A plant-derived quadrivalent virus like particle influenza vaccine induces cross-reactive antibody and T cell response in healthy adults.

Recent issues regarding efficacy of influenza vaccines have re-emphasized the need of new approaches to face this major public health issue. In a phase 1-2 clinical trial, healthy adults received one intramuscular dose of a seasonal influenza plant-based quadrivalent virus-like particle (QVLP) vaccine or placebo. The hemagglutination inhibition (HI) titers met all the European licensure criteria for the type A influenza strains at the 3µg/strain dose and for all four strains at the higher dosages 21days after immunization. High HI titers were maintained for most of the strains 6months after vaccination. QVLP vaccine induced a substantial and sustained increase of hemagglutinin-specific polyfunctional CD4 T cells, mainly transitional memory and TEMRA effector IFN-γ(+) CD4 T cells. A T cells cross-reactive response was also observed against A/Hong-Kong/1/1968 H3N2 and B/Massachusetts/2/2012. Plant-based QVLP offers an attractive alternative manufacturing method for producing effective and HA-strain matching seasonal influenza vaccines.

Projected impact of a plant-derived vaccine on the burden of seasonal influenza in Canada.

OBJECTIVE: The analysis estimates projected population outcomes resulting from the introduction of a plant-derived influenza vaccine formulated as quadrivalent virus-like particles (QVLP) in Canada. METHODS: Using Monte Carlo simulations, the number of influenza cases, general practitioner visits, inpatient admissions, intensive care unit (ICU) admissions, and deaths due to influenza-associated illness were estimated under no vaccination, plant-derived QVLP vaccines only, or egg-derived vaccines only. The base case analysis examined the adult Canadian population in two subgroups: 18-64 years of age during the 2017/18 season and 65+ years of age during the 2018/19 season. Efficacy data were obtained from QVLP clinical trials. Vaccine effectiveness data for egg-derived vaccines were calculated from observational studies from the corresponding influenza seasons. Scenario analyses examined the impact of varying absolute vaccine effectiveness or vaccination coverage from base case inputs. RESULTS: In the base case analysis, plant-derived QVLP vaccines led to an additional reduction in the burden of influenza over egg-derived vaccines for both population subgroups. In the 18-64 subgroup, QVLP vaccines were associated with 2.63% (48,029; 95% credible interval [Crl]: 42,723-53,336) fewer influenza cases than egg-derived vaccines. In the 65+ subgroup, QVLP vaccines led to 4.82% (27,918; 95% Crl: 25,440-30,397) fewer influenza cases, and reductions in the number of inpatient admissions by 4.77% (1167; 95% CrI: 851-1483) and deaths by 4.75% (326; 95% CrI: 107-546) compared to egg-derived vaccines. Further reductions were observed in scenario analyses considering the potential increase in vaccine coverage. CONCLUSION: Use of plant-derived QVLP influenza vaccines may contribute to greater reductions in influenza cases and influenza-related outcomes, including inpatient admissions and deaths, compared to egg-derived vaccines currently available in Canada.

Phase III: Randomized observer-blind trial to evaluate lot-to-lot consistency of a new plant-derived quadrivalent virus like particle influenza vaccine in adults 18-49 years of age.

BACKGROUND: The global reliance on eggs to produce most influenza vaccines has several limitations and new approaches to influenza vaccine production are needed. Herein we describe a phase 3, lot-to-lot consistency trial (NCT03321968) of a quadrivalent, recombinant, virus-like particle (VLP) influenza vaccine produced in plants. This platform is based on transient expression of proteins in Nicotiana benthamiana and yields VLPs bearing hemagglutinin (HA) protein trimers that are combined in a quadrivalent vaccine (QVLP). METHODS: The HAs targeted in this study were A/California/07/2009 H1N1, A/Hong Kong/4801/2014 H3N2, B/Brisbane/60/08 and B/Phuket/3073/2013: recommended for the 2016-2017 Northern Hemisphere season. Healthy adults 18-49 years of age (n = 1200) were randomized 1:1:1 to receive a 0.5 mL intramuscular injection of QVLP (30 µg HA/strain) from three sequential lots. Local and systemic reactions were monitored for 21 days post-vaccination and blood was collected pre-vaccination and at day 21 (D21) after vaccination to measure hemagglutination inhibition (HI) antibodies. RESULTS: Subject demographics were similar between groups and compliance with study procedures was 96.3%. The study population was 54.8% female, the mean age (±SD) was 29.9 ± 9.01 and the racial distribution was 77.8% Caucasian, 15.6% Asian, 5.8% Black/African American and 0.8% other. The HI responses met the Center for Biologics Evaluation and Research criteria for seroconversion (SCR ≥ 40%) and seroprotection rates (SPR ≥ 70%). The geometric mean fold rise in HI titers was ≥ 2.5 for all 4 strains for each lot. Lot-to-lot consistency was met with the 95% confidence intervals of the D21 mean geometric titre ratios falling between 0.67 and 1.5 for all four strains. No safety concerns were identified. Solicited adverse events were generally mild and transient: typical for what is reported after inactivated influenza vaccines. CONCLUSIONS: This study supported earlier findings of the safety profile and immunogenicity of the plant-derived QVLP and demonstrated the consistency with which it can be produced.