Elizabeth J McFarland1, Ruth A Karron2, Petronella Muresan3, Coleen K Cunningham4, Charlotte Perlowski5, Jennifer Libous5, Jennifer Oliva2, Patrick Jean-Philippe6, Jack Moye7, Elizabeth Schappell2, Emily Barr1, Vivian Rexroad8, Laura Fearn9, Mikhaela Cielo10, Andrew Wiznia11, Jaime G Deville12, Lijuan Yang13, Cindy Luongo13, Peter L Collins13, Ursula J Buchholz13. 1. Department of Pediatrics, University of Colorado Anschutz Medical Campus and Children's Hospital Colorado, Aurora, Colorado, USA. 2. Center for Immunization Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. 3. Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health/Frontier Science Foundation, Boston, Massachusetts, USA. 4. Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA. 5. FHI 360, Durham, North Carolina, USA. 6. Maternal, Adolescent and Pediatric Research Branch, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. 7. Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA. 8. Investigational Drug Service Pharmacy, Johns Hopkins Hospital, Baltimore, Maryland, USA. 9. Department of Pediatrics, Northwestern University Medical School and Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA. 10. Division of Infectious Diseases, Maternal Child & Adolescent Center, University of Southern California Keck School of Medicine, Los Angeles, California, USA. 11. Department of Pediatrics, Albert Einstein College of Medicine and Jacobi Medical Center, Bronx, New York, USA. 12. David Geffen School of Medicine at University of California Los Angeles, California, USA. 13. Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Abstract
BACKGROUND: Respiratory syncytial virus (RSV) is the leading viral cause of severe pediatric respiratory illness, and vaccines are needed. Live RSV vaccine D46/NS2/N/ΔM2-2-HindIII, attenuated by deletion of the RSV RNA regulatory protein M2-2, is based on previous candidate LID/ΔM2-2 but incorporates prominent differences from MEDI/ΔM2-2, which was more restricted in replication in phase 1. METHODS:RSV-seronegative children aged 6-24 months received 1 intranasal dose (105 plaque-forming units [PFUs] of D46/NS2/N/ΔM2-2-HindIII [n = 21] or placebo [n = 11]) and were monitored for vaccine shedding, reactogenicity, RSV-antibody responses and RSV-associated medically attended acute respiratory illness (RSV-MAARI) and antibody responses during the following RSV season. RESULTS: All 21 vaccinees were infected with vaccine; 20 (95%) shed vaccine (median peak titer, 3.5 log10 PFUs/mL with immunoplaque assay and 6.1 log10 copies/mL with polymerase chain reaction). Serum RSV-neutralizing antibodies and anti-RSV fusion immunoglobulin G increased ≥4-fold in 95% and 100% of vaccines, respectively. Mild upper respiratory tract symptoms and/or fever occurred in vaccinees (76%) and placebo recipients (18%). Over the RSV season, RSV-MAARI occurred in 2 vaccinees and 4 placebo recipients. Three vaccinees had ≥4-fold increases in serum RSV-neutralizing antibody titers after the RSV season without RSV-MAARI. CONCLUSIONS: D46/NS2/N/ΔM2-2-HindIII had excellent infectivity and immunogenicity and primed vaccine recipients for anamnestic responses, encouraging further evaluation of this attenuation strategy. CLINICAL TRIALS REGISTRATION: NCT03102034 and NCT03099291.
RCT Entities:
BACKGROUND:Respiratory syncytial virus (RSV) is the leading viral cause of severe pediatric respiratory illness, and vaccines are needed. Live RSV vaccine D46/NS2/N/ΔM2-2-HindIII, attenuated by deletion of the RSV RNA regulatory protein M2-2, is based on previous candidate LID/ΔM2-2 but incorporates prominent differences from MEDI/ΔM2-2, which was more restricted in replication in phase 1. METHODS:RSV-seronegative children aged 6-24 months received 1 intranasal dose (105 plaque-forming units [PFUs] of D46/NS2/N/ΔM2-2-HindIII [n = 21] or placebo [n = 11]) and were monitored for vaccine shedding, reactogenicity, RSV-antibody responses and RSV-associated medically attended acute respiratory illness (RSV-MAARI) and antibody responses during the following RSV season. RESULTS: All 21 vaccinees were infected with vaccine; 20 (95%) shed vaccine (median peak titer, 3.5 log10 PFUs/mL with immunoplaque assay and 6.1 log10 copies/mL with polymerase chain reaction). Serum RSV-neutralizing antibodies and anti-RSV fusion immunoglobulin G increased ≥4-fold in 95% and 100% of vaccines, respectively. Mild upper respiratory tract symptoms and/or fever occurred in vaccinees (76%) and placebo recipients (18%). Over the RSV season, RSV-MAARI occurred in 2 vaccinees and 4 placebo recipients. Three vaccinees had ≥4-fold increases in serum RSV-neutralizing antibody titers after the RSV season without RSV-MAARI. CONCLUSIONS: D46/NS2/N/ΔM2-2-HindIII had excellent infectivity and immunogenicity and primed vaccine recipients for anamnestic responses, encouraging further evaluation of this attenuation strategy. CLINICAL TRIALS REGISTRATION: NCT03102034 and NCT03099291.
Authors: P L Collins; M G Hill; E Camargo; H Grosfeld; R M Chanock; B R Murphy Journal: Proc Natl Acad Sci U S A Date: 1995-12-05 Impact factor: 11.205
Authors: Ruth A Karron; Peter F Wright; Robert B Belshe; Bhagvanji Thumar; Roberta Casey; Frances Newman; Fernando P Polack; Valerie B Randolph; Anne Deatly; Jill Hackell; William Gruber; Brian R Murphy; Peter L Collins Journal: J Infect Dis Date: 2005-03-01 Impact factor: 5.226
Authors: Ting Shi; David A McAllister; Katherine L O'Brien; Eric A F Simoes; Shabir A Madhi; Bradford D Gessner; Fernando P Polack; Evelyn Balsells; Sozinho Acacio; Claudia Aguayo; Issifou Alassani; Asad Ali; Martin Antonio; Shally Awasthi; Juliet O Awori; Eduardo Azziz-Baumgartner; Henry C Baggett; Vicky L Baillie; Angel Balmaseda; Alfredo Barahona; Sudha Basnet; Quique Bassat; Wilma Basualdo; Godfrey Bigogo; Louis Bont; Robert F Breiman; W Abdullah Brooks; Shobha Broor; Nigel Bruce; Dana Bruden; Philippe Buchy; Stuart Campbell; Phyllis Carosone-Link; Mandeep Chadha; James Chipeta; Monidarin Chou; Wilfrido Clara; Cheryl Cohen; Elizabeth de Cuellar; Duc-Anh Dang; Budragchaagiin Dash-Yandag; Maria Deloria-Knoll; Mukesh Dherani; Tekchheng Eap; Bernard E Ebruke; Marcela Echavarria; Carla Cecília de Freitas Lázaro Emediato; Rodrigo A Fasce; Daniel R Feikin; Luzhao Feng; Angela Gentile; Aubree Gordon; Doli Goswami; Sophie Goyet; Michelle Groome; Natasha Halasa; Siddhivinayak Hirve; Nusrat Homaira; Stephen R C Howie; Jorge Jara; Imane Jroundi; Cissy B Kartasasmita; Najwa Khuri-Bulos; Karen L Kotloff; Anand Krishnan; Romina Libster; Olga Lopez; Marilla G Lucero; Florencia Lucion; Socorro P Lupisan; Debora N Marcone; John P McCracken; Mario Mejia; Jennifer C Moisi; Joel M Montgomery; David P Moore; Cinta Moraleda; Jocelyn Moyes; Patrick Munywoki; Kuswandewi Mutyara; Mark P Nicol; D James Nokes; Pagbajabyn Nymadawa; Maria Tereza da Costa Oliveira; Histoshi Oshitani; Nitin Pandey; Gláucia Paranhos-Baccalà; Lia N Phillips; Valentina Sanchez Picot; Mustafizur Rahman; Mala Rakoto-Andrianarivelo; Zeba A Rasmussen; Barbara A Rath; Annick Robinson; Candice Romero; Graciela Russomando; Vahid Salimi; Pongpun Sawatwong; Nienke Scheltema; Brunhilde Schweiger; J Anthony G Scott; Phil Seidenberg; Kunling Shen; Rosalyn Singleton; Viviana Sotomayor; Tor A Strand; Agustinus Sutanto; Mariam Sylla; Milagritos D Tapia; Somsak Thamthitiwat; Elizabeth D Thomas; Rafal Tokarz; Claudia Turner; Marietjie Venter; Sunthareeya Waicharoen; Jianwei Wang; Wanitda Watthanaworawit; Lay-Myint Yoshida; Hongjie Yu; Heather J Zar; Harry Campbell; Harish Nair Journal: Lancet Date: 2017-07-07 Impact factor: 79.321
Authors: Zunlong Ke; Rebecca S Dillard; Tatiana Chirkova; Fredrick Leon; Christopher C Stobart; Cheri M Hampton; Joshua D Strauss; Devi Rajan; Christina A Rostad; Jeannette V Taylor; Hong Yi; Raven Shah; Mengtian Jin; Tina V Hartert; R Stokes Peebles; Barney S Graham; Martin L Moore; Larry J Anderson; Elizabeth R Wright Journal: Viruses Date: 2018-08-20 Impact factor: 5.048
Authors: Robert K M Choy; A Louis Bourgeois; Christian F Ockenhouse; Richard I Walker; Rebecca L Sheets; Jorge Flores Journal: Clin Microbiol Rev Date: 2022-07-06 Impact factor: 50.129
Authors: Catalina A Andrade; Gaspar A Pacheco; Nicolas M S Gálvez; Jorge A Soto; Susan M Bueno; Alexis M Kalergis Journal: Viruses Date: 2020-06-12 Impact factor: 5.048
Authors: Ruth A Karron; Jessica E Atwell; Elizabeth J McFarland; Coleen K Cunningham; Petronella Muresan; Charlotte Perlowski; Jennifer Libous; Stephen A Spector; Ram Yogev; Mariam Aziz; Suzanne Woods; Kimberli Wanionek; Peter L Collins; Ursula J Buchholz Journal: Am J Respir Crit Care Med Date: 2021-03-01 Impact factor: 21.405