MedPath

mRNA-1283.815 Advanced Drug Monograph

Published:May 16, 2025

Generic Name

mRNA-1283.815

A Comprehensive Report on the Next-Generation COVID-19 Vaccine: mRNA-1283.815 – Development, Clinical Profile, and Future Perspectives

1. Introduction to mRNA-1283 and the.815 Formulation

Overview of mRNA-1283 as a Next-Generation COVID-19 Vaccine

The ongoing evolution of SARS-CoV-2 necessitates the development of advanced vaccine candidates capable of providing robust and broad protection. mRNA-1283, developed by Moderna, Inc., represents such a next-generation COVID-19 vaccine.[1] It is engineered to offer potential advantages over earlier COVID-19 vaccines, including the prospect of enhanced immunogenicity, improved stability characteristics, and the possibility of dose-sparing, which could have significant implications for global vaccine supply and administration.[3] Furthermore, mRNA-1283 is a pivotal component in Moderna's strategy for developing combination vaccines, most notably mRNA-1083, which targets both influenza virus and SARS-CoV-2.[1]

Rationale for Development

The primary impetus for the development of mRNA-1283 stems from the dynamic nature of the SARS-CoV-2 virus and the public health imperative to maintain high levels of population immunity. The goals included creating a vaccine that could elicit a more potent or durable immune response, potentially against a wider array of viral variants, and addressing some of the logistical challenges encountered with first-generation mRNA vaccines.[2] The design of mRNA-1283, which focuses on key neutralizing epitopes of the SARS-CoV-2 spike protein, was intended to direct a more focused and potentially more effective immune response.[2]

The development trajectory of mRNA-1283, and specifically its.815 formulation, indicates a strategic iteration by Moderna on its foundational mRNA platform. This effort appears to extend beyond mere variant-specific updates of the original Spikevax (mRNA-1273) vaccine, aiming instead for fundamental enhancements to the vaccine backbone itself to improve both immunological performance and practical deployment. This is evidenced by the vaccine's unique antigen design, which encodes only the receptor-binding domain (RBD) and N-terminal domain (NTD) of the spike protein, rather than the full-length spike protein.[2] This design choice likely aims for a more concentrated immunogenic stimulus and may contribute to improved expression or stability. Additionally, the significant emphasis on achieving refrigerator stability and developing a pre-filled syringe presentation addresses well-documented logistical hurdles associated with earlier mRNA vaccines, thereby signaling an intent to create a more globally accessible and user-friendly product.[1] The concurrent development of mRNA-1283 as an integral part of combination vaccines, such as mRNA-1083 for influenza and COVID-19, further underscores a long-term strategic vision for this next-generation platform.[1]

Clarification of the ".815" Suffix - Targeting XBB.1.5

The nomenclature "mRNA-1283.815" specifically denotes the formulation of this next-generation vaccine candidate that has been adapted to target the Omicron XBB.1.5 variant of SARS-CoV-2.[9] This is analogous to Moderna's updated Spikevax formulation, mRNA-1273.815, which also targets the XBB.1.5 variant.[10] Part 2 of the pivotal NextCOVE (NCT05815498) Phase 3 clinical trial was designed to directly compare the XBB.1.5-adapted mRNA-1283.815 with the XBB.1.5-adapted mRNA-1273.815.[10]

The selection of the XBB.1.5 variant for the.815 formulation was in alignment with guidance from regulatory authorities for the Fall 2023 vaccination campaigns.[13] However, this choice inherently highlights the persistent challenge in vaccine development: the timeline required for clinical evaluation and manufacturing often struggles to keep pace with the rapid evolution of the virus. Consequently, a critical aspect of this report will be the assessment of the clinical data generated for an XBB.1.5-targeted vaccine in the context of subsequently dominant SARS-CoV-2 lineages, such as JN.1 and its descendants (e.g., KP.2, KP.3), and more recently emerging variants like LP.8.1.[14] While XBB.1.5 was the recommended target when the NextCOVE Part 2 trial was likely initiated in mid-2023 [9], by early to mid-2024, variants such as JN.1 and its sublineages (KP.2, KP.3) had become predominant.[11] Further evolution by early 2025 saw LP.8.1 emerge as a key variant, with the European Medicines Agency (EMA) recommending it as a target for the 2025/2026 vaccination campaigns.[15] Therefore, the efficacy and immunogenicity data derived from mRNA-1283.815 against XBB.1.5 require careful interpretation regarding its potential utility against these antigenically distinct, newer variants.

Key Differentiating Features Claimed

Moderna has highlighted several potential advantages for the mRNA-1283 platform:

  • Enhanced Immunogenicity: The vaccine is designed to elicit higher or more durable immune responses, potentially at lower dosage levels compared to the original mRNA-1273 vaccine.[1]
  • Improved Storage and Stability: mRNA-1283 is engineered for stability at standard refrigerator temperatures (2°C to 5°C), which would significantly ease logistical burdens associated with distribution and storage, particularly in comparison to the ultra-cold chain requirements of some earlier mRNA vaccines.[1]
  • Presentation: The vaccine is anticipated to be available in a pre-filled syringe format, which could simplify administration for healthcare providers and potentially broaden access in diverse healthcare settings.[1]

2. Mechanism of Action and Formulation Details

Core mRNA Technology

mRNA-1283.815, like other Moderna vaccines, is based on messenger RNA (mRNA) technology. The vaccine delivers mRNA molecules that encode specific viral antigens into host cells. Once inside the cells, the mRNA instructs the cellular machinery to produce these antigens. The host immune system then recognizes these antigens as foreign and mounts an immune response, including the generation of antibodies and cellular immunity, thereby preparing the body to defend against a future infection with the actual virus.[9] Importantly, the mRNA in the vaccine does not integrate into the host cell's DNA and is naturally degraded by the body after it has served its purpose. The vaccine does not contain any live virus and therefore cannot cause COVID-19.[9]

Antigens Encoded by mRNA-1283

A key distinction of the mRNA-1283 platform lies in its antigen design. Unlike mRNA-1273 (Spikevax), which encodes the full-length SARS-CoV-2 spike (S) protein, mRNA-1283 encodes only two specific segments of the S protein: the Receptor Binding Domain (RBD) and the N-terminal Domain (NTD).[2] These regions are known to be immunodominant—meaning they are primary targets of the immune response—and contain critical epitopes for the generation of neutralizing antibodies that can block viral entry into host cells.[2] More specifically, some sources describe the antigen produced by mRNA-1283 as a chimeric protein (NTD-RBD-HATM), where the NTD and RBD are connected by a flexible peptide linker and anchored to a transmembrane domain derived from influenza hemagglutinin.[8]

This targeted antigen design is a strategic choice. By focusing the immune response on these critical neutralizing epitopes, there is a potential for a more efficient and potent immune reaction per microgram of mRNA administered. This approach might also reduce the metabolic load on host cells, as they are not required to synthesize the entire, larger spike protein. The shorter mRNA sequence inherent in this design is also hypothesized to contribute to higher levels of protein expression from a smaller amount of mRNA and may enhance the stability of the mRNA molecule itself.[4] This efficiency could be a contributing factor to the observed dose-sparing effect, where lower doses of mRNA-1283 (e.g., 10 µg for mRNA-1283.815) have demonstrated comparable or superior immunogenicity to higher doses of mRNA-1273 (e.g., 50 µg for mRNA-1273.815).[10]

Delivery System

While not explicitly detailed for mRNA-1283.815 in all provided documents, it is presumed that the vaccine utilizes Lipid Nanoparticles (LNPs) as its delivery system. This is consistent with Moderna's established mRNA vaccine platform technology.[4] LNPs are essential for protecting the fragile mRNA molecules from degradation by enzymes in the body and for facilitating their efficient uptake into target cells, where the mRNA can then be translated into the antigenic proteins.

Formulation Advantages (mRNA-1283 platform)

The mRNA-1283 platform has been developed with specific formulation advantages in mind, aimed at overcoming some of the practical limitations of earlier mRNA vaccines:

  • Refrigerator Stability: A significant claimed advantage is the vaccine's stability at standard refrigerator temperatures (variously cited as 2°C to 8°C or 2°C to 5°C).[1] This represents a substantial logistical improvement over vaccines requiring ultra-cold storage (e.g., -70°C or -20°C), simplifying storage, transportation, and handling at vaccination sites globally. The shorter mRNA construct of mRNA-1283, encoding only the NTD and RBD, is likely a direct contributor to this enhanced stability, as shorter RNA strands can be inherently more resilient to degradation than longer ones.[4]
  • Pre-filled Syringe Presentation: mRNA-1283 is intended to be available in a pre-filled syringe format.[1] This presentation can reduce the burden on healthcare providers by minimizing vaccine preparation steps, reducing the risk of dosing errors, and potentially speeding up the administration process during mass vaccination campaigns.

These formulation characteristics—improved refrigerator stability and a pre-filled syringe option—are not merely conveniences. They are crucial factors that can enhance the equitable global deployment of the vaccine, particularly in resource-limited settings or during large-scale public health initiatives. This positions mRNA-1283 as a potentially more practical and versatile option for broader and more sustained vaccination efforts beyond acute pandemic response scenarios.

3. Preclinical Development Highlights

The progression of mRNA-1283 to clinical trials was underpinned by a series of preclinical studies that indicated its potential as an improved COVID-19 vaccine.

Immunogenicity and Protection (General mRNA-1283 platform)

Preclinical investigations, primarily conducted in murine models, consistently demonstrated that the mRNA-1283 platform could induce robust immune responses. These responses included the generation of both neutralizing antibodies (nAbs) and binding antibodies (bAbs) at levels comparable to, or in some instances greater than, those elicited by the original mRNA-1273 vaccine, particularly when lower doses of mRNA-1283 were administered.[3]

Furthermore, these preclinical studies provided evidence of protection against viral challenge with various SARS-CoV-2 strains. Immunized animals showed protection against infection or disease when exposed to wild-type SARS-CoV-2, as well as variants of concern such as Beta, Delta, and Omicron (specifically BA.1).[3] In K18-hACE2 transgenic mice, which express the human ACE2 receptor and are susceptible to severe COVID-19, immunization with mRNA-1283 conferred degrees of protection from challenge with SARS-CoV-2 Delta and Omicron variants that were similar to those achieved with mRNA-1273, across all vaccine dosages tested.[3] These findings suggested that the NTD-RBD focused antigen design was a viable and effective strategy for eliciting protective immunity.

Dose-Sparing Potential

A significant observation from the preclinical development program was the potential for dose-sparing with mRNA-1283. Animal studies indicated that mRNA-1283 could achieve comparable immunogenicity to mRNA-1273 but at substantially lower mRNA doses.[4] This was an important finding, as a dose-sparing vaccine offers several advantages: more doses can be manufactured from a given amount of raw material, potentially increasing overall vaccine supply, and lower antigen doses can sometimes be associated with reduced reactogenicity, which may improve vaccine tolerance and acceptance. These preclinical observations provided a strong scientific rationale for investigating lower doses (e.g., 10 µg) of mRNA-1283 in subsequent human clinical trials, compared to the 50 µg or 100 µg doses typically used for mRNA-1273. This dose-sparing potential was later corroborated in Phase 1 human trials, where a 10 µg dose of mRNA-1283 demonstrated immunogenicity comparable to that of 100 µg of mRNA-1273.[3]

Improved Stability

Preclinical evaluations also lent support to the claim of improved storage stability for mRNA-1283. These studies indicated that mRNA-1283 formulations maintained their integrity and potency under standard refrigeration conditions (2°C to 8°C) better than mRNA-1273 formulations.[3] This enhanced stability profile was considered a key advantage for global distribution and deployment, especially in regions with limited access to ultra-cold chain infrastructure.

mRNA-1283.815 (XBB.1.5) Specific Preclinical Data

While extensive preclinical data specifically for the mRNA-1283.815 (XBB.1.5-adapted) formulation are not extensively detailed in the available information, the general preclinical success of the mRNA-1283 platform against a range of variants, including the Omicron BA.1 sublineage, provided a solid foundation for its adaptation to newer variants like XBB.1.5.[3] Regulatory presentations concerning Moderna's 2023-2024 XBB.1.5 vaccine (mRNA-1273.815) do mention that Moderna generated preclinical data for new candidate vaccines. This included comparisons of investigational JN.1 and KP.2-adapted vaccines against the XBB.1.5 vaccine in mice. However, specific preclinical immunogenicity or protection data for mRNA-1283.815 itself is not explicitly provided in these particular documents.[23] The advancement of mRNA-1283.815 into Phase 3 trials was largely predicated on the robust performance of the underlying mRNA-1283 platform and the established process for adapting mRNA vaccines to new viral variants.

The preclinical validation of mRNA-1283's improved stability and dose-sparing characteristics carried significant implications beyond basic immunogenicity. These features positioned mRNA-1283 as a more versatile platform, potentially better suited for global vaccination campaigns, particularly in settings constrained by cold-chain logistics or where maximizing the number of available doses from limited manufacturing capacity is paramount. This made it an attractive candidate for pandemic preparedness and response in diverse global health environments.

4. Clinical Development Program Overview

The clinical development of mRNA-1283 has been characterized by a rapid, iterative approach, with vaccine formulations being adapted across Phase 1, 2a, and 3 trials to address the evolving SARS-CoV-2 variant landscape and emerging immunogenicity and safety data. This agility is a recognized strength of mRNA vaccine technology.

Phase 1 Trial (NCT04813796)

The initial human study of mRNA-1283 (NCT04813796) was a Phase 1 trial designed to evaluate the safety, reactogenicity, and immunogenicity of various doses of mRNA-1283 (10 µg, 30 µg, and 100 µg as a two-dose regimen administered 28 days apart, and a 100 µg single dose) in healthy adults aged 18-55 years. These were compared against a standard two-dose regimen of mRNA-1273 (100 µg).[2]

Key findings from this Phase 1 trial were encouraging. No significant safety concerns were identified. All two-dose regimens of mRNA-1283, importantly including the lowest 10 µg dose level, induced robust neutralizing antibody (nAb) and binding antibody (bAb) responses. These responses were comparable to those generated by the 100 µg dose of mRNA-1273 when tested against the ancestral SARS-CoV-2 strain (Wuhan-Hu-1 with D614G mutation) and the Beta (B.1.351) variant.[3] While effective, solicited systemic adverse reactions, such as fatigue and headache, were reported more frequently with the higher dose levels of mRNA-1283.[4] This trial provided crucial early evidence supporting the dose-sparing potential of the mRNA-1283 platform.

Phase 2a Trial (NCT05137236)

Following the promising Phase 1 results, a Phase 2a trial (NCT05137236) was initiated. This was a dose-ranging, observer-blind, randomized study conducted in adults (aged ≥18 years) who had previously been vaccinated with mRNA-1273, designed to evaluate mRNA-1283 as a booster dose.[2]

Part A of this study assessed single booster doses of a monovalent mRNA-1283 formulation (targeting the original SARS-CoV-2 strain) at 2.5 µg, 5 µg, and 10 µg, as well as a bivalent formulation, mRNA-1283.211 (targeting the original strain and the Beta variant), at 5 µg and 10 µg doses.[5] Subsequently, an open-label Part B was added to evaluate a monovalent Omicron BA.1-adapted version of the vaccine, mRNA-1283.529, at 5 µg and 10 µg dose levels, reflecting the emergence of the Omicron variant.[5]

The results from the Phase 2a trial indicated that all dose levels of the mRNA-1283 vaccines were well-tolerated as boosters. The mRNA-1283 booster doses (original strain) effectively increased nAb responses against both the D614G (ancestral-like) strain and the Beta variant, with these responses being higher than those previously observed with mRNA-1273 boosters. The Omicron BA.1-adapted mRNA-1283.529 also successfully boosted nAb responses against the Omicron BA.1 variant. Notably, antibody responses were reported to remain detectable for up to a year post-vaccination.[5] This study further reinforced the immunogenicity of mRNA-1283 as a booster and demonstrated its adaptability to new variants.

Pivotal Phase 3 NextCOVE Trial (NCT05815498; mRNA-1283-P301)

The cornerstone of the late-stage clinical development is the pivotal Phase 3 NextCOVE trial (also identified as mRNA-1283-P301, NCT05815498). This large-scale, randomized, observer-blind, active-controlled study enrolled approximately 11,400 individuals aged 12 years and older across sites in the United States, the United Kingdom, and Canada.[1] The trial was designed with two main parts to evaluate different formulations of mRNA-1283 against corresponding formulations of the licensed Spikevax (mRNA-1273) vaccine.

  • Part 1 of the NextCOVE trial compared mRNA-1283.222, presumed to be a bivalent formulation of mRNA-1283 targeting the Omicron BA.4/BA.5 subvariants, against mRNA-1273.222, which was Moderna's licensed Omicron BA.4/BA.5 bivalent vaccine.[1] Interim results from this part, announced in March 2024, indicated that mRNA-1283.222 elicited a higher immune response against both the Omicron BA.4/BA.5 variants and the original (ancestral) virus strains of SARS-CoV-2 when compared to mRNA-1273.222. This benefit was reported to be most pronounced in participants over the age of 65 years.[1]
  • Part 2 of the NextCOVE trial is of primary relevance to this report. It was designed to compare mRNA-1283.815, the XBB.1.5 monovalent formulation of mRNA-1283 administered at a 10 µg dose, with mRNA-1273.815, the XBB.1.5 monovalent updated version of Spikevax, administered at a 50 µg dose.[9]

A consistent pattern emerging from these early clinical trials was the capacity of mRNA-1283 to elicit comparable or even superior immunogenicity at markedly lower doses (e.g., 10 µg) relative to its predecessor, mRNA-1273 (which typically utilized 50 µg or 100 µg doses).[3] This dose-sparing characteristic represents a key potential advantage of the mRNA-1283 platform. Furthermore, the clinical development program, through its inclusion of active comparators such as licensed versions of Spikevax (mRNA-1273.222 and mRNA-1273.815), was strategically designed to directly demonstrate the "next-generation" attributes and potential benefits of mRNA-1283, rather than merely assessing its efficacy in isolation.[1] Successfully meeting non-inferiority criteria and, in some aspects, demonstrating superiority against an established and effective vaccine, sets a high evidentiary bar and strengthens the potential clinical case for mRNA-1283's adoption, contingent upon regulatory approval.

5. Pivotal Phase 3 NextCOVE Trial (NCT05815498) - mRNA-1283.815 Focus

Part 2 of the NextCOVE trial (NCT05815498) is central to understanding the clinical profile of mRNA-1283.815, as it directly compared this XBB.1.5-adapted next-generation vaccine with Moderna's XBB.1.5-adapted Spikevax.

Study Design (Part 2)

This part of the trial was a randomized, observer-blind, active-controlled study involving participants aged 12 years and older.[1] Participants received a single intramuscular injection of either mRNA-1283.815 (formulated at a 10 µg dose and targeting the Omicron XBB.1.5 variant) or mRNA-1273.815 (Moderna's updated Spikevax, formulated at a 50 µg dose, also targeting XBB.1.5).[9] The primary objectives included the evaluation of relative vaccine efficacy (rVE), safety, reactogenicity, and immunogenicity of mRNA-1283.815 compared to mRNA-1273.815.[12]

Clinical Efficacy (mRNA-1283 vs. mRNA-1273 platform)

A press release from Moderna in June 2024 announced that mRNA-1283 (likely referring to data predominantly from or inclusive of the.815 formulation evaluated in NextCOVE Part 2, or combined data from the overall NextCOVE program) met its primary efficacy endpoint. The vaccine demonstrated non-inferior vaccine efficacy against COVID-19 when compared to Spikevax (mRNA-1273). Furthermore, a higher efficacy was observed in adults aged 18 years and older for mRNA-1283 compared to Spikevax, with a consistent trend towards higher efficacy also noted in the subset of adults aged 65 years and older.[18]

An indirect treatment comparison (ITC) published in February 2025, which incorporated data from the NextCOVE trial (specifically comparing the BA.4/BA.5 bivalent version of mRNA-1283 against the BA.4/BA.5 bivalent version of mRNA-1273) alongside other studies, suggested that the mRNA-1283 (BA.4/BA.5 bivalent) formulation exhibited a higher relative vaccine efficacy (rVE) against symptomatic COVID-19 compared to BNT162b2 (Pfizer-BioNTech). This effect was particularly notable in adults aged 65 years and older, where the rVE was estimated at 22.8%.[6] While this ITC pertains to a different variant formulation of mRNA-1283, it provides supportive evidence for the general efficacy potential of the mRNA-1283 platform.

Immunogenicity against XBB.1.5 (mRNA-1283.815 vs. mRNA-1273.815)

Detailed immunogenicity data against the Omicron XBB.1.5 variant from Japanese participants enrolled in the NCT05815498 trial were presented in a poster in April 2025.[10] These data are critical for assessing the performance of mRNA-1283.815.

Key findings include:

  • Primary Immunogenicity Objective Met: mRNA-1283.815 (10 µg) successfully met the prespecified non-inferiority criteria for immunogenicity when compared to mRNA-1273.815 (50 µg). Furthermore, mRNA-1283.815 elicited statistically significantly higher neutralizing antibody (nAb) responses against the Omicron XBB.1.5 variant at Day 29 post-vaccination.
  • Geometric Mean Titers (GMTs) against XBB.1.5 (Day 29):
  • mRNA-1283.815: 1726.4
  • mRNA-1273.815: 1510.1
  • Geometric Mean Fold Rise (GMFR) from pre-dose levels (Day 29):
  • mRNA-1283.815: 14.90
  • mRNA-1273.815: 11.28
  • Geometric Mean Ratio (GMR) of nAb responses (mRNA-1283.815 / mRNA-1273.815) at Day 29: The GMR was 1.195 (95% Confidence Interval [CI]: 1.028-1.389). Since the lower bound of the 95% CI is greater than 1, this indicates a statistically significantly higher immune response for mRNA-1283.815.
  • Seroresponse Rates (SRR) against XBB.1.5 (Day 29):
  • mRNA-1283.815: 92.2%
  • mRNA-1273.815: 86.8%
  • The difference in SRR was 5.4% (95% CI: 0.8-10.2), favoring mRNA-1283.815.
  • Age-Stratified GMRs against XBB.1.5 (Day 29): The GMRs were consistent across age groups, with numerically the highest GMR observed in participants aged ≥65 years:
  • ≥12 to <18 years: 1.2 (95% CI: 0.9-1.6)
  • ≥18 to <65 years: 1.2 (95% CI: 1.0-1.4)
  • ≥65 years: 1.3 (95% CI: 0.9-1.9)

These results are summarized in Table 1.

Table 1: Comparative Immunogenicity of mRNA-1283.815 (10 µg) vs. mRNA-1273.815 (50 µg) against Omicron XBB.1.5 (Day 29 Post-Vaccination, Japanese Participants from NCT05815498)

(Data sourced from 10)

Immunogenicity ParametermRNA-1283.815 (10 µg) (n=334)mRNA-1273.815 (50 µg) (n=334)GMR (95% CI) or SRR Difference (95% CI)
GMT against XBB.1.5 (Day 29)1726.4 (1523.1-1957.0)1510.1 (1333.5-1710.0)1.195 (1.028-1.389)a
GMFR from pre-dose (Day 29)14.90 (13.14-16.90)11.28 (9.83-12.95)N/A
SRR against XBB.1.5 (Day 29)92.2% (88.8-94.9)86.8% (82.7-90.3)5.4% (0.8-10.2)b
GMR (XBB.1.5, Day 29) by Age:
≥12 to <18 years (n=70/68)3359.4 (2762.1-4085.9)c2705.1 (2195.2-3333.3)c1.2 (0.9-1.6)
≥18 to <65 years (n=195/197)1418.2 (1205.5-1668.5)c1408.9 (1205.8-1646.3)c1.2 (1.0-1.4)
≥65 years (n=69/69)1531.9 (1130.7-2075.5)c1036.3 (753.3-1425.6)c1.3 (0.9-1.9)

GMT: Geometric Mean Titer; GMFR: Geometric Mean Fold Rise; GMR: Geometric Mean Ratio; SRR: Seroresponse Rate; CI: Confidence Interval; N/A: Not Applicable.

*$^{\text{a}}GMRofmRNA−1283.815tomRNA−1273.815basedonGLSM(GeometricLeastSquaresMean).∗∗^{\text{b}}DifferenceinSeroresponseRates.∗∗^{\text{c}}$Reported as Day 29 GMC (Geometric Mean Concentration) in source, assumed equivalent to GMT for this table.*

The superior immunogenicity of mRNA-1283.815 (10 µg) against the XBB.1.5 variant compared to mRNA-1273.815 (50 µg) is a noteworthy finding.10 This achievement validates the design principles of the next-generation platform, demonstrating its capability for enhanced potency even at a substantially reduced mRNA dose. Such an improvement carries positive implications for manufacturing scalability, potentially allowing for a greater number of doses to be produced, and could also contribute to a more favorable reactogenicity profile. The consistent trend of superior immunogenicity across different age groups, including the numerically highest GMR in individuals aged ≥65 years, is particularly significant, as this demographic is at an elevated risk for severe outcomes from COVID-19 and often exhibits a less robust immune response to vaccination.

### Immunogenicity against Other Variants (Ancestral, BA.4/BA.5 - from mRNA-1283.222 or general mRNA-1283 platform)

Data from Part 1 of the NextCOVE trial, which likely evaluated the BA.4/BA.5 bivalent formulation mRNA-1283.222 against mRNA-1273.222, indicated that mRNA-1283 elicited a higher immune response against both the Omicron BA.4/BA.5 variants and the original (ancestral) SARS-CoV-2 strains compared to mRNA-1273.222. This benefit was reported to be most pronounced in participants older than 65 years.1 Supporting this, a Taylor & Francis publication analyzing NextCOVE data also noted that mRNA-1283 (referring to the BA.4/BA.5 bivalent formulation) induced higher nAb titers against BA.4/BA.5 and the original strain, with GMRs of 1.3 (for the overall population aged ≥12 years) and 1.8 (for those aged ≥65 years) when compared to the BA.4/BA.5 bivalent version of mRNA-1273.6

### Cross-Neutralization against JN.1, KP.2, KP.3, LP.8.1 (Inferred from mRNA-1273.815 and related XBB.1.5 vaccines)

Crucially, direct clinical data on the cross-neutralizing antibody responses of mRNA-1283.815 against later circulating variants such as JN.1, KP.2, KP.3, or LP.8.1 are not available in the provided information; the poster detailing results from Japanese participants in NCT05815498 focused specifically on immunogenicity against XBB.1.5.10

In the absence of such direct data for mRNA-1283.815, insights can be drawn from studies of Moderna's XBB.1.5-updated Spikevax (mRNA-1273.815), which shares the same XBB.1.5 antigen target, and from preclinical studies involving XBB.1.5-based vaccines:

* **Human Data for mRNA-1273.815 (XBB.1.5 Spikevax update) 23:**

* At Day 29 post-booster, mRNA-1273.815 elicited nAb GMTs of 2711 against XBB.1.5, 466 against JN.1 (GMFR 11.2), 381 against JN.1.23, and 269 against KP.2 (GMFR 7.5).

* By Day 181 post-booster, these GMTs had waned to 771 against XBB.1.5, 155 against JN.1 (GMFR 3.7), 121 against JN.1.23, and 89 against KP.2 (GMFR 2.4).

These data (summarized in Table 2) indicate that while the XBB.1.5-targeted mRNA-1273.815 does induce cross-neutralizing antibodies against JN.1 and KP.2, these titers are substantially lower than those against the homologous XBB.1.5 strain and decline over a six-month period.

* **Mice Data (mRNA-1273.815 vs. JN.1/KP.2-adapted vaccines) 11:**

* Preclinical studies in mice showed that the XBB.1.5 vaccine (mRNA-1273.815) induced comparatively poor neutralization of JN.1 and KP.2 when compared directly to JN.1- or KP.2-matched vaccines. Conversely, the JN.1- and KP.2-matched vaccines effectively cross-neutralized other JN.1 sublineages like KP.3, LA.2, and XEC, but did not effectively neutralize the more antigenically distant XBB.1.5. This highlights the significant antigenic distance between XBB.1.5 and the JN.1 lineage.

* **Human Data (mRNA-1273.167 [JN.1-adapted] and mRNA-1273.712 [KP.2-adapted] vaccines) 26:**

* Clinical studies with these more recent JN.1- and KP.2-adapted versions of mRNA-1273 demonstrated that they increased nAb responses against their respective matched variants and also showed cross-neutralization against other JN.1 lineage subvariants including KP.3.1.1, XEC, and LP.8.1. However, a reduction in cross-neutralization efficacy was generally observed when tested against these diverse subvariants compared to the specific variant the vaccine was matched to (e.g., JN.1).

**Table 2: Neutralizing Antibody Titers of Moderna's XBB.1.5 Vaccine (mRNA-1273.815) against XBB.1.5, JN.1, KP.2 (Human Data from Study 205J)**

*(Data sourced from 23)*

| Variant | GMT at Day 29 Post-Vaccination | GMFR from pre-boost (Day 29) | GMT at Day 181 Post-Vaccination | GMFR from pre-boost (Day 181) |

|-----------|--------------------------------|------------------------------|---------------------------------|-------------------------------|

| XBB.1.5 | 2711 | 17.5 | 771 | 5.2 |

| JN.1 | 466 | 11.2 | 155 | 3.7 |

| JN.1.23 | 381 | 12.3 | 121 | 3.9 |

| KP.2 | 269 | 7.5 | 89 | 2.4 |

*GMT: Geometric Mean Titer; GMFR: Geometric Mean Fold Rise. Confidence Intervals were not specified in the source for all values.*

The absence of direct human cross-neutralization data for mRNA-1283.815 against the later variants (JN.1, KP.2, KP.3, and LP.8.1) represents a critical information gap in the provided materials. While the performance of mRNA-1273.815 offers a useful proxy, the distinct NTD-RBD antigen design inherent to the mRNA-1283 platform could theoretically modulate the breadth and specificity of the immune response in ways different from the full-length spike antigen of mRNA-1273. This lack of specific data makes it more challenging to definitively predict mRNA-1283.815's effectiveness against currently dominant or emerging viral strains. Regulatory bodies and public health authorities rely heavily on such variant-specific neutralization data when formulating vaccine recommendations. Although the broader mRNA-1283 platform demonstrated encouraging responses to earlier variants like BA.4/BA.5 and ancestral strains with different formulations 1, the substantial antigenic shift observed with the emergence of JN.1 and its progeny necessitates specific evaluation.

The observed higher efficacy of the mRNA-1283 platform, whether from the.222 BA.4/BA.5 version directly or via indirect comparisons 6, when compared to mRNA-1273 and potentially BNT162b2, may be attributable to its focused NTD-RBD antigen design. This design could lead to more efficient or qualitatively different immune responses.2 If this enhanced immunogenicity and efficacy profile holds true for future variant-adapted versions of mRNA-1283 (e.g., an LP.8.1-adapted version), and assuming timely adaptation to these circulating variants, the mRNA-1283 platform could emerge as a preferred vaccine option. The higher antibody titers observed for mRNA-1283.815 against XBB.1.5 10 are generally correlated with better protection. Should this translate into broader cross-neutralization or more durable protection against new variants—a point not yet fully substantiated for mRNA-1283.815 against the latest strains within these documents—its public health impact would be considerable.

## 6. Safety and Tolerability Profile

### Overall Safety Profile (mRNA-1283 platform)

Across its clinical development program, the mRNA-1283 vaccine platform has generally demonstrated a safety profile similar to that of Moderna's already approved COVID-19 vaccines, such as Spikevax (mRNA-1273).1 Broader safety surveillance of XBB.1.5-containing mRNA vaccines, as of March 2024, had not identified any new safety signals or medical topics of concern, supporting a favorable benefit-risk assessment for these types of vaccines.23

### Data from Phase 3 NextCOVE Trial (mRNA-1283.815 vs. mRNA-1273.815 - Japanese Participants)

Specific safety and reactogenicity data comparing mRNA-1283.815 (10 µg) with mRNA-1273.815 (50 µg) from the Japanese cohort of the NCT05815498 study provide valuable insights.10

* **Solicited Local Adverse Reactions (within 7 days post-vaccination):**

* **Pain at injection site:** This was the most frequently reported local reaction. Participants receiving mRNA-1283.815 (10 µg) reported numerically lower rates of any pain (73.4%) and Grade 3 pain (0.3%) compared to those receiving mRNA-1273.815 (50 µg) (79.3% any pain, 1.2% Grade 3 pain).

* **Erythema (Redness):** Incidence was lower in the mRNA-1283.815 group (5.1%) compared to the mRNA-1273.815 group (9.3%).

* **Swelling (Hardness):** Similarly, lower incidence was observed for mRNA-1283.815 (4.8%) versus mRNA-1273.815 (8.4%).

* **Axillary swelling or tenderness:** Reported less frequently in the mRNA-1283.815 group (6.0%) than in the mRNA-1273.815 group (10.5%).

* **Solicited Systemic Adverse Reactions (within 7 days post-vaccination):**

* **Headache:** mRNA-1283.815 group reported 26.1% any headache (0.9% Grade 3), compared to 32.0% any headache (1.8% Grade 3) in the mRNA-1273.815 group.

* **Fatigue:** Incidence of any fatigue was 25.5% (1.2% Grade 3) for mRNA-1283.815, versus 32.3% (2.1% Grade 3) for mRNA-1273.815.

* **Myalgia (Muscle pain):** Reported by 16.2% (0.6% Grade 3) in the mRNA-1283.815 group, compared to 25.4% (1.2% Grade 3) in the mRNA-1273.815 group.

* **Arthralgia (Joint pain):** Incidence was 9.0% (0.3% Grade 3) for mRNA-1283.815, versus 12.0% (0.3% Grade 3) for mRNA-1273.815.

* **Chills:** Reported by 7.8% (0.3% Grade 3) in the mRNA-1283.815 group, compared to 11.4% (0.3% Grade 3) in the mRNA-1273.815 group.

* **Nausea/Vomiting:** Similar low rates were observed: 3.6% (0% Grade 3) for mRNA-1283.815 and 3.9% (0% Grade 3) for mRNA-1273.815.

* **Fever (≥38.0°C):** Incidence of fever was lower in the mRNA-1283.815 group (1.5%) compared to the mRNA-1273.815 group (3.0%).

* **Unsolicited Adverse Events (AEs):** The rates of unsolicited AEs were comparable between the two groups, with 13.2% in the mRNA-1283.815 group and 14.1% in the mRNA-1273.815 group. The majority of these events were mild or moderate in severity.

* **Serious Adverse Events (SAEs):** One SAE (COVID-19 pneumonia) was reported in the mRNA-1283.815 group; this event was assessed by the investigator as unrelated to the study vaccine. No SAEs were reported in the mRNA-1273.815 group. No deaths were reported in either group during the observation period covered by this dataset.

These safety findings are detailed in Table 3.

**Table 3: Incidence of Solicited Local and Systemic Adverse Reactions within 7 Days of Vaccination: mRNA-1283.815 (10 µg) vs. mRNA-1273.815 (50 µg) (Japanese Participants from NCT05815498)**

*(Data sourced from 10)*

| Adverse Reaction Category & Specific Event | mRNA-1283.815 (10 µg) (N=334) | mRNA-1273.815 (50 µg) (N=334) |

|--------------------------------------------|-------------------------------|-------------------------------|

| **Solicited Local Adverse Reactions** | | |

| Pain at Injection Site (Any / Grade 3) | 73.4% / 0.3% | 79.3% / 1.2% |

| Erythema (Redness) (Any / Grade 3) | 5.1% / 0% | 9.3% / 0% |

| Swelling (Hardness) (Any / Grade 3) | 4.8% / 0% | 8.4% / 0% |

| Axillary Swelling/Tenderness (Any / Grade 3) | 6.0% / 0% | 10.5% / 0.3% |

| **Solicited Systemic Adverse Reactions** | | |

| Headache (Any / Grade 3) | 26.1% / 0.9% | 32.0% / 1.8% |

| Fatigue (Any / Grade 3) | 25.5% / 1.2% | 32.3% / 2.1% |

| Myalgia (Any / Grade 3) | 16.2% / 0.6% | 25.4% / 1.2% |

| Arthralgia (Any / Grade 3) | 9.0% / 0.3% | 12.0% / 0.3% |

| Chills (Any / Grade 3) | 7.8% / 0.3% | 11.4% / 0.3% |

| Nausea/Vomiting (Any / Grade 3) | 3.6% / 0% | 3.9% / 0% |

| Fever (≥38.0°C / ≥39.0°C) | 1.5% / 0.3% | 3.0% / 0.3% |

| **Unsolicited Adverse Events (Any)** | 13.2% | 14.1% |

| **Serious Adverse Events** | 0.3% (1 event)$^{d}$ | 0% |

Grade 3 local reactions are defined as: Pain: significant pain, prevents daily activity; Erythema/Swelling: >10 cm; Axillary Swelling/Tenderness: prevents daily activity. Grade 3 systemic reactions are defined as: prevents daily activity; Fever: ≥39.0°C.

$^{\text{d}}$One SAE (COVID-19 pneumonia) deemed unrelated to study vaccine.

The data from the Japanese cohort of the NextCOVE trial suggest that the 10 µg dose of mRNA-1283.815 exhibits a generally more favorable reactogenicity profile compared to the 50 µg dose of mRNA-1273.815.[10] This is evidenced by numerically lower rates of most solicited local and systemic adverse reactions. Such an improvement in tolerability, particularly if observed consistently across larger and more diverse global populations, is a significant finding. This potentially lower reactogenicity is likely linked to the lower mRNA dose (10 µg for mRNA-1283.815 versus 50 µg for mRNA-1273.815). Thus, the dose-sparing characteristic of mRNA-1283 not only offers potential benefits in terms of manufacturing and supply but may also translate to better vaccine tolerance. When combined with the superior immunogenicity against the XBB.1.5 variant, this enhanced tolerability strengthens the overall benefit-risk profile of mRNA-1283.815. A vaccine that is both highly immunogenic and associated with a milder side effect profile could be particularly advantageous for future booster campaigns and for individuals who may have experienced more pronounced reactions to previous, higher-dose mRNA vaccines, potentially leading to improved vaccine uptake and adherence in the population.

7. Regulatory Status and Future Perspectives

Biologics License Application (BLA) for mRNA-1283

Moderna has actively pursued regulatory approval for its next-generation COVID-19 vaccine platform, mRNA-1283. The company submitted a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for mRNA-1283, utilizing a priority review voucher to expedite the review process.[2] The FDA accepted this BLA and has assigned a Prescription Drug User Fee Act (PDUFA) goal date of May 31, 2025.[2] It is important to note that this BLA likely pertains to the mRNA-1283 platform itself, demonstrating its safety and effectiveness (potentially based on data from one or more variant formulations like mRNA-1283.815). The specific variant composition of any approved mRNA-1283 vaccine that would be commercially available would be expected to align with the FDA's recommendations for the relevant vaccination season at the time of potential approval and subsequent manufacturing campaigns.

The PDUFA date of May 31, 2025, for the mRNA-1283 platform approval is a critical milestone. However, it also means that if approved based on the existing data package, which heavily features the XBB.1.5-targeted mRNA-1283.815, its initial market availability would occur at a time when the XBB.1.5 variant is antigenically distant from the then-circulating or recommended target strains, such as KP.2 or the emerging LP.8.1.[14] This scenario underscores the likelihood that Moderna would need to rapidly generate and submit bridging data for an mRNA-1283 backbone adapted to the latest recommended viral strain (e.g., an mRNA-1283.LP.8.1 formulation) to ensure the commercialized product is optimally matched to the prevailing epidemiological situation. Moderna has previously demonstrated its capacity for such rapid adaptation with its mRNA-1273 platform.[11]

Alignment with Global Health Recommendations on Antigen Composition

The selection of appropriate viral antigens for COVID-19 vaccines is a continuous process guided by global surveillance of SARS-CoV-2 evolution.

  • FDA (2024-2025 Season): For the 2024-2025 vaccination season, the FDA advised manufacturers that the preferred JN.1-lineage target for COVID-19 vaccine formulations should be the KP.2 strain, if feasible. Subsequently, updated mRNA vaccines from Moderna (Spikevax) and Pfizer-BioNTech (Comirnaty) targeting the KP.2 strain received approval or emergency use authorization.[14]
  • WHO (May 2025 Statement): Looking ahead, the World Health Organization's Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC), in its May 15, 2025 statement, advised that monovalent JN.1 or KP.2 vaccines remain appropriate antigens for use in upcoming vaccination programs.[15] Significantly, the TAG-CO-VAC also identified monovalent LP.8.1 as a suitable alternative vaccine antigen. This is based on the increasing global proportion of LP.8.1, its antigenic relatedness to JN.1/KP.2 (though with some distinct characteristics), and data indicating that while JN.1 or KP.2 vaccines induce cross-neutralizing antibodies against LP.8.1, these titers may be modestly lower than against the homologous (vaccine-matched) strains.[15]
  • EMA (May 2025 Recommendation for 2025/2026): The European Medicines Agency's Emergency Task Force (ETF), also in May 2025, specifically recommended updating COVID-19 vaccines to target the LP.8.1 variant for the 2025/2026 vaccination campaign, citing its increasing prevalence. The EMA acknowledged that JN.1 or KP.2 targeted vaccines could still be utilized in 2025 until LP.8.1-adapted vaccines become available.[16]

This evolving landscape of recommendations, from XBB.1.5 (relevant for the.815 formulation's Phase 3 trial) to JN.1/KP.2, and now towards LP.8.1, all within approximately a year to eighteen months, exemplifies the rapid pace of SARS-CoV-2 evolution and the challenge it poses for vaccine strain selection and deployment.[14]

Potential Role in Combination Vaccines

mRNA-1283 is positioned as a critical component of Moderna's strategy for developing combination respiratory vaccines. Specifically, it is part of the investigational vaccine mRNA-1083, which aims to provide protection against both seasonal influenza and COVID-19 in a single injection.[1] Moderna has shared positive Phase 3 immunogenicity data for mRNA-1083 in adults aged 50 years and older and has proceeded with regulatory filings for this combination product.[30] The improved stability and lower dose requirement of the mRNA-1283 platform make it an attractive component for such combination vaccines. A lower dose for the COVID-19 component could be advantageous in managing the overall antigen load and reactogenicity profile of a multi-component vaccine, thereby enhancing its tolerability and feasibility for routine use. The success of mRNA-1083 is intrinsically linked to the effectiveness and safety of its constituent parts, including mRNA-1283.

8. Expert Discussion and Insights

Critical Analysis of the Overall Data Package for mRNA-1283.815

The available data for mRNA-1283.815, the XBB.1.5-adapted formulation of Moderna's next-generation COVID-19 vaccine, presents a compelling case for the platform's advancements. The Phase 3 NextCOVE trial data from Japanese participants clearly demonstrate superior immunogenicity against the XBB.1.5 variant when mRNA-1283.815 (10 µg) is compared to the XBB.1.5-adapted Spikevax, mRNA-1273.815 (50 µg).[10] This finding, achieved with a five-fold lower mRNA dose, is a significant validation of the next-generation platform's design and potential for enhanced potency.

The safety profile of mRNA-1283.815 also appears favorable. Data from the same study cohort suggest a trend towards improved reactogenicity, with numerically lower rates of common solicited local and systemic adverse reactions compared to the higher-dose comparator.[10] This is a crucial attribute for vaccine acceptance and adherence.

However, the primary limitation of the current data package for mRNA-1283.815 is the absence of direct human clinical trial results detailing its cross-neutralizing capabilities against more recent and currently dominant SARS-CoV-2 variants, such as JN.1, KP.2, KP.3, and the emerging LP.8.1. While inferences can be drawn from the performance of mRNA-1273.815 (which shares the XBB.1.5 target) [23] and from preclinical studies of the broader mRNA-1283 platform against other variants, these are indirect measures. The unique NTD-RBD antigen design of mRNA-1283 could potentially influence the breadth of the immune response differently than full-length spike antigens, making direct assessment essential.

Evaluation of Strengths and Limitations

Strengths:

  • Superior Immunogenicity against Target Strain: Demonstrated higher neutralizing antibody responses against XBB.1.5 compared to mRNA-1273.815, and achieved this at a significantly lower dose (10 µg vs. 50 µg).[10]
  • Improved Stability: The mRNA-1283 platform is designed for refrigerator stability (2°C to 8°C), offering substantial logistical advantages over vaccines requiring ultra-cold storage.[1]
  • Potential for Pre-filled Syringe Presentation: This can simplify administration and reduce healthcare provider burden.[1]
  • Favorable Safety and Tolerability: Clinical data suggest a safety profile similar to existing mRNA vaccines, with a trend towards lower reactogenicity for the 10 µg dose of mRNA-1283.815 compared to the 50 µg dose of mRNA-1273.815.[10]
  • Strong Platform for Rapid Adaptation: The underlying mRNA technology allows for relatively quick adaptation of the vaccine to new viral variants.

Limitations:

  • Antigenic Mismatch for Current Use: The XBB.1.5 variant targeted by mRNA-1283.815 is no longer the dominant circulating strain globally. Variants like KP.2 and LP.8.1 are now of greater concern.[14]
  • Lack of Direct Cross-Neutralization Data: No direct human clinical data are available from the provided sources on the performance of mRNA-1283.815 against JN.1, KP.2, KP.3, or LP.8.1. Its effectiveness against these strains must be inferred.
  • PDUFA Timeline vs. Viral Evolution: The PDUFA goal date of May 31, 2025, for the mRNA-1283 platform means that any initial approval will likely be for a platform whose specific XBB.1.5 variant data is already outdated relative to circulating strains.

Potential Impact on COVID-19 Pandemic Management

The mRNA-1283 platform holds considerable promise for future COVID-19 pandemic management and endemic control. If its key advantages—dose-sparing immunogenicity, enhanced stability, and favorable tolerability—can be consistently maintained as the vaccine is adapted to new, prevailing SARS-CoV-2 variants, it could become a preferred technology. The improved logistical profile (refrigerator stability, pre-filled syringes) could significantly enhance vaccine accessibility and uptake in diverse global settings, including resource-limited countries. Furthermore, if the lower dose indeed translates to consistently lower reactogenicity, it may improve public acceptance and adherence to recommended vaccination schedules, particularly if frequent (e.g., annual) boosters are required. Its role as a component in combination respiratory vaccines, like mRNA-1083, could also simplify immunization programs.

The success of mRNA-1283 in eliciting higher immune responses with a lower dose, as demonstrated with the.815 formulation against XBB.1.5 [10], may signal a broader shift in mRNA vaccine dosing strategies. This efficiency could potentially extend beyond COVID-19 to other mRNA-based vaccines in development, offering benefits in terms of manufacturing cost, production scalability, and vaccine tolerability. If this dose-sparing efficacy is maintained across different variant adaptations of mRNA-1283, the platform would become highly competitive.

Considerations for Public Health and Future Vaccine Strategies

The development and evaluation of mRNA-1283.815 underscore the dynamic interplay between vaccine innovation and rapid viral evolution. The journey from XBB.1.5 as a target to the current focus on JN.1 descendants and LP.8.1 highlights the continuous need for agile vaccine strategies. Platforms like mRNA-1283, which are amenable to rapid updates, are crucial in this context. However, the inherent time lag between the identification of a new variant of concern, the recommendation for a vaccine update, and the subsequent manufacturing and deployment of the updated vaccine remains a significant operational challenge.

The cross-neutralization data available for the XBB.1.5-targeted mRNA-1273.815 vaccine, showing reduced but still present activity against JN.1 and KP.2 [23], suggest that while updated vaccines are preferable, previous generation vaccines may still offer some level of protection against drifted variants. This reinforces the importance of timely vaccination with currently available recommended vaccines.

The WHO and EMA guidance towards LP.8.1 for the 2025/2026 season [15] clearly directs vaccine manufacturers, including Moderna, to focus their adaptation efforts for the mRNA-1283 platform on this or antigenically similar variants for upcoming vaccination campaigns. The BLA for the mRNA-1283 platform, if approved, will likely serve as a foundational regulatory approval, upon which future variant-adapted versions can be introduced via supplemental applications or established strain change mechanisms.

An important immunological consideration for long-term vaccine strategy, though not directly addressed for mRNA-1283.815 in the provided documents, is the phenomenon of immune imprinting (also known as original antigenic sin). As individuals accumulate diverse immune histories from multiple infections and/or vaccinations with different spike protein versions, the way their immune systems respond to new variant-adapted vaccines can be influenced. The focused NTD-RBD antigen design of mRNA-1283 might interact with this phenomenon in ways that differ from full-length spike vaccines, an area that will warrant ongoing immunological investigation to optimize long-term protection.

9. Conclusions

The mRNA-1283.815 vaccine, Moderna's next-generation candidate targeting the SARS-CoV-2 Omicron XBB.1.5 variant, has demonstrated significant promise in its clinical development program. Key conclusions from the available data are:

  1. Enhanced Immunogenicity at Lower Dose: mRNA-1283.815 (10 µg) elicited statistically significantly higher neutralizing antibody responses against the XBB.1.5 variant compared to mRNA-1273.815 (50 µg) in Phase 3 clinical trial participants.[10] This confirms the dose-sparing potential and enhanced potency of the mRNA-1283 platform against its target strain.
  2. Favorable Safety and Tolerability: The safety profile of mRNA-1283.815 is comparable to existing mRNA vaccines, with data suggesting a trend towards lower reactogenicity at the 10 µg dose compared to the 50 µg dose of its comparator.[10] This could improve vaccine acceptance.
  3. Logistical Advantages: The mRNA-1283 platform is designed for refrigerator stability and potential pre-filled syringe presentation, which would simplify global deployment and administration.[1]
  4. Antigenic Relevance Challenge: While mRNA-1283.815 performed well against XBB.1.5, this variant is no longer predominant. Direct clinical data on the cross-neutralization efficacy of mRNA-1283.815 against currently circulating variants like KP.2, KP.3, and the emerging LP.8.1 are lacking in the provided information. Its performance against these strains must be inferred from related vaccines and preclinical platform data.
  5. Regulatory Path and Future Adaptation: Moderna has filed a BLA for the mRNA-1283 platform with the FDA, with a PDUFA date of May 31, 2025.[2] The ultimate utility of the platform will depend on its rapid and effective adaptation to future SARS-CoV-2 variants as recommended by global health authorities (e.g., LP.8.1 for the 2025/2026 season).
  6. Role in Combination Vaccines: mRNA-1283 is a key component of Moderna's investigational influenza/COVID-19 combination vaccine, mRNA-1083, for which positive Phase 3 data have been reported.[1] The characteristics of mRNA-1283 are well-suited for such combination strategies.

In summary, mRNA-1283 represents a significant advancement in mRNA vaccine technology, offering the potential for improved immunogenicity at lower doses with enhanced logistical features. While the specific.815 (XBB.1.5) formulation's direct applicability is tempered by ongoing viral evolution, the underlying platform has demonstrated strong potential. Its future impact will be contingent on successful adaptation to emerging variants and continued demonstration of safety and efficacy in the evolving COVID-19 landscape. The pending regulatory decision on the platform will be a critical step, likely paving the way for subsequent variant-adapted versions aligned with public health needs.

Works cited

  1. Moderna Achieves Positive Interim Results from Phase 3 Trial of Next-Generation COVID-19 Vaccine, accessed May 16, 2025, https://investors.modernatx.com/news/news-details/2024/Moderna-Achieves-Positive-Interim-Results-from-Phase-3-Trial-of-Next-Generation-COVID-19-Vaccine/default.aspx
  2. mRNA 1283 - AdisInsight, accessed May 16, 2025, https://adis.springer.com/drugs/800062563?userId=53596662&bpIds=3001514672&checksum=7f5382b6636efba9a435b21d331673acf5d5c815-1616504051656-7b7fb43f36e5f45c694e931b9ad0a15fe990ceb1c744afeb2d18dc4086fd29d4e7e2023afcee3d3d2167c4808a7750acb28447bacaa6580f4c419dc370db77e4
  3. mRNA-1283 - Drug Targets, Indications, Patents - Patsnap Synapse, accessed May 16, 2025, https://synapse.patsnap.com/drug/ba0c7c5c00094ef9adc742541179df26
  4. Interim analysis of a phase 1 randomized clinical trial on the safety and immunogenicity of the mRNA-1283 SARS-CoV-2 vaccine in adults - PubMed Central, accessed May 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10128428/
  5. Safety and Immunogenicity of SARS-CoV-2 Spike Receptor-Binding Domain and N-Terminal Domain mRNA Vaccine | The Journal of Infectious Diseases | Oxford Academic, accessed May 16, 2025, https://academic.oup.com/jid/article/231/4/e754/7951371
  6. Full article: Indirect comparison of the relative vaccine effectiveness ..., accessed May 16, 2025, https://www.tandfonline.com/doi/full/10.1080/03007995.2025.2466726?src=
  7. Moderna Expands the Field of mRNA Medicine with Positive Clinical Results Across Cancer, Rare Disease, and Infectious Disease, accessed May 16, 2025, https://investors.modernatx.com/news/news-details/2023/Moderna-Expands-the-Field-of-mRNA-Medicine-with-Positive-Clinical-Results-Across-Cancer-Rare-Disease-and-Infectious-Disease/default.aspx
  8. Phase III NextCOVE Trial Data Show Efficacy of Moderna's Next-Generation COVID-19 Vaccine, accessed May 16, 2025, https://www.appliedclinicaltrialsonline.com/view/phase-iii-nextcove-trial-data-show-efficacy-of-moderna-s-next-generation-covid-19-vaccine
  9. NextCove mRNA Covid Vax-12 and Up - Research Your Health, accessed May 16, 2025, https://www.researchyourhealth.com/nextcove-mrna-covid-vax-12-and-up.html
  10. s29.q4cdn.com, accessed May 16, 2025, https://s29.q4cdn.com/435878511/files/doc_presentations/2025/Apr/14/COVID-Poster-P301-Japan-Data-Poster-30.pdf
  11. mRNA-1273 vaccines adapted to JN.1 or KP.2 elicit cross-neutralizing responses against the JN.1 sublineages of SARS-CoV-2 in mice - PubMed, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/40056804/
  12. A Study of mRNA-1283 Injection Compared With mRNA-1273 ..., accessed May 16, 2025, https://www.ngram.com/trials/NCT05815498
  13. Safety and Immunogenicity of XBB.1.5-Containing mRNA Vaccines - medRxiv, accessed May 16, 2025, https://www.medrxiv.org/content/10.1101/2023.08.22.23293434v2
  14. FDA Approves and Authorizes Updated mRNA COVID-19 Vaccines to Better Protect Against Currently Circulating Variants, accessed May 16, 2025, https://www.fda.gov/news-events/press-announcements/fda-approves-and-authorizes-updated-mrna-covid-19-vaccines-better-protect-against-currently
  15. Statement on the antigen composition of COVID-19 vaccines, accessed May 16, 2025, https://www.who.int/news/item/23-12-2024-statement-on-the-antigen-composition-of-covid-19-vaccines
  16. ETF recommends updating COVID-19 vaccines to target new LP.8.1 ..., accessed May 16, 2025, https://www.ema.europa.eu/en/news/etf-recommends-updating-covid-19-vaccines-target-new-lp81-variant
  17. Statement on the antigen composition of COVID-19 vaccines, accessed May 16, 2025, https://www.who.int/news/item/15-05-2025-statement-on-the-antigen-composition-of-covid-19-vaccines
  18. Moderna Announces Positive Phase 3 Efficacy Data for mRNA-1283 ..., accessed May 16, 2025, https://investors.modernatx.com/news/news-details/2024/Moderna-Announces-Positive-Phase-3-Efficacy-Data-for-mRNA-1283-the-Companys-Next-Generation-COVID-19-Vaccine/default.aspx
  19. Investigational COVID-19 Vaccine Shows Non-Inferior Efficacy vs. Spikevax in Phase III Trial, accessed May 16, 2025, https://www.appliedclinicaltrialsonline.com/view/moderna-covid19-vaccine-efficacy-spikevax-trial
  20. Advances in mRNA-Based Cancer Vaccines - PMC, accessed May 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10611059/
  21. Therapeutic Glossary | mRNA-1283 - NIH NCATS - OpenData Portal, accessed May 16, 2025, https://opendata.ncats.nih.gov/covid19/therapeutic-glossary/VGhlcmFwZXV0aWNHbG9zc2FyeTozNjE3
  22. Interim analysis of a phase 1 randomized clinical trial on the safety and immunogenicity of the mRNA-1283 SARS-CoV-2 vaccine in adults - PubMed, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/37074202/
  23. www.fda.gov, accessed May 16, 2025, https://www.fda.gov/media/179142/download
  24. Safety and Immunogenicity of SARS-CoV-2 Spike Receptor-Binding Domain and N-Terminal Domain mRNA Vaccine - PubMed, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/39792478/
  25. mRNA Vaccines Comparison for COVID-19 Prevention · Phase 3 · 2025 Trial | Power, accessed May 16, 2025, https://sites.withpower.com/trial/phase-3-covid-19-2-2023-c947d
  26. Immunogenicity of JN.1- and KP.2-Encoding mRNA COVID-19 Vaccines Against JN.1 Subvariants in Adult Participants | medRxiv, accessed May 16, 2025, https://www.medrxiv.org/content/10.1101/2025.05.02.25325954v1
  27. (PDF) Immunogenicity of JN.1- and KP.2-Encoding mRNA COVID-19 Vaccines Against 1 JN.1 Subvariants in Adult Participants - ResearchGate, accessed May 16, 2025, https://www.researchgate.net/publication/391519079_Immunogenicity_of_JN1-_and_KP2-Encoding_mRNA_COVID-19_Vaccines_Against_1_JN1_Subvariants_in_Adult_Participants
  28. Immunogenicity of JN.1- and KP.2-Encoding mRNA COVID-19 Vaccines Against JN.1 Subvariants in Adult Participants | medRxiv, accessed May 16, 2025, https://www.medrxiv.org/content/10.1101/2025.05.02.25325954v1.full
  29. Press release issued by Moderna, Inc. dated January 13, 2025 - SEC.gov, accessed May 16, 2025, https://www.sec.gov/Archives/edgar/data/1682852/000168285225000002/exhibit991-01132025.htm
  30. Moderna Provides Business and Pipeline Updates at 43rd Annual J.P. Morgan Healthcare Conference, accessed May 16, 2025, https://investors.modernatx.com/news/news-details/2025/Moderna-Provides-Business-and-Pipeline-Updates-at-43rd-Annual-J.P.-Morgan-Healthcare-Conference/default.aspx
  31. Moderna Reports First Quarter 2025 Financial Results and Provides Business Updates, accessed May 16, 2025, https://investors.modernatx.com/news/news-details/2025/Moderna-Reports-First-Quarter-2025-Financial-Results-and-Provides-Business-Updates/default.aspx
  32. Types of data requested to inform May 2025 COVID-19 vaccine antigen composition deliberations - World Health Organization (WHO), accessed May 16, 2025, https://www.who.int/news/item/25-03-2025-types-of-data-requested-to-inform-may-2025-covid-19-vaccine-antigen-composition-deliberations

Published at: May 16, 2025

This report is continuously updated as new research emerges.

© Copyright 2025. All Rights Reserved by MedPath
HomeTerms & ConditionsPrivacy Policy