How do updated formulations (variants of concern) affect the mechanism of Elasomeran?

Abstract

Updated mRNA-1273 formulations targeting SARS-CoV-2 variants of concern alter the immune response mechanism through differential neutralizing antibody profiles while maintaining the platform’s core immunological pathways. Monovalent variant-specific vaccines (mRNA-1273.351 targeting B.1.351, mRNA-1273.529 targeting BA.1) demonstrated superior neutralizing antibody responses against their target variants, with geometric mean ratios of 1.67-1.77 for BA.1 formulations and twofold improvements for B.1.351 formulations, but showed reduced cross-reactivity against ancestral strains with fourfold lower neutralization against WA1/2020 D614G. Bivalent formulations (mRNA-1273.211, mRNA-1273.214) balanced this trade-off by maintaining or improving ancestral strain neutralization (GMR 1.11 against D614G for BA.1-bivalent) while achieving GMT ratios ≥1 against all variants of concern tested. All updated formulations induced robust anamnestic B cell memory responses when used as boosters, with variant-modified boosters showing 34.9-61.6 fold increases in neutralization against target variants, restoring immunity that had waned 6-7 fold against wild-type and 24-69 fold against variants over 6 months. Cellular immune mechanisms, including CD4+ and CD8+ T cell responses measured in preclinical models, showed similar activation patterns to the original vaccine, with effector T cell expansion but not effector-memory phenotypes and waning within 6 months. However, longitudinal studies revealed progressive viral escape from updated vaccine-induced immunity, with newer variants continuing to evade even XBB.1.5-updated formulations, indicating that antigenic drift outpaces the vaccine update cycle despite mechanistic improvements in neutralizing breadth and depth.

Methods

We analyzed 10 sources from an initial pool of 200, using 8 screening criteria. Each paper was reviewed for 8 key aspects that mattered most to the research question. More on methods.

Paper search

We performed a semantic search across over 138 million academic papers from the Elicit search engine, which includes all of Semantic Scholar and OpenAlex.

We ran this query: "How do updated formulations (variants of concern) affect the mechanism of Elasomeran?"

The search returned 200 total results from Elicit.

Screening

We screened in sources based on their abstracts that met these criteria:

• Vaccine Type and Formulation: Does this study investigate Elasomeran (mRNA-1273, Moderna COVID-19 vaccine) updated formulations specifically designed to target SARS-CoV-2 variants of concern (Alpha, Beta, Gamma, Delta, Omicron, or subsequent WHO-designated variants)?
• Mechanistic Outcomes: Does this study report mechanistic outcomes including immunogenicity, antibody responses, T-cell responses, vaccine efficacy, or molecular mechanisms of action?
• Comparative or Descriptive Data: Does this study provide comparative data between updated formulations and original formulations, other updated formulations, or descriptive mechanistic data on updated formulations?
• Study Design: Is this study a randomized controlled trial, cohort study, case-control study, cross-sectional study, in vitro study, animal study, systematic review, or meta-analysis?
• Updated Formulation Focus: Does this study investigate updated variant formulations (rather than focusing solely on the original Elasomeran formulation without investigation of updated variants)?
• Elasomeran Relevance: Does this study investigate Elasomeran or include comparison to Elasomeran (rather than focusing solely on other COVID-19 vaccines like Pfizer-BioNTech, Johnson & Johnson, or AstraZeneca without Elasomeran investigation)?
• Mechanistic Data Inclusion: Does this study include mechanistic investigation (rather than reporting only safety, adverse events, epidemiological outcomes, or logistical data without mechanistic components)?
• Study Rigor: Is this study a full research article with adequate detail (rather than a case report, case series, editorial, commentary, or conference abstract)?

Results

Characteristics of Included Studies

The systematic review identified 10 sources examining updated mRNA-1273 (Elasomeran) formulations targeting SARS-CoV-2 variants of concern. Full texts were available for 6 studies, while 4 were available as abstracts only.

The studies examined three main categories of updated formulations: monovalent variant-specific vaccines (mRNA-1273.351 targeting B.1.351, mRNA-1273.529 targeting BA.1, XBB.1.5 booster), bivalent original+variant vaccines (mRNA-1273.211 combining original and B.1.351, mRNA-1273.214 combining original and BA.1), and later-generation bivalent vaccines targeting Omicron BA.4-5 subvariants. The dose for clinical formulations was consistently 50 μg, while preclinical studies used high doses (5 μg) and low doses (0.25 μg) to model varying immune responses.

Immunological Mechanisms Assessed

Studies evaluated multiple immunological mechanisms to characterize how updated formulations affect the immune response to SARS-CoV-2 variants.

Neutralizing antibody responses were the primary mechanism assessed across all studies. Clinical trials used pseudovirus neutralization assays, while preclinical studies employed live virus FRNT methods. The clinical studies by A. Choi et al. validated their neutralization assays against both lentivirus-based and VSV-based pseudovirus systems. Cellular immune responses were characterized primarily in preclinical models, with CD8+ and CD4+ T cell responses measured through peptide stimulation and interferon-γ production. Human studies noted the presence of S-specific CD4 and CD8 T cells, with expansion of effector T cells but not effector-memory phenotypes. B cell memory was inferred from anamnestic responses to booster doses in clinical trials.

Variant Testing Panels

Updated formulations were tested against comprehensive panels of SARS-CoV-2 variants to assess both homologous and cross-reactive immune responses.

All studies tested cross-reactive immunity beyond the homologous variant targeted by each updated formulation. The most challenging variant across studies was B.1.351 (Beta), which showed the greatest resistance to neutralization by both original and updated formulations. Studies testing B.1.617.2 (Delta) consistently found lower neutralizing titers against this variant compared to ancestral strains. The comprehensive panel tested by A. Roederer et al. included 131 individual mutations across 48 named variants, revealing progressive viral escape from vaccine-induced immunity over time.

Effects of Updated Formulations on Neutralizing Antibody Responses

Superiority Against Homologous Variants

Updated formulations demonstrated superior neutralizing antibody responses against their target variants compared to the original mRNA-1273 vaccine.

The BA.1-containing boosters showed 67-77% higher neutralizing antibody titers against Omicron BA.1 compared to the original vaccine at 3 months post-booster. For B.1.351-targeted formulations, the variant-specific mRNA-1273.351 vaccine induced 35-fold increases in neutralization titers post-boost, with geometric mean titers approximately twofold higher than the original vaccine. The bivalent mRNA-1273.211 formulation showed particularly strong responses, with a 61.6-fold increase in neutralization against B.1.351.

Cross-Variant Protection

Updated formulations maintained varying levels of cross-protection against non-target variants.

The bivalent formulations demonstrated the most balanced cross-variant protection. The BA.1-bivalent vaccine showed slight improvement over the original vaccine against the ancestral D614G strain (GMR 1.11), while the BA.1-monovalent showed a modest 20% reduction (GMR 0.80), both meeting non-inferiority criteria. The B.1.351-targeted monovalent vaccine (mRNA-1273.351) showed a trade-off, with fourfold lower neutralization against ancestral strains but twofold higher neutralization against B.1.351. In contrast, the bivalent mRNA-1273.211 formulation achieved broad cross-variant neutralization with GMT ratios ≥1 against all variants of concern tested and showed a 46.4-fold increase against the wild-type D614G virus.

Booster Effects on Waning Immunity

Booster doses with updated formulations restored and enhanced neutralizing antibody titers that had declined over time.

Prior to booster administration, neutralizing antibodies against variants had waned substantially from peak levels observed one month after the primary series. Neutralization titers against B.1.351, P.1, and B.1.617.2 were either low or undetectable at approximately 6 months post-primary vaccination. Both original and variant-modified boosters induced anamnestic responses indicative of robust B cell memory, with post-booster titers reaching or exceeding peak titers measured after the primary series. Two weeks after booster vaccination, neutralization titers increased to levels similar to or higher than peak titers after primary vaccination for both wild-type and variant viruses.

Effects on Cellular Immune Responses

Preclinical studies characterized T cell responses to updated formulations, while clinical data on cellular immunity were limited.

Both original and updated mRNA formulations induced CD4+ and CD8+ T cell responses that were detectable in preclinical models. However, clinical observations indicated that mRNA vaccines activate S-specific CD4 and CD8 T cells but do not expand effector-memory phenotypes, a limitation that appears consistent across formulations. T cell responses generally waned within 6 months post-vaccination, though T cells with stem cell memory phenotypes could potentially persist longer. The inflammatory signature remained similar between original and updated formulations, with elevated IL-17 concentrations observed across mRNA vaccines.

Durability of Immune Mechanisms

The persistence of immune responses varied by formulation type and dose level.

The BA.1-containing boosters maintained superior neutralizing antibody responses against Omicron BA.1 compared to the original vaccine through 3 months post-booster. With the original mRNA-1273 vaccine, neutralizing antibody titers showed a 6-7 fold decrease against wild-type D614G and a more dramatic 24-69 fold decrease against B.1.351 and P.1 variants over 6 months following the primary series. The rate of waning was particularly pronounced for the B.1.351 variant, with neutralizing antibodies dropping considerably by 6 months. Peak antibody responses occurred at 4 weeks post-vaccination for original formulations and remained detectable up to 6 months, albeit at reduced levels.

Updated formulations showed improved persistence against their target variants. The XBB.1.5 booster demonstrated better maintenance of neutralization against newer variants compared to original formulations, with the first booster administered 8-9 months after primary vaccination and the second booster 4-6 months later. However, neutralization activity declined over time even with updated boosters, particularly against emerging variants like JN.1.

Protection Against Breakthrough Infections

Data on breakthrough infection rates with updated formulations compared to original vaccines were limited, with most studies focusing on immunogenicity rather than clinical outcomes.

Preclinical studies revealed that breakthrough infections occurred primarily with the B.1.617.2 (Delta) variant, particularly when using low-dose vaccine formulations designed to model suboptimal immune responses. These breakthrough infections led to viral pneumonia with inflammation and airspace consolidation in K18-hACE2 mice. The effectiveness of variant-specific vaccines appeared superior against homologous strains, with updated formulations inducing greater antibody responses and conferring more protection against their target variants. Updated bivalent vaccines targeting Omicron variants offered increased protection against new Omicron subvariants compared to monovalent vaccines, though the original vaccines showed a significant decrease in protection against Omicron variants, with efficacy dropping to 30% after three doses.

Synthesis

The findings reveal systematic patterns in how updated mRNA-1273 formulations alter immunological mechanisms, with heterogeneity explained by specific variant targets, formulation strategy (monovalent vs bivalent), and the evolutionary timing of SARS-CoV-2 variants tested.

Variant-Specific vs Broad Protection Trade-offs

Monovalent variant-specific vaccines (mRNA-1273.351, mRNA-1273.529) consistently showed superior neutralization against their target variants—with geometric mean ratio increases of 1.67-1.77 for BA.1 formulations and twofold improvements for B.1.351 formulations—but demonstrated reduced neutralization against ancestral strains, with fourfold lower geometric mean titers against WA1/2020 D614G. This pattern reflects the antigenic distance between variant spike proteins and the immunodominant epitopes recognized by vaccine-induced antibodies. In contrast, bivalent formulations (mRNA-1273.211, mRNA-1273.214) maintained or improved ancestral strain neutralization while still boosting variant-specific responses. The BA.1-bivalent vaccine achieved a GMR of 1.11 against D614G, and mRNA-1273.211 showed a 46.4-fold increase against wild-type virus with GMT ratios ≥1 against all variants of concern. This breadth advantage comes at a modest cost: bivalent vaccines showed slightly lower peak titers against target variants (GMR 1.67) compared to monovalent formulations (GMR 1.77) for BA.1, suggesting antigenic competition or epitope masking when both ancestral and variant spike proteins are co-delivered.

Dose-Dependent Breakthrough Risk

The preclinical studies using high (5 μg) versus low (0.25 μg) doses revealed a critical threshold effect for protection. High-dose formulations of all vaccines—whether original mRNA-1273, variant-specific mRNA-1273.351, or bivalent mRNA-1273.211—conferred protection against weight loss and lung pathology across all tested variants including B.1.617.2 (Delta). However, low-dose formulations showed breakthrough lung infections and pneumonia specifically with B.1.617.2 in K18-hACE2 mice, despite producing approximately tenfold lower neutralizing activity. Notably, a minimum neutralizing titer of approximately 5000 was required to prevent lung infection, and low-dose vaccines fell below this threshold for certain variants. This dose-response relationship suggests that as immunity wanes over time in vaccinated populations—mimicking the reduced magnitude seen with low-dose vaccination—breakthrough infections become more likely, particularly with antigenically distant variants like B.1.617.2 that showed four-to-fivefold lower neutralizing responses across all vaccine types. The clinical relevance is supported by the observation that neutralizing antibodies declined 6-7 fold against D614G and 24-69 fold against B.1.351 and P.1 over 6 months following primary vaccination, potentially dropping below protective thresholds for some individuals and variants.

Temporal Evolution and Escape Dynamics

The longitudinal analysis across 2020-2024 revealed progressive viral escape from both original and updated vaccine-induced immunity. While many individual mutations emerging between 2020-2022 escaped sera from primary vaccination, few escaped boosted sera. However, newer variants demonstrated progressive loss of neutralization regardless of vaccine doses received. The bivalent booster improved neutralization against contemporaneous strains but not against JN.1, and the XBB.1.5 booster significantly increased titers against newer variants except JN.1. This pattern cannot be explained by simple waning immunity, as participants received up to 6 mRNA vaccines including updated formulations. Instead, the data suggest that SARS-CoV-2 evolution is outpacing vaccine updates. Each seasonal booster improves titers against contemporaneous strains, but novel variants continue to evade updated mRNA vaccines, demonstrating that antigenic drift occurs faster than the vaccine development-deployment cycle. The mechanistic basis likely involves progressive accumulation of mutations in immunodominant epitopes: the comprehensive testing panel of 131 mutations across 48 variants showed that newer variants like JN.1 carry combinations of mutations that collectively confer escape, even from updated boosters targeting XBB.1.5.

Booster-Mediated Memory Recall

The ability of updated formulation boosters to rescue waning immunity provides insight into B cell memory mechanisms. Six to eight months after primary vaccination, neutralizing antibodies against variants like B.1.351 and P.1 were low or undetectable. However, booster doses—whether with original mRNA-1273 or variant-modified formulations—increased neutralization titers to levels similar to or higher than peak titers after primary vaccination within two weeks, with statistically significant increases observed for mRNA-1273 and mRNA-1273.211 (P<0.0001). Importantly, the original mRNA-1273 booster induced a 16.7-fold increase against wild-type D614G, demonstrating robust homologous recall, while variant-modified boosters showed particularly strong responses: mRNA-1273.351 induced a 34.9-fold increase against B.1.351 and mRNA-1273.211 showed a 61.6-fold increase. These anamnestic responses indicative of robust B cell memory suggest that memory B cells formed during primary vaccination can be reactivated by booster antigens, even when those antigens differ antigenically from the priming strain. The magnitude of the response (up to 61.6-fold) implies affinity maturation and clonal expansion of memory cells, with cross-reactive memory B cells responding to shared epitopes between variants. This mechanism explains why both homologous and heterologous boosters effectively restore immunity, though variant-matched boosters achieve higher peak titers against their specific targets through preferential activation of variant-specific clones.