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Safety and Immunogenicity of a Recombinant RSV F Protein Nanoparticle Vaccine Manufactured in Insect Cells: a Phase I Dose and Formulation-finding Trial in Adults Authors: G. Glenn1, P.A. Piedra2, R. Raghunandan1, E. Kpamegan1, N. Thomas1, L. Fries1,

G. Smith1

Affiliations: 1 Novavax Inc., Rockville MD, USA and 2 Baylor College of Medicine, Houston TX, USA

Respiratory syncytial virus (RSV) is responsible for a major respiratory disease burden concentrated at the extremes of age: in infants and young children and the elderly. Passive immunoprophylaxis is available for high-risk infants, but no safe and efficacious vaccine is available. The objectives of this trial were to describe the safety and immunogenicity of ascending doses of a recombinant vaccine produced in insect cells and comprising nanoparticles of RSV F protein trimers, with or without adsorption to AlPO4. Healthy adults (N = 150; mean age 31.3 years; 59% female; 76% white, 18% African-American) were enrolled in 6 sequential cohorts, each including 20 active vaccine and 5 placebo recipients. Test articles were given as 2-dose series at a 30 day interval; RSV F antigen was tested at doses of 5, 15, 30 and 60µg adsorbed to AlPO4, and 30 and 60µg without adjuvant. Safety was monitored by soliciting local and systemic symptoms for 7 days after each dose, and by ascertainment of all adverse events (AEs) from days 0 to 60, and serious AEs (SAEs) and significant new medical conditions (SNMCs) for 6 months. A safety monitoring committee reviewed short-term safety and approved continued dose-escalation. Immunogenicity was assessed by titration of F protein-specific IgG by ELISA and RSV neutralizing antibodies by plaque-reduction assay (PRN) for RSV/A and a previously-published (Piedra, et al. Pediatr Infect Dis J 1996; 15:23) microneutralization (MN), assay for both RSV/A and B. The vaccine was well-tolerated. The most common local AEs were pain (21% vaccinees vs. 3% placebo recipients) and tenderness (32% vaccinees vs. 10% placebo recipients); these were typically mild, showed little dose-response, and did not increase after the 2nd dose. Solicited systemic reactogenicity was generally indistinguishable between vaccinees and placebo recipients. Through study day 60, there were no deaths and a single SAE (appendicitis in a placebo recipient). Unsolicited AEs occurred with similar frequencies across treatment groups; SNMCs were reported in 8 subjects, comprised heterogeneous diagnoses, and were more common among placebo (10%) than vaccine recipients (4%). F protein-specific IgG titers did not change significantly in placebo recipients, but rose

in a dose-responsive manner from 4.4-fold (5µg dose with AlPO4) to 14.0-fold (60µg dose with AlPO4) after the first dose and 7.1-fold (5µg dose with AlPO4) to 19.1-fold (60µg dose with AlPO4) after the 2nd dose. In contrast, anti-F titers rose 8 to 11 fold in recipients of unadjuvanted vaccine and showed no significant impact of the second dose. Statistically-significant increases in RSV/A PRN geometric mean titers were seen in the 30 and 60µg with AlPO4 dose groups after 1 dose, and also in the 15µg with AlPO4 group after 2 doses. Similar responses were seen using the MN method for both RSV/A and RSV/B: median MN titers rose by 1.5 to 2 log2 with larger rises occurring in subjects with the lowest baseline titers. In the 30 and 60µg with AlPO4 groups, 100% of subjects attained post-immunization MN titers exceeding the 6.0 log2 titer described by Piedra, et al (Vaccine 2003; 21:3479) as a minimal protective threshold for RSV/A-related hospitalization; and > 90% of subjects exceeded the 8.0 log2 protective threshold for RSV/B. Recombinant RSV F protein nanoparticle vaccine was well-tolerated in adults and induced F protein-specific IgG associated with enhanced neutralization of RSV/A and B. Further development for elderly and/or maternal immunization indications is warranted; with a potential for pediatric use pending additional safety experience.