TY - JOUR
T1 - Live-attenuated respiratory syncytial virus vaccine candidate with deletion of RNA synthesis regulatory protein M2-2 is highly immunogenic in children
AU - McFarland, Elizabeth J.
AU - Karron, Ruth A.
AU - Muresan, Petronella
AU - Cunningham, Coleen K.
AU - Valentine, Megan E.
AU - Perlowski, Charlotte
AU - Thumar, Bhagvanji
AU - Gnanashanmugam, Devasena
AU - Siberry, George Kelly
AU - Schappell, Elizabeth
AU - Barr, Emily
AU - Rexroad, Vivian
AU - Yogev, Ram
AU - Spector, Stephen A.
AU - Aziz, Mariam
AU - Patel, Nehali
AU - Cielo, Mikhaela
AU - Luongo, Cindy
AU - Collins, Peter L.
AU - Buchholz, Ursula J.
N1 - Funding Information:
Financial support. This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) (grant numbers UM1AI068632 [IMPAACT LOC], UM1AI068616 [IMPAACT SDMC], UM1AI106716 [IMPAACT LC]) to the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network, with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health. C.L., P.L.C., and U.J.B. were supported by the Intramural Program of the NIAID. Work at University of Colorado Anschutz Medical Campus and Children’s Hospital Colorado was supported in part by a Clinical and Translational Science Award from the National Center for Advancing Translational Sciences/ NIH (grant number UL1 TR001082). Work at Duke University was supported in part by the Duke University Center for AIDS Research, an NIH funded program (grant number 5P30 AI064518).
Funding Information:
This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) (grant numbers UM1AI068632 [IMPAACT LOC], UM1AI068616 [IMPAACT SDMC], UM1AI106716 [IMPAACT LC]) to the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network, with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health. C.L., P.L.C., and U.J.B. were supported by the Intramural Program of the NIAID. Work at University of Colorado Anschutz Medical Campus and Children’s Hospital Colorado was supported in part by a Clinical and Translational Science Award from the National Center for Advancing Translational Sciences/NIH (grant number UL1 TR001082). Work at Duke University was supported in part by the Duke University Center for AIDS Research, an NIH funded program (grant number 5P30 AI064518).
Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - Background. Live respiratory syncytial virus (RSV) candidate vaccine LIDΔM2-2 is attenuated by deletion of the RSV RNA regulatory protein M2-2, resulting in upregulated viral gene transcription and antigen expression but reduced RNA replication. Methods. RSV-seronegative children ages 6–24 months received a single intranasal dose of 10 5 plaque forming units (PFU) of LIDΔM2-2 (n = 20) or placebo (n = 9) (NCT02237209, NCT02040831). RSV serum antibodies, vaccine infectivity, and reactogenicity were assessed. During the following RSV season, participants were monitored for respiratory illness and pre- and post-RSV season serum antibodies. Results. Vaccine virus was shed by 95% of vaccinees (median peak titers of 3.8 log 10 PFU/mL by quantitative culture and 6.3 log 10 copies/mL by PCR); 90% had ≥4-fold rise in serum neutralizing antibodies. Respiratory symptoms and fever were common in vaccine (95%) and placebo (78%). One vaccinee had grade 2 rhonchi concurrent with vaccine shedding, rhinovirus, and enterovirus. Eight of 19 vaccinees versus 2 of 9 placebo recipients had substantially increased RSV antibody titers after the RSV season without medically attended RSV disease, indicating anamnestic vaccine responses to wild-type RSV without significant illness. Conclusion. LIDΔM2-2 had excellent infectivity and immunogenicity, encouraging further study of vaccine candidates attenuated by M2-2 deletion. Clinical Trials Registration. NCT02237209, NCT02040831.
AB - Background. Live respiratory syncytial virus (RSV) candidate vaccine LIDΔM2-2 is attenuated by deletion of the RSV RNA regulatory protein M2-2, resulting in upregulated viral gene transcription and antigen expression but reduced RNA replication. Methods. RSV-seronegative children ages 6–24 months received a single intranasal dose of 10 5 plaque forming units (PFU) of LIDΔM2-2 (n = 20) or placebo (n = 9) (NCT02237209, NCT02040831). RSV serum antibodies, vaccine infectivity, and reactogenicity were assessed. During the following RSV season, participants were monitored for respiratory illness and pre- and post-RSV season serum antibodies. Results. Vaccine virus was shed by 95% of vaccinees (median peak titers of 3.8 log 10 PFU/mL by quantitative culture and 6.3 log 10 copies/mL by PCR); 90% had ≥4-fold rise in serum neutralizing antibodies. Respiratory symptoms and fever were common in vaccine (95%) and placebo (78%). One vaccinee had grade 2 rhonchi concurrent with vaccine shedding, rhinovirus, and enterovirus. Eight of 19 vaccinees versus 2 of 9 placebo recipients had substantially increased RSV antibody titers after the RSV season without medically attended RSV disease, indicating anamnestic vaccine responses to wild-type RSV without significant illness. Conclusion. LIDΔM2-2 had excellent infectivity and immunogenicity, encouraging further study of vaccine candidates attenuated by M2-2 deletion. Clinical Trials Registration. NCT02237209, NCT02040831.
KW - Immunogenicity
KW - Live attenuated viral vaccine
KW - Neutralizing antibodies
KW - Pediatric RSV vaccine
KW - RNA regulatory protein M2-2
KW - Respiratory syncytial virus
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U2 - 10.1093/infdis/jiy040
DO - 10.1093/infdis/jiy040
M3 - Article
C2 - 29509911
AN - SCOPUS:85050730453
SN - 0022-1899
VL - 217
SP - 1347
EP - 1355
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 9
ER -