Nanoparticle-Mediated Cytoplasmic Delivery of Messenger RNA Vaccines: Challenges and Future Perspectives

Wu, Zimei; Li, Tonglei

doi:10.1007/s11095-021-03015-x

Cited by 80 publications

(74 citation statements)

References 26 publications

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“…The currently administered COVID-19 vaccines by Pfizer-BioNTech and Moderna both use a novel technique in which messenger RNA (mRNA) encoding the full-length viral spike protein is encapsulated in lipid nanoparticles to stimulate the production of the viral protein in the recipient's own cells, thereby provoking an immune response [72]. mRNA itself is highly immunogenic, but components of the lipid nanoparticles such as polyethylene glycol might also cause the observed reactive lymphadenopathy [73][74][75][76]. Due to the postulated strong immune response after mRNA COVID-19 vaccination, time spans of lymph node enlargement have been longer than in previous cases of vaccine-associated lymphadenopathy [77], where reactions occurred shortly after vaccination and disappeared rapidly within 14 days [54].…”

Section: Discussionmentioning

confidence: 99%

Fine needle aspiration in COVID-19 vaccine-associated lymphadenopathy

et al. 2021

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AIMS: With ongoing intensive vaccination programme against COVID-19, numerous cases of adverse reactions occur, some of which represent rare events. Enlargement of the injection site's draining lymph nodes is increasingly reported, but is not yet widely recognised as being possibly associated with recent vaccination. As patients at risk of a severe course of COVID-19, indicated by their medical history such as a previous diagnosis of malignancy, receive priority vaccination, newly palpable lymph nodes raise concerns of disease progression. In this case series, we report on five patients who presented with enlarged lymph nodes after COVID-19 vaccination.METHODS: Sonography guided fine needle aspiration (FNA) was performed in five patients presenting with PETpositive and/or enlarged lymph nodes after COVID-19 vaccination with either the Pfizer-BioNTech or Moderna vaccine.RESULTS: COVID-19 vaccination had been carried out in all cases, with an interval of between 3 and 33 days prior to FNA. Three of five patients had a history of neoplasms. The vaccine was administered into the deltoid muscle, with subsequent enlargement of either the cervical, supra-, infra-or retroclavicular, or axillary lymph nodes, in four out of five cases ipsilaterally. In all cases, cytology and additional analyses showed a reactive lymphadenopathy without any sign of malignancy.CONCLUSIONS: Evidence of newly enlarged lymph nodes after recent COVID-19 vaccination should be considered reactive in the first instance, occurring owing to stimulation of the immune system. A clinical follow-up according to the patient's risk profile without further diagnostic measures is justified. In the case of preexisting unilateral cancer, vaccination should be given contralaterally whenever possible. Persistently enlarged lymph nodes should be re-evaluated (2 to) 6 weeks after the second dose, with additional diagnostic tests tailored to the clinical context. Fine needle aspiration is a well established, safe, rapid and cost-effective method to investigate an underlying malignancy, especially metastasis. Recording vaccination history, including date of injection, site and vaccine type, as well as communicating this information to treating physicians of different specialties is paramount for properly handling COVID-19 vaccine-associated lymphadenopathy.

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Section: Discussionmentioning

confidence: 99%

Fine needle aspiration in COVID-19 vaccine-associated lymphadenopathy

et al. 2021

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“…Infiltrating antigen presenting cells (APCs), dendritic cells and even muscle cells themselves at the site of the injection are the main target of liposome-bearing RNA vaccines, along with other immune cells in the draining lymph nodes [18]. All these cells would hence uptake vaccine-bearing liposome particles, a process followed by cytoplasmic release of mRNA, which will then be translated into mature S (spike) protein, further expressed at the cell surface though major histocompatibility complex (MHC) I and II pathways [19]. Although it is theoretically conceivable that some amounts of endogenously generated SARS-CoV-2 spike protein could reach the bloodstream by direct exocytosis or intracellular release after disruption of muscle or immune cells membrane integrity, this concentration is perhaps too low to be quantified using conventional analytical techniques, such as ELISAs.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive assessment of humoral response after Pfizer BNT162b2 mRNA Covid-19 vaccination: a three-case series

Danese

Montagnana

Salvagno

et al. 2021

Preprint

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Background. Since universal vaccination is a pillar against coronavirus disease 2019 (COVID-19), monitoring anti-SARS-CoV-2 neutralizing antibodies is essential for deciphering post-vaccination immune response. Methods. Three healthcare workers received 30 μg BNT162b2 mRNA Covid-19 Vaccine, followed by a second identical dose, 21 days afterwards. Venous blood was drawn at baseline and at serial intervals, up to 63 days afterwards, for assessing total immunoglobulins (Ig) anti-RBD (receptor binding domain), IgG anti-S1/S2, IgG anti-RBD, IgM anti-RBD, IgM anti-N/S1 and IgA anti-S1. Results. All subjects were SARS-CoV-2 seronegative at baseline. Total Ig anti-RBD, IgG anti-S1/S2 and IgG anti-RBD levels increased between 91-368 folds until 21 days after the first vaccine dose, then reached a plateau. The levels raised further after the second dose (by ~30-, ~8- and ~8-fold, respectively), peaking at day 35, but then slightly declining and stabilizing ~50 days after the first dose. IgA anti-S1 levels increased between 7-11 days after the first dose, slightly declined before the second dose, after which levels augmented by ~24-fold from baseline. The anti-RBD and anti-N/S1 IgM kinetics were similar to that of anti-S1 IgA, though displaying substantially weaker increases and modest peaks, only 4 to 7-fold higher than baseline. Highly significant inter-correlation was noted between total Ig anti-RBD, anti-S1/S2 and anti-RBD IgG (all r=0.99), whilst other anti-SARS-CoV-2 antibodies displayed lower, though still significant, correlations. Serum spike protein concentration was undetectable at all time points. Conclusions. BNT162b2 mRNA vaccination generates a robust humoral immune response, especially involving IgG and IgA, magnified by the second vaccine dose.

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“…The last generation of lipid-based mRNA-lipid nanoparticles vaccines (mRNA-LNPs) was found to be especially convenient, since they conjugate many technical, biological and clinical advantages [ 6 ]. The major technical advantages of these mRNA-LNPs are represented by their ability to closely reproduce natural viral infection without delivering viral particles (mRNA penetrates the host cells and is translated into antigen viral proteins mounted at cell surface or released in the surrounding environment), the potentially lower immunogenicity and cytotoxicity of nanoparticles, the capability to deliver multimeric antigens which may hence allow the rapid reengineering of the formulation with inclusion of new polymorphisms [ 7 , 8 ]. With respect to the biological aspects, the currently used mRNA-LNPs contain genetic material encoding a recombinant form of SARS-CoV-2 spike protein with its receptor-binding domain (RBD), and are hence effective to stimulate B cells to generate neutralizing antibodies directed against the spike protein, thus reducing binding effectiveness with receptors at the host cell surface (especially with angiotensin converting enzyme 2; ACE2), and enhancing virus inactivation and clearance.…”

Section: Introductionmentioning

confidence: 99%

Anti-SARS-CoV-2 Receptor-Binding Domain Total Antibodies Response in Seropositive and Seronegative Healthcare Workers Undergoing COVID-19 mRNA BNT162b2 Vaccination

et al. 2021

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Background: This study monitored total anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) RBD (receptor-binding domain) antibodies levels in a large population of healthcare workers undergoing mRNA COVID-19 vaccination. Methods. The study population consisted of employees of Pederzoli Hospital of Peschiera del Garda (Verona, Italy), who underwent voluntary vaccination with two doses of COVID-19 mRNA BNT162b2 (Comirnaty; Pfizer Inc). Venous blood was drawn immediately before the first vaccine dose, as well as 21 days (immediately before second vaccine dose) and 50 days afterwards. Humoral response was assessed with Roche Elecsys Anti-SARS-CoV-2 S total antibodies, on Roche Cobas 6000 (Roche Diagnostics). Results: The final study population consisted of 925 subjects (mean age, 44 ± 13 years; 457 women), 206 (22.3%) anti-SARS-CoV-2 baseline seropositive. The increase of total anti-SARS-CoV-2 RBD antibodies levels 21 days after the first vaccine dose was ~3 orders of magnitude higher in seropositive than in seronegative individuals (11782 vs. 42 U/mL; p < 0.001). Total anti-SARS-CoV-2 RBD antibodies levels further increased by over 30-fold after the second vaccine dose in baseline seronegative subjects, while such increase was only ~1.3-fold in baseline seropositive subjects. In multivariate analysis, total anti-SARS-CoV-2 RBD antibodies level was inversely associated with age after both vaccine doses and male sex after the second vaccine dose in baseline seronegative subjects, while baseline antibodies value significantly predicted immune response after both vaccine doses in baseline seropositive recipients. Conclusion: Significant difference exists in post-mRNA COVID-19 vaccine immune response in baseline seronegative and seropositive subjects, which seems dependent on age and sex in seronegative subjects, as well as on baseline anti-SARS-CoV-2 antibodies level in seropositive patients.

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Nanoparticle-Mediated Cytoplasmic Delivery of Messenger RNA Vaccines: Challenges and Future Perspectives

Cited by 80 publications

References 26 publications

Fine needle aspiration in COVID-19 vaccine-associated lymphadenopathy

Fine needle aspiration in COVID-19 vaccine-associated lymphadenopathy

Comprehensive assessment of humoral response after Pfizer BNT162b2 mRNA Covid-19 vaccination: a three-case series

Anti-SARS-CoV-2 Receptor-Binding Domain Total Antibodies Response in Seropositive and Seronegative Healthcare Workers Undergoing COVID-19 mRNA BNT162b2 Vaccination

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