SARS-CoV-2 recombinant spike ferritin nanoparticle vaccine adjuvanted with Army Liposome Formulation containing monophosphoryl lipid A and QS-21: a phase 1, randomised, double-blind, placebo-controlled, first-in-human clinical trial

Brittany L Ober Shepherd; Paul T Scott; Jack N Hutter; Christine Lee; Melanie D McCauley; Ivelese Guzman; Christopher Bryant; Sarah McGuire; Jessie Kennedy; Wei-Hung Chen; Agnes Hajduczki; Thembi Mdluli; Anais Valencia-Ruiz; Mihret F Amare; Gary R Matyas; Mangala Rao; Morgane Rolland; John R Mascola; Stephen C De Rosa; M Juliana McElrath; David C Montefiori; Leonid Serebryannyy; Adrian B McDermott; Sheila A Peel; Natalie D Collins; M Gordon Joyce; Merlin L Robb; Nelson L Michael; Sandhya Vasan; Kayvon Modjarrad; EID-030 Study Group

doi:10.1016/S2666-5247(23)00410-X

SARS-CoV-2 recombinant spike ferritin nanoparticle vaccine adjuvanted with Army Liposome Formulation containing monophosphoryl lipid A and QS-21: a phase 1, randomised, double-blind, placebo-controlled, first-in-human clinical trial

Lancet Microbe. 2024 May 15:S2666-5247(23)00410-X. doi: 10.1016/S2666-5247(23)00410-X. Online ahead of print.

Authors

Brittany L Ober Shepherd¹, Paul T Scott², Jack N Hutter³, Christine Lee³, Melanie D McCauley¹, Ivelese Guzman³, Christopher Bryant⁴, Sarah McGuire⁴, Jessie Kennedy⁴, Wei-Hung Chen¹, Agnes Hajduczki¹, Thembi Mdluli¹, Anais Valencia-Ruiz¹, Mihret F Amare¹, Gary R Matyas¹, Mangala Rao¹, Morgane Rolland¹, John R Mascola⁵, Stephen C De Rosa⁶, M Juliana McElrath⁶, David C Montefiori⁷, Leonid Serebryannyy⁵, Adrian B McDermott⁸, Sheila A Peel³, Natalie D Collins³, M Gordon Joyce¹, Merlin L Robb⁹, Nelson L Michael¹⁰, Sandhya Vasan¹, Kayvon Modjarrad¹¹; EID-030 Study Group

Collaborators

EID-030 Study Group:
Beza Gebrehana¹², Melissa E Greenleaf¹², Melinda J Hamer¹², Nathan K Jansen¹², Xiaotang Jing¹², Jael Kagai¹², Kamila Kourbanova¹², Michael A Koren¹², Monica L Martin¹², Kathryn McGuckin Wuertz¹², Jason A Regules¹², Aaron D Sanborn¹², David Wallace¹², Lei Zhu¹², Gregory D Gromowski¹², Courtney Corbitt¹³, Janice M Darden¹³, Vincent Dussupt¹³, Emily S Golub¹³, Jarrett A Headley¹³, Umair M Jarral¹³, Jocelyn King¹³, Shelly J Krebs¹³, Jenny Lay¹³, Regina Lilly¹³, Jennifer Lynch¹³, Elizabeth J Martinez¹³, Sandra V Mayer¹³, Samantha McGeehon¹³, Hyunna Lee¹³, Steven Schech¹³, Mekdi Tadesse¹³, Paul V Thomas¹³, Yahel Romem¹³, Erifile Zografos¹³, Bob C Lin¹⁴, Sandeep R Narpala¹⁴, Lingshu Wang¹⁴, Nicole A Doria-Rose¹⁴, Robin E Carroll¹⁴, Amanda Eaton¹⁵, Emily D Badraslioglu¹⁶, Jason M Koontz¹⁶, Ugo E Nwaeze¹⁶, Peter Dawson¹⁷, Alexander J Noll¹⁷, Christine M Orndahl¹⁷, Amy Bray¹⁷, Ricardo Carrion Jr¹⁸, Jean Patterson¹⁸, Viraj Kulkarni¹⁸, Cory Hallam¹⁸, Olga Gonzalez¹⁸, Michal Gazi¹⁸

Affiliations

¹ Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
² Walter Reed Army Institute of Research, Silver Spring, MD, USA; Global Clinical Development, Vaccines, Merck, Rahway, NJ, USA.
³ Walter Reed Army Institute of Research, Silver Spring, MD, USA.
⁴ The Emmes Company, Rockville, MD, USA.
⁵ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁶ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Departments of Lab Medicine and Pathology, University of Washington, Seattle, WA, USA.
⁷ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA; Department of Surgery, Duke University School of Medicine, Durham, NC, USA.
⁸ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA; Immunology, Sanofi Vaccines, Lyon, France.
⁹ Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
¹⁰ Walter Reed Army Institute of Research, Silver Spring, MD, USA. Electronic address: nelson.l.michael2.civ@health.mil.
¹¹ Walter Reed Army Institute of Research, Silver Spring, MD, USA; Vaccine Research and Development, Pfizer, Pearl River, NY, USA.
¹² Walter Reed Army Institute for Research, Silver Spring, MD, USA.
¹³ Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
¹⁴ Vaccine Research Center, National Institute of Allergy and Infectious Disease, Bethesda, MD, USA.
¹⁵ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
¹⁶ Office of Regulated Activities [ORA] within the US Army Medical Research and Development Fort Detrick, MD, USA.
¹⁷ The EMMES Company, Rockville, MD, USA.
¹⁸ Texas Biomedical Research Institute San Antonio, TX, USA.

PMID: 38761816
DOI: 10.1016/S2666-5247(23)00410-X

Abstract

Background: A self-assembling SARS-CoV-2 WA-1 recombinant spike ferritin nanoparticle (SpFN) vaccine co-formulated with Army Liposomal Formulation (ALFQ) adjuvant containing monophosphoryl lipid A and QS-21 (SpFN/ALFQ) has shown protective efficacy in animal challenge models. This trial aims to assess the safety and immunogenicity of SpFN/ALFQ in a first-in-human clinical trial.

Methods: In this phase 1, randomised, double-blind, placebo-controlled, first-in-human clinical trial, adults were randomly assigned (5:5:2) to receive 25 μg or 50 μg of SpFN/ALFQ or saline placebo intramuscularly at day 1 and day 29, with an optional open-label third vaccination at day 181. Enrolment and randomisation occurred sequentially by group; randomisation was done by an interactive web-based randomisation system and only designated unmasked study personnel had access to the randomisation code. Adults were required to be seronegative and unvaccinated for inclusion. Local and systemic reactogenicity, adverse events, binding and neutralising antibodies, and antigen-specific T-cell responses were quantified. For safety analyses, exact 95% Clopper-Pearson CIs for the probability of any incidence of an unsolicited adverse event was computed for each group. For immunogenicity results, CIs for binary variables were computed using the exact Clopper-Pearson methodology, while CIs for geometric mean titres were based on 10 000 empirical bootstrap samples. Post-hoc, paired one-sample t tests were used to assess the increase in mean log-10 neutralising antibody titres between day 29 and day 43 (after the second vaccination) for the primary SARS-CoV-2 targets of interest. This trial is registered at ClinicalTrials.gov, NCT04784767, and is closed to new participants.

Findings: Between April 7, and June 29, 2021, 29 participants were enrolled in the study. 20 individuals were assigned to receive 25 μg SpFN/ALFQ, four to 50 μg SpFN/ALFQ, and five to placebo. Neutralising antibody responses peaked at day 43, 2 weeks after the second dose. Neutralisation activity against multiple omicron subvariants decayed more slowly than against the D614G or beta variants until 5 months after second vaccination for both dose groups. CD4⁺ T-cell responses were elicited 4 weeks after the first dose and were boosted after a second dose of SpFN/ALFQ for both dose groups. Neutralising antibody titres against early omicron subvariants and clade 1 sarbecoviruses were detectable after two immunisations and peaked after the third immunisation for both dose groups. Neutralising antibody titres against XBB.1.5 were detected after three vaccinations. Passive IgG transfer from vaccinated volunteers into Syrian golden hamsters controlled replication of SARS-CoV-1 after challenge.

Interpretation: SpFN/ALFQ was well tolerated and elicited robust and durable binding antibody and neutralising antibody titres against a broad panel of SARS-CoV-2 variants and other sarbecoviruses.

Funding: US Department of Defense, Defense Health Agency.

Published by Elsevier Ltd.

Associated data

ClinicalTrials.gov/NCT04784767