Originally published by 2 Minute Medicine® (view original article). Reused on AccessMedicine with permission.

1. A plant-derived, virus-like particle displays the SARS-CoV-2 spike glycoprotein and appears to be a promising candidate for a vaccine.

2. Adverse outcomes were mild-to-moderate, transient, and dependent on adjuvant.

Evidence Rating Level: 1 (Excellent)

Study Rundown:

Available vaccines for COVID-19 are proving to be effective and safe. However, the demand for vaccines across the globe exceeds the current supply. This suggests that different formulations may serve a useful purpose in inoculating communities that continue to experience increased rates of COVID-19 infections.

This Phase 1 observer-blinded, dose-escalated, randomized, controlled trial tested the safety and immunogenicity of a plant-derived, virus-like particle produced in plants that displays the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (CoVLP NCT04450004). Across various intramuscular doses both alone and adjuvanted, adverse effects were generally mild and transient, with adjuvanted groups showing more moderate symptoms. Outcome measures such as neutralizing antibodies, interferon-γ, and interleukin-4 suggested promising cellular responses.

Overall, this study found that CoVLP is well-tolerated and produces a promising immune response against the spike protein. Research needs to continue and recruit a more diverse sample to ensure safety and immunogenicity for other groups of people. However, given the history of VLPs, it is possible that this plant-derived particle could prevent further infections and increase the supply of global vaccines for COVID-19.

In-Depth [randomized controlled trial]:

COVID-19 is a global health concern that has exhibited numerous waves. Infection rates have declines in some countries, allowing for loosening of restrictions, while other countries are experiencing the worst part of the pandemic. It is unclear whether or not the current vaccines will be capable of demonstrating efficacy against all variant types, particularly in understudied countries. Further, demand for accessible vaccines currently exceeds the supply. This situation suggests that new formulations may harbor utility as the world attempts to overcome infection. This Phase 1 observer-blinded, dose-escalation, randomized, controlled trial aimed to assess the safety and immunogenicity of a plant-derived, virus-like particle that possesses the SARS-CoV-2 spike glycoprotein (CoVLP NCT04450004). BLPs have been successful with human papilloma virus and hepatitis B. For this study, main outcomes were serum neutralizing antibodies (NAbs), interferon-γ, interleukin-4, and convalescent sera.

A total of 180 (M [SD] age = 34.3 [9.0] years, 56.7% female, 95.6% White) participants in Canada were screened for SARS-CoV-2 antibodies and were found seronegative, using a commercial enzyme-linked immunosorbent assay (ELISA) that targeted the nucleocapsid protein. This study used a two-dose intramuscular injection system 21 days apart, with doses at 3.75ug, 7.5ug, or 15ug. Participants were randomly assigned to a dose and 178 (98.9%) received both injections. Three formulation groups were also included: unadjuvanted CoVLP, CoVLP+AS03, CoVLP+CpG1018. Twenty participants were assigned to each group. Data on adverse events were collected during an immediate 15-minute observation period following injections, during telephone calls on Day 1 and Day 8, and during an in-person visit on Day 3. Adverse events were primarily mild-to-moderate, transient, and dose-dependent. The only grade 3 event was related to fatigue and dissipated the same day. In the unadjuvanted CoVLP and ClVLP+CpG1018 groups, events were similar after the first and second doses. In the CoVLP+AS03 group, events increased after the second dose. However, there was no consistent effect of dose level on safety outcomes in any group. Approximately 74.3% of participants reported an adverse event after the first dose and 68.5% reported more than one adverse event after the second dose. Most of these reported events were local reactions (66.5%), pain at the injection site (66.5%), as well as headache and fatigue (33.1%). Six participants (3.3%) reported grade 3 redness at injection site, swelling at injection site, general discomfort, and fatigue. Unadjuvanted CoVLP demonstrated no detectable antibody response after the first dose and were modest upon second dose. There was a dose effect with the adjuvanted groups, though, such that IgG titers and NAb responses at Day 21 were readily detectable. Notably, NAb levels in groups that received adjuvants were either equivalent or greater than participants recovering from natural COVID-19 infection, with ten times the titers in COVID-19 convalescent sera. Every participant who received CoVLP+AS03 seroconverted in the anti-spike IgG ELISA and both neutralization assays, irrespective of dose level.

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