Live-attenuated respiratory syncytial virus vaccine candidate with deletion of RNA synthesis regulatory protein M2-2 is highly immunogenic in children

Elizabeth J. McFarland, Ruth A Karron, Petronella Muresan, Coleen K. Cunningham, Megan E. Valentine, Charlotte Perlowski, Bhagvanji Thumar, Devasena Gnanashanmugam, George K. Siberry, Elizabeth Schappell, Emily Barr, Vivian Rexroad, Ram Yogev, Stephen A. Spector, Mariam Aziz, Nehali Patel, Mikhaela Cielo, Cindy Luongo, Peter L. Collins, Ursula J. Buchholz

Research output: Contribution to journalArticle

Abstract

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 105 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 log10 PFU/mL by quantitative culture and 6.3 log10 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.

Original languageEnglish (US)
Pages (from-to)1347-1355
Number of pages9
JournalJournal of Infectious Diseases
Volume217
Issue number9
DOIs
StatePublished - May 1 2018

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Respiratory Syncytial Virus Vaccines
Attenuated Vaccines
Respiratory Syncytial Viruses
RNA
Vaccines
Proteins
Placebos
Antibodies
Serum
Rhinovirus
Viral Genes
Viral Antigens
Enterovirus
Respiratory Sounds
Virus Diseases
Neutralizing Antibodies
Viral Load
Fever
Clinical Trials

Keywords

  • Immunogenicity
  • Live attenuated viral vaccine
  • Neutralizing antibodies
  • Pediatric RSV vaccine
  • Respiratory syncytial virus
  • RNA regulatory protein M2-2

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

Cite this

Live-attenuated respiratory syncytial virus vaccine candidate with deletion of RNA synthesis regulatory protein M2-2 is highly immunogenic in children. / McFarland, Elizabeth J.; Karron, Ruth A; Muresan, Petronella; Cunningham, Coleen K.; Valentine, Megan E.; Perlowski, Charlotte; Thumar, Bhagvanji; Gnanashanmugam, Devasena; Siberry, George K.; Schappell, Elizabeth; Barr, Emily; Rexroad, Vivian; Yogev, Ram; Spector, Stephen A.; Aziz, Mariam; Patel, Nehali; Cielo, Mikhaela; Luongo, Cindy; Collins, Peter L.; Buchholz, Ursula J.

In: Journal of Infectious Diseases, Vol. 217, No. 9, 01.05.2018, p. 1347-1355.

Research output: Contribution to journalArticle

McFarland, EJ, Karron, RA, Muresan, P, Cunningham, CK, Valentine, ME, Perlowski, C, Thumar, B, Gnanashanmugam, D, Siberry, GK, Schappell, E, Barr, E, Rexroad, V, Yogev, R, Spector, SA, Aziz, M, Patel, N, Cielo, M, Luongo, C, Collins, PL & Buchholz, UJ 2018, 'Live-attenuated respiratory syncytial virus vaccine candidate with deletion of RNA synthesis regulatory protein M2-2 is highly immunogenic in children', Journal of Infectious Diseases, vol. 217, no. 9, pp. 1347-1355. https://doi.org/10.1093/infdis/jiy040
McFarland, Elizabeth J. ; Karron, Ruth A ; Muresan, Petronella ; Cunningham, Coleen K. ; Valentine, Megan E. ; Perlowski, Charlotte ; Thumar, Bhagvanji ; Gnanashanmugam, Devasena ; Siberry, George K. ; Schappell, Elizabeth ; Barr, Emily ; Rexroad, Vivian ; Yogev, Ram ; Spector, Stephen A. ; Aziz, Mariam ; Patel, Nehali ; Cielo, Mikhaela ; Luongo, Cindy ; Collins, Peter L. ; Buchholz, Ursula J. / Live-attenuated respiratory syncytial virus vaccine candidate with deletion of RNA synthesis regulatory protein M2-2 is highly immunogenic in children. In: Journal of Infectious Diseases. 2018 ; Vol. 217, No. 9. pp. 1347-1355.
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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 K.

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.

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 105 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 log10 PFU/mL by quantitative culture and 6.3 log10 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.

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KW - Immunogenicity

KW - Live attenuated viral vaccine

KW - Neutralizing antibodies

KW - Pediatric RSV vaccine

KW - Respiratory syncytial virus

KW - RNA regulatory protein M2-2

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