scholarly journals Comparison of Personal and Shared Frameshift Neoantigen Vaccines in a Mouse Mammary Cancer Model.

2020 ◽  
Author(s):  
Milene Peterson ◽  
Sierra Nicole Murphy ◽  
John Lainson ◽  
Jian Zhang ◽  
Luhui Shen ◽  
...  
Keyword(s):  
Immune Response ◽  
Cancer Vaccines ◽  
Lung Metastases ◽  
T Cell Response ◽  
Control Group ◽  
Cancer Model ◽  
Secondary Tumor ◽  
Humoral Immune ◽  
Dna Mutations ◽  
Number Of Patients

Abstract Background: It is widely hoped that personal cancer vaccines will extend the number of patients benefiting from checkpoint and other immunotherapies. However, it is clear creating such vaccines will be challenging. It requires obtaining and sequencing tumor DNA/RNA, predicting potentially immunogenic neoepitopes and manufacturing a one-use vaccine. This process takes time and considerable cost. Importantly, most mutations will not produce an immunogenic peptide and many patient’s tumors do not contain enough DNA mutations to make a vaccine. We have discovered that frameshift peptides (FSP) created from errors in the production of RNA rather than from DNA mutations are potentially a rich source of neoantigens for cancer vaccines. These errors are predictable, enabling the production of a FSP microarray. Previously we found that these microarrays can identify both personal and shared neoantigens. Here, we compared the performance of personal cancer vaccines (PCVs) with that of a shared antigen vaccine, termed Frameshift Antigen Shared Therapeutic (FAST) vaccine , using the 4T1 breast cancer model. Sera from 4T1-tumor bearing mice were assayed on the peptide microarray containing 200 Fs neoantigens, for the PCV, the top 10 candidates were select and personal vaccines constructed and administrated to the respective mice. For the FAST, we selected the top 10 candidates with higher prevalence among all the mice challenged. Seven to 12 days challenged mice were immunized, combined or not with immune checkpoint inhibitor (ICI) (αPD-L1 and αCTLA-4). Primary and secondary tumor clearance and growth were evaluated as well as cellular and humoral immune response against the vaccine targets by IFN-γ ELISPOT and ELISA. Lastly, we analyzed the immune response of the FAST-vaccinated mice by flow cytometry in comparison to the control group. Results: We found that PCVs and FAST vaccines both reduced primary tumor incidence and growth as well as lung metastases when delivered as monotherapies or in combination with ICI. Additionally, the FAST vaccine induces a robust and effective T-cell response. Conclusions: These results suggest that FSPs produced from RNA-based errors are potent neoantigens that could enable production of off-the-shelf shared antigen vaccines for solid tumors with efficacy comparable to that of PCVs.

scholarly journals Comparison of Personal and Shared Frameshift Neoantigen Vaccines in a Mouse Mammary Cancer Model.

2020 ◽  
Author(s):  
Milene Peterson ◽  
Sierra Nicole Murphy ◽  
John Lainson ◽  
Jian Zhang ◽  
Luhui Shen ◽  
...  
Keyword(s):  
Immune Response ◽  
Cancer Vaccines ◽  
Checkpoint Inhibitor ◽  
Lung Metastases ◽  
Cancer Model ◽  
Secondary Tumor ◽  
Dna Mutation ◽  
Humoral Immune ◽  
Number Of Patients ◽  
4T1 Breast Cancer

Abstract Background: It is widely hoped that personal cancer vaccines will extend the number of patients benefiting from checkpoint and other immunotherapies. However, it is clear creating such vaccines will be challenging. It requires obtaining and sequencing tumor DNA/RNA, predicting potentially immunogenic neoepitopes and manufacturing one-use vaccine. This process takes time and considerable cost. Importantly, most mutations will not produce an immunogenic peptide and many patient’s tumors do not contain enough DNA mutations to make a vaccine. We have discovered that Frameshift peptides (FSP) created from errors in the production of RNA rather than from DNA mutation are potentially a rich source of neoantigens for cancer vaccines. These errors are predictable, enabling the production of a FSP microarray. Previously we found that these microarrays can identify both personal and shared neoantigens.Methods: Here, we compared the performance of personal cancer vaccines (PCVs) with that of a shared antigen vaccine, termed Frameshift Antigen Shared Therapeutic (FAST) vaccine , using the 4T1 breast cancer model. Sera from 4T1-tumor bearing mice were assayed on the peptide microarray containing 200 FS neoantigens and for the PCV, the top 10 candidates were select and personal vaccines constructed and administrated to the respective mice. For the FAST, we selected the top 10 candidates with higher prevalence among all the mice challenged. Seven to 12-days challenged mice were immunized, combined or not with checkpoint inhibitor (CPI) (αPD-L1 and αCTLA-4). Primary and secondary tumor clearance and growth were evaluated as well as both cellular and humoral immune response against the vaccines targets by IFN-γ ELISPOT and ELISA. Lastly, we analyzed the immune response of the FAST-vaccinated mice by flow cytometry in comparison to control group.Results: We found that PCVs and FAST vaccines both reduced primary tumor incidence and growth as well as lung metastases when delivered as monotherapies or in combination with checkpoint inhibitor antibodies. Additionally, the FAST vaccine induces a robust and effective T-cell response.Conclusions: These results suggest that FSPs produced from RNA-based errors are potent neoantigens that could enable production of off-the-shelf shared antigen vaccines for solid tumors with efficacy comparable to that of PCVs.

scholarly journals Immune response of calves inoculated with proteins ofAnaplasma marginale bound to an immunostimulant complex

2013 ◽  
Vol 22 (2) ◽  
pp. 253-259 ◽  
Author(s):  
Marcela Ribeiro Gasparini ◽  
Rafael Felipe da Costa Vieira ◽  
Denise Amaral Gomes do Nascimento ◽  
João Luis Garcia ◽  
Odilon Vidotto ◽  
...  
Keyword(s):  
Immune Response ◽  
Current Knowledge ◽  
Surface Proteins ◽  
Control Group ◽  
Humoral Immune ◽  
The Third ◽  
Additional Testing ◽  
Major Surface Proteins ◽  
Cattle Herds ◽  
Major Surface

Despite our current knowledge of the immunology, pathology, and genetics of Anaplasma marginale, prevention in cattle is currently based on old standbys, including live attenuated vaccines, antibiotic treatment, and maintaining enzootic stability in cattle herds. In the present study, we evaluated the use of an immunostimulant complex (ISCOMATRIX) adjuvant, associated with a pool of recombinant major surface proteins (rMSP1a, rMSP1b, rMSP4 and rMSP5) to improve the humoral immune response triggered in calves mainly by IgG2. Ten calves were divided in three groups: 4 calves were inoculated with the ISCOMATRIX/rMSPs (G1); 2 calves were inoculated with ISCOMATRIX adjuvant (G2); and 4 calves received saline (G3). Three inoculations were administered at 21-day intervals. In G1, the calves showed significant increases in total IgG, IgG1 and IgG2 levels 21 days after the second inoculation, compared to the control group (p < 0.05), and G1 calves remained above the cut-off value 28 days after the third inoculation (p < 0.05). The post-immunized sera from calves in G1 reacted specifically for each of the rMSPs used. In conclusion, the ISCOMATRIX/rMSPs induced antigen-specific seroconversion in calves. Therefore, additional testing to explore the protection induced by rMSPs, both alone and in conjunction with proteins previously identified as subdominant epitopes, is warranted.

scholarly journals Preclinical studies of immunogenity, protectivity, and safety of the combined vector vaccine for prevention of the middle east respiratory syndrome

Acta Naturae ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 114-123
Author(s):  
Inna V. Dolzhikova ◽  
D. M. Grousova ◽  
O. V. Zubkova ◽  
A. I. Tukhvatulin ◽  
A. V. Kovyrshina ◽  
...  
Keyword(s):  
Immune Response ◽  
Middle East ◽  
Mortality Rate ◽  
Receptor Gene ◽  
Human Adenovirus ◽  
T Cell Response ◽  
Middle East Respiratory Syndrome ◽  
Vector Vaccine ◽  
Humoral Immune ◽  
Cellular Immune

The Middle East Respiratory Syndrome (MERS) is an acute inflammatory disease of the respiratory system caused by the MERS-CoV coronavirus. The mortality rate for MERS is about 34.5%. Due to its high mortality rate, the lack of therapeutic and prophylactic agents, and the continuing threat of the spread of MERS beyond its current confines, developing a vaccine is a pressing task, because vaccination would help limit the spread of MERS and reduce its death toll. We have developed a combined vector vaccine for the prevention of MERS based on recombinant human adenovirus serotypes 26 and 5. Studies of its immunogenicity have shown that vaccination of animals (mice and primates) induces a robust humoral immune response that lasts for at least six months. Studies of the cellular immune response in mice after vaccination showed the emergence of a specific CD4+ and CD8+ T cell response. A study of the vaccine protectivity conducted in a model of transgenic mice carrying the human DPP4 receptor gene showed that our vaccination protected 100% of the animals from the lethal infection caused by the MERS-CoV virus (MERS-CoV EMC/2012, 100LD50 per mouse). Studies of the safety and tolerability of the developed vaccine in rodents, rabbits, and primates showed a good safety profile and tolerance in animals; they revealed no contraindications for clinical testing.

scholarly journals The expression of an intraspecific aggressive reaction in the face of a stressor agent alters the immune response in rats

2005 ◽  
Vol 65 (2) ◽  
pp. 203-209 ◽  
Author(s):  
J. M. Barreto-Medeiros ◽  
E. G. Feitoza ◽  
K. Magalhães ◽  
R. R. da Silva ◽  
F. M. Manhães-de-Castro ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Humoral Response ◽  
Aggressive Response ◽  
Control Group ◽  
Blood Samples ◽  
Humoral Immune ◽  
The Face ◽  
Intraspecific Aggressiveness ◽  
Specific Humoral Response

The repercussion on the immune response of the expression of intraspecific aggressiveness in the face of a stressor agent was investigated in rats. Ninety-day-old animals were divided into three groups: the control group (only immunological measurements were performed), the foot-shock (FS) (animals individually receiving FS), and the intraspecific aggressive response (IAR) group (animals receiving FS and presenting IAR). For immunological measurements, blood samples were collected promptly at 7 and 15 days after FS or IAR. The FS reduced the total leukocyte amount presented. However, aggressiveness triggered not only reduction of the leukocytes, but also lymphocyte decrease and neutrophil increase. Moreover, an elevation in total leukocytes associated with an increase in the humoral immune response was also observed one week after IAR. In this study, the expression of intraspecific aggressiveness in the face of a stressor seemed to activate the immune system and to potentiate the antigen specific humoral response.

scholarly journals RNA Transcription and Splicing Errors as a Source of Cancer Frameshift Neoantigens for Vaccines

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Luhui Shen ◽  
Jian Zhang ◽  
HoJoon Lee ◽  
Milene Tavares Batista ◽  
Stephen Albert Johnston
Keyword(s):  
Immune Response ◽  
Cancer Therapy ◽  
Antibody Response ◽  
Cancer Vaccines ◽  
Checkpoint Inhibitors ◽  
Peptide Array ◽  
Rna Transcription ◽  
Dna Mutations ◽  
Tumor Dna

Abstract The success of checkpoint inhibitors in cancer therapy is largely attributed to activating the patient’s immune response to their tumor’s neoantigens arising from DNA mutations. This realization has motivated the interest in personal cancer vaccines based on sequencing the patient’s tumor DNA to discover neoantigens. Here we propose an additional, unrecognized source of tumor neoantigens. We show that errors in transcription of microsatellites (MS) and mis-splicing of exons create highly immunogenic frameshift (FS) neoantigens in tumors. The sequence of these FS neoantigens are predictable, allowing creation of a peptide array representing all possible neoantigen FS peptides. This array can be used to detect the antibody response in a patient to the FS peptides. A survey of 5 types of cancers reveals peptides that are personally reactive for each patient. This source of neoantigens and the method to discover them may be useful in developing cancer vaccines.

scholarly journals Impact of Prebiotics and Synbiotics Administered in ovo on the Immune Response against Experimental Antigens in Chicken Broilers

Animals ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 643
Author(s):  
Tadeusz Stefaniak ◽  
Jan P. Madej ◽  
Stanisław Graczyk ◽  
Maria Siwek ◽  
Ewa Łukaszewicz ◽  
...  
Keyword(s):  
Immune Response ◽  
Humoral Immune Response ◽  
Physiological Saline ◽  
Treated Group ◽  
Delayed Type Hypersensitivity ◽  
Saline Control ◽  
Control Group ◽  
In Ovo ◽  
Humoral Immune ◽  
Air Chamber

The effect of the in ovo application of selected prebiotics and synbiotics on the humoral immune response against T-dependent (SRBC) and T-independent (dextran) antigens and delayed-type hypersensitivity (DTH) to phytohemagglutinin was studied. On the 12th day of incubation, 800 eggs (Ross 308) were divided into five groups and injected into the egg air chamber with prebiotic inulin (Pre1), Bi2tos (Pre2), a synbiotic composed of inulin and Lactococcus lactis subsp. lactis IBB SL1 (Syn1), a synbiotic composed of Bi2tos and L. lactis subsp. cremoris IBB SC1 (Syn2), and physiological saline (control group; C). The chickens were immunized twice at the 7th and 21st day of life with SRBC and dextran. A DTH test was performed on the 7th, 21st, and 35th day. The application of prebiotics and synbiotics had no significant effect on the humoral immune response. SRBC-immunized in ovo Pre1- and Pre2-treated chickens showed significantly higher serum IgG levels than the control. A significant effect on the DTH reaction was detected on the 7th (Pre1 < C) and 21st (Pre2 > Syn2) day. However; Bi2tos may transiently stimulate the cellular immune response on the 21st day. It may be concluded that the application of inulin in an egg air chamber on the 12th day of incubation may stimulate the secondary immune response. The inulin-treated group exhibited a lower mortality rate than the control group.

Combining chemotherapy and programmed death 1 (PD-1) blockade to induce a T-cell response in patients with metastatic triple negative breast cancer (mTNBC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11563-11563 ◽  
Author(s):  
Elias Obeid ◽  
Chun Zhou ◽  
Alexander Macfarlane ◽  
R. Katherine Alpaugh ◽  
Cecilia McAleer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Function ◽  
T Cell Response ◽  
Number Of Patients ◽  
Correlative Studies ◽  
Immune Changes

11563 Background: Correlative studies to determine the effect of combining chemotherapy (CT) simultaneously with checkpoint inhibition on the peripheral immune response are planned as part of a clinical trial in MTNB. The trial design is a Safety run-in, into a randomized phase II trial of combination pembrolizumab (P) with carboplatin (C) and gemcitabine (G) in patients with mTNBC. One key concern is that CT may suppress immune cell function, thereby diminishing the efficacy of PD-1 blockade. Methods: Patients with a diagnosis of mTNBC are recruited to this trial with a Safety Run-in (N = 6-12 subjects), followed by a randomized design of C + G with/without P (2:1 randomization, N = 75). Safety run-in consists of P 200 mg on day 1 of each 21-day cycle, and C (AUC2) + G (800mg/m2) on days 1 and 8. Patients are consented for a peripheral blood (PB) collection pre-cycle 1 and on day 1 of cycle 3, in order to phenotype immune system changes by flow-cytometry. Results: Six patients have been recruited as of this interim analysis. Data from PB analysis of 3 on-treatment patients is available. In 2 subjects, the activation marker CD69 increased on CD4+ and CD8+ T cells from baseline, indicating enhanced T cell function. Also the ratio of CD8+ T cells to regulatory T cells (CD25high CD127low) has increased. Both patients expressed PD-1 on T cells at baseline. The 2 subjects with evidence for enhanced immune response have a continued clinical benefit (12 cycles subject 1, 8 cycles subject 2). In contrast, subject 3 (who discontinued P and received corticosteroids for grade a 2 immune-related hepatitis during cycle 2) lacked expression of PD-1 on T cells and did not exhibit these immune changes, and her disease clinically progressed after 4 cycles of CT. Conclusions: Although comprising a very limited number of patients, early analysis from our correlative studies of combining CT with the PD-1 blockade revealed evidence for effective immune stimulation in two subjects. Furthermore, immune changes accompanied a lasting clinical response. Although early, we conclude that combining CT with checkpoint blockade can achieve its goal of unleashing an anti-tumor immune response in mTNBC patients. Clinical trial information: NCT02755272.

scholarly journals Systemic COVID-19 vaccination also enhances the humoral immune response after SARS CoV-2 infection in the population of an oncology hospital in Poland. Criteria for COVID-19 re-immunization are needed.

2021 ◽  
Author(s):  
Piotr Kosiorek ◽  
Dorota Kazberuk ◽  
Anna Hryniewicz ◽  
Robert Milewski ◽  
Samuel Stróż ◽  
...  
Keyword(s):  
Immune Response ◽  
Humoral Immune Response ◽  
Post Infection ◽  
Half Life ◽  
Humoral Response ◽  
Control Group ◽  
Igg Antibodies ◽  
Hospital Laboratory ◽  
Humoral Immune ◽  
Chemiluminescent Immunoassay

Abstract Systemic vaccination of the BNT162b2 mRNA stimulates humoral response. Our study aimed to compare the intensity of humoral immune response, measured by SARS CoV-2 IgG, SARS CoV-2 IgM, and neutralization S-RBD IgG antibodies level, post COVID-19 vaccination versus post-SARS COV-2 infection. We analysed 1060 people in the following groups: convalescents, healthy vaccinated, vaccinated with COMIRNATY, AstraZeneca, Moderna, Johnson & Johnson, and vaccinated SARS CoV-2 convalescents. A concentration of SARS CoV-2 IgG, SARS CoV-2 IgM, and neutralizing S-RBD IgG was estimated in hospital laboratory by chemiluminescent immunoassay - CLIA, MAGLUMI. Results: 1. We observed a rise of antibodies response in both convalescent SARS CoV-2 and COVID-19 vaccinated groups 2. The level of all antibodies’ concentrations in vaccinated COVID-19 convalescents was significantly higher. 3. We differentiated asymptomatic SARS CoV-2 convalescents from the control group. Based on our analysis, we suggest that it is essential to monitor SARS CoV-2 antibodies concentrations as an indicator of asymptomatic COVID-19 infection and equivalent to the effectiveness of humoral response in convalescents and vaccinated people. Considering the time-limited nature of the effects of post-infection SARS CoV-2 recovery or vaccination, among others physiological half-life, we suggested monitoring IgG antibodies level as a criterium for the next vaccination.

scholarly journals Differences in systemic humoral immune response among Balb/c mice administered with probiotic, LPS Escherichia coli, and probiotic-LPS E. coli

2019 ◽  
Author(s):  
Kurniawan Taufiq Kadafi ◽  
Satrio Wibowo
Keyword(s):  
Escherichia Coli ◽  
Immune Response ◽  
Humoral Immune Response ◽  
Control Group ◽  
E Coli ◽  
Humoral Immune ◽  
Treatment Regimens ◽  
Humoral Immune Responses ◽  
Group 4 ◽  
Group 2

Background and Objectives: The aim of this study was to compare the systemic humoral immune responses, including IgE, IgA, IgG and IgM levels in Balb/c mice administered a probiotic, LPS derived from Escherichia coli (E.coli), and probiot- ic-LPS derived from E. coli. Materials and Methods: Thirty-two male Balb/c mice, 10-12 weeks of age with body weight ranging from 30-40 g were randomly divided into four experimental groups (n=8). The treatment regimens were as follows: Group 1, mice did not receive LPS or probiotic (control group); Group 2, mice received only LPS on the first day; Group 3, mice received probi- otic for 7 days; Group 4, mice received LPS on the first day, and then continued, with probiotic for 7 days. The mice were observed for 8 days, and then, euthanized the next day (day 9). The serum was collected, and the levels of IgE, IgA, IgG and IgM were measured using ELISA. Results: The humoral immune response was higher in the presence of a probiotic compared to that in the control; IgE (9.02 ± 0.58 units/ml, p=0.000), IgA (3.26 ± 0.99 units/ml, p=0.316), IgG (7.29 ± 0.24 units/ml, p=0.000), and IgM (4.01 ± 2.98 units/ml, p=0.505). When administered with LPS E. coli along with probiotic, the humoral immune response was the highest; IgE (10.68 ± 1.63 units/ml, p=0.000), IgA (8.34 ± 1.47 units/ml, p=0.000), IgG (9.96 ± 0.98 units/ml, p=0.000), and IgM (4.31 ± 1.05 units/ml, p=0.319) compared to the control group. Conclusion: Probiotic-LPS derived from E. coli treatment induced a higher humoral immune response (highest IgE, IgA, IgG and IgM levels) compared to treatment with probiotic only.

scholarly journals Humoral immune response of Salmonella typhimurium and Salmonella enteritidis sonicated antigens in rabbits

2012 ◽  
Vol 36 (0E) ◽  
pp. 84-88
Author(s):  
Ekram A. Al-Samarrae
Keyword(s):  
Immune Response ◽  
Salmonella Typhimurium ◽  
Humoral Immune Response ◽  
Salmonella Enteritidis ◽  
Agglutination Test ◽  
Control Group ◽  
Whole Cell ◽  
Humoral Immune ◽  
The Third ◽  
Infected Goat

Salmonella typhimurium and salmonella enteritidis were isolated from infected goat andprepared an antigens of whole cell sonicated antigen of S.typhimurium(WCS.Ag.S.typhimurium ),whole cell sonicated antigen of S.enteritidis (WCS.Ag.S.entertidis) and combination of whole cell sonicated antigen (Salmonella typhimurium andSalmonella enteritidis) (CWS.Ag) . Their efficacy was evaluated by using tube agglutinationtest and enzyme linked immune sorbent assay (ELISA). Twenty rabbits were randomlydivided into four groups; the 1st group was immunized by WCS. Ag - Salmonella enteritidis,2nd group immunized by (WCS Ags .typhimurium), 3rd group immunized by CWCS.Agcompound and 4th left as control group which injected by physiological buffer saline (pH7.2). The antibody titer was increased in after the day 12, first, second and third months ofimmunization by agglutination test. IgG concentration was done by ELISA at the same time;which were recorded a higher significant differences (p˂ 0.01) at the first month in the groupimmunized by CWS Ag (449.65 ±38.6 1ng/ml IgG and 952± 20.85 antibodies titer )compared with other immunized groups ( WCS – Ag – S. enteritidis andWCS.Ag.S.typhimurium ). Also, the IgG concentration and antibodies titer are still higher inthe second and the third months in the immunized group by CWCS.Ag. 218.90± 6.69ng/ml,528± 68.58 and 89.55± 2.63ng/ml, 280± 49.98 respectively with significant differences (p˂0.01) compared with the immunized groups (WCS.Ag.S. entertidis and WCS. Ag.S.typhimurium) and also, they are significant (p˂ 0.01) when compared with the control groupResearch

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