A third dose of the unmodified COVID-19 mRNA vaccine CVnCoV enhances quality and quantity of immune responses

Lenart, Klara; Hellgren, Fredrika; Ols, Sebastian; Yan, Xianglei; Cagigi, Alberto; Cerveira, Rodrigo Arcoverde; Winge, Inga; Hanczak, Jakub; Mueller, Stefan O.; Jasny, Edith; Schwendt, Kim; Rauch, Susanne; Petsch, Benjamin; Loré, Karin

doi:10.1016/j.omtm.2022.10.001

Cited by 25 publications

(21 citation statements)

References 72 publications

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“…In the current study, we observed that the mRNA vaccine induced a strong and transient type I IFN response (IFNα, CXCL11), as well as monocyte activation evidenced by MCP-1 secretion and increased levels of intermediate monocyte differentiation within 24 h of administration. We and others have previously found a similar activation profile after administration of nucleosidemodified and unmodified mRNA vaccines 23,[35][36][37]45 . Intermediate monocytes are important for antigen presentation to CD4+ T cells 46 and to support the differentiation of naïve B cells into antibodysecreting plasmablasts 47 .…”

Section: Discussionsupporting

confidence: 72%

Unmodified rabies mRNA vaccine elicits high cross-neutralizing antibody titers and diverse B cell memory responses

et al. 2023

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Licensed rabies virus vaccines based on whole inactivated virus are effective in humans. However, there is a lack of detailed investigations of the elicited immune response, and whether responses can be improved using novel vaccine platforms. Here we show that two doses of a lipid nanoparticle-formulated unmodified mRNA vaccine encoding the rabies virus glycoprotein (RABV-G) induces higher levels of RABV-G specific plasmablasts and T cells in blood, and plasma cells in the bone marrow compared to two doses of Rabipur in non-human primates. The mRNA vaccine also generates higher RABV-G binding and neutralizing antibody titers than Rabipur, while the degree of somatic hypermutation and clonal diversity of the response are similar for the two vaccines. The higher overall antibody titers induced by the mRNA vaccine translates into improved cross-neutralization of related lyssavirus strains, suggesting that this platform has potential for the development of a broadly protective vaccine against these viruses.

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Section: Discussionsupporting

confidence: 72%

Unmodified rabies mRNA vaccine elicits high cross-neutralizing antibody titers and diverse B cell memory responses

et al. 2023

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“…Plasma antibody avidity were tested for by an anti-SARS-CoV-2 ELISA 56 , 60 . Briefly, 96-half well plates were coated with 50 ng/well of the recombinant SARS-CoV-2 spike protein.…”

Section: Methodsmentioning

confidence: 99%

Delayed generation of functional virus-specific circulating T follicular helper cells correlates with severe COVID-19

Charles

Cagigi

et al. 2023

Nat Commun

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Effective humoral immune responses require well-orchestrated B and T follicular helper (Tfh) cell interactions. Whether these interactions are impaired and associated with COVID-19 disease severity is unclear. Here, longitudinal blood samples across COVID-19 disease severity are analysed. We find that during acute infection SARS-CoV-2-specific circulating Tfh (cTfh) cells expand with disease severity. SARS-CoV-2-specific cTfh cell frequencies correlate with plasmablast frequencies and SARS-CoV-2 antibody titers, avidity and neutralization. Furthermore, cTfh cells but not other memory CD4 T cells, from severe patients better induce plasmablast differentiation and antibody production compared to cTfh cells from mild patients. However, virus-specific cTfh cell development is delayed in patients that display or later develop severe disease compared to those with mild disease, which correlates with delayed induction of high-avidity neutralizing antibodies. Our study suggests that impaired generation of functional virus-specific cTfh cells delays high-quality antibody production at an early stage, potentially enabling progression to severe disease.

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“…However, the precise contributions of the nucleoside-modified mRNA vs. LNP components to the overall immune response have not yet been clearly ascertained. In a rhesus macaque model, local inflammation occurs at the site of injection of either nucleoside-modified or unmodified mRNA-LNP vaccines, with infiltration of several immune cell types such as neutrophils, DCs and monocytes 33 , 34 . In our study both unmodified mLNP-RBD and LNP-1-RBD vaccine candidates fully protect transgenic mice against infection, indicating that both the intrinsic immunostimulatory nature of unmodified RBD-mRNA and the composition of the LNP used to deliver the mRNA vaccine could synergistically induce productive immunity.…”

Section: Discussionmentioning

confidence: 99%

Modulating the immune response to SARS-CoV-2 by different nanocarriers delivering an mRNA expressing trimeric RBD of the spike protein: COVARNA Consortium

Marcos-Villar,

Perdiguero,

Anthiya

et al. 2024

npj Vaccines

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Vaccines based on mRNA technology have revolutionized the field. In fact, lipid nanoparticles (LNP) formulated with mRNA are the preferential vaccine platform used in the fight against SARS-CoV-2 infection, with wider application against other diseases. The high demand and property right protection of the most potent cationic/ionizable lipids used for LNP formulation of COVID-19 mRNA vaccines have promoted the design of alternative nanocarriers for nucleic acid delivery. In this study we have evaluated the immunogenicity and efficacy of different rationally designed lipid and polymeric-based nanoparticle prototypes against SARS-CoV-2 infection. An mRNA coding for a trimeric soluble form of the receptor binding domain (RBD) of the spike (S) protein from SARS-CoV-2 was encapsulated using different components to form nanoemulsions (NE), nanocapsules (NC) and lipid nanoparticles (LNP). The toxicity and biological activity of these prototypes were evaluated in cultured cells after transfection and in mice following homologous prime/boost immunization. Our findings reveal good levels of RBD protein expression with most of the formulations. In C57BL/6 mice immunized intramuscularly with two doses of formulated RBD-mRNA, the modified lipid nanoparticle (mLNP) and the classical lipid nanoparticle (LNP-1) were the most effective delivery nanocarriers at inducing binding and neutralizing antibodies against SARS-CoV-2. Both prototypes fully protected susceptible K18-hACE2 transgenic mice from morbidity and mortality following a SARS-CoV-2 challenge. These results highlight that modulation of mRNAs immunogenicity can be achieved by using alternative nanocarriers and support further assessment of mLNP and LNP-1 prototypes as delivery vehicles for mRNA vaccines.

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A third dose of the unmodified COVID-19 mRNA vaccine CVnCoV enhances quality and quantity of immune responses

Cited by 25 publications

References 72 publications

Unmodified rabies mRNA vaccine elicits high cross-neutralizing antibody titers and diverse B cell memory responses

Unmodified rabies mRNA vaccine elicits high cross-neutralizing antibody titers and diverse B cell memory responses

Delayed generation of functional virus-specific circulating T follicular helper cells correlates with severe COVID-19

Modulating the immune response to SARS-CoV-2 by different nanocarriers delivering an mRNA expressing trimeric RBD of the spike protein: COVARNA Consortium

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