scholarly journals Directing an mRNA-LNP vaccine toward lymph nodes improves humoral and cellular immunity against SARS-CoV-2

2021 ◽  
Author(s):  
David M. Francis ◽  
Runqiang Chen ◽  
Sahba Khorsandzadeh ◽  
Qidong Hu ◽  
Xiaoxuan Lyu ◽  
...  
Keyword(s):  
South African ◽  
Cellular Immunity ◽  
Neutralizing Antibodies ◽  
T Cell Response ◽  
Delivery Device ◽  
Drug Delivery Device ◽  
Humoral And Cellular Immunity ◽  
Messenger Ribonucleic Acid ◽  
Draining Lymph Node ◽  
Nanoparticle Formulation

AbstractThe exploration and identification of safe and effective vaccines for the SARS-CoV-2 pandemic has captured the world’s attention and remains an ongoing issue in order to protect against emerging variants of concern (VoCs) while generating long lasting immunity. Here, we report the synthesis of a novel messenger ribonucleic acid (mRNA) encoding the spike protein in a lipid nanoparticle formulation (LNP) (STI-7264) that generates robust humoral and cellular immunity following immunization of C57Bl6 mice. In efforts to continually improve immunity, a lymphatic drug delivery device (MuVaxx) was engineered and tested to modulate immune cells at the injection site (epidermis and dermis) and draining lymph node (LN) to elicit adaptive immunity. Using MuVaxx, immune responses were elicited and maintained at a 10-fold dose reduction compared to traditional intramuscular (IM) administration as measured by anti-spike antibodies, cytokine producing CD8 T cells, and neutralizing antibodies against the Washington (Wild Type, WT) and South African (beta) variants. Remarkably, a 4-fold elevated T cell response was observed in MuVaxx administered vaccination as compared to that of IM administered vaccination. Thus, these data support further investigation into STI-7264 and lymphatic mediated delivery using MuVaxx for SARS-CoV-2 and VoCs vaccines.

scholarly journals A class II MHC-targeted vaccine elicits immunity against SARS-CoV-2 and its variants

2021 ◽  
Vol 118 (44) ◽  
pp. e2116147118
Author(s):  
Novalia Pishesha ◽  
Thibault J. Harmand ◽  
Paul W. Rothlauf ◽  
Patrique Praest ◽  
Ryan K. Alexander ◽  
...  
Keyword(s):  
Cellular Immunity ◽  
Neutralizing Antibodies ◽  
High Titer ◽  
Developed Countries ◽  
Class Ii ◽  
T Cell Response ◽  
Humoral And Cellular Immunity ◽  
Histocompatibility Complex ◽  
Class Ii Mhc ◽  
Antigen Presenting

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 100 million infections and millions of deaths. Effective vaccines remain the best hope of curtailing SARS-CoV-2 transmission, morbidity, and mortality. The vaccines in current use require cold storage and sophisticated manufacturing capacity, which complicates their distribution, especially in less developed countries. We report the development of a candidate SARS-CoV-2 vaccine that is purely protein based and directly targets antigen-presenting cells. It consists of the SARS-CoV-2 Spike receptor-binding domain (SpikeRBD) fused to an alpaca-derived nanobody that recognizes class II major histocompatibility complex antigens (VHHMHCII). This vaccine elicits robust humoral and cellular immunity against SARS-CoV-2 and its variants. Both young and aged mice immunized with two doses of VHHMHCII-SpikeRBD elicit high-titer binding and neutralizing antibodies. Immunization also induces strong cellular immunity, including a robust CD8 T cell response. VHHMHCII-SpikeRBD is stable for at least 7 d at room temperature and can be lyophilized without loss of efficacy.

scholarly journals Synthetic SARS-CoV-2 Spike-Based DNA Vaccine Elicits Robust and Long-Lasting Th1 Humoral and Cellular Immunity in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Sawsan S. Alamri ◽  
Khalid A. Alluhaybi ◽  
Rowa Y. Alhabbab ◽  
Mohammad Basabrain ◽  
Abdullah Algaissi ◽  
...  
Keyword(s):  
Dna Vaccine ◽  
Cellular Immunity ◽  
Neutralizing Antibodies ◽  
Humoral Response ◽  
Igg Antibodies ◽  
Free System ◽  
Humoral And Cellular Immunity ◽  
Global Pandemic ◽  
Therapeutic Measures ◽  
Needle Injection

The ongoing global pandemic of coronavirus disease 2019 (COVID-19) calls for an urgent development of effective and safe prophylactic and therapeutic measures. The spike (S) glycoprotein of severe acute respiratory syndrome-coronavirus (SARS-CoV-2) is a major immunogenic and protective protein and plays a crucial role in viral pathogenesis. In this study, we successfully constructed a synthetic codon-optimized DNA-based vaccine as a countermeasure against SARS-CoV-2, denoted VIU-1005. The design was based on a codon-optimized coding sequence of a consensus full-length S glycoprotein. The immunogenicity of the vaccine was tested in two mouse models (BALB/c and C57BL/6J). Th1-skewed systemic S-specific IgG antibodies and neutralizing antibodies (nAbs) were significantly induced in both models 4 weeks after three injections with 100 μg of the VIU-1005 vaccine via intramuscular needle injection but not intradermal or subcutaneous routes. Such immunization induced long-lasting IgG and memory T cell responses in mice that lasted for at least 6 months. Interestingly, using a needle-free system, we showed an enhanced immunogenicity of VIU-1005 in which lower or fewer doses were able to elicit significantly high levels of Th1-biased systemic S-specific immune responses, as demonstrated by the significant levels of binding IgG antibodies, nAbs and IFN-γ, TNF and IL-2 cytokine production from memory CD8+ and CD4+ T cells in BALB/c mice. Furthermore, compared to intradermal needle injection, which failed to induce any significant immune response, intradermal needle-free immunization elicited a robust Th1-biased humoral response similar to that observed with intramuscular immunization. Together, our results demonstrate that the synthetic VIU-1005 candidate DNA vaccine is highly immunogenic and capable of inducing long-lasting Th1-skewed humoral and cellular immunity in mice. Furthermore, we show that the use of a needle-free system could enhance the immunogenicity and minimize doses needed to induce protective immunity in mice, supporting further preclinical and clinical testing of this candidate vaccine.

scholarly journals Early immune response in mice immunized with a semi-split inactivated vaccine against SARS-CoV-2 containing S protein-free particles and subunit S protein

2020 ◽  
Author(s):  
Marek Petráš ◽  
Petr Lesný ◽  
Jan Musil ◽  
Radomíra Limberková ◽  
Alžběta Pátíková ◽  
...  
Keyword(s):  
Cellular Immunity ◽  
Neutralizing Antibodies ◽  
Immune Cell ◽  
Geometric Mean ◽  
Inactivated Vaccine ◽  
S Protein ◽  
Humoral And Cellular Immunity ◽  
Wide Range ◽  
Immune Cell Response ◽  
Th1 And Th2 Lymphocytes

AbstractThe development of a vaccine against COVID-19 is a hot topic for many research laboratories all over the world. Our aim was to design a semi-split inactivated vaccine offering a wide range of multi-epitope determinants important for the immune system including not only the spike (S) protein but also the envelope, membrane and nucleocapsid proteins. We designed a semi-split vaccine prototype consisting of S protein-depleted viral particles and free S protein. Next, we investigated its immunogenic potential in BALB/c mice. The animals were immunized intradermally or intramuscularly with the dose adjusted with buffer or addition of aluminum hydroxide, respectively. The antibody response was evaluated by plasma analysis at 7 days after the first or second dose. The immune cell response was studied by flow cytometry analysis of splenocytes. The data showed a very early onset of both S protein-specific antibodies and virus-neutralizing antibodies at 90% inhibition regardless of the route of vaccine administration. However, significantly higher levels of neutralizing antibodies were detected in the intradermally (geometric mean titer - GMT of 7.8 ± 1.4) than in the intramuscularly immunized mice (GMT of 6.2 ± 1.5). In accordance with this, stimulation of cellular immunity by the semi-split vaccine was suggested by elevated levels of B and T lymphocyte subpopulations in the murine spleens. These responses were more predominant in the intradermally immunized mice compared with the intramuscular route of administration. The upward trend in the levels of plasmablasts, memory B cells, Th1 and Th2 lymphocytes, including follicular helper T cells, was confirmed even in mice receiving the vaccine intradermally at a dose of 0.5 μg.We demonstrated that the semi-split vaccine is capable of eliciting both humoral and cellular immunity early after vaccination. Our prototype thus represents a promising step toward the development of an efficient anti-COVID-19 vaccine for human use.

scholarly journals Comparison of SARS-CoV-2- and HCoV-Specific T Cell Response Using IFN-γ ELISpot

Diagnostics ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1439
Author(s):  
Laura Thümmler ◽  
Sina Schwarzkopf ◽  
Dietmar Knop ◽  
J. Alexander Ross ◽  
Victoria Berg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cellular Immunity ◽  
Neutralizing Antibodies ◽  
Herd Immunity ◽  
T Cell Responses ◽  
Cross Reactivity ◽  
T Cell Response ◽  
Cell Responses ◽  
Ifn Γ

Herd immunity is essential to control severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), especially in immunocompromised patients. Convalescent individuals should be vaccinated later due to vaccine shortage, as studies show that neutralizing antibodies generated during infection are stable for at least 6 months. Cellular immunity is also detectable for months. However, there is evidence of cross-reactivity of T cells with human endemic coronaviruses (HCoVs). Here, we show that cross-reactivity—which may prevent the specific detection of SARS-CoV-2-specific T cell responses—can be avoided if cells are stimulated with the N-terminus of the spike protein in IFN-γ ELISpot. In contrast to previous studies, we examined T-cell responses against all four known HCoVs using IFN-γ ELISpot in 19 convalescent volunteers and 10 fully vaccinated volunteers. In addition, we performed Spearman analyses to detect cross-reactivity of T cells. We observed no correlation between T-cell responses against SARS-CoV-2 and human endemic coronaviruses, either in the whole cohort or in the individual groups. The use of the respective stimuli could lead to a more accurate assessment of cellular immunity in recovered individuals. This testing procedure could help to define the best time point at which convalescents should receive SARS-CoV-2 vaccination.

scholarly journals A Highly Conserved Peptide Vaccine Candidate Activates Both Humoral and Cellular Immunity Against SARS-CoV-2 Variant Strains

2021 ◽  
Vol 12 ◽  
Author(s):  
Fengxia Gao ◽  
Jingjing Huang ◽  
Tingting Li ◽  
Chao Hu ◽  
Meiying Shen ◽  
...  
Keyword(s):  
T Cell ◽  
Cellular Immunity ◽  
Vaccine Candidate ◽  
Protective Efficacy ◽  
Peptide Vaccine ◽  
T Cell Response ◽  
Antigenic Peptide ◽  
Specific Antibodies ◽  
Humoral And Cellular Immunity ◽  
Potential Vaccine

Facing the imminent need for vaccine candidates with cross-protection against globally circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants, we present a conserved antigenic peptide RBD9.1 with both T-cell and B-cell epitopes. RBD9.1 can be recognized by coronavirus disease 2019 (COVID-19) convalescent serum, particularly for those with high neutralizing potency. Immunization with RBD9.1 can successfully induce the production of the receptor-binding domain (RBD)-specific antibodies in Balb/c mice. Importantly, the immunized sera exhibit sustained neutralizing efficacy against multiple dominant SARS-CoV-2 variant strains, including B.1.617.2 that carries a point mutation (SL452R) within the sequence of RBD9.1. Specifically, SY451 and SY454 are identified as the key amino acids for the binding of the induced RBD-specific antibodies to RBD9.1. Furthermore, we have confirmed that the RBD9.1 antigenic peptide can induce a S448-456 (NYNYLYRLF)-specific CD8+ T-cell response. Both RBD9.1-specific B cells and the S448-456-specific T cells can still be activated more than 3 months post the last immunization. This study provides a potential vaccine candidate that can generate long-term protective efficacy over SARS-CoV-2 variants, with the unique functional mechanism of activating both humoral and cellular immunity.

scholarly journals Self-Assembling Nanovaccine Enhances Protective Efficacy Against CSFV in Pigs

2021 ◽  
Vol 12 ◽  
Author(s):  
Ze-Hui Liu ◽  
Hui-Ling Xu ◽  
Guang-Wei Han ◽  
Li-Na Tao ◽  
Ying Lu ◽  
...  
Keyword(s):  
Cellular Immunity ◽  
Neutralizing Antibodies ◽  
Protective Efficacy ◽  
Genetically Engineered ◽  
Swine Industry ◽  
Antigen Uptake ◽  
Virus Challenge ◽  
Humoral And Cellular Immunity ◽  
Self Assembling

Classical swine fever virus (CSFV) is a highly contagious pathogen, which pose continuous threat to the swine industry. Though most attenuated vaccines are effective, they fail to serologically distinguish between infected and vaccinated animals, hindering CSFV eradication. Beneficially, nanoparticles (NPs)-based vaccines resemble natural viruses in size and antigen structure, and offer an alternative tool to circumvent these limitations. Using self-assembling NPs as multimerization platforms provides a safe and immunogenic tool against infectious diseases. This study presented a novel strategy to display CSFV E2 glycoprotein on the surface of genetically engineered self-assembling NPs. Eukaryotic E2-fused protein (SP-E2-mi3) could self-assemble into uniform NPs as indicated in transmission electron microscope (TEM) and dynamic light scattering (DLS). SP-E2-mi3 NPs showed high stability at room temperature. This NP-based immunization resulted in enhanced antigen uptake and up-regulated production of immunostimulatory cytokines in antigen presenting cells (APCs). Moreover, the protective efficacy of SP-E2-mi3 NPs was evaluated in pigs. SP-E2-mi3 NPs significantly improved both humoral and cellular immunity, especially as indicated by the elevated CSFV-specific IFN-γ cellular immunity and >10-fold neutralizing antibodies as compared to monomeric E2. These observations were consistent to in vivo protection against CSFV lethal virus challenge in prime-boost immunization schedule. Further results revealed single dose of 10 μg of SP-E2-mi3 NPs provided considerable clinical protection against lethal virus challenge. In conclusion, these findings demonstrated that this NP-based technology has potential to enhance the potency of subunit vaccine, paving ways for nanovaccine development.

scholarly journals Longitudinal characterization of humoral and cellular immunity in hospitalized COVID-19 patients reveal immune persistence up to 9 months after infection

2021 ◽  
Author(s):  
John Tyler Sandberg ◽  
Renata Varnaitė ◽  
Wanda Christ ◽  
Puran Chen ◽  
Jagadeeswara R. Muvva ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cellular Immunity ◽  
Symptom Onset ◽  
Neutralizing Antibodies ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
Immune Memory ◽  
Humoral And Cellular Immunity ◽  
Cell Responses

AbstractBackgroundInsights into early, specific humoral and cellular responses to infection with SARS-CoV-2, as well as the persistence and magnitude of resulting immune memory is important amidst the ongoing pandemic. The combination of humoral and cellular immunity will most likely contribute to protection from reinfection or severe disease.MethodsHere, we conducted a longitudinal study on hospitalized moderate and severe COVID-19 patients from the acute phase of disease into convalescence at five- and nine-months post symptom onset. Utilizing flow cytometry, serological assays as well as B cell and T cell FluoroSpot assays, we assessed the magnitude and specificity of humoral and cellular immune memory during and after human SARS-CoV-2 infection.FindingsDuring acute COVID-19, we observed an increase in germinal center activity, a substantial expansion of antibodysecreting cells, and the generation of SARS-CoV-2-neutralizing antibodies. Despite gradually decreasing antibody levels, we show persistent, neutralizing antibody titers as well as robust specific memory B cell responses and polyfunctional T cell responses at five- and nine-months after symptom onset in both moderate and severe COVID-19 patients. Long-term SARS-CoV-2 specific responses were marked by preferential targeting of spike over nucleocapsid protein.ConclusionsOur findings describe the initiation and, importantly, persistence of cellular and humoral SARS-CoV-2 specific immunological memory in hospitalized COVID-19 patients long after recovery, likely contributing towards protection against reinfection.

scholarly journals COVID-19 in a pediatric cancer patient with T-lymphoblastic lymphoma: Response to convalescence plasma and subsequent induction of SARS-CoV-2 specific humoral and cellular immunity despite strong B-cell lymphopenia

2021 ◽  
Vol 2 (3) ◽  
Author(s):  
Arne Simon ◽  
◽  
Tabea Reinhardt ◽  
Sascha Meyer ◽  
Yeliz Baltaci ◽  
...  
Keyword(s):  
Cancer Patient ◽  
Cellular Immunity ◽  
Pediatric Cancer ◽  
Passive Immunization ◽  
T Cell Response ◽  
Lymphoblastic Lymphoma ◽  
Humoral And Cellular Immunity ◽  
Pediatric Cancer Patient ◽  
Pediatric Cancer Patients ◽  
T Lymphoblastic Lymphoma

We report on an 11-year old pediatric cancer patient with T-lymphoblastic lymphoma who acquired a severe SARS-CoV-2 pneumonia immediately after the start of oral maintenance treatment with mercaptopurine. He was admitted to our hospital on day 7 after onset of symptoms (day 5 after diagnosis). Due to respiratory failure, he was transferred to the pediatric intensive care unit (from day 8 for 5 days) for high-flow-nasal cannula respiratory support. Treatment consisted of intravenous methylprednisolone and ceftriaxone. Because anti-SARS-CoV-2 antibodies were not detectable, he received two units of COVID-19 convalescence plasma containing high-titer neutralizing anti-SARS-CoV-2 antibodies (day 8 and day 9). Anti-SARS-CoV-2 antibodies increased to a maximum of 725 IU/L on day 10. Clinically, this was accompanied by a gradual decrease in oxygen demand and an overall clinical improvement. Remarkably, the patient started to mount a humoral immune response with continuously increasing anti-SARS-CoV-2 antibodies from day 15 up to 35.698 AU/ml on day 51 with extremely low (< 0.4%; < 0.01 x 109/L) detectible CD19-positive B-lymphocytes in his peripheral blood. Moreover, a strong SARS-CoV-2 specific CD4 and CD8 T cell response was induced with a predominance of CD8 T cells towards NCAP. This finding indicates that passive immunization facilitated active induction of both humoral and cellular immunity. This also suggests that active immunization may be feasible and effective in pediatric cancer patients despite B-lymphocytopenia.

scholarly journals SARS-CoV-2 mRNA vaccine BNT162b2 elicited a robust humoral and cellular response against SARS-CoV-2 variants.

2021 ◽  
Author(s):  
Daniele Lilleri ◽  
Irene Cassaniti ◽  
Federica Bergami ◽  
Elena Percivalle ◽  
Elisa Gabanti ◽  
...  
Keyword(s):  
T Cell ◽  
South African ◽  
Neutralizing Antibodies ◽  
Healthcare Workers ◽  
Cellular Response ◽  
Vaccine Dose ◽  
T Cell Response ◽  
Cell Responses ◽  
Lower Effect ◽  
Humoral And Cellular Response

Abstract BNT162b2 vaccine was introduced in Italy on 27th December 2020 and healthcare workers were rapidly vaccinated. In this study, we demonstrated that one vaccine dose was sufficient for eliciting a sustained humoral and cell-mediated response in SARS-CoV-2 experienced healthcare workers but had a lower effect in SARS-CoV-2 naïve subjects. However, 98% naïve subjects developed both neutralizing antibodies and Spike-specific T-cells after the second dose. Moreover, the antibody and T-cell responses were effective against viral variants since a partial reduction in antibody response was observed only against the South-African variant in SARS-CoV-2 naïve individuals, while the T-cell response was less affected.

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