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Clinical Trial
. 2024 Jun;5(6):e581-e593.
doi: 10.1016/S2666-5247(23)00410-X. Epub 2024 May 15.

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  1 , Paul T Scott  2 , Jack N Hutter  3 , Christine Lee  3 , Melanie D McCauley  1 , Ivelese Guzman  3 , Christopher Bryant  4 , Sarah McGuire  4 , Jessie Kennedy  4 , Wei-Hung Chen  1 , Agnes Hajduczki  1 , Thembi Mdluli  1 , Anais Valencia-Ruiz  1 , Mihret F Amare  1 , Gary R Matyas  1 , Mangala Rao  1 , Morgane Rolland  1 , John R Mascola  5 , Stephen C De Rosa  6 , M Juliana McElrath  6 , David C Montefiori  7 , Leonid Serebryannyy  5 , Adrian B McDermott  8 , Sheila A Peel  3 , Natalie D Collins  3 , M Gordon Joyce  1 , Merlin L Robb  9 , Nelson L Michael  10 , Sandhya Vasan  1 , Kayvon Modjarrad  11 ; EID-030 Study Group
Collaborators, Affiliations
Clinical Trial

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 et al. Lancet Microbe. 2024 Jun.

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.

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Conflict of interest statement

Declaration of interests The opinions expressed herein are those of the authors and should not be construed as official or representing the views of the US Department of Defense or the Department of the Army. MGJ and KM are named inventors on international patent application WO/2021/178971 A1 entitled “Vaccines against SARS-CoV-2 and other coronaviruses.” MGJ is a co-inventor on international patent application WO/2018/081318 and a US patent (number 10,960,070) entitled “Pre-fusion coronavirus Spike proteins and their use.” GRM is a named inventor on US patent (number 11,583,578) entitled “Compositions and Methods for Vaccine Delivery”, issued Feb 21, 2023. MGJ, W-HC, AH, and KM are named inventors on patent application: VACCINES AGAINST CORONAVIRUSES, serial number: 63/400 334. PTS is currently an employee of Merck. KM is currently an employee of Pfizer. ABM is currently an employee of Sanofi Pasteur. All other authors declare no competing interests.

Figures

Figure 1.
Figure 1.
CONSORT Diagram.
Figure 2A-B.
Figure 2A-B.
The percentages of participants reporting solicited adverse events, comprised of (A) systemic and (B) local reactogenicity symptoms, are summarized by maximum severity over the 8 days post-each study vaccination and post-any study vaccination.
Figure 3.
Figure 3.. Binding Antibody Geometric Mean Titer (GMT) to SARS-CoV-2 Proteins, by Group and Protein
(A) GMTs over time and associated 95% CIs (B) individual participant titers, with boxes and horizontal bars to denote interquartile range (IQR) and median, respectively. Whisker endpoints are equal to the maximum and minimum values. Arrows indicate timing of study vaccinations.
Figure 4A-F.
Figure 4A-F.. Pseudovirus Neutralizing Antibody Geometric Mean IC50 Titer Against SARS-CoV-2, by Group and Variant
(A) and (C) GMTs over time and associated 95% CIs (B) and (D) Individual participant titers, with boxes and horizontal bars to denote interquartile range (IQR) and median, respectively. Whisker endpoints are equal to the maximum and minimum values. Grey boxes indicate upper limit of detection for these validated assays. Arrows at the base of the Figure indicate day of vaccination. (E-F) A heatmap of reciprocal neutralization titers (ID50) against variant of concern authentic viruses for study day 43 (two weeks post second vaccination), study day 181 (day of third vaccination), and study day 195 (two weeks post third vaccination). Data is shown for the nine volunteers included in the 25μg group of the trial. Variants of concern are displayed according to a phylogenetic tree of the spike proteins used in these neutralization assays. Sarbecoviruses (F) are displayed according to a phylogenetic tree of the spike proteins used in these neutralization assays. Titers are colored and phylogenetic trees are sized according to the displayed scale.
Figure 4A-F.
Figure 4A-F.. Pseudovirus Neutralizing Antibody Geometric Mean IC50 Titer Against SARS-CoV-2, by Group and Variant
(A) and (C) GMTs over time and associated 95% CIs (B) and (D) Individual participant titers, with boxes and horizontal bars to denote interquartile range (IQR) and median, respectively. Whisker endpoints are equal to the maximum and minimum values. Grey boxes indicate upper limit of detection for these validated assays. Arrows at the base of the Figure indicate day of vaccination. (E-F) A heatmap of reciprocal neutralization titers (ID50) against variant of concern authentic viruses for study day 43 (two weeks post second vaccination), study day 181 (day of third vaccination), and study day 195 (two weeks post third vaccination). Data is shown for the nine volunteers included in the 25μg group of the trial. Variants of concern are displayed according to a phylogenetic tree of the spike proteins used in these neutralization assays. Sarbecoviruses (F) are displayed according to a phylogenetic tree of the spike proteins used in these neutralization assays. Titers are colored and phylogenetic trees are sized according to the displayed scale.
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References

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