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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mRNA Vaccines against SARS-CoV-2: Advantages and Caveats

M. Echaide, Luisa Chocarro de Erauso, A. Bocanegra, E. Blanco, G. Kochan, D. Escors

International Journal of Molecular Sciences·

2023·

62 citations

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Updated Formulation

- Specific vaccine name/code: Comirnaty and Spikevax - Variant(s) targeted: BA.4-5 Omicron variants - Type of formulation: Bivalent (original + variant) - Dose amount: Not specified - Difference from original mRNA-1273: Includes additional mRNAs targeting Omicron variants

Immunological Mechanisms

- Neutralizing antibody responses: Induction of high titers of neutralizing antibodies; detectable up to six months post-vaccination. - T-cell responses: Activation of S-specific CD4 and CD8 T cells; expansion of effector T cells but not effector-memory T cells. - Durability measures: Antibody titers remain detectable up to six months post-vaccination; T-cell responses generally lost six months post-vaccination. - Mechanistic pathway analysis: Induction of elevated IL-17 concentrations indicating a strong inflammatory response.

Variant Testing Panel

- Ancestral/original strain: D614G - Specific variants of concern tested: Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), Omicron (B.1.1.529) - Nomenclature used: WHO names (Alpha, Beta, Delta, Omicron), Pango lineages (B.1.1.7, B.1.351, B.1.617.2, B.1.1.529) - Testing was done against the variant the updated formulation was designed for (Omicron) and other variants for cross-reactivity

Comparative Mechanism Results

- Geometric mean titers/ratios with confidence intervals: Not mentioned - Fold-change differences in antibody levels: Not mentioned - Statistical significance of differences (p-values, confidence intervals): Not mentioned - Superiority, non-inferiority, or inferiority results: Updated formulations are superior in generating higher titers of Omicron-specific neutralizing antibodies - Cross-variant protection differences: Updated formulations offer increased protection against new Omicron subvariants - Breadth vs depth of immune responses: Not mentioned - Direction of effect: Better for updated formulations in terms of generating higher titers of Omicron-specific neutralizing antibodies

Vaccination Regimen

- Primary vaccination series: Up to three doses allowed, with a possibility of a fourth dose for vulnerable individuals. - Booster dose administration: Frequent booster doses with monovalent or bivalent mRNA vaccines. - Updated formulations: Bivalent vaccines (Comirnaty and Spikevax) targeting Omicron variants. - Timing between doses: Not explicitly mentioned, but frequent booster doses are recommended due to waning immunity. - Previous vaccine types received: Homologous vaccination regimen (same type of mRNA vaccine). - Concurrent administration with other vaccines: Not mentioned. - Schedule used: 2-dose primary series, with booster doses as needed.

Breakthrough Protection

- Breakthrough infection rates by variant: Not mentioned - Disease severity in breakthrough cases: Not mentioned - Viral load differences during breakthrough: Not mentioned - Protection against symptomatic vs asymptomatic infection: Not mentioned - Effectiveness estimates comparing updated vs original formulations: Updated bivalent vaccines offer increased protection against Omicron subvariants compared to monovalent vaccines. - Duration of protection differences: Not mentioned

Study Population

- Age groups studied: Pediatric (<16 years), Adult, Elderly (>65 years) - Prior SARS-CoV-2 infection status: Not mentioned - Immunocompromised status: Organ-transplanted patients, patients with multiple sclerosis, patients with certain types of cancers - Time since last vaccination or infection: Not mentioned - Geographic location: Not mentioned - Sample size for mechanism analyses: Not mentioned

Mechanism Durability

- Time points measured: Up to six months post-vaccination. - Rate of antibody waning over time: Antibody titers decrease six months after the second dose and again after booster doses. - Persistence differences between updated vs original formulations: Bivalent vaccines offer increased protection and higher titers of neutralizing antibodies compared to monovalent vaccines. - Memory response durability: T cells with a stem cell memory phenotype could persist for decades, but specific CD4 and CD8 T cells are generally lost six months post-vaccination. - When peak responses occurred: Peak IgG titers occur in the fourth week post-vaccination. - Whether mechanism differences were maintained over time: The paper does not provide detailed comparisons of persistence between updated and original formulations.

The application of BNT162b2 and mRNA-1273 vaccines against SARS-CoV-2 infection has constituted a determinant resource to control the COVID-19 pandemic. Since the beginning of 2021, millions of doses have been administered in several countries of North and South America and Europe. Many studies have confirmed the efficacy of these vaccines in a wide range of ages and in vulnerable groups of people against COVID-19. Nevertheless, the emergence and selection of new variants have led to a progressive decay in vaccine efficacy. Pfizer–BioNTech and Moderna developed updated bivalent vaccines—Comirnaty and Spikevax—to improve responses against the SARS-CoV-2 Omicron variants. Frequent booster doses with monovalent or bivalent mRNA vaccines, the emergence of some rare but serious adverse events and the activation of T-helper 17 responses suggest the need for improved mRNA vaccine formulations or the use of other types of vaccines. In this review, we discuss the advantages and limitations of mRNA vaccines targeting SARS-CoV-2 focusing on the most recent, related publications.

1.Introduction

Coronaviruses comprise a group of pathogens affecting many vertebrate species, from birds to humans [1]. These viruses generally cause respiratory and enteric diseases, but some coronavirus species can cause other diseases such as hepatitis or encephalitis in non-human vertebrates. Coronaviruses are single-stranded positive-sense RNA (+ssRNA) viruses belonging to the Coronaviridae family [2]. Their genome encodes replicase/transcriptase proteins, structural proteins and a set of non-structural proteins linked to their virulence and proofreading activities of the replicase complex [3,4]. The coronavirus virion contains a helical nucleoprotein made of a single +ssRNA genome bound to the nucleocapsid protein (N) [5]. This nucleoprotein is further organized into a packed internal core, enveloped by the virus membrane which derives from the endoplasmic reticulum/Golgi. The spike (S), membrane (M) and envelope (E) proteins are the main structural proteins inserted into the virus envelope [6]. The spike protein is further organized into trimers, forming the "corona" of peplomers that gives rise to the name of the family (Figure 1 ). In 2003, an outbreak of infectious pneumonia put the international community into high alert, leading to the discovery of severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1), the first human pathogen of the family to cause lethal disease [7,8]. That first outbreak was controlled until a second one caused by a closely related coronavirus, SARS-CoV-2, originated one of the most severe pandemics in human history. The global epidemic was so dramatic that it accelerated the engineering of vaccines targeting SARS-CoV-2 at rates never seen before. The previous experience with other coronaviruses, including SARS-CoV-1 and MERS-CoV [9][10][11], prompted the selection of the spike protein as the main immunogen the S protein is one of the most immunogenic, at least in raising neutralizing antibody responses. Among all the potential types, mRNA vaccines soon became the primary candidates. Vaccines based on antigen delivery through mRNA are produced by a simple and fast procedure which consists of the amplification of the RNA nucleotide sequence encoding the open reading frame of the desired gene, plus further modifications to enhance stability and translation. The procedure is performed in automatized factories in which the risk of contamination with unrelated material is very low [14].

The first mRNA vaccine for infectious diseases was developed against influenza A in 2012. In vivo experiments in mice showed specific B-and T-cell based protection. The efficacy of the vaccine was also proven in ferrets and pigs [15]. After that, various mRNA vaccines were tested in animal models to evaluate their efficacy against the Zika virus, Ebola virus, cytomegalovirus and human immunodeficiency virus (VIH), among others [16][17][18][19][20][21].

Several vaccines have been developed for SARS-CoV-2 to reduce its transmission and virulence. Among other adenoviral and protein-based vaccines, the European Medicines Agency (EMA) authorized two mRNA vaccines for human use, BNT162b2/Pfizer-BioN-Tech and mRNA-1273/Moderna, in December 2020 and January 2021, respectively.

The BNT162b2 vaccine consists of a lipid nanoparticle, which contains an mRNA encoding the full-length spike protein with two proline substitutions (in positions 986 and 987) in the S2 subunit to maintain the protein in the prefusion conformation [22,23]. Similarly, the mRNA-1273 vaccine consists of a lipid nanoparticle capsule constituted by four lipids, which also carries an mRNA encoding the SARS-CoV-2 full-length spike glycoprotein with the intact furin cleavage site and the two proline substitutions in the S2 subunit [24,25]. Up to three doses of these vaccines have been allowed and even four doses in vulnerable people at risk [26][27][28].

The lipid nanoparticle (LNP) of BNT162b2 is composed of ALC-0159 (2[polyethylene glycol)-2000]-N,N-ditetradecylacetamide) and DSPC (1,2-distearoyl-sn-glycero-3- Vaccines based on antigen delivery through mRNA are produced by a simple and fast procedure which consists of the amplification of the RNA nucleotide sequence encoding the open reading frame of the desired gene, plus further modifications to enhance stability and translation. The procedure is performed in automatized factories in which the risk of contamination with unrelated material is very low [14].

Several vaccines have been developed for SARS-CoV-2 to reduce its transmission and virulence. Among other adenoviral and protein-based vaccines, the European Medicines Agency (EMA) authorized two mRNA vaccines for human use, BNT162b2/Pfizer-BioNTech and mRNA-1273/Moderna, in December 2020 and January 2021, respectively.

The lipid nanoparticle (LNP) of BNT162b2 is composed of ALC-0159 (2[polyethylene glycol)-2000]-N,N-ditetradecylacetamide) and DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) which play an important role in the formation of a stable lipid-bilayer nanoparticle. The LNP is structurally supported by cholesterol. Finally, the ALC-0315 ((4-hydroxybutyl) azanediyl)-bis(hexane-6,1-diyl)-bis(2-hexyldecanoate)) is the fundamental component for mRNA delivery into the cell. In addition, the vaccine is supplemented with salt buffers in order to balance the pH, and sucrose to protect the vaccine during freezing. Similarly, the mRNA-1273 LNP is stabilized by polyethylene glycol (PEG) 2000 DMG and DSPC, which form a lipid bilayer that is structurally supported by cholesterol. In contrast to BNT162b2 LNP, it carries lipid SM-102 in order to release the mRNA into the cell. This vaccine is also supplemented with salt buffers to balance the pH and with sucrose that serves as cryo-protectant.

LNP based-vaccines present a challenge due to the lack of thermostability and ultracold storage requirements, a fact that has limited their use in resource-poor countries. In addition, lipid and cholesterol excipients make the vaccines prone to oxidative degradation, which could decrease the stability of the vaccines. Furthermore, these BNT162b2 and mRNA-1273 mRNA vaccines, in particular, could pose a challenge in terms of delivery due to the long ribonucleic acids (4284 and 4004 nucleotides, respectively) with a number of modified nucleosides.

The BNT162b2 vaccine has been approved in 85 countries from North and South America and Europe; while mRNA-1273 has been distributed in 45 countries in Europe and North America [29].

Millions of doses of these mRNA vaccines have been administered worldwide during the pandemic. This has allowed the consolidation of the efficacy and safety data on these vaccines, and confirmed the decay in efficacy associated with the relatively short duration of protection. Data on protection against SARS-CoV-2 emerging variants have also been obtained. Here, we discuss the advantages and limitations of these mRNA vaccines and the recent adaptations approved for SARS-CoV-2 Omicron variants.

2.Advantages and Caveats of Efficacy and Safety of mRNA SARS-CoV-2 Vaccines

The advantages of the BNT162b2 and mRNA-1273 vaccines in terms of efficacy were readily noticeable right at the beginning of their administration to the general population. The application of these vaccines was quickly associated with a decrease in COVID-19 symptomatology and spread [30]. Their fast efficacy was caused by a combination of factors: the induction of high titers of neutralizing antibodies, the activation of T-cell responses, and a demonstrated efficacy within different population groups, including vulnerable people such as the elderly.

In contrast, over the course of time, we have been aware of some of their limitations, especially after the selection and propagation of variants. The most significant are the rare but serious adverse events specifically associated with these mRNA vaccines, short-lived protection, reduced efficacy towards variants of concern and the activation of Th17 immune responses which can exacerbate inflammatory reactions.

2.1.Induction of Neutralising Antibodies and T-Cell Activation

In phase three of their respective clinical trials, vaccination with BNT162b2 and mRNA-1273 vaccines provided protection against symptomatic COVID-19 in 95 and 94.1% of the vaccinated participants, respectively. These trials were carried out in groups of subjects with ages ranging from 16 to 55. Their efficacy was also proven in older adults comprising the population most vulnerable to COVID-19 (>65 years of age) and also in adolescents (<16 years of age) [23,24,[31][32][33]. Further studies confirmed the efficacy of these vaccines against the SARS-CoV-2 original strain by the fast induction of high titers of IgM and IgG antibodies specific towards the S protein, and with potent neutralizing capacities. These antibody titers remained detectable up to six months post-vaccination. Additionally, some studies evaluated the generation of T-cell responses towards S-derived peptides, demonstrating the presence of S-specific CD4 and CD8 T cells within 10 days to 9 weeks following the first and second dose, or even up to 6 months post-vaccination in healthy donors [29,[34][35][36][37][38][39][40][41][42]. Furthermore, third and fourth doses led to improved immune responses compared to two doses of mRNA vaccines, leading to a peak in IgG titers in the fourth week postvaccination [43][44][45].

2.2.Efficacy in Vulnerable Populations

However, it turned out that not all vulnerable groups of people benefit from the current mRNA vaccines. This is specially the case for organ-transplanted patients or patients suffering multiple sclerosis. These patients did not benefit from BNT162b2 and mRNA-1273 vaccines due to their immunosuppressive treatments [46][47][48][49][50][51][52][53]. On the other hand, the efficacy of these vaccines has been demonstrated in patients with several types of cancers. Most studies highlight the induction of S-specific antibodies after mRNA vaccination in solid-tumor patients and oncohematological patients. This is especially true in the third week after the administration of the second dose, reaching similar numbers of antibody titers as healthy donor groups [54][55][56][57][58][59][60]. Some studies also detected CD4 and CD8 T cells specific for the S protein in solid-tumor patients up to 6 months post-vaccination. In these latter cases, the antibody titers were comparable to those achieved in healthy donors vaccinated with the mRNA vaccines [42,[61][62][63]. Nevertheless, patients with hematological cancers and vaccinated with the mRNA vaccines presented decreased numbers of specific-T cells compared to healthy individuals [63,64]. The specific studies are summarized in Table 1 .

2.3.Duration of Protection

As reported by several studies, S-specific IgGs induced by mRNA vaccines decrease 6 months after the second dose of mRNA vaccination [42,65]. As mentioned previously, the third and fourth dose further significantly increase IgG titers compared to titers achieved in subjects vaccinated with only two doses; however, IgG titers again decrease six months after the booster dose [44,66]. It needs to be highlighted that in patients with cancer, the persistence of antibody responses is generally shorter compared to healthy subjects following vaccination [67,68].

According to the duration of T cell responses, some studies reported the expansion of vaccine-specific T cells with a stem cell memory phenotype (T SMC ). This is an important observation, because these T cells could persist for decades, providing long-term protection against SARS-CoV-2. However, in general terms, the specific CD4 and CD8 T cells are generally lost 6 months post-vaccination [69]. T-cell responses can be studied in more detail by analysing the phenotype of T cells expanded following vaccination with the mRNA vaccines. For example, CD62L and CD45RA expression in T cells was assessed by us in a recent study [42]. CD62L and CD45RA surface markers are involved in lymphocyte migration to inflammation sites and participate in T-cell receptor (TCR) signal transduction during antigen recognition [70]. In human T cells, these markers can be used to identify four types according to their differentiation degree: naïve (CD62L+ CD45RA+), central memory (CD62L+ CD45RA neg ), effector memory (CD62L neg CD45RA neg ) and effector T cells (CD62L neg CD45RA neg ) [71,72]. Our study reported that both healthy individuals and patients with cancer without previous SARS-CoV-2 infection showed an expansion of effector T cells (CD62L-CD45RA+) after mRNA vaccination. However, importantly, these mRNA vaccines did not expand T cells with an effector-memory phenotype (CD62L-CD45RA-). This is in stark contrast to vaccination of individuals who had had a previous SARS-CoV-2 infection. In these subjects, vaccination achieved the expansion of effector memory T cells [42] (Figure 2 ).

According to the duration of T cell responses, some studies reported the expansio of vaccine-specific T cells with a stem cell memory phenotype (TSMC). This is an importa observation, because these T cells could persist for decades, providing long-term prote tion against SARS-CoV-2. However, in general terms, the specific CD4 and CD8 T cells a generally lost 6 months post-vaccination [69]. T-cell responses can be studied in more d tail by analysing the phenotype of T cells expanded following vaccination with the mRN vaccines. For example, CD62L and CD45RA expression in T cells was assessed by us in recent study [42]. CD62L and CD45RA surface markers are involved in lymphocyte m gration to inflammation sites and participate in T-cell receptor (TCR) signal transductio during antigen recognition [70]. In human T cells, these markers can be used to identi four types according to their differentiation degree: naïve (CD62L+ CD45RA+), centr memory (CD62L+ CD45RA neg ), effector memory (CD62L neg CD45RA neg ) and effector T cel (CD62L neg CD45RA neg ) [71,72]. Our study reported that both healthy individuals and p tients with cancer without previous SARS-CoV-2 infection showed an expansion of effe tor T cells (CD62L-CD45RA+) after mRNA vaccination. However, importantly, the mRNA vaccines did not expand T cells with an effector-memory phenotype (CD62L CD45RA-). This is in stark contrast to vaccination of individuals who had had a previou SARS-CoV-2 infection. In these subjects, vaccination achieved the expansion of effecto memory T cells [42] (Figure 2 ).

2.4.Activation of the T-Helper 17 Responses

In many cases, SARS-CoV-2 leads to the death of the patient by exerting an exacerbated inflammatory response within the lungs of infected patients. Some studies have linked the establishment of a Th17-type of T-cell response during COVID-19 with the activation of a pro-inflammatory cytokine cascade (cytokine storm) [73,74]. For most vaccines targeting infectious agents, it would be desirable to elicit immune responses of the Th1 and Th2 types. These responses are efficacious in raising antiviral immunity while activating antibody responses. Th1 responses are regulated by T cells which mainly express IFN-gamma and IL-2, and they have a key role in attracting immune cells to the site of infection and in mediating the T-cell cytotoxicity of infected cells; Th2 responses are regulated by T cells expressing mainly IL-4 and IL-10, and they are involved in efficacious antibody production and airway inflammation observed in some respiratory diseases [75]. On the other hand, Th17 responses are regulated by T cells expressing IL-17, IL-6 and IFN-gamma. Th17 responses are fast, strong inflammatory reactions which can be critical in situations of high immuno-logical stress. However, Th17 responses imbalance Th1-Th2 immunity, contributing to the exacerbation of inflammation, and in the case of SARS-CoV-2, its pathogenesis [73,[75][76][77]. Recent studies have reported the induction of elevated concentrations of IL-17 after mRNA vaccination, indicating that mRNA vaccines trigger this strong inflammatory response [78] (Figure 3 ). Indeed, our study described an enhancement of this response in vaccinated oncologic patients without previous SARS-CoV-2 infection [42]. These results indicated that mRNA vaccination in patients with cancer can potentiate their chronic inflammatory status often originated and exacerbated by solid tumors, or their treatments [79][80][81][82][83][84][85].

press IFN-gamma and IL-2, and they have a key role in attracting immune cells to the site of infection and in mediating the T-cell cytotoxicity of infected cells; Th2 responses are regulated by T cells expressing mainly IL-4 and IL-10, and they are involved in efficacious antibody production and airway inflammation observed in some respiratory diseases [75]. On the other hand, Th17 responses are regulated by T cells expressing IL-17, IL-6 and IFNgamma. Th17 responses are fast, strong inflammatory reactions which can be critical in situations of high immunological stress. However, Th17 responses imbalance Th1-Th2 immunity, contributing to the exacerbation of inflammation, and in the case of SARS-CoV-2, its pathogenesis [73,[75][76][77]. Recent studies have reported the induction of elevated concentrations of IL-17 after mRNA vaccination, indicating that mRNA vaccines trigger this strong inflammatory response [78] (Figure 3 ). Indeed, our study described an enhancement of this response in vaccinated oncologic patients without previous SARS-CoV-2 infection [42]. These results indicated that mRNA vaccination in patients with cancer can potentiate their chronic inflammatory status often originated and exacerbated by solid tumors, or their treatments [79][80][81][82][83][84][85].

2.5.Loss of Efficacy towards Variants of Concern

The coronavirus S protein is the largest and most exposed antigen of the viral particle. Three molecules of the S protein form the coronavirion peplomer, which confers entry to the cell and tissue tropism [4,86]. For SARS-CoV-2, the receptor for the S protein is the ACE2 surface protein [87]. This fact makes the S gene subject to strong selective pressure from the immune system, which leads to viral escape mechanisms by increasing the number of mutations, specially concentrated in the proximities of the receptor-binding domain (RBD) (Figure 4 ). As most SARS-CoV-2 vaccines utilize the S protein sequence from the original Wuhan strain, these escape mutants can also escape from immune responses caused by the vaccines. This, in turn, results in a subsequent decrease in efficacy for all vaccines which use the original S protein sequence. The decline in the protection of the population against SARS-CoV-2 caused by the selection of new variants has prompted the redesign of mRNA vaccines. This is the advantage of mRNA vaccines, which allow fast modifications by just changing the immunogenic transgene to target variants. Pfizer-BioNTech and Moderna brought to the market two bivalent vaccines-Comirnaty and Spikevax-containing mRNAs encoding the spike protein of the original variant together with BA.4-5 Omicron variants [114,115]. Booster doses with these vaccines seem to offer increased protection against new Omicron subvariants, generating higher titers of Omicron-specific neutralizing antibodies than monovalent vaccines [115,116]. Nevertheless, long-term follow-up studies should be carried out to obtain more solid and robust data on the impact on the protection and spreading of the virus in the human population.

2.6.Adverse Events Caused by mRNA Vaccines

It has to be remarked that no serious adverse effects were described in the clinical trials assessing mRNA vaccines BNT162b2 and mRNA-1273 which led to their approval [22,33]. However, the administration of millions of vaccine doses has uncovered rare adverse events and complications, characterized by a diversity of symptoms. In general terms, complications from SARS-CoV-2 infection outweigh the risk of suffering these rare adverse effects following vaccination. Nevertheless, it is necessary to follow the evolution of the affected population to identify causal agents of adverse events to either improve vaccine formulations, or to better allocate the populations that need vaccination.

Two large-scale studies were carried out in the United Kingdom in about 40 million people vaccinated with sequential doses of the adenovirus-based ChAdOx1 vaccine or mRNA vaccines to evaluate cardiac adverse events. The results showed the occurrence of myocarditis in 0.004 and 0.007% of the vaccinated people with ChAdOx1 and mRNA vaccines, respectively. A statistical analysis of the data in both studies uncovered an increased risk of suffering myocarditis after the first dose of ChAdOx1 and BNT162b2 vaccine than The first dominant D614G substitution in the spike protein arose in the B.1.1.7 variant, more commonly known as Alpha SARS-CoV-2 variant (Figure 4 ). It has to be noted that this mutation is outside the RBD, but it nevertheless increased viral replication and transmission. Several studies later demonstrated that the D614G mutation did not decrease the protection conferred by mRNA-vaccines, which was maintained at a 94-95% of efficacy and generating comparable titers of neutralizing antibodies compared to the efficacy towards the original Wuhan strain [88,89]. Several other mutations were selected. For example, E484K, N501Y and K417N mutations in the B.1.351 variant, also known as Beta (Figure 4 ). These mutations were reported to cause a decline in efficacy of mRNA vaccines. The neutralizing capacities of sera from mRNA-1273-and BNT162b2-vaccinated individuals was approximately 10-fold lower towards this variant compared to the original strain [90,91]. Even so, mRNA vaccines continued to be effective against the spreading and pathogenesis of SARS-CoV-2. This was in contrast to the adenoviral-vectored ChAdOx1 vaccine, which was associated with a significant decrease in efficacy against this variant [92].

The COVID-19 strain B.1.617.2 (Delta) contained 18 novel mutations compared to the original strain [93] (Figure 4 ). These changes increased the transmission rate of the virus and increased its affinity to lung epithelial cells [94]. In particular, E484Q and L452R mutations enhanced immunological evasion and resistance to neutralizing antibodies from vaccinated individuals and convalescent people [95]. The protective efficacy of mRNA vaccines decreased to 88% for this variant [96], with a subsequent decrease in protection against infection six months post-vaccination [97]. In addition, the B.1.617.2 + AY sub-variants (Delta plus) selected an extra mutation (K417N) which potentiated escape from neutralizing antibodies generated by the original vaccines [94,98]. Moreover, a recent comparative study of S mutations in Alpha, Beta and Delta variants highlighted the progressive capacity of the virus strains to enter cells independently of S protein-ACE2 interactions. This fact augments transmissibility of the virus as the number of mutations increases [99]. This situation is not novel with coronaviruses, as it is likely that some coronavirus species can use a co-receptor to modulate the in vivo tissue tropism [86,[100][101][102].

A variant of high interest was selected in regions with a high percentage of vaccinated population, suggesting that this variant was an escape mutant from the vaccines themselves. This variant was termed B.1.1.529, or Omicron, and its S gene accumulated more than 30 mutations compared to the original strain [98,103] (Figure 4 ). T478K, Q293K, Q498R and E484A contributed to an elevated transmission rate and evasion from neutralizing antibodies [104]. Due to this enhanced escaping capacity, the protection achieved with BNT162b2 and mRNA-1273 vaccines decreased to 30% after three doses, and to 47.2% in older adults [93,[105][106][107][108][109][110][111][112]. This variant is still evolving, leading to Omicron sub-variants such as BQ, XBB and BF.7, with high capacities to avoid neutralizing antibodies elicited by the original vaccines [108,113].

The decline in the protection of the population against SARS-CoV-2 caused by the selection of new variants has prompted the redesign of mRNA vaccines. This is the advantage of mRNA vaccines, which allow fast modifications by just changing the immunogenic transgene to target variants. Pfizer-BioNTech and Moderna brought to the market two bivalent vaccines-Comirnaty and Spikevax-containing mRNAs encoding the spike protein of the original variant together with BA.4-5 Omicron variants [114,115]. Booster doses with these vaccines seem to offer increased protection against new Omicron subvariants, generating higher titers of Omicron-specific neutralizing antibodies than monovalent vaccines [115,116]. Nevertheless, long-term follow-up studies should be carried out to obtain more solid and robust data on the impact on the protection and spreading of the virus in the human population.

It has to be remarked that no serious adverse effects were described in the clinical trials assessing mRNA vaccines BNT162b2 and mRNA-1273 which led to their approval [22,33]. However, the administration of millions of vaccine doses has uncovered rare adverse events and complications, characterized by a diversity of symptoms. In general terms, complications from SARS-CoV-2 infection outweigh the risk of suffering these rare adverse effects following vaccination. Nevertheless, it is necessary to follow the evolution of the affected population to identify causal agents of adverse events to either improve vaccine formulations, or to better allocate the populations that need vaccination.

Two large-scale studies were carried out in the United Kingdom in about 40 million people vaccinated with sequential doses of the adenovirus-based ChAdOx1 vaccine or mRNA vaccines to evaluate cardiac adverse events. The results showed the occurrence of myocarditis in 0.004 and 0.007% of the vaccinated people with ChAdOx1 and mRNA vaccines, respectively. A statistical analysis of the data in both studies uncovered an increased risk of suffering myocarditis after the first dose of ChAdOx1 and BNT162b2 vaccine than after the further booster doses of the mRNA-1273 vaccine [117,118]. These studies indicated that especially males under 40 years of age had an elevated risk [119]. A study carried out in the USA over large-scale databases reported an elevated occurrence of myocarditis or pericarditis in mRNA-vaccinated people between 18 and 25 years of age following the second dose, without significant differences between BNT162b2 and mRNA-1273 vaccine formulations [120]. On the other hand, no clear association between vaccination and cardiac arrhythmia has been demonstrated, as most cases occurred after SARS-CoV-2 infection and this can be a confounding factor [117]. These adverse events have been therefore stated in the official websites of Comirnaty and Spikevax and by the European Medicine Agency (EMA), more specifically occurrence of myocarditis and pericarditis in some vaccinated people (https://www.comirnaty.com/, https://spikevax.com /, https://www.ema.europa.eu/en/documents/prac-recommendation/signal-assessment -report-myocarditis-pericarditis-spikevax-previously-covid-19-vaccine-moderna-covid_en .pdf, https://www.ema.europa.eu/en/documents/prac-recommendation/signal-assess ment-report-myocarditis-pericarditis-spikevax-previously-covid-19-vaccine-moderna-co vid_en.pdf; accessed on 20 March 2023). Isolated cases of vasospastic angina and Takotsubo cardiomyopathy have also been observed after mRNA vaccination. In addition, there are reported cases of myocardial infarction, stroke and pulmonary embolism in people older than 75 years of age after BNT162b2.

To date, although with less solid data, other consequences associated with the vaccines have been detected and reported. For example, alterations in the menstrual cycle such as abnormal bleeding and delayed menstruation following the second booster dose of the BNT162b2 vaccine [121,122]. Studies reporting the main adverse events are summarized in Table 2 . Interestingly, recent data have reported that consuming alcohol, tobacco or drugs, apart from decreasing the humoral response generated by BNT162b2 mRNA vaccine, also activates the ACE2 receptor enhancing the "spike effect" of COVID-19 vaccines. The "spike effect" refers to the interaction of the endogenous spike protein with the ACE2 receptor, resembling the COVID-19 pathology and leading to rare neurological complication, such as Guillain-Barre syndrome and Bell's palsy.

3.Conclusions

The use of mRNA vaccines targeting the spike protein of SARS-CoV-2 has constituted one of the main barriers in the battle against this pandemic. It is estimated that SARS-CoV-2 vaccines, including those based on adenovirus vectors, protein-based vaccines and mRNA vaccines have saved the lives of around 20 million people worldwide [123]. Even so, it is necessary to review all the updated information on the efficacy and safety of these vaccines during the development and evolution of the pandemic. It is also important to evaluate the changes in vaccine policy, now that a very large number of people have been infected with SARS-CoV-2 and present a degree of protection. Indeed, the frequent administration of booster doses due to the loss of post-vaccination immunity is causing some experts to warn about a possible link between immune exhaustion and frequent vaccination [124]. There is some experimental evidence pointing towards this direction, as observed in a recent study of cancer patients following three doses of BNT162b2 [125].

In addition, the increasing number of mutations within the S protein of emerging variants and the progressive decrease in efficacy of mRNA vaccines suggest that vaccine formulations should be changed by including additional viral targets. For example, some studies including our own have highlighted the role of the N and M proteins of the SARS-CoV-2 virus in the generation of notable antibody and cellular responses [42]. The advantage of incorporating these viral immunogens is that they are subject to lower selective pressure compared to the S protein. Their mutational burden is by comparison much lower than that of the S protein. Hence, using these virus structural proteins could lead to more robust and durable immune responses without the need for regularly changing the S protein strain in vaccine formulations [126].

It also needs to be stressed that improved vaccine formulations should lead to activation of Th1 and Th2 responses to the detriment of Th17 responses. This could circumvent the exacerbated inflammation caused after vaccination which could be linked to serious adverse effects. In addition to vaccine formulation, the fact that these vaccines contain long ribonucleic acids with a number of modified nucleosides, could result in the preparation of batches with identical properties. This, together with the lack of thermostability, suggests that protein-based vaccines are a preferable option to avoid these challenges.

Using other types of vaccines, such as viral-vectored vaccines or protein-based vaccines, or forgoing booster doses, should be considered for people who are predisposed to suffer cardiac adverse effects, especially during periods of the active spread of new variants of the SARS-CoV-2 virus.

availability

Data Availability Statement: This manuscript does not contain data.

Conflicts of Interest:

The authors declare no conflict of interest.

Acknowledgements

Acknowledgments:We are grateful to the patients and their families who generously participated in the studies by our group.

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