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. 2025 Nov 26;12(12):ofaf689.
doi: 10.1093/ofid/ofaf689. eCollection 2025 Dec.

Phase 1 Randomized Controlled Trial of the Safety and Immunogenicity of the SARS-CoV-2 (Omicron BA.5) mRNA-CR-04 Vaccine in Adults 18-49 Years of Age

Abdi Naficy  1 , Mireille Venken  2 , Yingmei Xi  3 , Mark Loughrey  4 , Giulietta Maruggi  5 , Hema Sharma  6 , Kunal Aggarwal  7 , Daniel Brune  8 , Bach-Yen Nguyen  1
Affiliations

Phase 1 Randomized Controlled Trial of the Safety and Immunogenicity of the SARS-CoV-2 (Omicron BA.5) mRNA-CR-04 Vaccine in Adults 18-49 Years of Age

Abdi Naficy et al. Open Forum Infect Dis. .

Abstract

Background: This study (NCT05972993) evaluated a novel mRNA vaccine construct using the SARS-CoV-2 BA.5 Spike (S) protein as the model antigen (mRNA-CR-04).

Methods: This first-in-human Phase 1, randomized, placebo-controlled trial enrolled 72 participants in Part A (sentinel vaccination and dose escalation) and 42 in Part B (dose exploration). Adult participants 18-49 years of age were randomized in 3 groups to receive one dose of mRNA-CR-04 (either 10, 30, or 100 µg) or placebo (3:1) in Part A, and 3 µg, 10 µg, or placebo (3:3:1) in Part B. Vaccine safety and immunogenicity in terms of neutralizing titers were assessed until 6 months postinvestigational product administration.

Results: Solicited adverse events (AEs) were mostly mild to moderate and transient. In Part A, Grade 3 reactogenicity was only observed in the 100 µg group (n = 3, 16.7%), and Grade 3 nonsolicited AEs only occurred as causally unrelated serious AEs in 2 participants. No safety concerns deemed causally related to mRNA-CR-04 were raised on review of clinical safety data and clinical laboratory test results. All doses elicited notable neutralizing titers against the vaccine-encoded SARS-CoV-2 BA.5 variant and induced cross-neutralizing titers against the wild type (D614G) variant. The magnitude of the immune response tended to increase with dose. Neutralizing titers waned by Month 6 but remained above baseline levels.

Conclusions: The investigational mRNA-CR-04 vaccine was generally well tolerated, and all doses induced a robust immune response against the encoded antigen at doses ranging between 3 and 100 µg. Further investigation of potential vaccine candidates using this novel mRNA platform is warranted.

Keywords: COVID-19; immunogenicity; mRNA; safety; vaccine.

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Conflict of interest statement

Potential conflicts of interest. Abdi Naficy, Mireille Venken, Mark Loughrey, Giulietta Maruggi, Hema Sharma, Kunal Aggarwal and Bach-Yen Nguyen are employed by and hold financial equities in GSK. Yingmei Xi was employed by GSK at the time of study. Giulietta Maruggi is named on the following patent: Recombinant RNA molecules comprising untranslated regions or segments encoding spike protein from the omicron strain of severe acute respiratory coronavirus-2—Bennasser Y., Kim Y., Maruggi G., Mousavi K., Wahome N., Westerbeck J.W., Zwierzyna M.A., Yazdi A.—PCT/IB2023/056264 (GSK patent). These authors declare no other financial or non-financial relationships and activities. Daniel Brune declares no financial and non-financial relationships and activities and no conflicts of interest. All other authors report no potential conflicts.

Figures

Figure 1.
Figure 1.
Study design. D: Day; iSRC: internal safety review committee; M: Month; mRNA: mRNA-CR-04 vaccine; n: number of participants; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SE: Solicited events; SRT: safety review team; TC: telephone call; V: Visit. * TC1 D2 only for sentinel participants in each group. ** The first participant enrolled in Group 1. *** TC1 review by the SRT on blinded data.
Figure 2.
Figure 2.
Solicited adverse events by dose group and maximum grade: (A) Part A, (B) Part B. Ab.: abdominal; Lymph: ipsilateral axillary lymphadenopathy Intensity scales for solicited events are provided in the Supplement.
Figure 3.
Figure 3.
Unadjusted geometric mean titers for neutralizing titers against SARS-CoV-2 BA.5 by time point: (A) Part A, (B) Part B (per-protocol set). SARS-CoV-2: severe acute respiratory syndrome coronavirus 2 Circles represent individual datapoints, horizontal line represents the assay lower limit of quantitation, whiskers indicate 95% confidence intervals.
See this image and copyright information in PMC

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