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.

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The hemagglutinination inhibition (HI) response remains the gold standard used for the licensure of influenza vaccines. However, cell-mediated immunity (CMI) deserves more attention, especially when evaluating H5N1 influenza vaccines that tend to induce poor HI response. In this study, we measured the humoral response (HI) and CMI (flow cytometry) during a Phase II dose-ranging clinical trial (NCT01991561). Subjects received two intramuscular doses, 21 days apart, of plant-derived virus-like particles (VLP) presenting the A/Indonesia/05/2005 H5N1 influenza hemagglutinin protein (H5) at the surface of the VLP (H5VLP). The vaccine was co-administrated with Alhydrogel® or with a glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE). We demonstrated that low doses (3.75 or 7.5 μg H5VLP) of GLA-SE-adjuvanted vaccines induced HI responses that met criteria for licensure at both antigen doses tested. Alhydrogel adjuvanted vaccines induced readily detectable HI response that however failed to meet licensure criteria at any of three doses (10, 15 and 20 μg) tested. The H5VLP also induced a sustained (up to 6 months) polyfunctional and cross-reactive HA-specific CD4+ T cell response in all vaccinated groups. Interestingly, the frequency of central memory Th1-primed precursor cells before the boost significantly correlated with HI titers 21 days after the boost. The ability of the low dose GLA-SE-adjuvanted H5VLP to elicit both humoral response and a sustained cross-reactive CMI in healthy adults is very attractive and could result in significant dose-sparing in a pandemic situation.

SummaryHuman intravenous immunoglobulin (IVIg) and anti‐D immunoglobulin preparations are used in the treatment of immune thrombocytopenic purpura (ITP). One mechanism proposed to explain their therapeutic effects in ITP patients is the induction of expression of anti‐inflammatory cytokines, such as interleukin (IL)‐10 or IL‐1ra, leading to a reduction of phagocytic activity of the reticuloendothelial system. However, increased expression of pro‐inflammatory cytokines was also noted following treatment of ITP patients, raising doubt on the actual contribution of anti‐inflammatory cytokines in the therapeutic effects of IVIg and anti‐D immunoglobulins. The present study evaluated the in vivo modulation of expression of a large array of inflammatory cytokines using a mouse model of thrombocytopenia. IVIg was not found to modulate cytokine expression although it efficiently prevented thrombocytopenia. In contrast, protective (M1/69) and non‐protective (TER‐119) anti‐mouse red blood cell (RBC) antibodies (mimicking anti‐D treatment) both increased the expression of CXCL‐1 and CXCL‐5. Thus, there was no relationship between inflammatory cytokine expression and prevention of thrombocytopenia by IVIg or anti‐mouse RBC in the ITP mouse model. These results suggest that the increase in cytokine expression observed in ITP patients following IVIg or anti‐D infusion is not required for their therapeutic effects but may rather represent a side‐effect of the treatment.