Elicit: Impact of Variants on Elasomeran Mechanism

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Impact of Variants on Elasomeran Mechanism

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May 5, 2026

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

Updated mRNA-1273 formulations shift the neutralizing antibody response toward enhanced variant-specific recognition while maintaining the core B cell memory and T cell activation mechanisms of the original vaccine platform, with bivalent versions balancing variant-targeted depth against cross-reactive breadth.

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

Records from Elicit search

n = 200

Papers screened using: Vaccine Type and Formulation, Mechanistic Outcomes, Comparative or Descriptive Data, Study Design, Updated Formulation Focus, Elasomeran Relevance, Mechanistic Data Inclusion, Study Rigor

n = 200

Papers screened out

n = 190

Papers included for extraction

n = 10

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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.

We retrieved 200 papers most relevant to the query for screening.

Screening

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

We considered all screening questions together and made a holistic judgement about whether to screen in each paper.

Data extraction

We asked a large language model to extract each data column below from each paper. We gave the model the extraction instructions shown below for each column.

Extract details about the updated mRNA vaccine formulation studied that targets variants of concern, including:

Extract all immunological mechanisms measured to assess how the updated formulation works, including:

Extract which SARS-CoV-2 variants the immune mechanisms were tested against, including:

Extract quantitative comparisons of immune mechanisms between original mRNA-1273 and updated formulations, including:

Extract vaccination context that could affect immune mechanisms, including:

Extract data on breakthrough infections and protection specifically related to updated formulations vs original, including:

Extract population characteristics that could affect immune mechanisms with updated formulations, including:

Extract data on how long the immune mechanisms persist with updated formulations compared to original, including:

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.

Study

Full text retrieved?

Updated formulation(s)

Study type

Population

Primary focus

Ivan T Lee et al., 2023

No

BA.1-monovalent (mRNA-1273.529), BA.1-bivalent (mRNA-1273.214)

Phase 3 RCT

Adults ≥16 years, UK

3-month safety and immunogenicity of BA.1-containing boosters

Kai Wu et al., 2021

No

mRNA-1273.351, mRNA-1273.211

Preclinical (mice)

Mice

Variant vaccine neutralization as primary or booster series

A. Choi et al., 2021

Yes

mRNA-1273.351, mRNA-1273.211

Phase 2a clinical trial

Healthy adults (mean ages 47.5-63.8 years), US

Safety and immunogenicity of variant-modified boosters

K. Wu et al., 2021

Yes

mRNA-1273.351, mRNA-1273.211

Phase 2 clinical trial

Adults ≥18 years, US

Preliminary safety and immunogenicity of variant vaccine booster

M. Koch et al., 2021

No

mRNA-1273.351, mRNA-1273.211

Preclinical (mice)

Mice

Variant vaccine neutralization and cross-protection

Baoling Ying et al., 2021

Yes

mRNA-1273.351, mRNA-1273.211

Preclinical (mice)

129S2 and K18-hACE2 mice

Protective activity against ancestral and variant strains

Baoling Ying et al., 2021a

Yes

mRNA-1273.351

Preclinical (mice)

129S2 and K18-hACE2 mice

Protection against variants with suboptimal immunity

M. Echaide et al., 2023

Yes

Bivalent vaccines (Comirnaty, Spikevax) targeting BA.4-5 Omicron

Review

Multiple populations including elderly, pediatric, immunocompromised

Advantages and limitations of mRNA vaccines against variants

A. Roederer et al., 2024

Yes

XBB.1.5 monovalent booster

Prospective cohort

Adults (median 33) and elderly (median 72), COVID-naive

Evolution of viral escape from vaccine immunity

A. Pegu et al., 2021

No

None (durability study of original mRNA-1273)

Clinical immunogenicity study

Vaccine recipients

Durability of antibodies against variants

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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.

Mechanism type

Measurement methods

Studies assessing

Neutralizing antibodies

Pseudovirus neutralization assays (lentivirus-based, VSV-based); live virus focus-reduction neutralization test (FRNT)

All clinical and preclinical studies

Binding antibodies

ELISA measuring IgG against recombinant spike proteins

Preclinical studies

CD8+ T cell responses

H-2b-restricted immunodominant peptides, IFN-γ production

Preclinical studies

CD4+ T cell responses

H-2b-restricted immunodominant peptides, IFN-γ production; S-specific CD4 T cells

Preclinical studies and review

B cell memory

Anamnestic response to boosting

Clinical booster studies

Durability

Persistence at Day 29 and Month 3; up to 6 months post-vaccination

Clinical studies

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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.

Study

Ancestral strain

Variants of concern tested

Variant formulation designed for

Cross-reactivity assessed

Ivan T Lee et al., 2023

D614G

BA.1 Omicron

BA.1

Yes (D614G)

Kai Wu et al., 2021

Wild-type

B.1.351 (Beta)

B.1.351

Yes (broad cross-variant)

A. Choi et al., 2021

D614G

B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta)

B.1.351

Yes (multiple VOCs)

K. Wu et al., 2021

Wild-type

B.1.351, P.1

B.1.351

Yes (P.1)

M. Koch et al., 2021

Wild-type

B.1.351 (Beta)

B.1.351

Yes (broad)

Baoling Ying et al., 2021

WA1/2020 D614G

B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta)

B.1.351

Yes (multiple)

Baoling Ying et al., 2021a

WA1/2020 D614G, D614G/N501Y

B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta)

B.1.351

Yes (multiple)

M. Echaide et al., 2023

D614G

B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), B.1.1.529 (Omicron)

BA.4-5 Omicron

Yes (multiple)

A. Roederer et al., 2024

Wuhan-Hu-1, D614G, WA1/2020

Beta (K417N/E484K/N501Y), Gamma, Delta (L452R/P681R), Omicron (BA.5, BQ.1.1, JN.1)

XBB.1.5

Yes (comprehensive panel)

A. Pegu et al., 2021

Not mentioned

B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.429 (Epsilon), B.1.526 (Iota), B.1.617.2 (Delta)

None (original vaccine)

Yes (multiple VOCs)

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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.

Study

Updated formulation

Target variant

Comparison to original mRNA-1273

GMR or fold-change

Statistical significance

Ivan T Lee et al., 2023

BA.1-monovalent

BA.1 Omicron

Superior at Month 3

GMR 1.77 (96% CI 1.55-2.02)

Yes

Ivan T Lee et al., 2023

BA.1-bivalent

BA.1 Omicron

Superior at Month 3

GMR 1.67 (96% CI 1.54-1.81)

Yes

A. Choi et al., 2021

mRNA-1273.351 (50 μg)

B.1.351

Numerically greater titers

34.9-fold increase

Not confirmed

A. Choi et al., 2021

mRNA-1273.211 (50 μg)

B.1.351

Numerically greater titers

61.6-fold increase

P<0.0001

K. Wu et al., 2021

mRNA-1273.351

B.1.351

Superior neutralization

1400 vs 864 ID50 GMT

35-fold increase

Baoling Ying et al., 2021

mRNA-1273.351

B.1.351

Twofold higher GMTs

Twofold vs mRNA-1273

Superiority noted

Baoling Ying et al., 2021a

mRNA-1273.351

B.1.351

Twofold higher GMTs

Twofold vs mRNA-1273

Superior against B.1.351

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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.

Formulation

Ancestral strain response

Non-target variant responses

Direction of effect

BA.1-monovalent

GMR 0.80 (95% CI 0.71-0.90) vs D614G

Non-inferior against D614G

Maintained

BA.1-bivalent

GMR 1.11 (96% CI 1.03-1.18) vs D614G

Non-inferior against D614G

Slightly improved

mRNA-1273.351

Fourfold lower GMTs vs WA1/2020 D614G

Lower against historical strains

Trade-off

mRNA-1273

Better against WA1/2020

Less reduction vs B.1.351

Broader baseline

mRNA-1273.211

46.4-fold increase vs D614G

GMT ratio ≥1 against all VOCs/VOIs

Broadest protection

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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.

Study

Pre-booster titers

Post-booster titers

Magnitude of increase

Timing

A. Choi et al., 2021

Waned significantly vs peak at Month 1

mRNA-1273: 16.7-fold vs D614G

Significant (P<0.0001)

~6 months post-primary

A. Choi et al., 2021

Low/undetectable vs B.1.351, P.1, B.1.617.2

mRNA-1273.211: 61.6-fold vs B.1.351

Significant (P<0.0001)

~6 months post-primary

K. Wu et al., 2021

Low/below quantification 6-8 months post-primary

Similar to or higher than peak post-primary at 2 weeks post-boost

Robust memory response

2 weeks post-boost

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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.

Mechanism

Findings with updated formulations

Comparison to original

CD8+ T cells

Responses measured via H-2b peptides and IFN-γ production

Not directly compared

CD4+ T cells

Responses measured via H-2b peptides and IFN-γ production

Not directly compared

Effector T cells

Expansion observed with mRNA vaccines

Similar to original

Effector-memory T cells

Not expanded by mRNA vaccines

Limitation of platform

T cell durability

Generally lost 6 months post-vaccination

Similar to original

IL-17 production

Elevated concentrations indicating inflammatory response

Shared mechanism

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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.

Study

Formulation

Time point assessed

Neutralizing antibody persistence

Comparison to peak

Ivan T Lee et al., 2023

BA.1-monovalent, BA.1-bivalent

Month 3 post-booster

Superior vs mRNA-1273 against BA.1

Maintained superiority

A. Choi et al., 2021

Original mRNA-1273

6 months post-primary

6-7 fold decrease vs D614G; 24-69 fold decrease vs B.1.351/P.1

Peak at Month 1

K. Wu et al., 2021

mRNA-1273.351

6-8 months post-primary

Low/undetectable before boost

Waning evident

A. Roederer et al., 2024

XBB.1.5 booster

After multiple doses

Improved persistence vs original

Better against newer variants

M. Echaide et al., 2023

Original formulations

Up to 6 months

Detectable but decreased

Peak at 4 weeks

A. Pegu et al., 2021

Original mRNA-1273

6 months

Persisted but B.1.351 dropped considerably

Variant-specific waning

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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.

Aspect

Findings

Study population

B.1.617.2 breakthrough

Higher rates with low-dose formulations

K18-hACE2 mice

Disease severity

Viral pneumonia with inflammation in breakthrough cases

Preclinical models

Dose-response relationship

Low-dose (0.25 μg) showed breakthroughs vs high-dose (5 μg)

129S2 and K18-hACE2 mice

Variant-specific protection

Updated formulations offered better protection vs homologous strains

Preclinical models

Omicron protection

Updated bivalent vaccines increased protection vs monovalent

Clinical populations

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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.

References

A. Pegu, S. O'connell, S. Schmidt, S. O'Dell, C. A. Talana, and 27 more\ (2021).Durability of mRNA-1273 vaccine–induced antibodies against SARS-CoV-2 variants. Science

Kai Wu, A. Choi, M. Koch, Sayda M. Elbashir, LingZhi Ma, and 20 more\ (2021).Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice. bioRxiv

A. Choi, M. Koch, Kai Wu, L. Chu, LingZhi Ma, and 17 more\ (2021).Safety and immunogenicity of SARS-CoV-2 variant mRNA vaccine boosters in healthy adults: an interim analysis. Nature Medicine

M. Echaide, Luisa Chocarro de Erauso, A. Bocanegra, E. Blanco, G. Kochan, and 1 more\ (2023).mRNA Vaccines against SARS-CoV-2: Advantages and Caveats. International Journal of Molecular Sciences

K. Wu, A. Choi, M. Koch, L. Ma, A. Hill, and 15 more\ (2021).Preliminary Analysis of Safety and Immunogenicity of a SARS-CoV-2 Variant Vaccine Booster. medRxiv

M. Koch, Sayda M. Elbashir, Angela Woods, C. Henry, Charis Palandjian, and 14 more\ (2021).Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice. Vaccine

Baoling Ying, Bradley M. Whitener, L. VanBlargan, Ahmed O. Hassan, S. Shrihari, and 15 more\ (2021).Protective activity of mRNA vaccines against ancestral and variant SARS-CoV-2 strains. Science Translational Medicine

A. Roederer, Yi Cao, K. S. Denis, M. Sheehan, Chia Jung Li, and 8 more\ (2024).Ongoing evolution of SARS-CoV-2 drives escape from mRNA vaccine-induced humoral immunity. medRxiv

Baoling Ying, Bradley M. Whitener, L. VanBlargan, Ahmed O. Hassan, S. Shrihari, and 15 more\ (2021).Protective activity of mRNA vaccines against ancestral and variant SARS-CoV-2 strains. bioRxiv

Ivan T Lee, Catherine A Cosgrove, P. Moore, M. Bula, Philip A. Kalra, and 23 more\ (2023).2363. Three-Month Safety and Immunogenicity of Bivalent SARS-CoV-2 Omicron-Containing Booster Vaccines: Interim Results From a Phase 3, Randomized, Observer-Blind, Active-Controlled Trial. Open Forum Infectious Diseases

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Safety and immunogenicity of SARS-CoV-2 variant mRNA vaccine boosters in healthy adults: an interim analysis

A. Choi, M. Koch, Kai Wu, L. Chu, LingZhi Ma, A. Hill, N. Nunna, Wenmei Huang, J. Oestreicher, T. Colpitts, H. Bennett, H. Legault, Y. Paila, B. Nestorova, B. Ding, D. Montefiori, R. Pajon, Jacqueline M. Miller, B. Leav, A. Carfi, R. McPhee, D. Edwards

Nature Medicine·

2021·

330 citations

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Updated Formulation

- Specific vaccine name/code: mRNA-1273.351, mRNA-1273.211 - Variant(s) targeted: B.1.351 (Beta) - Type of formulation: mRNA-1273.351 is monovalent variant-specific; mRNA-1273.211 is multivalent - Dose amount: 50 μg for both mRNA-1273.351 and mRNA-1273.211 - Difference from original mRNA-1273: Targets variants of concern, specifically B.1.351 for mRNA-1273.351 and includes both original strain and B.1.351 variant for mRNA-1273.211

Immunological Mechanisms

- Neutralizing antibody responses: Measured using clinically validated lentivirus-based PsVN assay and research-grade VSV-based PsVN assay. - Binding antibody responses: Not mentioned. - T-cell responses: Not mentioned. - Cellular immune responses: Anamnestic response indicative of robust B cell memory response. - Durability measures: Increased neutralizing antibody titers over time. - Mechanistic pathway analysis: Not mentioned.

Variant Testing Panel

- Ancestral/original strain: Wild-type D614G virus - Specific variants of concern tested: B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta) - Nomenclature used: WHO names and Pango lineages - Testing was done against the variant the updated formulation was designed for vs other variants (cross-reactivity)

Comparative Mechanism Results

- Geometric mean titers/ratios with confidence intervals: - mRNA-1273 (50 µg): 16.7-fold increase against wild-type D614G - mRNA-1273.351 (50 µg): 11.3-fold increase against wild-type D614G, 34.9-fold increase against B.1.351 - mRNA-1273.211 (50 µg): 46.4-fold increase against wild-type D614G, 61.6-fold increase against B.1.351 - mRNA-1273.351 (20 µg): 9.2-fold increase against wild-type D614G, 33.7-fold increase against B.1.351 - Fold-change differences in antibody levels: - mRNA-1273.211 showed significant increases against B.1.427/B.1.429 and B.1.526 - Statistical significance of differences: - Significant increases observed for mRNA-1273 and mRNA-1273.211 (P < 0.0001) - Superiority, non-inferiority, or inferiority results: - mRNA-1273.351 and mRNA-1273.211 may produce numerically greater neutralizing antibody titers against B.1.351 compared to mRNA-1273 - Cross-variant protection differences: - All boosters increased neutralization titers against key VOCs and VOIs - Breadth vs depth of immune responses: - Multivalent mRNA-1273.211 showed a GMT ratio rise ≥1 against all VOCs and VOIs - Direction of effect: - Generally positive, with increased or equivalent neutralization titers against various variants

Vaccination Regimen

- Primary vaccination series: 2 doses of mRNA-1273 - Number of prior doses before updated formulation: 2 - Timing between doses: Approximately 6 months between primary series completion and booster dose - Previous vaccine types received: Homologous (mRNA-1273) and heterologous (variant-modified mRNAs) - Concurrent administration with other vaccines: Not mentioned - Schedule used: 2-dose primary series followed by a single booster dose

Breakthrough Protection

Not mentioned (the paper does not provide specific data on breakthrough infection rates by variant, disease severity in breakthrough cases, viral load differences, or effectiveness estimates comparing updated vs original formulations)

Study Population

- Age groups studied: Adult (mean ages: 63.8, 53.9, 55.6, 47.5 years) - Prior SARS-CoV-2 infection status: Not mentioned - Immunocompromised status: Not mentioned - Time since last vaccination or infection: Approximately 6 months - Geographic location: United States - Sample size for mechanism analyses: 20 participants per group

Mechanism Durability

- Time points measured: 1 month and 6 months post-vaccination - Rate of antibody waning: 6-to 7-fold decrease in GMTs against wild-type D614G; 24-to 69-fold decrease against B.1.351 and P.1 over 6 months - Persistence differences: Updated formulations increased neutralizing antibody titers against VOCs - Memory response durability: Strong anamnestic responses indicative of robust B cell memory - Peak responses: 1 month after primary series - Mechanism differences maintained over time: Yes, with updated formulations showing superior titers against some VOCs

The emergence of SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs) with decreased susceptibility to neutralization has generated interest in assessments of booster doses and variant-specific vaccines. Clinical trial participants who received a two-dose primary series of the COVID-19 vaccine mRNA-1273 approximately 6 months earlier entered an open-label phase 2a study (NCT04405076) to evaluate the primary objectives of safety and immunogenicity of a single booster dose of mRNA-1273 or variant-modified mRNAs, including multivalent mRNA-1273.211. As the trial is currently ongoing, this exploratory interim analysis includes preliminary descriptive results only of four booster groups (n = 20 per group). Immediately before the booster dose, neutralizing antibodies against wild-type D614G virus had waned (P < 0.0001) relative to peak titers against wild-type D614G measured 1 month after the primary series, and neutralization titers against B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) VOCs were either low or undetectable. Both the mRNA-1273 booster and variant-modified boosters were safe and well-tolerated. All boosters, including mRNA-1273, numerically increased neutralization titers against the wild-type D614G virus compared to peak titers against wild-type D614G measured 1 month after the primary series; significant increases were observed for mRNA-1273 and mRNA-1273.211 (P < 0.0001). In addition, all boosters increased neutralization titers against key VOCs and VOIs, including B.1.351, P.1. and B.1.617.2, that were statistically equivalent to peak titers measured after the primary vaccine series against wild-type D614G virus, with superior titers against some VOIs. This trial is ongoing. Preliminary and exploratory analyses show that a third dose of the COVID-19 vaccine mRNA-1273 or variant-modified boosters can boost levels of neutralizing antibodies against SARS-CoV-2 variants.

S

everal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines targeting the viral spike (S) protein have been developed 1 . One such vaccine, mRNA-1273 (Moderna), a lipid nanoparticle-encapsulated mRNA vaccine encoding the S protein of the Wuhan-Hu-1 isolate with two proline mutations introduced to stabilize the S protein into the prefusion conformation, had an acceptable safety profile and induced anti-SARS-CoV-2 immune responses in phase 1 (NCT04283461) 2,3 and phase 2 (NCT04405076) 4 trials in adults. In the phase 3 Coronavirus Efficacy (COVE) trial (NCT04470427), mRNA-1273 provided 94% efficacy against symptomatic COVID-19 disease in more than 30,000 participants 5 . Subsequently, mRNA-1273 received emergency use authorization from several global regulatory bodies, including the U.S. Food and Drug Administration [6][7][8] .

Although SARS-CoV-2 vaccines, such as mRNA-1273, are highly effective in reducing detectable symptomatic infections and severe complications of Coronavirus Disease 2019 (COVID-19) 5 , several viral variants with changes in the S protein have emerged, some of which have been identified as VOCs (Alpha (B.1.1.7), Beta (B.1.351), 0][11] . Statistical models predict that protection from severe COVID-19 might be driven by neutralizing antibody levels considerably lower than the neutralizing responses elicited by mRNA vaccines 12 . Furthermore, a rapid anamnestic response might be generated upon subsequent exposure to VOCs by vaccination-induced germinal center memory B cells 13 . However, reduced efficacy against the B.1.351 (refs. 14,15 ) and B.1.617.2 (ref. 16 ) variants has been reported for some COVID-19 vaccines.

In a previous study, the neutralizing capacity of sera collected from participants 7 d after completion of the mRNA-1273 primary series against VOCs 17,18 was assessed using a previously described research grade vesicular stomatitis virus (VSV)-based SARS-CoV-2 pseudovirus neutralization (PsVN) assay 19 . Neutralizing antibody titers measured in sera from eight mRNA-1273 phase 1 trial participants were reduced 2.1-to 8.4-fold against the B.1.617.2, P.1 and B.1.351 variants 17,18 . Currently, a neutralizing antibody titer threshold predictive of protection from SARS-CoV-2 infection in humans is unknown. However, the reduction of in vitro neutralizing antibody titers against variants relative to the wild-type D614G virus raises the possibility of breakthrough infections and waning efficacy for the current SARS-CoV-2 vaccines.

To address this potential risk, modified versions of the prototype mRNA-1273 vaccine that contain the genetic sequence of the variant S protein continue to be developed. These variant vaccines are designed to stimulate an immune response against key sites of neutralization that have been altered on the S protein of variant viruses and, in the case of a multivalent vaccine, simultaneously against the wild-type strain. Here we report data from an exploratory interim analysis of the preliminary safety and immunogenicity of single booster doses of mRNA-1273 (50 µg), modified mRNA-1273.351

Results

Participants. Among 186 participants who received two primary doses of mRNA-1273 (100 µg) in the blinded phase of the P201 study 4 and subsequently received one booster dose of mRNA-1273 (50 µg) in the mRNA-1273 booster phase, 20 participants were randomly selected for inclusion in this interim analysis based on visit assessments completed and sample availability of pre-booster sera (Fig. 1 ).

Among 14,711 participants who received two primary doses of mRNA-1273 (100 µg) in the phase 3 COVE trial 5 , 60 participants were selected to enter the mRNA-1273 variant booster phase of the P201 trial and received a single booster dose of mRNA-1273.351 (50 μg; n = 20), mRNA-1273.211 (50 μg; n = 20) or mRNA-1273.351 (20 μg; n = 20). As one participant from the 20-μg mRNA-1273.351 group was lost to follow-up at day 29 and, thus, excluded, the analysis sample size for this cohort is 19.

The baseline demographic characteristics of the four groups of participants who received booster doses of the parent mRNA-1273 vaccine or the modified mRNA-1273 vaccines were generally similar (Table 1 ). Most of the participants were white and not Hispanic or Latino. The mean age of participants who received boosters of mRNA-1273 (50 µg), mRNA-1273.351 (50 µg), mRNA-1273.211 (50 µg) or mRNA-1273.351 (20 µg) was 63.8, 53.9, 55.6 and 47.5 years, respectively. The duration (mean (s.d.)) between completion of the mRNA-1273 primary series and the booster dose for mRNA-1273 (50 µg), mRNA-1273.351 (50 µg), mRNA-1273.211 (50 µg) or mRNA-1273.351 (20 µg) was 6.7 (0.5), 6.2 (0.3), 6.2 (0.4) and 6.2 (0.3) months, respectively.

Safety. The percentages of participants with solicited local and systemic adverse reactions (ARs) were generally similar among the booster groups (Fig. 2 and Supplementary Table 1 ); most solicited local and systemic ARs were mild (grade 1) or moderate (grade 2). Frequencies of any grade 3 solicited local or systemic ARs after the booster doses ranged from 10% to 15%, and there were no grade 4 solicited local or systemic ARs. The most common local AR was injection site pain. The most common systemic ARs after the booster doses were fatigue, headache, arthralgia and myalgia. Fever was reported by three participants (15.0%) after the booster dose of mRNA-1273 only. No serious ARs were reported.

Immunogenicity assessments. D614G and B.1.351 neutralization before and after booster. Wild-type D614G and B.1.351 neutralization were measured in samples collected immediately before the booster dose (day 1 (~6 months after the mRNA-1273 primary series)) and after the booster dose (day 29 in mRNA-1273 booster recipients and days 15 and 29 in mRNA-1273.351 and mRNA-1273.211 booster recipients) in a validated lentivirus PsVN assay. Sera from participants in the mRNA-1273 booster group were not assessed in the B.1.351 variant assay. The wild-type D614G virus was neutralized by most samples collected before the booster dose across all groups assessed (Fig. 3a ), whereas the neutralization titers for B.1.351 were low or non-detectable before the booster dose across all groups assessed (Fig. 3b ).

Neutralizing antibody titers against the wild-type D614G and B.1.351 viruses increased after each booster dose compared to day 1 titers (P < 0.0001 for all booster groups) (Fig. 3 ). Specifically, on day 29, geometric mean titers (GMTs) against the wild-type D614G virus were 16.7-, 11.3-, 46.4-and 9.2-fold higher than day 1 (pre-booster) titers in the mRNA-1273 (50 µg), mRNA-1273.351 (50 µg), mRNA-1273.211 (50 µg) and mRNA-1273.351 (20 µg) booster recipients, respectively (Fig. 3a ). Similarly, on day 29, GMTs against the B.1.351 variant were 34.9-, 61.6-and 33.7-fold higher than day 1 (pre-booster) titers in the mRNA-1273.351 (50 µg), mRNA-1273.211 (50 µg) and mRNA-1273.351 (20 µg) booster recipients, respectively (Fig. 3b ). These observations included participants who did not have measurable neutralizing antibodies against the wild-type D614G or B.1.351 virus before the booster dose but showed increases in their neutralizing antibody titers after the booster dose (Fig. 3 ); statistical analyses of this subgroup alone were not performed.

D614G and VOCs neutralization 1 and 6 months after primary series.

An exploratory analysis of the kinetics of the immune response at 1 and 6 months after the primary mRNA-1273 vaccination series was conducted across the four groups using the VSV-based PsVN assay. This assay was previously used to evaluate the neutralizing activity of serum from participants who received mRNA-1273 in a phase 1 trial against SARS-CoV-2 wild-type virus and variants 18 .

One month after the primary series, wild-type D614G neutralizing antibody GMT ranged from 1,210 to 2,213 across participants in the 50-µg booster groups (Fig. 4 ) and was 2,758 in the mRNA-1273.351 20-µg booster group (Supplementary Fig. 1 ). B.1.351 and P.1 neutralizing antibody GMTs were 13-to 14-fold lower and 5-to 6-fold lower, respectively, compared to wild-type D614G at the same time point in the 50-µg groups.

Simultaneous analysis of samples using the VSV PsVN assay showed that, approximately 6 months after the mRNA-1273 primary vaccination series, neutralizing antibody levels decreased (P < 0.0001) compared to peak titers against wild-type D614G measured 1 month after the primary series (GMTs against wild-type D614G were 6-to 7-fold lower, and GMTs against B.1.351 and P.1 were 24-to 69-fold lower) (Fig. 4a-c ). Neutralizing antibody levels against B.1.351 and P.1 were below the lower limit of quantification (LLOQ) of the assay in ~44% and 30% of samples, respectively. Neutralization of the B.1.617.2 variant was also reduced (P < 0.0001) 6 months after the completion of the primary series (Fig. 4d ). Sera from a random subset of the 20 participants in the mRNA-1273 booster group was used to assess neutralization of B.1.617.1 and B.1.617.2 (n = 11 for both) 6 months after the primary series and showed a 33-to 40-fold reduction in neutralizing antibody titers against B.1.617.1 and B.1.617.2 in comparison to peak titers measured against wild-type D614G 1 month after the primary series (full mRNA-1273 interim analysis cohort; n = 20). Neutralizing antibody titers against B.1.617.2 fell below the LLOQ of the assay in five of 11 samples.

D614G and VOCs neutralization after booster. Neutralizing antibody titers against the wild-type D614G virus were measured with the VSV-based PsVN assay using samples collected 2 weeks after the booster dose and were compared against wild-type D614G GMT benchmarks from samples collected 1 month after the primary series vaccination in each group. These benchmarks were used to determine whether the boosters reached the same neutralization level shown in the pivotal study where efficacy was demonstrated (that is, levels seen for wild-type D614G where 94% efficacy was measured) 5 . Using sera collected 1 month after the mRNA-1273 (100 µg) primary series, a GMT of 1,210 in the mRNA-1273 group (50 µg), 2,213 in the mRNA-1273.351 (50 µg), 1,397 in the mRNA-1273.211 (50 µg) and 2,758 in the mRNA-1273.351 (20 µg) groups were measured (Fig. 4a-c and Supplementary Fig. 1 ). Compared to the wild-type D614G benchmarks for each group, the booster vaccines yielded superior (mRNA-1273 and mRNA-1273.211) or equivalent (mRNA-1273.351) GMTs against the wild-type D614G virus. Wild-type D614G neutralization was 3.8-fold (P < 0.0001), 1.7-fold (P value not significant (NS)) and 4.4-fold (P < 0.0001) higher 2 weeks after 50-µg booster doses of mRNA-1273, mRNA-1273.351 and mRNA-1273.211, respectively, compared to peak titers against wild-type D614G measured 1 month after the primary series (Fig. 4a-c ). All three boosters, including mRNA-1273, increased neutralization against VOCs or VOIs to levels that were statistically equivalent to the wild-type D614G benchmarks, with superior titers measured versus some VOIs. Of the three booster vaccines assessed, the multivalent mRNA-1273.211 had the greatest increase in GMTs against all VOCs. Neutralization titers against B.1.351, P.1, B.1.427/B.1.429, B.1.526, B.1.617.1 and B.1.617.2 were 1.1-fold (P value NS), 1.4-fold (P value NS), 2.7-fold (P < 0.0001), 2.2-fold (P < 0.0001), 1.2-fold (P value NS) and 1.2-fold (P value NS) higher, respectively, 2 weeks after the mRNA-1273.211 booster compared to peak titers against the wild-type D614G measured 1 month after the primary series (Fig. 4c ).

Importantly, neutralizing antibody titers against wild-type D614G and B.1.351 measured using the clinically validated lentivirus and research grade VSV-based PsVN assays were highly correlated (r = 0.9161 against wild-type D614G and r = 0.9435 against B.1.351; Supplementary Fig. 2 ).

Discussion

This preliminary evaluation describes the antibody persistence of mRNA-1273 and the safety and immunogenicity of a booster dose Antibody titers against the wild-type D614G peaked 1 month after completion of the primary series and subsequently declined over the 5 months before the booster dose 18 . These results are consistent with those reported in a study using a lentiviral PsVN assay, in which monitoring of neutralizing antibody levels was performed up to 6 months after completion of the mRNA-1273 primary series 19 . Reduction of neutralizing antibody titers against B.1.351 and P.1 was evident 1 month after the primary series to a greater degree than that observed 7 d after the primary series 18 , likely due to further affinity maturation of B cells and alteration of the available antibody repertoire. Additional reduction or complete loss of detectible levels of neutralizing antibody ~6 months after the primary series was evident against B.1.351, P.1 and B.1.617.2. The safety profiles after single booster injections of mRNA-1273 (50 µg), mRNA-1273.351 (20 or 50 µg) and mRNA-1273.211 (50 µg) were generally similar to those observed after the mRNA-1273 primary series in the previously reported phase 2 and 3 studies 12,14 . The most common systemic ARs after the booster doses were fatigue, headache, arthralgia and myalgia, which occurred at similar-to-lower frequencies for the boosters than after receipt of the mRNA-1273 (100 μg) primary series.

Booster vaccination with mRNA-1273, mRNA-1273.351 and mRNA-1273.211 induced strong anamnestic responses, indicative of a robust B cell memory response 13 . Neutralizing antibody titers against the wild-type D614G virus after a booster dose were up to 4.4-fold higher than peak titers after the primary series.

Neutralizing antibody titers against several VOCs (that is, B.1.351, P.1 and B.1.617.2) increased after the booster dose, with titers against several variants approaching or exceeding those measured after the primary series against the wild-type D614G virus (Fig. 4 ). Increased titers against the VOCs suggest that further maturation of antibodies is feasible after a two-dose primary series of mRNA-1273, regardless of the composition of the booster dose. Furthermore, boosting with mRNA-1273.351 and mRNA-1273.211 appeared to produce numerically greater neutralizing antibody titers against the B.1.351 variant than with mRNA-1273, although formal conclusions regarding the significance of these differences cannot be made. The multivalent mRNA-1273.211 (50 µg) booster yielded a GMT ratio rise ≥1 against all VOCs and VOIs 2 weeks after the booster dose versus peak wild-type D614G titers measured 1 month after the primary series vaccination (Fig. 4c ). This rise was significant for B.1.427/B.1.429 and B.1.526, indicating that variant neutralization GMTs after the booster were higher than peak wild-type D614G virus GMTs after the primary series in the samples from this cohort, potentially increasing breadth of coverage against VOCs or VOIs. Generalized linear model was used to compare neutralization titers among groups; log 10 titer was regressed on group, and an individual-specific random effect was included to account for individual specific variability. Two-sided t-test was used for post hoc group comparisons. Sidak's method was used to adjust the P values for multiple comparisons. Statistical significance was determined at α < 0.01. ****P < 0.0001; ***P < 0.001; **P < 0.01; *P < 0.05. NAb, neutralizing antibody.

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There are some limitations related to this preliminary analysis. First, the results presented here are based on treatment groups that were not randomized. Instead, participants were assigned sequentially, given the different time frames of availability of the new vaccine formulations. The sample size was small (n = 20 per group) to facilitate rapid initiation of additional studies, which are needed to support the safe and effective use of a COVID-19 booster vaccine and to inform ongoing vaccination preparedness strategies regarding the need for booster doses as the pandemic evolves. Participants in this interim analysis were predominantly white and non-Hispanic or Latino (95-100% across booster groups), limiting generalizability to other races and ethnicities. Sex distributions and mean body mass index and age were not equivalent across the four booster groups; however, these differences are expected given the small cohort sizes. Although the lentiviral-based PsVN assay used in this evaluation is validated, the VSV-based PsVN assay used in the evaluation of samples against variants is a research grade assay that has not been validated. Nevertheless, the high correlation between the clinically validated lentivirus-based PsVN assay and research grade VSV-based PsVN assay provides support for the utility of the latter in improving the efficiency and time needed to perform such clinical analyses. Moreover, although these data are encouraging, in the absence of a correlate of protection it cannot be definitively determined whether the neutralization titers elicited by the mRNA-1273, mRNA-1273.351 and mRNA-1273.211 booster doses are protective against the B.1.351, P.1 or B.1.617.2 variants. Finally, because the participants in this study were originally enrolled in two different clinical trials, comparison of the results from mRNA-1273.211 and mRNA-1273.351 boosting with those of mRNA-1273 should be interpreted with caution.

The emergence of SARS-CoV-2 variants and the ability of the virus to partially overcome natural or vaccine-induced immunity has served as a call to action. Although a correlate of protection has not been established for SARS-CoV-2 infection or COVID-19 disease, lack of detectable neutralization against VOCs after ~6 months in some participants might be indicative of waning protection. However, it should be noted that an anamnestic response upon viral exposure is likely based on the induction of immune memory from the booster dose. The mRNA platform approach against SARS-CoV-2 VOCs in this trial appears to be effective in developing wild-type and variant-specific booster vaccines, with boosters increasing neutralizing titers against the wild-type D614G virus and against key VOCs and VOIs. Of note, significantly higher neutralizing titers against wild-type D614G, B. Immunogenicity assessments. Blood was collected 1 month after the primary vaccination series, immediately before the booster dose (day 1) and at days 8, 15, 29, 57 and 181 after the booster dose. In this interim analysis, neutralizing antibody titers of sera collected 1 month after the primary series, immediately before the booster dose and at days 15 and 29 after the booster dose are reported. A validated lentivirus PsVN assay (described below) was used to analyze samples collected immediately before the booster dose (day 1) and at days 15 and 29 after the booster. Additionally, a research grade recombinant VSV-based pseudovirus assay (described below) was used to assess neutralizing antibody titers against a panel of SARS-CoV-2 variants from sera collected 1 month after the primary series, immediately before the booster dose and day 15 after the booster dose. This assay has previously been used to evaluate neutralization against a panel of variants from sera collected 7 d after the primary series 18 .

Recombinant lentiviral-based PsVN assay (validated clinical assay).

SARS-CoV-2 neutralizing antibodies were quantified using lentivirus particles that incorporate SARS-CoV-2 S protein (Wuhan-Hu-1 isolate mutated to contain D614G) or the B.1.351 variant S protein (L18F-D80A-D215G-∆L242-∆A243-∆L2 44-K417N-E484K-N501Y-D614G-A701V) on their surface and express firefly luciferase reporter gene for quantitative measurements of infection by relative luminescence units (RLUs) as described 20 . The virus is applied to stably transduced 293T cells expressing high levels of angiotensin-converting enzyme 2 (ACE2) (293T/ACE2 cells), with or without pre-incubation with antibodies (control antibodies or serum samples); the presence of neutralizing antibodies reduces infection and results in lower RLUs. Serial dilution of antibodies or serum samples can be used to produce a dose-response curve. Neutralization is measured as the serum dilution at which the RLUs are reduced by 50% (50% inhibitory dilution (ID 50 )) relative to the mean RLUs in virus control wells (cells + virus but no control antibody or sample) after subtraction of the mean RLUs in cell control wells (cells only).

Recombinant VSV-based PsVN assay (research grade assay). To perform the recombinant VSV-based PsVN assay, codon-optimized full-length S protein of the D614G and variant sequences (Supplementary Table 2 ) were cloned into a pCAGGS vector. To make SARS-CoV-2 full-length S pseudotyped recombinant VSV-ΔG-firefly luciferase virus, BHK-21/WI-2 cells (Kerafast, EH1011) were transfected with the S expression plasmid and subsequently infected with VSVΔG-firefly-luciferase as previously described 21 . For the neutralization assay, serially diluted serum samples were mixed with pseudovirus and incubated at 37 °C for 45 min. The virus/serum mix was subsequently used to infect A549-hACE2-TMPRSS2 cells for 18 h at 37 °C before adding ONE-Glo reagent (Promega, E6120) for measurement of luciferase signal (RLU). The percentage of neutralization was calculated based on RLUs of the virus-only control and subsequently analyzed using 4-parameter logistic curve (Prism 8). Neutralization curves of SARS-CoV-2-negative human serum from two representative runs are presented in Supplementary Fig. 3 .

Statistical analysis.

No hypothesis testing and no formal power calculations were performed. This was an exploratory interim analysis, with the formal protocol-prespecified interim analysis pending the completion of the trial. This exploratory interim analysis was prepared to enable sharing of key neutralization results in light of the ongoing discussions around booster vaccines due to concerns with waning vaccine-induced immunity that is more pronounced with key VOCs. Descriptive summary statistics of the safety endpoints are provided; statistical tests were not performed for comparisons of these endpoints. Generalized linear model was used to compare neutralization titers between groups; log 10 titer was regressed on group, and an individual-specific random effect was included to account for individual-specific variability. Two-sided t-test was used for post hoc group comparisons. Sidak's method was used to adjust the P values for multiple comparisons. Statistical significance was determined at α < 0.01. GMTs and geometric mean fold rises (GMFRs) were calculated based on log-transformed titers, and two-sided 95% confidence intervals were based on the t-distribution of the log-transformed titers or the difference in the log-transformed titers for GMT and GMFR, respectively, and were then back-transformed to the original scale. Analysis of the study participant sera collected 1 month after the primary series was used to establish the GMT benchmarks for each group that were further used to derive GMT ratios after the booster dose. Spearman non-parametric correlation was used for assay correlation.

Reporting Summary. Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Data availability

The data supporting the findings of this study are available in this article and its Supplementary Information.

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booster. Further research is needed to determine the clinical significance of these preliminary results. Although this trial evaluated the performance of booster vaccines that encode the original strain or the B.1.351 S protein, this strategy could be employed in the future to vaccinate against new VOCs through the development of new variant-specific vaccines.

Online content

Any methods, additional references, Nature Research reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at https://doi.org/10.1038/ s41591-021-01527-y.

Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Methods

Study design. This ongoing phase 2a mRNA-1273 trial (protocol mRNA-1273-P201; NCT04405076, hereafter referred to as P201) is being conducted at eight sites in the United States and consists of three parts: a blinded phase where participants received two dose levels (50 or 100 µg) of mRNA-1273 primary series, which was previously published 4 , and two open-label intervention phases where participants who had previously received two primary doses of mRNA-1273 (100-µg dose group only) received either a booster dose of mRNA-1273 (50 µg; referred to herein as the 'mRNA-1273 booster phase') or mRNA-1273.351 (50 µg), mRNA-1273.211 (50 µg) or mRNA-1273.351 (20 µg; collectively, the three groups are referred to herein as the arms within the 'mRNA-1273 variant booster phase') (Fig. 1 ). Participants were enrolled sequentially into each booster arm. The objectives of these two open-label intervention phases were to assess the safety and immunogenicity of booster doses of mRNA-1273, mRNA-1273.211 and mRNA-1273.351. Additional details pertaining to study design are included in the Supplementary Methods.

All study materials, including the protocol, amendments and informed consent, were approved by a central institutional review board (Advarra). All participants provided written informed consent before enrollment and participation in study procedures. A safety monitoring committee (SMC), composed of external experts, reviewed data at prespecified time points during the blinded phase of the study. For the open-label phases, the SMC was informed of protocol amendments but met only on an ad hoc basis if any safety concerns arose; there were no significant safety concerns to trigger an ad hoc meeting of the SMC.

Participants. Eligible participants were healthy adults ≥18 years of age at the time of consent. To be eligible for inclusion into the mRNA-1273 booster phase, participants must have been previously enrolled in the blinded portion of the mRNA-1273 P201 study (NCT04405076) and received two doses of mRNA-1273 (50 or 100 µg). Only participants who received 100-µg doses of mRNA-1273 in the P201 study were included in this analysis. To be eligible for inclusion into the mRNA-1273 variant booster phase, participants must have been enrolled in the mRNA-1273-P301 COVE (NCT04470427) study and received two doses of mRNA-1273, with their second dose ≥6 months before enrollment in P201. Participants were enrolled in the blinded phase of the trial from 29 May 2020 to 8 July 2020. In the open-label phases, participants were enrolled from 28 January 2021 to 2 April 2021 in the mRNA-1273 booster phase (n = 345 enrolled) and from 10 March 2021 to 19 March 2021 in the mRNA-1273 variant booster phase (n = 60 enrolled). Study enrollment is complete, and the mRNA-1273 booster phase is expected to be completed in October 2021. Additional inclusion and exclusion criteria are provided in the protocol, which is included with the supplementary materials.

Vaccines. mRNA-1273 encodes the S protein of the Wuhan-Hu-1 isolate of SARS-CoV-2, whereas mRNA-1273.351 encodes the S protein of the SARS-CoV-2 B.1.351 variant; both vaccines include two proline mutations introduced to stabilize the S protein into the prefusion conformation (Supplementary Table 2 ). mRNA-1273.211 was a 1:1 mix of mRNA-1273 (25 µg) and mRNA-1273.351 (25 µg), for a total dose of 50 µg. All vaccines were formulated in lipid nanoparticles as previously described 5 .

Safety assessments.

Participants completed an electronic diary for 7 d after receiving the booster dose to record solicited systemic ARs, local ARs (including injection site erythema and swelling/induration) and daily oral body temperatures. Trained site personnel called participants to assess safety every 4 weeks for 6 months after the last dose.

Supplementary information

The online version contains supplementary material available at https://doi.org/10.1038/s41591-021-01527-y.

Correspondence and requests for materials should be addressed to Darin K. Edwards.

Peer review information Nature Medicine thanks the anonymous reviewers for their contribution to the peer review of this work. Peer review Information Alison Farrell is the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Reprints and permissions information is available at www.nature.com/reprints.

Acknowledgements

AcknowledgementsWe thank M. Brunner and M. Whitt at the University of Tennessee Health Science Center for their kind support on recombinant VSV-based SARS-CoV-2 pseudovirus production.We would like to thank C.-W. Hsiao at Moderna for statistical analysis of study results.Moreover, we would like to thank the Immune Assay Team at Duke University Medical Center (K.Engel, D. Beaumont, R. Beerman, K. Bradley, J. Chen, X. Daniell, T. Denny, E. Domin, A. Eaton, W. Feng, J. Gao, H. Gao, K. Greene, S. Hiles, M. Jessup-Cumming, L. Liu, K. Long, K. Lund, K. Lyons, C. McDanal, F. Suman, H. Tang, J. Tong and O. Widman) for their work on validated lentivirus PsVN assays supporting our clinical study evaluations.Medical writing and editorial assistance, under the direction of the authors, was provided by F. J. Dutko and J. E. Tomassini, consultants to Moderna, and K. Russin and S. Ramachandran of MEDiSTRAVA in accordance with Good Publication Practice (GPP3) guidelines and funded by Moderna.Employees of

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Abstract screening pilot

Abstract screening results

Extraction pilot

Extraction results

Research report

Modify setup

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