Next-Generation Vaccines against COVID-19 Variants: Beyond the Spike Protein

Bonam, Srinivasa Reddy; Hu, Haitao

doi:10.15212/zoonoses-2023-0003

Cited by 5 publications

(6 citation statements)

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“…11 Following intramuscular administration, lipid nanoparticlepackaged mRNA enters host cells via endocytosis and is translated into target proteins (as seen in Pfizer-BioNTech and Moderna vaccines) by ribosomes. 12,13 These proteins are then processed and presented as antigens on the cell surface by major histocompatibility complex (MHC) class I and II molecules, activating the T-cell receptor (TCR) and thereby stimulating the adaptive immune system. 14,15 In addition to cellular surface expression, these antigens/peptides were also being packaged into EVs.…”

Section: Discussionmentioning

confidence: 99%

In vitro mRNA‐S maternal vaccination induced altered immune regulation at the maternal‐fetal interface

Kammala,

Tatiparthy,

Thomas

et al. 2024

American J Rep Immunol

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BackgroundMaternal‐fetal immunology is intricate, and the effects of mRNA‐S maternal vaccination on immune regulation at the maternal‐fetal interface require further investigation. Our study endeavors to elucidate these immunological changes, enhancing our comprehension of maternal and fetal health outcomes. By analyzing immune profiles and cytokine responses, we aim to provide valuable insights into the impact of mRNA‐S vaccination on the delicate balance of immune regulation during pregnancy, addressing critical questions in the field of reproductive pharmacology.ObjectivesThis investigation sought to examine the prospective influence of mRNA‐S‐based vaccines and extracellular vesicles (EVs) containing the Spike (S) protein at the maternal‐fetal interface. Our primary emphasis was on evaluating their effects on maternal decidua cells and fetal chorion trophoblast cells (hFM‐CTCs).MethodsWe validated the generation of EVs containing the S protein from small human airway epithelial cell lines (HSAECs) following mRNA‐S vaccine exposure. We assessed the expression of angiotensin‐converting enzyme 2 (ACE2) gene and protein in fetal membranes and the placenta, with specific attention to decidual cells and fetal membrane chorion cells. To assess cellular functionality, these cells were exposed to both recombinant S protein and EVs loaded with S proteins (eSPs).ResultsOur findings revealed that cells and EVs subjected to mRNA‐S‐based vaccination exhibited altered protein expression levels of S proteins. At the feto‐maternal interface, both placental and fetal membrane tissues demonstrated similar ACE‐2 expression levels. Among individual cellular layers, syncytiotrophoblast cells in the placenta and chorion cells in the fetal membrane exhibited elevated ACE‐2 expression. Notably, EVs derived from HSAECs activated the MAPK pathway in decidual cells. Additionally, decidual cells displayed a substantial increase in gene expression of chemokines like CXCL‐10 and CXCL‐11, as well as proinflammatory cytokines such as IL‐6 in response to eSPs. However, the levels of Ccl‐2 and IL‐1β remained unchanged in decidual cells under the same conditions. Conversely, hFM‐CTCs demonstrated significant alterations in the proinflammatory cytokines and chemokines with respect to eSPs.ConclusionIn conclusion, our study indicates that mRNA‐S‐based maternal vaccination during pregnancy may influence the maternal‐fetal interface's COVID‐19 interaction and immune regulation. Further investigation is warranted to assess safety and implications.

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Section: Discussionmentioning

confidence: 99%

In vitro mRNA‐S maternal vaccination induced altered immune regulation at the maternal‐fetal interface

Kammala,

Tatiparthy,

Thomas

et al. 2024

American J Rep Immunol

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“…As a result, the recruited innate immune cells capture the LNPs and process them before their internalization. An optimal LNP composition is also known to increase the RNA uptake by splenic cells and to enhance the activation of innate immune responses by significantly inducing IL-6, CXCL1, CCL2, and CXCL10 [8]. Chemokines and cytokines are involved in the recruitment of monocytes and neutrophils.…”

Section: Discussionmentioning

confidence: 99%

“…A clear picture of the innate and adaptive immune mechanisms elicited by our mRNA vaccines, which lead to broad protection against SARS-CoV-2 variants, has yet to be elucidated. After the delivery of mRNA into the cell by LNPs, mRNA encounters several important cellular PRRs, such as TLR-3, TLR-7, and TLR-8 [5,7,8]. Recent studies indicate that LNPs have the ability to stimulate the immune system [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Innate and Adaptive Immune Parameters following mRNA Vaccination in Mice

Bonam,

Hazell,

Mathew

et al. 2024

Vaccines

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The COVID-19 pandemic has raised the standard regarding the current vaccine development pace, as several messenger RNA (mRNA)-lipid nanoparticle (LNP) vaccines have proved their ability to induce strong immunogenicity and protective efficacy. We developed 1-methylpseudouridine-containing mRNA-LNP vaccines, expressing either the more conserved SARS-CoV-2 nucleoprotein (mRNA-N) or spike protein (mRNA-S), both based on the prototypic viral sequences. When combining both mRNA-S and mRNA-N together (mRNA-S+N), the vaccine showed high immunogenicity and broad protection against different SARS-CoV-2 variants, including wildtype, Delta, BA.1, BA.5, and BQ.1. To better understand the mechanisms behind this broad protection obtained by mRNA-S+N, we analyzed innate and adaptive immune parameters following vaccination in mice. Compared to either mRNA-S or mRNA-N alone, mice vaccinated with mRNA-S+N exhibited an increase in the innate immune response, as depicted by the higher cytokine (IL-6 and chemokine (MCP-1) levels. In addition, lymph node immunophenotyping showed the maturation and activation of dendritic cells and natural killer cells, respectively. To understand the adaptive immune response, RNA-Seq analyses of the lung and spleen samples of the vaccinated mice were performed in parallel and revealed a stronger immune gene-expression profile in the lung than that in the spleen. Compared to mRNA-S alone, mRNA-S+N vaccination elicited higher levels of expression for genes involved in multiple immune pathways, including T cells, cytokine signaling, antigen presentation, B cells, and innate immunity. Together, our studies provide immunological insights into the mechanisms of broad protection conferred by dual mRNA vaccination against SARS-CoV-2 variants.

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“…Various strategies are being employed worldwide to develop COVID-19 vaccine candidates. Currently, the vaccines that have received approval for clinical trials are subunit vaccines (NVX-CoV2373 and ZF2001), mRNA vaccines (mRNA-1273, BNT162b2, and SYS6006), viral vectored vaccines (Ad26.COV2.S, ChAdOx1 nCoV-19, and Convidecia) and inactivated vaccines (CoronaVac and BBIBP-COrV) [ 2 – 5 ]. The subunit vaccine exhibits the highest safety profile among them [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…Currently, the vaccines that have received approval for clinical trials are subunit vaccines (NVX-CoV2373 and ZF2001), mRNA vaccines (mRNA-1273, BNT162b2, and SYS6006), viral vectored vaccines (Ad26.COV2.S, ChAdOx1 nCoV-19, and Convidecia) and inactivated vaccines (CoronaVac and BBIBP-COrV) [ 2 – 5 ]. The subunit vaccine exhibits the highest safety profile among them [ 5 , 6 ]. However, most developed vaccines primarily target the Spike (S) protein due to its recognition as the principal immune-associated in protecting against SARS-CoV-2 infection [ 7 – 9 ].…”

Section: Introductionmentioning

confidence: 99%

Double-layered N-S1 protein nanoparticle immunization elicits robust cellular immune and broad antibody responses against SARS-CoV-2

Li,

Chang,

Liu

et al. 2024

J Nanobiotechnol

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Background The COVID-19 pandemic is a persistent global threat to public health. As for the emerging variants of SARS-CoV-2, it is necessary to develop vaccines that can induce broader immune responses, particularly vaccines with weak cellular immunity. Methods In this study, we generated a double-layered N-S1 protein nanoparticle (N-S1 PNp) that was formed by desolvating N protein into a protein nanoparticle as the core and crosslinking S1 protein onto the core surface against SARS-CoV-2. Results Vaccination with N-S1 PNp elicited robust humoral and vigorous cellular immune responses specific to SARS-CoV-2 in mice. Compared to soluble protein groups, the N-S1 PNp induced a higher level of humoral response, as evidenced by the ability of S1-specific antibodies to block hACE2 receptor binding and neutralize pseudovirus. Critically, N-S1 PNp induced Th1-biased, long-lasting, and cross-neutralizing antibodies, which neutralized the variants of SARS-CoV-2 with minimal loss of activity. N-S1 PNp induced strong responses of CD4+ and CD8+ T cells, mDCs, Tfh cells, and GCs B cells in spleens. Conclusions These results demonstrate that N-S1 PNp vaccination is a practical approach for promoting protection, which has the potential to counteract the waning immune responses against SARS-CoV-2 variants and confer broad efficacy against future new variants. This study provides a new idea for the design of next-generation SARS-CoV-2 vaccines based on the B and T cells response coordination. Graphical Abstract

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Next-Generation Vaccines against COVID-19 Variants: Beyond the Spike Protein

Cited by 5 publications

References 95 publications

In vitro mRNA‐S maternal vaccination induced altered immune regulation at the maternal‐fetal interface

In vitro mRNA‐S maternal vaccination induced altered immune regulation at the maternal‐fetal interface

Innate and Adaptive Immune Parameters following mRNA Vaccination in Mice

Double-layered N-S1 protein nanoparticle immunization elicits robust cellular immune and broad antibody responses against SARS-CoV-2

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