a strategy reminiscent of that used for RVFV (see above). This VLP was tested in humans in a phase 1 trial which showed very favourable safety and tolerability as well as promising immunogenicity.…”

Biotechnological Insights on the Expression and Production of Antimicrobial Peptides in Plants

“…In addition, the regulatory approval of tobacco-produced HIV-neutralizing human monoclonal antibody 2G12 established the scientific, technical and regulatory framework for plant-derived recombinant proteins [ 117 ]. Recently, virus-like particle (VLP) influenza vaccine manufactured in plants has completed the phase III trial and plant-derived VLP vaccine for coronavirus disease produced in N. benthamiana has completed a Phase I trial [ 118 ]. Furthermore, number of PMPs are in various stages of clinical development which include vaccine antigens, enzymes, cytokines, monoclonal antibodies and their fragments and a few are approved [ 119 , 120 ].…”

Is it possible to ensure COVID19 vaccine supply by using plants?

“…The phase I clinical trial report of a plant derived Covid 19 vaccine, CoVLP by MedicagoInc, Canada brings new hope to save the human races in a green way. The original work was published by Ward et al, 2021 in Nature Medicine, explaining futuristic approach to meet the high demand for vaccines in most convenient way [ 22 ]. This technology utilizes Nicotiana benthamiana as plant system for the vaccine production and disarmed Agrobacterium tumefaciens for transfer of episomal DNA bearing SARS CoV-2 spike protein gene.…”