**5. Human Clinical Trials with H7N9 VLP Vaccines**

Two phase I clinical trials of experimental H7N9 VLP vaccines with, and without, adjuvant have been completed, NCT01897701 and NCT02078674. The first study enrolled 284 adults (≥18 years of age) in a randomized, observer-blinded, placebo-controlled clinical trial [79]. Interestingly enough, significant increases in N9 neuraminidase-inhibiting antibodies occurred in up to 71.9% of recipients of the vaccine without adjuvant, 92.0% of recipients of vaccine with 30 units of adjuvant, and 97.2% of recipients of vaccine with 60 units of adjuvant. Remarkably, the vaccines that were studied were released for human use within 3 months after the availability of the HA and NA sequences. This illustrates the possibility of rapid response to the public health emergency situations, such as in the case of pandemic influenza outbreaks, as well as other health emergencies such as the ongoing COVID-19 coronavirus pandemic.

In another previously reported phase I clinical trial, subjects vaccinated with two doses of an unadjuvanted H7N9 VLP vaccine responded poorly (15.6% seroconversion rates with 45 μg HA dose). In contrast, 80.6% of subjects receiving H7N9 VLP vaccine (5μg HA) with ISCOMATRIX adjuvant developed HAI responses [80]. The results suggest that adjuvants can be important component for the development of safe and effective H7N9 human vaccines [81].

Plant-derived quadrivalent seasonal VLP vaccine has been evaluated and elicited cross-reactive antibody and T cell response in healthy adults [82]. Although H7N9 antigens have not been included in this study, the confirmed safety profile of VLP in humans suggests an attractive alternative manufacturing method for producing effective and HA-strain matching influenza vaccines.
