A Randomized, Controlled, Observer-Blinded Phase 1 Study of the Safety and Immunogenicity of a Respiratory Syncytial Virus Vaccine With or Without Alum Adjuvant

The Journal of Infectious Diseases MAJOR ARTICLE A Randomized, Controlled, Observer-Blinded Phase 1 Study of the Safety and Immunogenicity of a Respiratory Syncytial Virus Vaccine With or Without Alum Adjuvant Joanne M. Langley,1 Naresh Aggarwal,2 Azhar Toma,3 Scott A. Halperin,1 Shelly A. McNeil,1 Laurence Fissette,4 Walthere Dewé,4 Maarten Leyssen,4 Jean-François Toussaint,4 and Ilse Dieussaert4 1 Canadian Center for Vaccinology, IWK Health Centre–Nova Scotia Health Authority–Dalhousie University, Halifax, 2Aggarwal and Associates Limited, Brampton, and 3Manna Research, Toronto, Canada; and 4Vaccine Discovery and Development, GSK Vaccines, Rixensart, Belgium (See the editorial commentary by Englund and Chu on pages 4–7.) Respiratory syncytial virus (RSV) is a leading cause of early childhood lower respiratory tract illness (LRTI), with an estimated 33 million episodes worldwide and 199 000 attributable deaths in low-resource countries each year [1]. In developed countries, RSV bronchiolitis and pneumonia lead to hospital admission in about 2% of infected infants [2, 3]. There are no preventive or therapeutic interventions currently available that adequately address this significant global public health problem. Maternal immunization is now an accepted method to reduce infant pertussis, tetanus, and influenza [4], although vaccine uptake remains low. The highest burden of childhood RSV- Received 19 May 2016; accepted 4 August 2016; published online 29 September 2016. Presented in part: 9th International Respiratory Syncytial Virus Symposium, Stellenbosch, South Africa, 9–13 November 2014. Correspondence: J. M. Langley, IWK Health Centre, Goldbloom Building, 4th floor, 5850 University Avenue, Halifax, Nova Scotia, B3K 6R8 Canada (). The Journal of Infectious Diseases® 2017;215:24–33 © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/ 4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, contact . DOI: 10.1093/infdis/jiw453 24 • JID 2017:215 (1 January) • Langley et al associated illness occurs in the first 6 months of life, and maternal RSV vaccination has thus been identified as a potential strategy to protect the infant [5]. Since most women of child-bearing age would have preexisting antibody from prior infection, a RSV vaccine given during the third trimester of pregnancy would be expected to boost preexisting antibody levels and result in increased passage of anti-RSV antibodies through the placental active-transport mechanism for immunoglobulin G (IgG). Maternal immunization potentially could also protect the infant through a reduced risk of infection transmission from the mother and, possibly, from passive immunity conferred through breast milk. RSV antibodies are known to be transferred efficiently across the placenta [6], and high cord blood RSV antibody levels are associated with a lower incidence of severe RSV-associated LRTI [7, 8]. The RSV F surface glycoprotein, which is highly conserved across A and B subgroup isolates and considered essential in disease pathogenesis [9], is a target for passive immunization with monoclonal antibodies [10], which reduce the risk of RSV-associated hospitalization. There is evidence that the prefusion conformation of the F glycoprotein, rather than the postfusion form, is the main target of naturally induced anti-RSV neutralizing antibody (nAb) in human serum [11] and, thus, Background. Respiratory syncytial virus (RSV) is a leading cause of childhood bronchiolitis and pneumonia, particularly in early infancy. Immunization of pregnant women could boost preexisting immune responses, providing passive protection to newborns through placental transfer of anti-RSV antibody. Methods. In this first-in-humans clinical trial of a purified recombinant RSV protein F vaccine engineered to preferentially maintain prefusion conformation (RSV-PreF), 128 healthy men 18–44 years old were randomized to one dose of a RSV-PreF vaccine containing 10, 30, or 60 µg of RSV-PreF antigen, with or without alum adjuvant, or control, and followed for one year for safety and immunogenicity outcomes. Results. Injection site pain was the most common adverse event, reported by up to 81.3% of participants. The highest RSV neutralizing antibody responses were in the 30 µg RSV-PreF/alum, 60 µg RSV-PreF/alum, and 60 µg RSV-PreF/nonadjuvant groups. Responses were evident on day 7, and 30 days after vaccination these participants had RSV-A neutralizing antibody titers of ≥1:512, and >70% had titers of 1:1024, with titers increasing by 3.2–4.9 fold. Responses remained high on day 60 but waned on days 180 and 360. Conclusions. The RSV-PreF vaccine elicited rapid RSV neutralizing antibody responses in healthy young men, with an acceptable adverse event profile. Keywords. respiratory syncytial virus; vaccine; maternal immunization; vaccine safety and immunogenicity. would be a preferred vaccine antigen. A specific epitope on the prefusion conformation, site ø (zero), is thought to be one of the major targets of RSV nAb [12] and results in potent neutralizing activity in animal models [13]. In this first-in-humans study, the safety, reactogenicity, and immunogenicity of a RSV vaccine for pregnant women, containing purified recombinant RSV glycoprotein F engineered to preferentially maintain prefusion conformation (RSV-PreF), was evaluated. METHODS Participants Eligible men were 18–44 years of age at the time of vaccination; healthy, based on medical history and clinical examination; able to comply with the protocol; and gave informed written consent. Women were excluded from participation on the guidance of the regulatory authority, which advised that later testing of this novel product could occur in women of childbearing age. Exclusionary criteria were immunocompromise, a family history of immunodeficiency, autoimmune disease, a malignancy within 5 years, a history of hypersensitivity to latex or any vaccine component, acute illness or fever, participation in another clinical study, receipt or intent to receive another vaccine 30 days previous to or after the study vaccine (with the exception of influenza vaccine, which could be administered ≥15 days before study vaccination), or receipt of either immunoglobulins or blood products within 3 months or previous RSV vaccination or any investigational product within 30 days. Any hematological or biochemical value outside the normal range at the local laboratory that was considered clinically significant by the investigator was also considered exclusionary; participants could be rescreened within 30 days. Vaccines The RSV-PreF anti (...truncated)