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

Coleen K Cunningham, Ruth Karron, Petronella Muresan, Elizabeth J McFarland, Charlotte Perlowski, Jennifer Libous, Bhagvanji Thumar, Devasena Gnanashanmugam, Jack Moye Jr, Elizabeth Schappell, Emily Barr, Vivian Rexroad, Mariam Aziz, Jaime Deville, Richard Rutstein, Lijuan Yang, Cindy Luongo, Peter Collins, Ursula Buchholz, International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) 2012 Study Team, Coleen K Cunningham, Ruth Karron, Petronella Muresan, Elizabeth J McFarland, Charlotte Perlowski, Jennifer Libous, Bhagvanji Thumar, Devasena Gnanashanmugam, Jack Moye Jr, Elizabeth Schappell, Emily Barr, Vivian Rexroad, Mariam Aziz, Jaime Deville, Richard Rutstein, Lijuan Yang, Cindy Luongo, Peter Collins, Ursula Buchholz, International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) 2012 Study Team

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.

Figures

Figure 1.
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.

References

    1. Shi T, McAllister DA, O’Brien KL, et al. . Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet 2017; 390:946–58.
    1. Groothuis JR, Simoes EA, Levin MJ, et al. . Prophylactic administration of respiratory syncytial virus immune globulin to high-risk infants and young children. The respiratory syncytial virus immune globulin study group. N Engl J Med 1993; 329:1524–30.
    1. Giersing BK, Vekemans J, Nava S, et al. . Report from the World Health Organization’s third Product Development For Vaccines advisory committee (PDVAC) meeting, Geneva, 8-10th June 2016. Vaccine 2017. In Press: doi:10.1016/j.vaccine.2016.10.090
    1. Acosta PL, Caballero MT, Polack FP. Brief history and characterization of enhanced respiratory syncytial virus disease. Clin Vaccine Immunol 2015; 23:189–95.
    1. Wright PF, Karron RA, Belshe RB, et al. . The absence of enhanced disease with wild type respiratory syncytial virus infection occurring after receipt of live, attenuated, respiratory syncytial virus vaccines. Vaccine 2007; 25:7372–8.
    1. Collins PL, Hill MG, Camargo E, et al. . Production of infectious human respiratory syncytial virus from cloned cDNA confirms an essential role for the transcription elongation factor from the 5’ proximal open reading frame of the M2 mRNA in gene expression and provides a capability for vaccine development. Proc Natl Acad Sci U S A 1995; 92:11563–7.
    1. Karron RA, Wright PF, Belshe RB, et al. . Identification of a recombinant live attenuated respiratory syncytial virus vaccine candidate that is highly attenuated in infants. J Infect Dis 2005; 191:1093–104.
    1. Collins PL, Murphy BR. Vaccines against human respiratory syncytial virus. In: Cane PA, ed. Respiratory Syncytial Virus. Amsterdam: Elsevier; 2007:233–77.
    1. Bermingham A, Collins PL. The M2-2 protein of human respiratory syncytial virus is a regulatory factor involved in the balance between RNA replication and transcription. Proc Natl Acad Sci U S A 1999; 96:11259–64.
    1. Karron RA, Luongo C, Thumar B, et al. . A gene deletion that up-regulates viral gene expression yields an attenuated RSV vaccine with improved antibody responses in children. Science Translational Medicine 2015; 7:312ra175.
    1. McFarland EJ, Karron RA, Muresan P, et al. ; International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) 2000 Study Team Live-attenuated respiratory syncytial virus vaccine candidate with deletion of RNA synthesis regulatory protein M2-2 is highly immunogenic in children. J Infect Dis 2018; 217:1347–55.
    1. Friedewald WT, Forsyth BR, Smith CB, et al. . Low-temperature-grown RS virus in adult volunteers. JAMA 1968; 204:690–4.
    1. Whitehead SS, Juhasz K, Firestone CY, et al. . Recombinant respiratory syncytial virus (RSV) bearing a set of mutations from cold-passaged RSV is attenuated in chimpanzees. J Virol 1998; 72:4467–71.
    1. Buchholz UJ, Cunningham CK, Muresan P, et al. ; International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1114 Study Team Live respiratory syncytial virus (RSV) vaccine candidate containing stabilized temperature-sensitivity mutations is highly attenuated in RSV-seronegative infants and children. J Infect Dis 2018; 217:1338–46.
    1. Karron RA, Buchholz UJ, Collins PL. Live-attenuated respiratory syncytial virus vaccines. Curr Top Microbiol Immunol 2013; 372:259–84.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner