VII 4

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. Glenn
1
, P.A. Piedra
2
, R. Raghunandan
1
, E. Kpamegan
1
, N. Thomas
1
, L. Fries
1
,
G. Smith
1

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 60g adsorbed to AlPO4, and
30 and 60g 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 2
nd
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 (5g dose with AlPO4) to 14.0-fold (60g
dose with AlPO4) after the first dose and 7.1-fold (5g dose with AlPO4) to 19.1-fold
(60g dose with AlPO4) after the 2
nd
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 60g with AlPO4 dose groups after 1 dose, and also in the 15g 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 60g 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.