Live-Attenuated Respiratory Syncytial Virus Vaccine With Deletion of RNA Synthesis Regulatory Protein M2-2 and Cold Passage Mutations Is Overattenuated

Abstract

Background: The live respiratory syncytial virus (RSV) candidate vaccine LIDcpΔM2-2 is attenuated through deletion of M2-2 and 5 cold-passage mutations.

Methods: RSV-seronegative children aged 6-24 months received a single intranasal dose of 10⁵ plaque-forming units (PFU) of LIDcpΔM2-2 or placebo. RSV serum antibodies, vaccine infectivity, and reactogenicity were assessed.

Results: Four of 11 (36%) vaccinees shed vaccine virus with median peak titers of 1.6 log₁₀ PFU/mL by quantitative culture and 4.5 log₁₀ copies/mL by polymerase chain reaction; 45% had ≥4-fold rise in serum-neutralizing antibodies. Respiratory symptoms or fever were common in vaccinees (64%) and placebo recipients (6/6, 100%).

Conclusions: RSV LIDcpΔM2-2 is overattenuated. Clinical Trial Numbers. NCT02890381, NCT02948127.

Keywords: RNA regulatory protein M2-2; immunogenicity; live-attenuated viral vaccine; neutralizing antibodies; pediatric RSV vaccine; respiratory syncytial virus.

Figure 1.

Serum respiratory syncytial virus (RSV) antibody titers in vaccine and placebo recipients. Serum RSV 60% plaque reduction neutralizing titers (PRNT₆₀) (A) and anti-RSV F IgG titers (B) were determined by complement-enhanced 60% plaque reduction neutralization assay and IgG-specific enzyme-linked immunosorbent assay against purified baculovirus-expressed F protein (provided by Novavax, Inc., Gaithersburg, MD), respectively, for vaccine (open circles and stars) and placebo (x’s) recipients in sera collected at pre-inoculation (screening), postinoculation (study day 56), and postsurveillance (after the RSV season, April 1 to 30 in the calendar year after the inoculation). Titers are expressed as the reciprocal log₂. The lines indicate median (solid line) and mean (dashed line) values. P values were determined by Wilcoxon rank-sum test. Five vaccine recipients who did not shed vaccine virus are indicated with the star symbol. The data from the postinoculation visit are missing for 1 placebo recipient.