Elicit: Immune Response to Elasomeran Vaccination

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Immune Response to Elasomeran Vaccination

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May 6, 2026

What is the evidence for immune response and protection after Elasomeran vaccination?

Evidence demonstrates that elasomeran vaccination induces robust immune responses and clinical protection across most populations, though patients with hematologic malignancies and those on B-cell-depleting therapies show attenuated responses that improve with additional doses.

Abstract

Elasomeran vaccination demonstrates high efficacy in healthy populations, with risk ratios of 0.08 for preventing COVID-19 and breakthrough infection rates of 0.23%. In immunocompromised populations, humoral responses vary substantially by underlying condition: seropositivity rates reach 95.2% in lung cancer patients, 91.7% in multiple myeloma, and 82% in rheumatic disease patients, but only 60-66% in hematologic malignancies. Cellular immune responses occur in approximately 46% of cancer patients, with most mounting both CD4+ and CD8+ T-cell responses. Antibody titers decline substantially over time, decreasing from median 429 to 139 BAU/mL between 36 days and 3 months post-vaccination, with 10% of initially seropositive patients converting to seronegative status. Response heterogeneity is explained by specific mechanisms: B-cell-depleting therapies (anti-CD20, anti-CD38) profoundly suppress antibody production, disease remission predicts superior response (median titers 1242 vs 221.5 U/ml), and mRNA vaccines induce higher antibody levels than viral vector vaccines. Additional doses substantially improve seroconversion in immunocompromised patients, increasing rates from 26% after two doses to 71.7% after four doses in kidney transplant recipients and from 69.6% to 95.7% after a second dose in AML/MDS patients. Clinical protection remains robust in most immunocompromised populations, with breakthrough infection rates of only 0.5% in lung cancer patients. The evidence indicates that while elasomeran induces strong immune responses in most populations, patients with hematologic malignancies and those receiving B-cell-depleting therapies require additional doses and may need more frequent boosting to maintain protective immunity.

Methods

We analyzed 10 sources from an initial pool of 200, using 7 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: Elasomeran Vaccination, Relevant Outcomes, Human Participants, Study Design, Sample Size, Full-Text Availability, Biological Outcomes Focus

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: “What is the evidence for immune response and protection after Elasomeran vaccination?”

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 study design characteristics relevant to evaluating elasomeran immune response and protection evidence, including:

Extract participant characteristics that may affect elasomeran immune response and protection, including:

Extract elasomeran vaccination protocol and completion details, including:

Extract antibody response measures after elasomeran vaccination, including:

Extract T-cell and cellular immune response measures after elasomeran vaccination, including:

Extract clinical protection effectiveness after elasomeran vaccination, including:

Extract factors that influenced immune response or protection after elasomeran vaccination, including:

Extract safety profile of elasomeran vaccination in the study population, including:

Results

Characteristics of Included Studies

Ten studies met the inclusion criteria, comprising two meta-analyses, one scoping review, and seven primary observational studies. Full text was available for six studies, while four studies were available only as abstracts.

Study

Full text retrieved?

Study Type

Sample Size

Population

Vaccination Details

K. Mancuso et al., 2021

No

Observational prospective study

96 MM patients

Multiple myeloma patients

BNT162b2 or mRNA-1273, 2 doses 3-4 weeks apart

M. Provencio et al., 2021

No

Observational cohort (SOLID substudy)

1,976 lung cancer patients

Lung cancer (67.6% stage IV)

Various vaccines, 2-dose series

P. Ratajczak et al., 2023

Yes

Meta-analysis of 8 RCTs

135,275 total participants

Healthy persons aged >16

BNT162b2 and mRNA-1273, 100 μg dose

Nina Kreuzberger et al., 2022

No

Scoping review

318 studies, >5 million participants

Immunocompromised populations

Various vaccines including mRNA-1273

Narcis-George Manolache et al., 2021

Yes

Observational cohort

231 IMID patients

Rheumatic diseases

AZD1222, BNT162b2, mRNA-1273, or JNJ-78436735

V. Pozdnyakova et al., 2021

Yes

Observational cohort (vaccine registry)

353 IBD patients

Inflammatory bowel disease

mRNA-1273, BNT162b2, or Ad26.CoV2.S

S. Ehmsen et al., 2021

Yes

Observational cohort

524 cancer patients

Solid (38%) and hematologic (62%) cancer

mRNA vaccines, 2 doses

M. Seija et al., 2022

Yes

Multicenter prospective observational

109 kidney transplant recipients

Kidney transplant recipients

Heterologous (4 doses) or homologous (3 doses) schemes

D. Martins-Branco et al., 2022

Yes

Meta-analysis of 89 records

30,183 cancer patients

Cancer patients (HM and SM)

Various vaccines including mRNA-1273

A. Jain et al., 2021

No

Observational cohort

46 patients (30 AML, 16 MDS)

Acute myeloid leukemia and myelodysplastic syndrome

mRNA-1273, 2 doses

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The studies predominantly enrolled immunocompromised populations, including patients with hematologic malignancies, solid tumors, transplant recipients, and autoimmune diseases. Most patients in cancer studies were receiving active treatment at vaccination. The median age ranged from 51 years in IBD patients to 68 years in AML/MDS patients. One meta-analysis focused exclusively on healthy populations over 16 years.

Humoral Immune Response

Seropositivity Rates in Healthy vs Immunocompromised Populations

In the healthy population meta-analysis, both BNT162b2 and mRNA-1273 demonstrated high efficacy in preventing COVID-19 compared to placebo (RR 0.08 [0.07, 0.09], p<0.00001). Breakthrough infection rates were substantially lower with elasomeran (0.23%) compared to placebo (3.29%).

Among immunocompromised populations, seropositivity rates varied considerably by underlying condition. In lung cancer patients, 95.2% achieved seropositivity two weeks after vaccination (threshold 7.1 BAU/mL), with geometric mean titers of 655.45 BAU/mL (95% CI 593.5-723.8). In rheumatic disease patients, 82% achieved optimal humoral response (anti-RBD Ab >141 BAU/ml). Among IBD patients, mRNA-1273 recipients showed 100% seropositivity at 2 weeks with log10 antibody levels of 4.20.

Population

Seropositivity Rate

Quantitative Titers

Time Point

Assay Method

Healthy (meta-analysis)

High efficacy (RR 0.08)

Not specified

14 days post-dose 2

Not specified

Lung cancer

95.2%

GMT 655.45 BAU/mL (95% CI 593.5-723.8)

2 weeks

Chemiluminescent microparticle immunoassay

Rheumatic diseases

82% optimal response

Responders: 245.4 ± 18.8 BAU/ml
Non-responders: 70.7 ± 44.9 BAU/ml

Post-vaccination

Elecsys anti-SARS-CoV-2

IBD (mRNA-1273)

100%

Log10: 4.20 at 2 weeks

2 weeks

Abbott SARS-CoV-2 IgG-II

Multiple myeloma

91.7%

Median 435 U/ml (range 0.4-2500)

1 month

ECLIA (Elecsys)

Solid cancer

93%

Median 429 BAU/mL at 36 days

36 days

Not specified

Hematologic cancer

66%

Median 429 BAU/mL at 36 days

36 days

Not specified

AML/MDS

95.7% after 2 doses

Mean 3806.5 after dose 2

Day 57

Two-step ELISA

Kidney transplant

71.7% (heterologous)
70.6% (homologous)

Higher in Seroconversion-2D group

Post-vaccination

Anti-RBD IgG assay

Cancer meta-analysis

80% within first month

Not specified

1 month

Not specified

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Patients with hematologic malignancies consistently demonstrated lower seropositivity rates compared to those with solid tumors. In the cancer meta-analysis, only 60% of hematologic malignancy patients achieved seropositivity versus 94% of solid malignancy patients. Similarly, in the Ehmsen study, solid cancer patients showed 93% seropositivity compared to 66% in hematologic cancer patients.

Antibody Durability

Several studies tracked antibody persistence over time. In lung cancer patients, antibody levels were maintained at both two weeks and six months post-vaccination. However, in the broader cancer population, median titers declined significantly from 429 BAU/mL at 36 days to 139 BAU/mL at 3 months. Among initially seropositive patients, 10% converted to seronegative status by 3 months, including 5 with solid cancer and 19 with hematologic cancer. An additional 24% of patients with borderline levels at 36 days became seronegative by 3 months.

Response to Multiple Doses

In kidney transplant recipients, seroconversion increased progressively with additional doses. After two initial doses, 26% achieved seroconversion. A third dose improved seroconversion by an additional 31.2%, resulting in final rates of 71.7% for the heterologous scheme (2 CoronaVac + 2 BNT162b2) and 70.6% for the homologous scheme (3 BNT162b2). Similarly, in AML/MDS patients, seropositivity increased from 69.6% after one dose to 95.7% after two doses, with mean antibody titers rising dramatically from 315 to 3806.5.

Cellular Immune Response

Limited data on cellular immunity were available. Among cancer patients receiving mRNA vaccination, 46% of solid cancer patients and 45% of hematologic cancer patients exhibited positive T-cell responses. Of those with positive responses, 76% of solid cancer patients and 81% of hematologic cancer patients mounted both CD4+ and CD8+ T-cell responses, while 23% and 18% respectively elicited only CD8+ responses. Notably, 76% of seronegative patients did not elicit a T-cell response. The cancer meta-analysis reported an overall cellular response rate of 61% (95% CI 44-76%), with 59% in hematologic malignancies and 68% in solid malignancies.

Multiple myeloma patients underwent IGRA testing for SARS-CoV-2 specific IFN-γ T-cell response at 3 and 12 months after the second dose, though specific results were not reported in the available abstract.

Clinical Protection Outcomes

Breakthrough infection data were limited. Among lung cancer patients, only 0.5% (10 patients) contracted SARS-CoV-2 within a median of 19 days (IQR 5-76) after full vaccination. In kidney transplant recipients, 10 patients experienced breakthrough infections during a 5-month follow-up, with no deaths reported.

Performance status and comorbidities significantly influenced clinical protection. Lung cancer patients with performance status ≥2 had higher odds of being seronegative (OR 4.38, 95% CI 2.24-8.55, p<0.001), as did those with comorbidities (OR 3.43, 95% CI 1.32-8.87, p=0.011).

Factors Modifying Immune Response

Cancer Treatment and Immunosuppression

Specific cancer treatments substantially impacted humoral response. In multiple myeloma patients, those receiving proteasome inhibitors had median antibody titers of 156 U/ml, while those on anti-CD38 monoclonal antibodies had median titers of 265 U/ml, both lower than other treatment groups. Conversely, patients receiving lenalidomide maintenance had median titers of 1681.2 U/ml, and those who had undergone autologous stem cell transplantation showed median titers of 1042 U/ml.

In hematologic cancer patients, anti-CD20 therapy was associated with seronegativity in 28% of patients, BTK inhibitor therapy in 11%, and chemotherapy in 25%. Steroid use (prednisolone >10mg) was significantly associated with seronegativity. Multivariate analysis confirmed significant associations between seronegative rates and steroid use, stem cell transplantation, type of cancer therapies, and cancer diagnosis.

Among kidney transplant recipients, mycophenolate treatment was identified as a significant factor reducing seroconversion. The time since transplantation also influenced response, with patients having less time post-transplant showing lower antibody levels.

Factor Category

Specific Factor

Effect on Response

Statistical Measure

Disease Status

Complete response (MM)

Higher Ab titers

OR 2.54 (95% CI 0.93-7.56)

Disease Status

Progressive disease (hematologic)

Associated with seronegativity

Significant association

Treatment

Lenalidomide maintenance (MM)

Higher Ab titers (median 1681.2 U/ml)

OR 4.53 (CI 484-1233)

Treatment

Anti-CD38 antibodies (MM)

Lower Ab titers (median 265 U/ml)

p<0.001

Treatment

Proteasome inhibitors (MM)

Lower Ab titers (median 156 U/ml)

p=0.003

Treatment

Anti-CD20 therapy

28% seronegativity

p<0.008

Treatment

BTK inhibitors

11% seronegativity

p=0.002

Treatment

Chemotherapy

25% seronegativity

p=0.02

Treatment

Steroids (prednisolone)

Associated with seronegativity

p=0.005

Treatment

Mycophenolate (KTR)

Lower seroconversion

Significant association

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Disease-Specific Response Patterns

Among hematologic malignancies, specific diagnoses showed markedly different seropositive rates. Only 11% of mantle cell lymphoma patients achieved seropositivity, while 55% of CLL/SLL patients and 62% of follicular lymphoma patients became seropositive. Higher rates were observed in marginal zone lymphoma (72%), multiple myeloma (80%), and diffuse large B cell lymphoma (85%).

Disease remission status also influenced response. In multiple myeloma, patients with very good partial response or better had median antibody titers of 1242 U/ml compared to 221.5 U/ml in those with lesser responses. Similarly, hematologic cancer patients in remission were more likely to be seropositive than those with progressive disease.

Vaccine-Specific Differences

In rheumatic disease patients, those receiving mRNA vaccines showed 85% optimal humoral response versus only 69% with viral vector vaccines. Multivariate analysis confirmed that vaccine type remained significantly associated with response when controlling for age, treatment, and time between vaccination and antibody measurement.

Among IBD patients, those receiving mRNA-1273 or BNT162b2 showed substantially higher antibody levels at both 2 and 8 weeks compared to Ad26.CoV2.S recipients. At 2 weeks, log10 antibody levels were 4.20 for mRNA-1273, 3.92 for BNT162b2, and only 1.96 for Ad26.CoV2.S. These differences persisted at 8 weeks (3.72, 3.41, and 2.65 respectively). Multivariate analysis demonstrated that both mRNA-1273 and BNT162b2 independently predicted higher antibody levels at week 2 (β 2.24 and 1.96 respectively) and week 8 (β 1.08 and 0.77 respectively).

Safety and Tolerability

Safety data were limited across studies. In AML/MDS patients, mild injection site pain, fatigue, headache, and arm swelling were the most common adverse events. Two AML patients experienced disease relapse post-vaccination, though no direct link to vaccination was established. The meta-analysis of RCTs found that BNT162b2 and mRNA-1273 administration was associated with higher proportions of adverse events compared to placebo (RR 2.14 [1.99, 2.29], p<0.00001), though serious adverse events showed no significant difference (RR 0.98 [0.89, 1.08], p=0.68). Identified serious adverse events potentially related to vaccination included hypersensitivity reactions, dermal filler reactions, Bell’s palsy, thromboembolism, and pericarditis, though specific rates were not provided.

Among lung cancer patients, the study concluded that patients could “safely achieve a strong immune response”, though specific adverse event data were not detailed. In kidney transplant recipients, during 5-month follow-up, two rejection episodes and one IgA nephropathy recurrence occurred, though causality with vaccination was not established.

Synthesis

The evidence demonstrates substantial heterogeneity in immune responses to elasomeran vaccination, which can be explained through several distinct mechanisms rather than representing contradictory findings.

Population-Specific Response Margins

The apparent discrepancy between high efficacy in healthy populations (RR 0.08 for preventing COVID-19) and variable seropositivity in immunocompromised groups reflects distinct immune capacity margins. Lung cancer patients achieved 95.2% seropositivity, multiple myeloma patients 91.7%, and rheumatic disease patients 82%, while hematologic malignancy patients showed only 60-66% seropositivity. These differences align with underlying B-cell function: solid tumors primarily affect tissue architecture rather than immune cell production, while hematologic malignancies directly impair lymphocyte development and antibody production. The finding that patients with B-cell malignancies (mantle cell lymphoma 11%, CLL/SLL 55%) showed the lowest response rates supports this mechanistic explanation.

Treatment-Dependent Immunosuppression Hierarchy

The variable impact of immunosuppressive treatments follows predictable patterns based on their mechanisms of action. B-cell-depleting therapies showed the strongest negative impact: anti-CD20 therapy associated with 28% seronegativity, while anti-CD38 antibodies in multiple myeloma yielded median titers of only 265 U/ml. These agents directly eliminate antibody-producing cells, explaining the profound suppression. In contrast, agents preserving B-cell populations but modulating their function showed intermediate effects: BTK inhibitors associated with 11% seronegativity, and mycophenolate in transplant recipients reduced but did not eliminate response. Treatments enhancing immune function showed opposite effects: patients on immunotherapy had decreased seronegativity odds (OR 0.25), while those receiving lenalidomide maintenance achieved median titers of 1681.2 U/ml, likely through immunomodulatory effects that enhance T-cell help for B-cell responses.

Temporal Dynamics and Dose-Response Relationships

The progressive increase in seroconversion with additional doses demonstrates a dose-response relationship rather than vaccine failure. Kidney transplant recipients improved from 26% after two doses to 71.7% after four doses, while AML/MDS patients increased from 69.6% to 95.7% after a second dose. This pattern suggests immunocompromised patients require greater antigenic stimulus to overcome suppression. The observed antibody decay (median titers declining from 429 to 139 BAU/mL between 36 days and 3 months) with 10% of initially seropositive patients converting to seronegative status indicates that maintenance of response may require more frequent boosting in these populations than in healthy individuals.

Disease State as Immune Capacity Indicator

Disease activity strongly predicted response, with patients in complete remission achieving median titers of 1242 U/ml versus 221.5 U/ml in those with lesser responses. This correlation likely reflects underlying immune competence: patients achieving disease control typically have better preserved immune function and lower disease burden. Progressive disease associated with higher seronegativity may result from both disease-related immune dysfunction and typically more intensive immunosuppressive treatment requirements.

Platform-Specific Immunogenicity

The superior performance of mRNA vaccines over viral vector vaccines in rheumatic disease patients (85% vs 69% optimal response) and consistently higher antibody levels with mRNA-1273 and BNT162b2 versus Ad26.CoV2.S in IBD patients (log10 values 4.20 and 3.92 vs 1.96 at 2 weeks) likely reflects fundamental differences in antigen presentation kinetics and magnitude. mRNA vaccines enable prolonged in situ antigen production, potentially compensating for impaired immune surveillance in immunocompromised patients. This advantage persisted even when controlling for immunosuppression status, suggesting platform-intrinsic rather than population-dependent differences.

References

P. Ratajczak, Zuzanna Banach, Dorota Kopciuch, A. Paczkowska, Tomasz Zaprutko, and 3 more\ (2023).Tozinameran (Pfizer, BioNTech) and Elasomeran (Moderna) Efficacy in COVID-19—A Systematic Review of Randomised Controlled Trial Studies. Healthcare

Nina Kreuzberger, C. Hirsch, M. Andreas, Lena Böhm, Paul J. Bröckelmann, and 18 more\ (2022).Immunity after COVID-19 vaccination in people with higher risk of compromised immune status: a scoping review. Cochrane Database of Systematic Reviews

K. Mancuso, E. Zamagni, V. Solli, L. Gabrielli, L. Pantani, and 14 more\ (2021).High Humoral Response after Anti-Sars-Cov-2 mRNA-Based Vaccines in Patients with Active Multiple Myeloma (MM) and Relationship with Disease Status/Line of Therapy. Blood

Narcis-George Manolache, V. Ursachi, A. Scohy, Charlotte Desmet, J. Yombi, and 2 more\ (2021).Attenuated anti-SARS-CoV-2 antibody response to vaccination in patients with rheumatic diseases. Journal of Infection

V. Pozdnyakova, G. Botwin, K. Sobhani, J. Prostko, J. Braun, and 45 more\ (2021).Decreased Antibody Responses to Ad26.COV2.S Relative to SARS-CoV-2 mRNA Vaccines in Patients With Inflammatory Bowel Disease. Gastroenterology

S. Ehmsen, A. Asmussen, S. Jeppesen, A. Nilsson, Sabina Østerlev, and 5 more\ (2021).Antibody and T cell immune responses following mRNA COVID-19 vaccination in patients with cancer. Cancer Cell

M. Seija, Florencia Rammauro, Javier Noboa, J. Santiago, N. Orihuela, and 38 more\ (2022).Humoral Response to Heterologous SARS-CoV-2 Vaccination in Kidney Transplant Patients Is Heterogeneous and Dose Dependent. Kidney International Reports

D. Martins-Branco, G. Nader-Marta, A. Tečić Vuger, V. Debien, L. Ameye, and 8 more\ (2022).Immune response to anti-SARS-CoV-2 prime-vaccination in patients with cancer: a systematic review and meta-analysis. Journal of Cancer Research and Clinical Oncology

A. Jain, Ning Dong, S. Ball, Elaine S Tan, Junmin Whiting, and 8 more\ (2021).Responses to Sars-Cov-2 Vaccines in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia. Blood

M. Provencio, A. Estival, Fernando Franco, G. López-Vivanco, M. Saigí, and 25 more\ (2021).Immunogenicity of COVID‑19 Vaccines in Lung Cancer Patients: A SOLID Substudy Interim Analysis. Social Science Research Network

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Tozinameran (Pfizer, BioNTech) and Elasomeran (Moderna) Efficacy in COVID-19—A Systematic Review of Randomised Controlled Trial Studies

P. Ratajczak, Zuzanna Banach, Dorota Kopciuch, A. Paczkowska, Tomasz Zaprutko, J. Krawczyk, Barbara Maciuszek-Bartkowska, K. Kus

Healthcare·

2023·

3 citations

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Study Design

- Study type: Meta-analysis of randomized controlled trials (RCTs) - Sample size for elasomeran recipients: Not explicitly mentioned - Control/comparison groups: Placebo - Follow-up duration: 35 days to 225 days - Primary vs secondary analysis: Primary analysis includes efficacy (clinical response) and adverse events (AEs); secondary analysis includes serious adverse events (SAEs) - Risk of bias indicators: Double-blind randomization; JADAD scale score of 4.5 out of 5; some concerns regarding bias due to deviations from intended interventions and randomization processes

Population Characteristics

- Age distribution: Healthy persons aged over 16 - Immunocompromising conditions: Excluded - Prior COVID-19 infection status: Not mentioned - Comorbidities affecting immune function: Not mentioned - Active cancer treatment status and type at vaccination: Not mentioned - Performance status or functional status measures: Not mentioned

Vaccination Details

- Dose administered: 100 μg - Vaccination schedule: Two doses administered on days 0 and 28 - Number of doses received by participants: Two doses - Completion rates for full vaccination series: Not explicitly mentioned - Time from last dose to outcome measurement: 14 days after the second dose - Any booster doses included in analysis: Not mentioned

Humoral Immune Response

- Seropositivity rates with thresholds used: Not mentioned - Quantitative antibody titers (geometric mean, median, range): Not mentioned - Antibody types measured (IgG anti-spike, neutralizing, anti-RBD): Neutralizing antibodies mentioned, but no specific types detailed - Assay methods and platforms used: Not mentioned - Seroconversion rates from baseline: Not mentioned - Antibody levels at different time points post-vaccination: Highest immunity observed 14 days after the second dose - Durability data (antibody persistence over months): Not mentioned

Cellular Immune Response

Not mentioned (the paper does not provide specific details on T-cell and cellular immune response measures after elasomeran vaccination)

Clinical Protection Outcomes

- COVID-19 breakthrough infection rates: 0.23% for elasomeran vs. 3.29% for placebo - Severity of breakthrough infections: Not mentioned - Hospitalizations and deaths due to COVID-19 post-vaccination: Not mentioned - Vaccine effectiveness percentages against infection: Risk ratio of 0.07 [0.05, 0.09] for elasomeran - Time to breakthrough infection from vaccination: Immunity observed 14 days after second dose for elasomeran - Variant-specific protection data: Not mentioned

Response Modifying Factors

- Specific treatments affecting response: Not mentioned - Disease status at vaccination: Not mentioned - Demographic factors affecting response: Age (healthy individuals aged over 16) - Laboratory parameters correlating with response: Not mentioned - Statistical analyses of predictors and odds ratios/effect sizes: Not mentioned

Safety and Tolerability

- Local reactions: Not specified (rates and severity) - Systemic reactions: Not specified (rates and severity) - Serious adverse events: Hypersensitivity reactions, dermal filler reactions, Bell's palsy, thromboembolism, pericarditis (no specific rates or severity) - Tolerability in immunocompromised populations: Not applicable (excluded from trials) - Disease progression or cancer-related outcomes: Not mentioned

Background: The objective of this research was to test the efficacy and safety profile of tozinameran (30 μg, BNT162b2, Pfizer, BioNTech) and elasomeran (100 μg, mRNA-1273, Moderna) in COVID-19 prevention in ≥16-year-old patients vaccinated with two doses. Methods: A meta-analysis of the literature was conducted using the MEDLINE and EMBASE databases, following inclusion and exclusion criteria. Eight RCTs have been selected. The results were presented using the risk ratio (RR) with a 95% confidence interval (CI). A fixed-effect model or random-effect model was applied based on the heterogeneity of the results. Results: BNT162b2 and mRNA-1273 vaccines are efficient in preventing COVID-19 in comparison to a placebo (MH, RR 0.08 [0.07, 0.09] p < 0.00001 (95% CI)). It was found that administering the vaccines BNT162b2 and mRNA-1273 was associated with a higher proportion of adverse events in comparison to the placebo (IV, RR 2.14 [1.99, 2.29] p < 0.00001 (95% CI)). Administering the vaccines BNT162b2 and mRNA-1273 was associated with a higher proportion of serious adverse events in comparison to the placebo (MH, RR 0.98 [0.89, 1.08] p = 0.68 (95% CI)). Conclusions: Tozinameran and elasomeran are effective and safe in preventing the occurrence of COVID-19.

1.Introduction

In the face of the COVID-19 pandemic, vaccines containing tozinameran (Pfizer) and elasomeran (Moderna) were approved for use in December 2020 and January 2021, respectively [1,2]. Both preparations are mRNA based [3].

SARS-CoV-2 is one of the viruses under constant evolution. The essential variants demonstrating increased virus transmission and pathogenicity (as of the first half of 2022) [4] In most cases, the characteristic symptoms of COVID-19 are similar to other respiratory diseases, making it difficult to diagnose and possibly enhancing the virus's spreading [5].

Tozinameran (Comirnaty ® , Pfizer, New York, NY, USA and BioNTech, Mainz, Germany), the Pfizer-BioNTech COVID-19 vaccine, is an mRNA-based vaccine developed by Pfizer and BioNTech to prevent COVID-19. The vaccine is highly effective in clinical trials, with an efficacy rate of 95% in preventing COVID-19 infections. The vaccine has been authorised for emergency use by regulatory agencies worldwide, including the FDA in the United States and the EMA in Europe. It has been administered to millions globally, and its safety and efficacy have been extensively studied and monitored. Its activity stimulates the immune system, conditioning the body's response to potential contact with the SARS-CoV-2 virus. It enables the immune system to produce antibodies and blood cells to neutralise the virus and provide protection against COVID-19 [6]. Messenger RNA with modified nucleosides is enclosed in lipid nanoparticles; thus, RNA may enter the host cells and develop antigen S expression of SARS-CoV-2. RNA codes S-protein on the entire length with two point mutations in the centre spiral, and, as a result of the amino acid's modification to proline, the S-protein becomes blocked in an antigen perforated prefusion conformation. As a result of the vaccine activity, patients develop an immune response-production of the neutralising antibodies and cell-mediated immunity-against the S-protein antigen [6].

Elasomeran, also known as the Moderna COVID-19 vaccine, is an mRNA-based vaccine developed by Moderna to prevent COVID-19. Like the Pfizer-BioNTech vaccine, it is highly effective in clinical trials in preventing COVID-19 infections. Like the Pfizer-BioNTech vaccine, elasomeran has been authorised for emergency use by regulatory agencies worldwide, including the FDA in the United States and the EMA in Europe [3]. It has also been extensively studied and monitored for its safety and efficacy. Elasomeran (Spikevax ® , Moderna, Cambridge, MA, USA) has the form of dispersion for injections and is an mRNA vaccine (with modified nucleosides). The vaccine contains mRNA in lipid nanoparticles coding the S-protein of SARS-CoV-2 modified with two substitutes of prolines in the heptad repeat domain 1 (S-2P), which allows the S-protein to be maintained in the prefusion conformation. After injection, the lipid particles are absorbed and RNA is delivered into the cells to enable protein translation and biosynthesis. Following the expression, the immune system recognises the S-protein as a foreign antigen, which induces the immune response from T and B lymphocytes and promotes the production of neutralising antibodies.

Randomised controlled trials (RCTs) are widely regarded as the most reliable means of establishing cause-and-effect relationships in clinical research [7]. Evidence-based medicine (EBM) emphasises the importance of seeking the best possible evidence for each patient, and RCTs are generally considered the highest-quality study design in this hierarchy [8]. RCTs are typically used to objectively evaluate the impact of an intervention (such as a drug or procedure) on a particular outcome. While some researchers may argue that other sources of knowledge should also be considered, it should be noted that RCTs are designed to minimise the influence of extraneous variables and provide a high level of experimental control. As a result, they are considered a particularly robust means of establishing causality between interventions and outcomes.

The research objective of this study was to answer the question: Are tozinameran (Pfizer, BioNTech) and elasomeran (Moderna) efficient and safe in COVID-19 prevention in patients vaccinated with two doses? A quantitative assessment was performed regarding the vaccines' efficacy about the number of patients who tested positive for COVID-19, and the safety profile based on the number of adverse events (AEs) (including serious adverse events SAEs) which were a consequence of the vaccines' administration. To obtain the highest quality of results, a sensitivity analysis was also performed. This paper is based solely on randomised controlled trials in the field of COVID-19 vaccines.

2.1.Inclusion/Exclusion Criteria

The trials which met the following criteria were included in the review (inclusion criteria):

Randomised controlled trial (highest quality of the data).

Double-blind.

The population covered by the trial included healthy persons aged over 16.

Patients were vaccinated with two doses of tozinameran (30 µg) or elasomeran (100 µg) vaccines.

The effects were compared to a placebo.

The measure of the vaccine's efficacy was the proportion of persons with or without a confirmed diagnosis of COVID-19 (based on RT-PCR test) 7 days after the 2nd dose of the BNT162b2 vaccine and 14 days after the 2nd dose of the mRNA-1273 vaccine.

Papers which met the following criteria were excluded from further analysis:

The trial did not include randomisation and double-blinding.

Patients did not receive two doses of either vaccine.

The comparator was not a placebo.

The vaccine doses were other than 30 µg of tozinameran and 100 µg of elasomeran.

2.2.Databases and Publication Search Methods

The available literature was reviewed using the MEDLINE database via the PubMed and EMBASE databases. The selected keywords for the search are presented in the Supplementary File, Tables S1 and S2 . The MESH vocabulary thesaurus and EMTREE extended the searched topics. The terms of Boole's logic AND and OR were applied during the search. The search was performed in February 2022 and included papers published since 2019.

2.3.Bibliographic Analysis

A bibliographic data analysis was conducted on the number of published studies in the MEDLINE databse via the PubMed database related to the analysed vaccines (tozinameran and elasomeran). Studies were searched using keyword combinations defined in Tables S1 and S1A , associating tozinameran or elasomeran with adverse events or outcome types. The number of RCTs, observational studies, meta-analyses, systematic reviews, case reports, clinical trials, and editorials in this pool were also determined by utilising the functionality available in PubMed. The time range of the publications covered the years 2020 to 2022.

The citation data of the studies included in the analysis were presented based on the results from the Web of Science website (as of 3 March 2023).

2.4.Data Selection and Collection

The selection of papers with the use of the inclusion/exclusion criteria and the website www.rayyan.ai was made by two independent researchers. The reviewers assessed the included publications and the conflicts were resolved by consultation. The respective phases of the selected papers are presented graphically with a PRISMA diagram [9] in Figure 1 .

The extracted data from each publication include the study's first author, the number of participants in the trial group and control group, the dose of the vaccine, the number of doses, the type of diagnostics applied, and the method of reporting the adverse events. The literature review was based on the evidence from randomised clinical trials evaluating the efficacy and safety in the light of the application of elasomeran and tozinameran in persons over the age of 16. No limitations were found regarding sex, race, ethnic origin, cultural groups, publication language, trial region, or virus variant. Literature references given in the papers were also analysed to find additional publications. Additional limitations are presented in the Supplementary File.

given in the papers were also analysed to find additional publications. Additional limitations are presented in the Supplementary File.

2.5.1.Assessment of the Risk of Bias and Missing Data

The risk of bias was assessed for each included study based on the available methodology [10,11] using the Review Manager 5.4. software. The resulting conflicts were explained by consultation. No missing data were confirmed.

2.5.2.Assessment of the Quality of Clinical Trials-JADAD Scale

Each RCT was assessed using the JADAD scale [12] to check its methodological quality (Supplementary File, Table S3 ). Each trial was scored on a scale from 0 to 5. Doubleblind randomisation was given a score of 1, while single-blind was given a score of 0.5.

2.5.3.Certainty of Evidence

Each reported outcome was assessed following the grading of recommendations, assessment, development and evaluation (GRADE) working group, using the GRADEpro tool (www.gradepro.org).

2.5.4.Outcome Measurement

Outcome measurements conducted during the review process were:

Vaccine efficacy was confirmed by the diagnosis of COVID-19 based on an RT-PCR test 7 days after the 2nd dose of the BNT162b2 vaccine and 14 days after the 2nd dose of the mRNA-1273 vaccine). The risk of bias was assessed for each included study based on the available methodology [10,11] using the Review Manager 5.4. software. The resulting conflicts were explained by consultation. No missing data were confirmed.

2.5.2.Assessment of the Quality of Clinical Trials-JADAD Scale

Each RCT was assessed using the JADAD scale [12] to check its methodological quality (Supplementary File, Table S3 ). Each trial was scored on a scale from 0 to 5. Double-blind randomisation was given a score of 1, while single-blind was given a score of 0.5.

2.5.3.Certainty of Evidence

2.5.4.Outcome Measurement

Outcome measurements conducted during the review process were:

Vaccine efficacy was confirmed by the diagnosis of COVID-19 based on an RT-PCR test 7 days after the 2nd dose of the BNT162b2 vaccine and 14 days after the 2nd dose of the mRNA-1273 vaccine).

The overall number of adverse events (AEs) such as erythema, tenderness, swelling, pain after injection, fever, headache, fatigue, myalgia, arthralgia, nausea, vomiting, and chills.

The number of serious adverse events (SAEs) (life-threatening) such as hypersensitivity reactions, dermal filler reactions, Bell's palsy, thromboembolism, and pericarditis.

2.5.5.Quantitative Synthesis of Included Trials

The data collected from the publications were entered into Review Manager 5.4. Afterwards, the data were verified by two authors. An MS Excel 2019 spreadsheet was also used for the initial stages of meta-analysis.

The analysis of dichotomous variables was presented with a risk ratio (RR) and the use of a 95% confidence interval (CI) [11,13]. The RR was calculated by dividing the risk of the outcome occurring in the intervention group by the risk of the same outcome occurring in the control group. A risk ratio of 1 means there is no difference in the risk between the two groups, while a risk ratio greater or lower than 1 indicates, respectively, a higher or lower risk in the intervention group compared to the control group. Due to the limited data, under the assessment of efficacy and safety profile of severe AEs the Mantel-Haenszel method and fixed-effect model were applied, as the analysed initial papers were found to demonstrate low heterogeneity-I 2 < 50% (if the heterogeneity of the included results was lower then 50%, a fixed-effect model was applied). In contrast, the inverse variance method was used to assess the safety profile for the general number of AEs. This analysis was applied if the included studies demonstrated high heterogeneity (I 2 > 50%), and, if so, the random-effect model was used. This is a model suitable for high heterogeneity because it specifies the wider confidence interval and allows the determination of the general effects measures compared to the fixed-effect model.

The Mantel-Haenszel method used in the fixed-effect model involves calculating a weighted average of the risk ratios from each study, with the weights determined by the size of each study. The method considers any differences in the characteristics of the studies, such as study design or population, and provides a pooled estimate of the effect size that is adjusted for these differences. On the other hand, in the inverse variance method, each study's effect size estimate is divided by its corresponding variance. The resulting value is known as the weighted effect size. The weights assigned to each study are the inverse of their variances. Studies with smaller variances, and thus more precise estimates, are given more weight in calculating the summary effect estimate.

A table summarising the initial trials included in the analysis and the meta-analysis results is presented in the Supplementary File (Table S4 ).

2.5.6.Assessment of the Heterogeneity of the Studies

The collected studies contain variables concerning the methodologies used, the characteristics of patients, and the studied interventions. Such differences lead to the occurrence of heterogeneity. Therefore, after extracting the basic values subject to the trial, it was assessed whether the data was sufficiently homogeneous to combine it in the meta-analysis.

The statistical heterogeneity was quantified with the use of the statistical test I 2 . The results were interpreted in compliance with the recommended methodology [11]. Forest plots generated using the Review Manager 5.4 software were also used in the heterogeneity assessment (visual interpretation).

3.1.Study Selection

In a review, 2202 publications were identified, of which 224 duplicates were rejected. Based on the titles and abstracts, 1911 studies were excluded due to the vaccines' improper population and type or dose. Sixty-seven publications were selected for further analysis, and eight papers were included in the review after a full-text analysis.

Studies not referring to the mRNA-1273 or BNT162b2 vaccines, or which did not contain data concerning the doses, 100 µg and 30 µg, respectively, were excluded from the analysis. Studies in which the results were compared to other vaccines without reference to a placebo were also excluded (Figure 1 ).

3.2.Characteristics of Studies Included in the Analysis

The review included eight studies. In two of them, patients aged over 16 were randomised [14,15]. Four studies covered patients aged over 18 [16][17][18][19]. In other studies [20,21], the trial group covered participants aged over 20. The pooled results are presented in Table S4 .

Patients with an immune disease reducing their immunity were excluded. All patients were administered the vaccine intramuscularly in two doses, BNT162b2 on days 0 and 21 and mRNA-1273 on days 0 and 28.

3.3.Assessment of the Quality of Studies Included in the Analysis

Each of the potential sources of bias was assessed as "high", "low", or "some concerns". The assessment of the "risk of bias 2.0" for the studies included in the analysis is presented graphically (Figure 2 ). None of the studies was assessed as being burdened with a high risk of bias.

and eight papers were included in the review after a full-text analysis.

Studies not referring to the mRNA-1273 or BNT162b2 vaccines, or which did not contain data concerning the doses, 100 μg and 30 μg, respectively, were excluded from the analysis. Studies in which the results were compared to other vaccines without reference to a placebo were also excluded (Figure 1 ).

3.2.Characteristics of Studies Included in the Analysis

3.3.Assessment of the Quality of Studies Included in the Analysis

Each of the potential sources of bias was assessed as "high", "low", or "some concerns". The assessment of the "risk of bias 2.0" for the studies included in the analysis is presented graphically (Figure 2 ). None of the studies was assessed as being burdened with a high risk of bias. It was also assessed whether the trials were randomised, blinded, or the number of excluded participants was provided. The studies included in the meta-analysis were good quality (a score of 4.5 score out of a possible 5 on the JADAD scale) (Supplementary File Table S5 ). It was also assessed whether the trials were randomised, blinded, or the number of excluded participants was provided. The studies included in the meta-analysis were good quality (a score of 4.5 score out of a possible 5 on the JADAD scale) (Supplementary File Table S5 ).

The GRADEpro tool was used to assess the certainty of the evidence. The assessed outcomes for the BNT162b2 vaccine were clinical response, high quality; AEs, high quality; and SAEs, moderate quality (Supplementary File, Table S6 ). The corresponding outcomes for the mRNA-1273 vaccine were clinical response, high quality; AEs, low quality; and SAEs, moderate quality (Supplementary File, Table S7 ).

3.4.Results of the Meta-Analysis

The efficacy (clinical response) assessment included two papers concerning the BNT162b2 [10,11] vaccine and two papers concerning the mRNA-1273 vaccine [12,14]. The AEs assessment included eight articles: four concerning BNT162b2 [14,15,19,20] and four concerning mRNA-1273 [16][17][18]21], which were additionally divided according to symptoms after the first and second doses of the vaccines. The eight previously mentioned papers were included in assessing the serious adverse events (SAEs): four concerning BNT162b2 and four involving mRNA-1273, but some of them [17,[19][20][21] did not report any serious adverse events.

3.5.Clinical Response

The results (Figure 3 ) show that both the BNT162b2 and mRNA-1273 vaccines were effective in preventing COVID-19 in comparison to the placebo (Mantel-Haenszel RR 0.08 [0.07, 0.09] p < 0.00001 (95% CI)). In total, four papers were included in the analysis. The number of patients was 67,617 for the tested intervention and 67,658 for the placebo. The total number of participants was 135,275. Statistical heterogeneity between the studies was low (I 2 = 29%). The results for the subgroups: BNT162b2 (Mantel-Haenszel method RR 0.08 [0.07, 0.11] p < 0.00001 (95% CI), I 2 = 61%); mRNA1273 (Mantel-Haenszel method RR 0.07 [0.05, 0.09] p < 0.00001 (95% CI), I 2 = 0%).

BNT162b2 [10,11] vaccine and two papers concerning the mRNA-1273 vaccine [12,14]. The AEs assessment included eight articles: four concerning BNT162b2 [14,15,19,20] and four concerning mRNA-1273 [16][17][18]21], which were additionally divided according to symptoms after the first and second doses of the vaccines. The eight previously mentioned papers were included in assessing the serious adverse events (SAEs): four concerning BNT162b2 and four involving mRNA-1273, but some of them [17,[19][20][21] did not report any serious adverse events.

The results (Figure 3 ) show that both the BNT162b2 and mRNA-1273 vaccines were effective in preventing COVID-19 in comparison to the placebo (Mantel-Haenszel RR 0.08 [0.07, 0.09] p < 0.00001 (95% CI)). In total, four papers were included in the analysis. The number of patients was 67,617 for the tested intervention and 67,658 for the placebo. The total number of participants was 135,275. Statistical heterogeneity between the studies was low (I 2 = 29%). The results for the subgroups: BNT162b2 (Mantel-Haenszel method RR 0.08 [0.07, 0.11] p < 0.00001 (95% CI), I 2 = 61%); mRNA1273 (Mantel-Haenszel method RR 0.07 [0.05, 0.09] p < 0.00001 (95% CI), I 2 = 0%).

3.6.Adverse Events

Based on the data obtained (Figure 4 ), it was found that administering the vaccines BNT162b2 and mRNA-1273 was associated with a higher proportion of AEs in comparison to the placebo (inverse variance RR 2.14 [1.99, 2.29] p < 0.00001 (95% CI)). The heterogeneity was 97% (I 2 = 97%). The count was 104,087 for the intervention group and 103,555 for the placebo group. Two subgroups were introduced in the analysis: one concerned the BNT162b2 vaccine and the other the mRNA-1273 vaccine, the analysis of which was additionally divided into AEs occurring after the first and second doses, according to the

Based on the data obtained (Figure 4 ), it was found that administering the vaccines BNT162b2 and mRNA-1273 was associated with a higher proportion of AEs in comparison to the placebo (inverse variance RR 2.14 [1.99, 2.29] p < 0.00001 (95% CI)). The heterogeneity was 97% (I 2 = 97%). The count was 104,087 for the intervention group and 103,555 for the placebo group. Two subgroups were introduced in the analysis: one concerned the BNT162b2 vaccine and the other the mRNA-1273 vaccine, the analysis of which was additionally divided into AEs occurring after the first and second doses, according to the reports on the trials. In both groups, a larger proportion of patients experiencing AEs existed in the group receiving the vaccine. Results for the subgroups: BNT162b2 (inverse variance RR 2.18 [2.12, 2,24] p < 0.00001 (95% CI), I 2 = 0%); mRNA-1273 (inverse variance RR 2.13 [1.96, 2.32] p < 0.00001 (95% CI), I 2 = 98%). The RR analysis for the events occurring after the first and second doses indicates a higher frequency of AEs after the second dose for both vaccines.

reports on the trials. In both groups, a larger proportion of patients experiencing AEs existed in the group receiving the vaccine. Results for the subgroups: BNT162b2 (inverse variance RR 2.18 [2.12, 2,24] p < 0.00001 (95% CI), I 2 = 0%); mRNA-1273 (inverse variance RR 2.13 [1.96, 2.32] p < 0.00001 (95% CI), I 2 = 98%). The RR analysis for the events occurring after the first and second doses indicates a higher frequency of AEs after the second dose for both vaccines.

3.7.Serious Adverse Events

Based on the data obtained (Figure 5 ), it was found that administering the vaccines BNT162b2 and mRNA-1273 was associated with a higher proportion of SAEs in comparison to the placebo (Mantel-Haenszel RR 0.98 [0.89, 1.08] p= 0.68 (95% CI)). The total heterogeneity was 5% (I 2 = 5%). The count was 74,409 for the intervention group and 74,189 for the placebo group. Results for the subgroups: BNT162b2

Based on the data obtained (Figure 5 ), it was found that administering the vaccines BNT162b2 and mRNA-1273 was associated with a higher proportion of SAEs in comparison to the placebo (Mantel-Haenszel RR 0.98 [0.89, 1.08] p= 0.68 (95% CI)). The total heterogeneity was 5% (I 2 = 5%). The count was 74,409 for the intervention group and 74,189 for the placebo group. Results for the subgroups: BNT162b2

3.8.Sensitivity Analysis

A sensitivity analysis was performed due to high heterogeneity (I 2 = 97%) (Figure 4 ) in the total number of AEs. Since the medications' manufacturers sponsored seven out of the eight papers in the analysis, no exclusion or sensitivity analysis concerning that fact was performed.

A sensitivity analysis was performed due to high heterogeneity (I 2 = 97%) (Figure 4 ) in the total number of AEs. Since the medications' manufacturers sponsored seven out of the eight papers in the analysis, no exclusion or sensitivity analysis concerning that fact was performed.

3.9.Sensitivity Analysis Based on Two Doses of the Vaccines

The initial division into subgroups concerning the BNT162b2 (results only after the second dose) and mRNA-1273 (results after the first and second doses) vaccines presented in Figure 4 was modified to subgroups concerning the analysis of the number of AEs observed separately after the first dose (only in the case of mRNA-1273) or after the second dose (BNT162b2 and mRNA-1273).

Four studies were identified in which the assessment was based on only one dose [16][17][18]21]. In the other studies, only information on the number of adverse events after the second dose was available. After the analysis, the heterogeneity ratio for the observation of adverse events after the second dose of the vaccines was reduced from 97% to 40% (Figure 6 ), which means the reduction of heterogeneity to a moderate value (inverse variance RR 2.17 [2.17, 2.22] p < 0.00001 (95% CI)). Heterogeneity for the first dose was reduced, however, it still demonstrated a high value of 79% (Figure 6 ) (inverse variance RR 1.86 [1.78, 1.94] p < 0.00001 (95% CI)).

3.10.Sensitivity Analysis Concerning Elasomeran

A sensitivity analysis of the number of AEs based only on the studies concerning elasomeran was also performed, as they demonstrated a higher level of heterogeneity (I 2 = 98%). The initial division (Figure 4 ) was modified into four subgroups concerning the analysis of the number of AEs observed (Figure 7 ): the first group (I) was concerned with the result after the first dose [16][17][18]21]; the second group (II) concerned the result after the second dose [16][17][18]21]; the third group (III) included small trials [17,21]; and the fourth group (IV) included large trials [16,18]. After the analysis, the heterogeneity ratio was reduced for subgroups I, II, and III, however, it still indicated significant heterogeneity for subgroup IV (the heterogeneity increased to 99%) (Figure 7 )

3.10.Sensitivity Analysis concerning Elasomeran

3.11.Publication Quantity and Citation Metrics

The analysis of the number of publications in the MEDLINE database via the PubMed database showed 4680 records related to tozinameran (88 studies were previously published as preprints) and 1643 records related to elasomeran (70 preprints). Among the records related to tozinameran, 693 papers were related to vaccine efficacy studies and 313 records covered adverse events. Regarding tozinameran, 45 RCTs, 225 observational studies, 32 meta-analyses, 75 systematic reviews, 635 case reports, 86 clinical trials, and 36 editorials were published. Most of the publications (4612 out of 4680) were in English. On the other hand, in the case of elasomeran, 269 records related to vaccine efficacy studies and 138 papers related to adverse events were found. A total of 30 RCTs, 68 observational studies, 24 meta-analyses, 55 systematic reviews, 250 case reports, 54 clinical trials, and 17 editorials were identified. Of the 1643 publications, 1620 were in English. The results are presented in Table 1 . Higher heterogeneity occurred among large trials (99%) and in those papers which analysed the results after one dose (79%).

4.Discussion

All of the studies included in the analysis were reliable (Figure 2 and Table S5 ), however, the risk of bias could not be excluded [10,11]. A high risk of bias was not identified in any of the studies. However, six out of the eight studies had "some concerns" regarding their quality, as evaluated by the risk of bias 2.0 method. In most cases, the concerns were based on bias due to deviations from the intended intervention (authors mainly did not provide proper adherence to the intervention method [15,17,[19][20][21]) as well as bias related to the randomisation process (no information about allocation sequence concealment) [14,15,[19][20][21].

The meta-analysis has proven the efficacy of elasomeran and tozinameran in preventing COVID-19 in persons over 16 years of age compared to a placebo (Figure 3 ). It was confirmed that COVID-19 occurred in 0.22% of patients vaccinated with tozinameran, in comparison to 2.57% in case of the placebo. In studies concerning elasomeran, COVID-19 occurred in 0.23% of patients vaccinated with mRNA-1273 and in 3.29% in the placebo group (Figure 3 ). All of the included studies demonstrated significant results differences between the administration of the active substance and the placebo. In earlier meta-analyses, such a relation was also shown, but in most cases the authors were also concerned with the vector vaccines, which led to high heterogeneity. For example, in the paper by Fan et al. 2021 [22], the efficacy of mRNA, vector, and inactivated vaccines was combined in the analyses, and the result was favourable for the vaccines, however, heterogeneity amounted to 99%. With such high heterogeneity values, the results should be interpreted with caution. Fan et al. 2021 [22] included in their analysis ten studies, however, these also included non-randomised trials. This paper's efficacy analysis involves four trials [14][15][16]18], all randomised and concerned with two vaccine doses.

The results of the meta-analysis concerning the total number of AEs indicate that they were more frequent in vaccinated patients (Figure 4 ). When the analysed technologies examine vaccines, one must reckon with the occurrence of AEs resulting from the activation of the immune system as a result of which the specific immunity against a pathogen is developed. One must also take into account allergic reactions, for instance, in the result of contact with polyethylene glycol present in mRNA vaccines, and the fact that most trials were carried out in the autumn-winter season, therefore, the symptoms reported as post-vaccination might have been caused by contact with another virus, e.g., influenza or RSV.

The analysis of serious AEs indicates that the analysed vaccines are relatively safe (Figure 5 ). In the group receiving a placebo, the occurrence of SAEs was less frequent in comparison to the group administered with BNT162b2, whereas in the placebo group, it was more frequent than in the group administered with mRNA-1723. This might be due to different qualifications of local or systemic events as SAEs, or non-reporting an event as serious if it was proven to be associated with the administered intervention. Additionally, in four out of the eight studies [17,[19][20][21] no SAEs were reported, both for the vaccines and the placebo; therefore, they were not included in the analysis.

General studies of the AEs indicated significant heterogeneity at the level of 98% (Figure 4 ), whereas the heterogeneity for the clinical response and SAEs analysis was 29% and 5%, respectively (Figures 3 and 5 ). Multiple factors may cause this increased heterogeneity, e.g., the region in which the trial was made, the age of the participants, and the trial date, because, depending on the time when the study was performed, a different variant of SARS-CoV-2 virus was active. Moreover, the duration of each of the trials was different (Table S4 ), and the follow-up of the participants lasted from 35 days [19] to a maximum of 225 days [18], which could be the reason for the more significant number of COVID-19 cases and AEs in the trials that lasted longer.

The duration of each trial also affects the determination of long-term immunity in patients vaccinated with two doses of the mRNA vaccine. Among the four studies included in the efficacy (clinical response) analysis, the longest was the trial by Sahly et al. 2021 [18], in which the patients' follow-up period was 225 days. The most accurate method of determining the duration of immunity would be the analysis of the antibodies present in the blood of vaccinated patients. Four out of the eight studies included in the meta-analysis described the influence of vaccines on the level of antibodies by providing the values of GMT, however, the results were too heterogeneous to perform a proper analysis [17,[19][20][21]. In trials concerning tozinameran, it was observed that the highest immunity occurred 7 days after taking the second dose [19] or was significantly increased on the 7th day after taking the second dose and maintained a similar value at least until day 35, marking the end of the results collection [20]. In the case of elasomeran, it was 14 days from the administration of the second dose [17,21]. This confirms that the method of case calculation assumed in this paper for the efficacy (clinical response) assessment (7 days after the second dose for the BNT162b2 vaccine and 14 days after the second dose for the mRNA-1273 vaccine) is correct.

Due to significant heterogeneity in the studies included in the analysis of general AEs (Figure 4 ), a double sensitivity analysis was performed. Statistical heterogeneity was quantified with the use of the statistical test I 2 . The first analysis was performed based on the number of vaccine doses (one or two doses regarding BNT162b2 and mRNA-1273). The second analysis concerned only elasomeran and was divided into four subgroups-results after the first dose, after the second dose, results from small trials and large studies. For the first analysis (Figure 6 ) there was a decrease of heterogeneity to a moderate value (40%) for the subgroup concerning AEs observed after the second dose of both vaccines. Moreover, in the case of the subgroup concerning AEs observed after only the first dose of elasomeran, a decrease in heterogeneity was also observed, however, the value was still too high (79%) (Figure 6 ). Therefore, the decision was made to perform a further sensitivity analysis, this time only for the vaccine based on elasomeran (Figure 7 ). For the subgroup of studies concerning the first dose, second dose, and small trials, the heterogeneity was reduced to 60-79%, whereas the results concerning large trials still demonstrated high heterogeneity (99%) [16,18] (Figure 7 ). So, the reduction of heterogeneity was only achieved in studies concerning events registered after the second dose in the analysis of both vaccines, probably because the analysed vaccines were described as two-dose interventions. The patient developed immunity against SARS-CoV-2 only after receiving an entire vaccination cycle. Reactions after the first dose were individual and dependent on the predisposition of each patient's immune system. A high diversity of patients could cause high heterogeneity in large trials [12,14]. Moreover, in both studies, the intervention was administered to patients with a higher risk of having contact with the SARS-CoV-2 virus or patients with chronic diseases affecting the risk of complications due to COVID-19. Chen et al. 2021 [23], in their analysis, also achieved a high heterogeneity ratio for mRNA vaccine studies, which they justified with the ambiguities in the occurrence of allergic reactions associated with patients' hypersensitivity to polyethene glycol (PEG) present in the vaccines.

Limitations

Despite a thorough search for publications in the MEDLINE and EMBASE databases, there is the risk that some available clinical trials or unpublished data were not identified. Additionally, all trials included in the analysis were short term (lasting 35 to 225 days), which limits the possibility of determining a long-term effect.

Eight publications were included in the meta-analysis, but half concerned studies on relatively small groups. Although all publications were high quality and randomised, one must be cautious when applying the results to the general population, as small trials tend to overestimate the effect compared with large studies. The trials were short term, and each participant's trial period differed. Thus, the median was applied to present the follow-up period. Patients with concurrent immune system diseases, chronic severe diseases, or unstable disease conditions were excluded from the trials, which may limit the possibility of referencing the results to a larger population.

The analysis of adverse events was characterised by a high heterogeneity of the effect measure, which could be caused by differences in the vaccination schedule, taking two doses of the same vaccine, which differently engaged the immune system, and differences in recording the adverse events, which could deliver imprecise results.

While counting the events, the cumulative results were applied without specifying the populations of subgroups, such as elderly patients or patients particularly exposed to contact with the SARS-CoV-2 virus. The differences between sexes or participants from various ethnic groups were not analysed either. Additionally, there were differences in classifying events as serious, systemic, and local.

The trials were relatively short term, therefore, under the assessment of serious adverse events, no data was obtained that would apply to long-term trials, so the safety assessment may be insufficient to specify the potential events occurring within a longer period after receiving the vaccine.

Considering the severity and rapidity of the COVID-19 pandemic outbreak in 2020-2022, conducting clinical trials was much accelerated. The continuously emerging, new, more virulent virus variants may distort the assessment of the vaccines' efficacy, depending on the period when they were performed.

Most of the trials included in the meta-analysis were financed by the manufacturers of the vaccines, therefore, one cannot exclude a conflict of interest that might have affected the reliability of the presented results. Seven out of the eight studies were sponsored by pharmaceutical companies manufacturing the vaccines (Pfizer/BioNTech, Moderna). One of the studies was supported by the pharmaceutical company Takeda.

5.Conclusions

It may be stated that both tozinameran and elasomeran are efficient in preventing COVID-19, however, the results must be referred to the general population with caution due to the short period of trials and the significant heterogeneity of publications included in the meta-analysis. Considering that the meta-analysis contained only eight randomised studies, further high-quality clinical trials must be carried out on the largest scale possible to verify and confirm the results.

availability

Data Availability Statement: All data analysed during the study are available on reasonable request.

Conflicts of Interest:

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the results reported in this paper.

Supplementary Materials:

The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/healthcare11111532/s1, Supplementary information contains PubMed and Embase search procedure, Jadad scale and score, summary results table, risk of bias assessment, GRADE assessment. Table S1 : MEDLINE via PubMed search result. Table S1A : Additional keywords used for data presentation in Table . 1 (manuscript). Tozinameran and elasomeran data in Medline via PubMed (2020-2022). Table S2 : EMBASE search result. Table S3 : JADAD Scale. Table S4 : Summary results of efficacy and safety of mRNA COVID-19 vaccines. Table S5 : JADAD score. Table S6 : Tozinameran GRADE assessment. Table S7 : Elasomeran GRADE assessment.

Author Contributions: P.R.: conceptualization, data curation, formal analysis, investigation, methodology, resources, software, supervision, validation, visualisation, writing-original draft, writingreview and editing. Z.B.: data curation, formal analysis, investigation, software, visualisation. D.K.: data curation, validation, writing-original draft, writing-review and editing. A.P.: data curation, validation, writing-original draft, writing-review and editing. T.Z.: data curation, validation, writing-original draft, writing-review and editing. J.K.: data curation, validation, writing-original draft, writing-review and editing. B.M.-B.: writing-review and editing. K.K.: conceptualization, methodology, resources, supervision, validation, writing-original draft, writing-review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

Funding: This research received no specific grant from public, commercial, or not-for-profit funding agencies.
Institutional Review Board Statement: Not applicable.Informed Consent Statement: Not applicable.

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