Self-Amplifying mRNA COVID-19 vaccine demonstrates superior immune response compared with mRNA vaccine at 12 months post-vaccination- Seqirus/CSL

The data, presented as a poster at the OPTIONS XII for the Control of Influenza conference, highlights 12-month follow-up analysis of the Phase III trial conducted in Japan by Meiji Seika Pharma, evaluating a booster dose of ARCT154, showing that the vaccine elicited superior immunogenicity and antibody persistence over Comirnaty for up to 12 months postvaccination, against multiple SARS-CoV-2 strains and in both younger and older adult age groups.

"The 12-month results from the ARCT 154 study continue to establish the durability of immune response from this self-amplifying mRNA vaccine and reinforce the ability of this vaccine to provide protection against COVID-19 at lower doses compared to conventional mRNA vaccines," said Jonathan Edelman, M.D., Senior Vice President, Vaccines Innovation Unit, CSL. "We are proud to showcase at the 2024 OPTIONS conference with these important data about the first sa-mRNA COVID-19 vaccine now approved in Japan."

Additional data presented by CSL and Arcturus finds that the bivalent formula, ARCT 2301, developed on the same platform as ARCT 154, induces superior immunogenicity over conventional bivalent mRNA vaccine Comirnaty that persists against key variants up to six months post-vaccination.

"The recent surge in COVID-19 infections and the emerging new variants illustrate the critical need for vaccines that provide a longer duration of protection compared to conventional mRNA vaccines," said Igor Smolenov, M.D., Ph.D. Chief Development Officer of Arcturus Therapeutics. "These compelling new studies reaffirm that these sa-mRNA vaccines have the potential to offer potent protection against COVID-19."

The COVID-19 vaccine from this sa-mRNA platform targeted against the JN.1 variant is approved in Japan for immunization against COVID-19 in adults 18 years and older and is being sold under the trade name Kostaive. 

ARCT-154 12-month Study Design and Results; The randomized, double-blind, active-controlled Phase III study was conducted at 11 clinical sites in Japan. The study enrolled 828 adults ho had previously been fully immunized with three doses of mRNA vaccine(s). Participants were randomized equally to receive a booster dose of either ARCT 154 or Comirnaty. Immune responses were measured as neutralizing antibodies against the Wuhan-Hu-1 and Omicron BA.4-5 strains in sera obtained at Day 1 before booster vaccination, and Days 29, 91, 181, and 361 after vaccination of participants who were seronegative for SARS-CoV-2 nucleocapsid protein (N-protein), considered to be an indicator of recent COVID-19 infection. At the same timepoints neutralizing antibodies against Delta, Omicron BA.2, Omicron BA.2.86, and Omicron XBB.1.5.6 variants were measured in subsets of participants (~30 per group). Responses are expressed as group geometric mean titers (GMT) with 95% confidence intervals, and geometric mean titer ratio (GMTR) between the two vaccine groups at each timepoint.

At Day 29, neutralizing antibodies (GMTs unadjusted) against the Wuhan-Hu-1 strain in ARCT 154 recipients (n = 378) were superior to those in the Comirnaty group (n = 374): GMT = 5390 (95% CI: 4899–5931) vs. 3738 (3442–4060), a GMT ratio of 1.44 (1.27–1.64). This advantage persisted through all time points.  At Day 361 (unadjusted) GMTs were 3396 (3019–3821) and 1771 (1532–2047) in ARCT 154 (n = 272) and Comirnaty (n = 266) groups, a GMT ratio of 1.92 (1.59–2.31). Differences were also observed in responses against Omicron BA.4-5, with GMT ratios of 1.31 (1.07–1.59) at Day 29 and 1.89 (1.42– 2.50) at Day 361. A subset of subjects who were seronegative for N-protein displayed similar differences in immune responses between ARCT 154 and Comirnaty against the Delta, Omicron BA.2, BA.2.86, and XBB.1.5.6 variants at Day 361. The GMT ratios were 1.88 (0.79–4.49) against Delta, 2.34 (1.06–5.17) against Omicron BA.2, 2.51 (1.00–6.31) against Omicron BA.2.86 and 2.81 (1.09–7.28) against Omicron XBB.1.5.6

Bivalent 6-month Study Design and Results; In this randomized, multicenter, Phase III, observer-blind, active-controlled trial in Japan, fully-immunized (3‒5 doses of mRNA vaccine) adults were randomized 1:1 to receive a booster dose of ARCT 2301 or Comirnaty Original/BA.4-5. The primary objective was to demonstrate non-inferiority of the immunogenicity of ARCT-2301 vs. Comirnaty Original/BA.4-5 at Day 29 as neutralizing antibody GMT and seroresponse rates (SRR) against Omicron BA.4-5. Key secondary outcomes included titers of neutralizing antibodies against Wuhan-Hu-1 and Omicron XBB.1.5.

Between September and November 2023, 930 men and women (19‒80 years) with at least three prior mRNA COVID-19 vaccinations were enrolled at nine medical centers in Japan and administered ARCT 2301 (n = 465) or Comirnaty Original/BA.4-5 (n = 465) boosters. At Day 29 ARCT 2301 (n = 398) induced superior neutralizing antibody responses vs. Comirnaty (n = 405) against Omicron BA.4-5 (GMT ratio 1•49 [95% CI: 1.26–1.76], SRR difference 7.2% [95% CI: 0.6–13.7]), and against Wuhan-Hu-1 (GMT ratio 1.45 [1.28–1.63], SRR difference 12.5% [5.9–19.0]). The difference persisted through six months with GMT ratios of 2.17 (95% CI: 1.75-2.69) and 1.98 (95% CI: 1.69-2.31), respectively. Antibody responses against Omicron XBB.1.5 were also higher after ARCT 2301 vs. Comirnaty (GMT ratio 1.63 [1.36–1.94], SRR difference 16.7% [10.1–23.2]).

About sa-mRNA
mRNA vaccines help protect against infectious diseases by providing a blueprint for cells in the body to make a protein to help our immune systems recognize and fight the disease. Unlike standard mRNA vaccines, self-amplifying mRNA vaccines instruct the body to make more mRNA and protein to boost the immune response.