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1
Lin, Wen-Hsuan, Chien-Hsiung Pan, Robert Adams, Brandi Ford, Beth Laube, John Mikszta, Vince Sullivan, and Diane Griffin. "Route of immunization influences the induction of humoral, cellular and protective immunity by live attenuated measles vaccine in rhesus macaques (52.11)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 52.11. http://dx.doi.org/10.4049/jimmunol.184.supp.52.11.
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Abstract Measles is a leading cause of vaccine-preventable mortality worldwide. To facilitate vaccine distribution, aerosol immunization has been proposed, but the immune response induced, and protection afforded, by live attenuated measles virus (MV) vaccine (LAV) given by the respiratory route have not been systematically studied. Rhesus macaques were immunized with liquid or powder LAV through a nebulizer, an endotracheal tube, or parenterally by intramuscular injection. The method of immunization significantly influenced the induction of the humoral and cellular immune responses to LAV, but the effect on the cellular immune response was not correlated with the effect on the humoral response. For instance, nebulizer immunization induced good T cell, but poor antibody responses. Intratracheal challenge with wild type MV showed that respiratory immunization did not fully prevent infection. However, animals primed with nebulizer LAV showed accelerated viral clearance from both blood and respiratory tract that coincided with faster and higher levels of MV-specific recall CD4+/CD8+ T-cell responses compared to controls. Therefore, the route of immunization influences the induction of humoral, cellular and protective immune responses to measles vaccine. Protection correlates with neutralizing antibody and not with T-cell responses. Although, memory T cells alone are not sufficient for preventing MV infection, a robust recall T cell response does accelerate viral clearance.
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Ovsyannikova, Inna G., Neelam Dhiman, Robert M. Jacobson, Robert A. Vierkant, and Gregory A. Poland. "Frequency of Measles Virus-Specific CD4+ and CD8+ T Cells in Subjects Seronegative or Highly Seropositive for Measles Vaccine." Clinical Diagnostic Laboratory Immunology 10, no. 3 (May 2003): 411–16. http://dx.doi.org/10.1128/cdli.10.3.411-416.2003.
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ABSTRACT The protective effect of measles immunization is due to humoral and cell-mediated immune responses. Little is known about cell-mediated immunity (CMI) to measles vaccine virus, the relative contribution of CD4+ and CD8+ T cells to variability in such immune responses, and the immunologic longevity of the CMI after measles vaccination in humans. Our study characterizes cellular immune response in subjects seronegative or highly seropositive for measles vaccine immunoglobulin G-specific antibody, aged 15 to 25 years, previously immunized with two doses of measles-mumps-rubella II vaccine. We evaluated the ability of subjects to respond to measles vaccine virus by measuring measles virus-specific T-cell proliferation. We examined the frequencies of measles virus-specific memory Th1 and Th2 cells by an ELISPOT assay. Our results demonstrated that proliferation of T cells in seronegative subjects was significantly lower than that for highly seropositive subjects (P = 0.003). Gamma interferon (IFN-γ) secretion predominated over interleukin 4 (IL-4) secretion in response to measles virus in both groups. The median frequency of measles virus-reactive CD8+ T cells secreting IFN-γ was 0.09% in seronegative subjects and 0.43% in highly seropositive subjects (P = 0.04). The median frequency of CD4+ T cells secreting IL-4 in response to measles virus was 0.03% in seronegative subjects and 0.09% in highly seropositive subjects (P = 0.005). These data confirm the presence of measles virus-specific cellular immune responses post-measles vaccine immunization in humans. The detection of measles virus-induced IFN-γ and IL-4 production by ELISPOT can be used to identify measles virus-specific low-frequency memory T cells in subjects immunized with measles vaccine. These differences agree in directionality with the observed antibody response phenotype.
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Toptygina, A. P., Yu Yu Andreev, M. A. Smerdova, A. Yu Zetkin, and T. G. Klykova. "Formation of humoral and cellular immunity to measles vaccine in adults." Russian Journal of Infection and Immunity 10, no. 1 (April 7, 2020): 137–44. http://dx.doi.org/10.15789/2220-7619-foh-1334.
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Despite adherence to the policy of mass measles vaccination in the majority of countries, this infection still remains far from being fully eradicated. Measles outbreaks are reported worldwide, when the vast majority of cases are recorded in subjects of 18—35 years of age. Studies on assessing measles IgG antibody level in different regions of Russia reveal increased percentage of measles seronegative subjects among young adults. Current study was aimed at investigating formation of humoral and cellular immunity after measles vaccination in seronegative adults aged 18 to 30 years old. There were enrolled 50 measles seronegative healthy volunteers aged 18 to 30 years old. Level of anti-measles IgM and IgG antibodies was measured by ELISA (Vector-Best, Russia). Subclasses of measles specific IgG antibodies were analyzed by ELISA, by replacing IgG conjugate for IgG1, IgG2, IgG3, IgG4 conjugates, whereas measles specific IgA antibodies were estimated by ELISA with IgA conjugate (Polygnost, Russia) at a concentration of 1 μg/ml. Antibody avidity was assessed by ELISA (Euroimmun, Germany). Cell-mediated measles immunity was estimated by CD107a surface expression on CD8hi T cell subset stimulated by measles virus-derived antigens. A specific cellular response to measles antigens before vaccination was detected in 50% of examined subjects, whereas 40% samples showed no signs of cellular immune response, with 10% of remaining cases described as equivocal. It was found that 6 weeks after vaccination all vaccinated subjects developed measles specific IgG antibodies at protective level reaching 1.33 (0.85—1.82) IU/ml [Me (LQ—UQ)]. Anti-measles IgA antibodies were of 0.655 (0.423—1.208) IU/ml [Me (LQ—UQ)]. However, no measles specific IgM antibodies were detected 6 weeks after vaccination. In addition, primary type of immune response (dominant low-avidity anti-measles antibodies IgG3 subclass) to measles vaccination was observed in 24 out of 50 subjects, whereas 26 subjects developed secondary type of immune response (high-avidity anti-measles antibodies dominated by IgG1 subclass). A measles specific cellular immune response was observed in 47 of the 50 examined subjects, and in 3 volunteers it was equivocal. Further analysis revealed a cohort of subjects who were not vaccinated against measles (18 subjects), although 60% of them provided medical record on previous dual measles vaccination occurred in childhood. Another cohort consisted of subjects who had medical record of measles vaccination in childhood (32 subjects), but lost protective measles antibodies produced by plasma cells (23 subjects), and memory T cells (3 subjects), or measles antibodies and memory B cells (6 subjects) over time. Such pattern evidences that measles-specific cellular and humoral arms immune responses were developed and maintained independently of each other.
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Fitriah, Munawaroh, and Jusak Nugraha. "Immunogenicity Assessment on Clinical Trials of SARS-CoV-2 Vaccines." INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY 28, no. 2 (June 3, 2022): 202–8. http://dx.doi.org/10.24293/ijcpml.v28i2.1975.
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Various strategies for dealing with COVID-19 have been carried out since the WHO declared COVID-19 as an international health emergency. One of the preventive strategies is the development of vaccines. Various vaccines have been developed worldwide. As of April 13, 2021, there were 184 vaccine candidates in the pre-clinical phase and 16 vaccine candidates currently in phase III clinical trials using several platforms, such as inactivated viruses, vector viruses, and protein subunits, and mRNA. Clinical trials of the SARS-CoV-2 vaccine include a screening test consisting of thorough physical examination and laboratory tests. The safety of clinical trials is evaluated based on laboratory test results referring to the standard toxicity grading scale. Immunogenicity assessment at the stage of clinical trials of vaccines includes assessment of humoral and cellular immunogenicity. The humoral immunogenicity test measures the ability of antibodies to neutralize the virus with the live virus neutralization test, Pseudo Virus Neutralization Test (pVNT), and Surrogate Virus Neutralization Test (sVNT) method. The cellular immunogenicity response aims to assess the immune response that leads to the Th1-cell phenotype. The COVID-19 vaccine under development is expected to trigger a helper 1 (Th1) cell response. Th1-producing Interferon-g (IFNg) is formed during acute viral infection, and Th1-type immune response correlates with milder disease. This is one of the considerations in vaccination. Th1-cell phenotype as part of cellular immunogenicity can be evaluated with ELISPOT, interferon-gamma release assay, and flow cytometry using blood samples that have been cultured with the administration of specific SARS-CoV-2 peptides. This literature review aims to study various immunogenicity assessments in the laboratory for clinical trials of COVID-19 vaccines.
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CZĘŚCIK, AGNIESZKA, MILENA DUNAL-SZCZEPANIAK, AGNIESZKA TRZCIŃSKA, and JOANNA SIENNICKA. "Response of Viral Specific CD4 T Cells to in vitro Stimulation with Vaccine and Wild Measles Virus Strains in Vaccinated and Naturally Infected Subjects." Polish Journal of Microbiology 63, no. 2 (2014): 203–9. http://dx.doi.org/10.33073/pjm-2014-026.
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With the implementation of the WHO strategic plan for the elimination of measles, the number of measles cases in European Region has decreased. However, outbreaks are still observed. Although most measles cases affect unvaccinated individuals, cases with vaccinated persons are also reported. Furthermore, it was described that a high percentage of young people in Poland exhibit no presence of anti-MeV IgG despite the high level of vaccination covering no less than 97% of the Polish population. Strong evidence exists that immunity to measles is complex and depends on both the humoral and cellular response and although antibodies have been used as correlates of immunity, it is increasingly being considered that antibody-based definitions of vaccine success or failure may be incomplete. Here, we investigated immunity to measles as the reactivity of CD4 T cells to stimulation with vaccine as well as wild strains of measles virus (MeV) isolated in Poland, in young vaccinated persons and subjects infected naturally. Evidence for the presence of MeV-specific memory cells years after infection or vaccination was found, however the cells ofvaccinees and naturally infected subjects reacted differently in contact with wild and vaccine MeV strains. Furthermore, the presence of a significant proportion of non-responder vaccinees was observed. In conclusion, our results may have implications for studies on the monitoring of the complexity of post-vaccine immune response.
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Gerna, Giuseppe, Chiara Fornara, Milena Furione, and Daniele Lilleri. "Congenital Human Cytomegalovirus Infection: A Narrative Review of Maternal Immune Response and Diagnosis in View of the Development of a Vaccine and Prevention of Primary and Non-Primary Infections in Pregnancy." Microorganisms 9, no. 8 (August 16, 2021): 1749. http://dx.doi.org/10.3390/microorganisms9081749.
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Congenital cytomegalovirus infection (cCMV) may affect about 1% of all newborns all over the world as a result of either a primary or recurrent human cytomegalovirus (HCMV) infection. While about 90% of infants affected by cCMV are asymptomatic at birth, the remaining 10% are symptomatic often with neurodevelopmental impairment and sensorineural hearing loss. In view of identifying the best approach to vaccine prevention of cCMV, this review will examine the most important steps made in the study of the immune response to, and diagnosis of, HCMV infection. The maternal immune response and immune correlates of protection are being partially identified with a partial contribution given by our laboratory. The diagnosis of primary infection is often difficult to achieve in the first three months of pregnancy, which is the time primarily involved in virus transmission to the fetus in association with the most severe symptoms and sequelae. Prevention of cCMV is anticipated by prevention of primary infection in early pregnancy by means of different measures, such as (i) behavioral-educational measures, (ii) immunoglobulin administration, (iii) antiviral treatment with valaciclovir. However, the most promising approach to cCMV prevention appears to be the development of a non-living vaccine, including at least three viral antigens: gB, pentamer complex gHgLpUL128L, and pp65, which have been shown to be able to stimulate both the humoral and the cellular arms of the maternal immune response. Primary HCMV infection may be managed in pregnancy by counseling of the couples involved by a team of specialists that includes virologists, obstetricians, infectivologists and neonatologists.
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Witkowski, Wojciech, Sarah Gerlo, Evelien De Smet, Magdalena Wejda, Delphine Acar, Steven Callens, Stefan Heytens, et al. "Humoral and Cellular Responses to COVID-19 Vaccination Indicate the Need for Post-Vaccination Testing in Frail Population." Vaccines 10, no. 2 (February 8, 2022): 260. http://dx.doi.org/10.3390/vaccines10020260.
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Despite the high efficacy of the BNT162b2 vaccine in the general population, data on its immunogenicity among frail elderly individuals are limited. Recently, levels of anti-SARS-CoV-2 spike IgG antibodies and serum neutralization titers were confirmed as good immune markers of protection against the virus, with evidence showing a reverse correlation between these two parameters and susceptibility to infection. Here we analyzed sera from 138 nursing home residents (median age of 88.9 years) and 312 nursing home staff (median age of 50.7 years) to determine the humoral response to two doses of the BNT162b2 vaccine, and found markedly decreased serum anti-spike antibody levels and neutralization titers in the nursing home resident (NHR) group, with over 11% non-responders compared to only 1.3% among the controls. Moreover, three months post-vaccination, a significant decrease in antibody titers was observed in COVID-19-naive nursing home residents. Subsequent flow cytometry and interferon gamma secretion analyses indicated that antibody non-responders among NHRs also failed to mount cellular responses. The presented data emphasize that additional measures are needed in the population of frail elderly individuals. Given the high proportion of non-responders among NHRs, continued monitoring should be considered in this group.
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Olszewska, Wieslawa, Charalambos D. Partidos, and Michael W. Steward. "Antipeptide Antibody Responses following Intranasal Immunization: Effectiveness of Mucosal Adjuvants." Infection and Immunity 68, no. 9 (September 1, 2000): 4923–29. http://dx.doi.org/10.1128/iai.68.9.4923-4929.2000.
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ABSTRACT Toxicity is a major factor limiting the development and use of potent adjuvants for human mucosally delivered vaccines. Novel adjuvant formulations have recently become available, and in the present study two have been used for intranasal immunization with a synthetic peptide immunogen (MAP-M2). This peptide represents a multiple antigenic peptide containing multiple copies of a mimotope M2, a peptide mimic of a conformational epitope of the fusion protein of measles virus. MAP-M2 was administered intranasally to experimental animals together with synthetic oligodeoxynucleotides containing unmethylated CpG motifs with or without a mutant of wild-type enterotoxin of Escherichia coli (LTR72). The combination of the mutant toxin LTR72 and the CpG repeats, codelivered with a peptide immunogen, induced both local and systemic peptide- and pathogen-specific humoral and cellular immune responses comparable to those obtained after intranasal immunization with the wild-type toxin LT. In addition, this combination of adjuvants induced a predominantly immunoglobulin G2a antibody response. If both the LTR72 and CpG adjuvants are shown to be safe for use in humans, this particular combination would appear to have potential as an adjuvant for mucosally delivered vaccines in humans.
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Rodríguez Hernández, Carmen, and Juan Carlos Sanz Moreno. "Immunity against SARS-CoV-2: walking to the vaccination." Revista Española de Quimioterapia 33, no. 6 (September 11, 2020): 392–98. http://dx.doi.org/10.37201/req/086.2020.
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The coronavirus are a wide group of viruses among that the SARS-CoV-2 is included (family Coronaviridae, subfamily Coronavirinae, genus Betacoronavirus and subgenus Sarbecovirus). Its main structural proteins are the membrane (M), the envelope (E), the nucleocapsid (N) and spike (S). The immune response to SARS-CoV-2 involves the cellular and the humoral sides, with neutralizing antibodies fundamentally directed against the S antigen. Although the seroprevalence data are frequently assumed as protection markers, no necessarily they are. In Spain, it is estimated that, to assure the herd immunity, at least four-fifths of the population should be immunoprotected. Due the high fatality rate of COVID-19, the acquisition of the protection only by the natural infection it not assumable and other measures as the mass immunization are required. Currently, there are several vaccine prototypes (including life virus, viral vectors, peptides and proteins and nucleic acid) in different phase of clinical evaluation. Foreseeably, some of these news vaccines would be soon commercially available. In this text, aspects related to these issues are reviewed.
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Gracheva, Anastasiia V., Ekaterina R. Korchevaya, Roman V. Samoilikov, Daria I. Smirnova, Irina А. Leneva, Artem A. Poromov, Andrey А. Pankratov, et al. "Аttenuation мarkers of cold-adapted SARS-CoV-2 variants." Medical academic journal 2, no. 2 (November 6, 2022): 79–88. http://dx.doi.org/10.17816/maj108725.
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BACKGROUND: Unprecedented anti-epidemic measures and the widespread use of vaccines against COVID-19 have reduced the rate of hospitalization and mortality from the disease, but have not stopped the SARS-CoV-2 pandemic spread. The development of live vaccines against COVID-19, capable of providing the formation of a long-term humoral and cellular immune response and cross-protection against new SARS-CoV-2 variants of concern, is relevant. Previously at the I.I. Mechnikov Research Institute of Vaccines and Sera SARS-CoV-2 cold-adapted (ca, cold-adapted) variants were obtained. This work is aimed to search for methodological approaches that allow in vitro screening studies to assess the attenuation (att) phenotype of ca SARS-CoV-2 variants.
MATERIALS AND METHODS: The SARS-CoV-2 laboratory strain Dubrovka and its variants were cultured in Vero and Calu-3 cells. Quantitation of the virus was carried out by titration in Vero cells and by real-time RT-PCR. The attenuation (att) phenotype of SARS-CoV-2 variants was determined on an animal model of COVID-19 on Syrian hamsters.
RESULTS: In experiments on Syrian hamsters, the presence of the att phenotype in the ca variants of the virus was established. Animals infected with virus ca variants had significantly less weight lost, had less viral load in the lungs and brain and less pronounced pathological changes in the lungs compared to infection with the virulent strain. In vitro experiments on Vero and Calu-3 cells revealed probable attenuation markers of the virus ca variants for syrian hamsters: (1) ability to reproduce at low temperature (ca phenotype); (2) inability to reproduce at 39 C (ts phenotype); (3) changes in the species and tissue specificity of the virus.
CONCLUSIONS: The developed methodological approaches to the identification of SARS-CoV-2 attenuation markers are a valuable tool for monitoring the stability of the phenotype of candidate vaccine strains.
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H.R., Teni, Wisnu Barlıanto, I. Wayan Arsana Wıyasa, H. M. S. Kusuma, Tita Sari, and Novilia Bachtıar. "Analysis of specific antibody and cellular immune response to first-dose measles vaccine Edmonston-Zagreb (EZ) in 9-month-old infants." Allergologia et Immunopathologia 49, no. 3 (May 1, 2021): 193–201. http://dx.doi.org/10.15586/aei.v49i3.6.
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Background: Measles vaccinations have been suggested to provide immune protection and decreased measles incidence. However, there was a limited study evaluating how the measles vaccine elicits specific immune responses.Objective: This study aimed to evaluate both humoral and cellular immunity to first-dose measles vaccine Edmonston-Zagreb (EZ) in 9-month-old Indonesian infants.Methods: A cohort study was conducted on 9-month-old infants who got the first-dose of measles vaccine EZ. Measles-specific immunoglobulin G (IgG) antibody serum levels were measured using plaque-reduction microneutralization assay. Peripheral blood mononuclear cells were stimulated with a measles-specific peptide to identify a cellular immune response. Quantification of CD4+ and CD8+ T-cells producing interferon-gamma (IFN-ɣ) and interleu-kin 17-A (IL-17A) were conducted by flow cytometry. Humoral and cellular immune response parameters were analyzed over time.Results: The prevalence of seropositivity rates was 85.8% at 1-month after vaccination and 16.67% at 6-months postvaccination. Measles-specific IgG antibodies increased significantly at 1-month after measles vaccination. However, they decreased significantly 6-months after vaccination. IFN-ɣ and IL-17A secreting T-cells increased significantly at 1-month after measles vaccination. Interestingly, a significant decrease of IFN-ɣ and IL-17A secreting CD4+ T cells was noticed 6-months postvaccination compared to IFN-ɣ and IL-17A secreting CD8+ T cells. Conclusion: Our study suggests that the first-dose measles vaccine on 9-months-old infants seems to induce both humoral and cellular immune responses that decline 6-months after vaccination.
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Al-Gburi, Sarah, Haidar Kadhim, and Haider Ghazi. "Association of CD46 Cellular Receptor Gene SNP in Measles Vaccine Response." Iraqi Journal of Medical Sciences 18, no. 1 (June 30, 2020): 39–46. http://dx.doi.org/10.22578/ijms.18.1.6.
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Background: Measles is a highly contagious viral disease. It remains an important cause of death among young children globally, despite the availability of a safe and effective vaccine. Measles transmitted via droplets from the nose, mouth or throat of infected persons. Objective: To evaluate the immune response to measles infection among immunized school aged children, and to detect the cluster of differentiation 46 single nucleotide polymorphism (CD46 SNP) in association with the immune response. Methods: The current study is a cross sectional study including 158 hospitalized patients were previously vaccinated with two doses of measles-mumps-rubella vaccine. The ages of patients were 5-10 years school aged children. All samples were collected from blood collection unit in Al-Imamein Al-Kadhimein Medical city during the period from December 2018 to April 2019. The detection was based on the presence of IgG Antibody to measles. The positive results were considered according to enzyme linked immunosorbant assay and conventional polymerase chain reaction to detect CD46 SNP. Results: Among those 158 subjects' male children count for 62% and female children were 38%. Forty-one (41) immunized children (with mean age 7.98±1.92 years) were low immune response to measles vaccine (MV). On the other hand, only two cases (with mean age 5.50±0.71 years) were negative to measles virus vaccine. Conclusion: Ensuring two doses of MV give protective immune response to MV may declines with aging. CD46 cellular receptor gene SNP (rs7144) may play role in reduction in immune response to MV. Keywords: Measles, MMR, CD46, SNP, Iraq Citation: Al-Gburi SAJ, Kadhim HS, Ghazi HF. Association of CD46 Cellular Receptor Gene SNP in measles vaccine response. Iraqi JMS. 2020; 18(1): 39-46. doi: 10.22578/IJMS.18.1.6
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Smerdova, M. A., A. P. Toptygina, Yu Yu Andreev, S. V. Sennikova, A. Yu Zetkin, T. G. Klykova, and S. I. Belyakov. "Humoral and cellular immunity to measles and rubella virus antigens in healthy subjects." Russian Journal of Infection and Immunity 9, no. 3-4 (November 15, 2019): 607–11. http://dx.doi.org/10.15789/2220-7619-2019-3-4-607-611.
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An issue of eradicating measles and rubella virus-induced infections currently remains unresolved, despite existing effective methods for specific prophylaxis and WHO’s commitment to a mass vaccination policy. While improving epidemic situation, analysis of new challenges, such as measles incidence in adults, especially in adults vaccinated in childhood, is of particular interest. The aim of the study was to analyze serum measles and rubella virus-specific IgG antibodies in young healthy people and estimate antigen-specific cellular immune response in seronegative subjects. There were examined 100 healthy adults aged 18–30 years old. Level of serum specific IgG was measured by ELISA (Vector-Best, Russia). Antigen-specific cellular immune response was assessed by magnitude of surface CD107a expression on CD8hi T cells challenged by measles and rubella virus-derived antigens. It was found that average level of antibodies against rubella virus comprised 175.5 IU/ml, 49% of which recovered after rubella, 46% were vaccinated, whereas 5% subjects contained no virus-specific antibodies. In addition, mean level of anti-measles virus antibodies was below protective magnitude, among which 1% subjects recovered after measles, 31% displayed post-vaccination immunity, 55% subjects were seronegative, and 13% had equivocal levels of specific antibodies. Thus, 68% subjects were unprotected against measles virus based on the level of serum virus-specific antibodies. Moreover, 40 out of 68 subjects were vaccinated against measles in childhood. Additional screening adult subjects for intensity of measles and rubella virus-specific cellular immunity demonstrated that 57.37% of them contained peripheral blood CD8 T cells against measles virus and 59.01% — against rubella virus. Further analysis allowed to identify 4 subgroups displaying: 1) high level of virus-specific antibodies and T cells; 2) neither antibodies nor specific T-cells reaching as low as 20% of baseline group; 3) high antibody level combined with low amount of specific T cells; and 4) low antibody level combined with high level of specific T cells. thus, it may be assumed that cellular and humoral immune arms are maintained independently and being active for a long term after vaccination. Preserving a specific T-cell immunity seems to provide protection against infection, thereby accounting for the lack of measles manifestation in all seronegative subjects.
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López, Barriga, Lorente, and Mir. "Immunoproteomic Lessons for Human Respiratory Syncytial Virus Vaccine Design." Journal of Clinical Medicine 8, no. 4 (April 10, 2019): 486. http://dx.doi.org/10.3390/jcm8040486.
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Accurate antiviral humoral and cellular immune responses require prior recognition of antigenic peptides presented by human leukocyte antigen (HLA) class I and II molecules on the surface of antigen-presenting cells. Both the helper and the cytotoxic immune responses are critical for the control and the clearance of human respiratory syncytial virus (HRSV) infection, which is a significant cause of morbidity and mortality in infected pediatric, immunocompromised and elderly populations. In this article we review the immunoproteomics studies which have defined the general antigen processing and presentation rules that determine both the immunoprevalence and the immunodominance of the cellular immune response to HRSV. Mass spectrometry and functional analyses have shown that the HLA class I and II cellular immune responses against HRSV are mainly focused on three viral proteins: fusion, matrix, and nucleoprotein. Thus, these studies have important implications for vaccine development against this virus, since a vaccine construct including these three relevant HRSV proteins could efficiently stimulate the major components of the adaptive immune system: humoral, helper, and cytotoxic effector immune responses.
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Hocknell, Peter K., Rebecca D. Wiley, Xiuqing Wang, Thomas G. Evans, William J. Bowers, Tomas Hanke, Howard J. Federoff, and Stephen Dewhurst. "Expression of Human Immunodeficiency Virus Type 1 gp120 from Herpes Simplex Virus Type 1-Derived Amplicons Results in Potent, Specific, and Durable Cellular and Humoral Immune Responses." Journal of Virology 76, no. 11 (June 1, 2002): 5565–80. http://dx.doi.org/10.1128/jvi.76.11.5565-5580.2002.
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ABSTRACT Herpes simplex virus type 1 (HSV-1) infects a wide range of cells, including dendritic cells. Consequently, HSV-1 vectors may be capable of eliciting strong immune responses to vectored antigens. To test this hypothesis, an HSV-1 amplicon plasmid encoding human immunodeficiency virus type 1 gp120 was constructed, and murine immune responses to helper virus-free amplicon preparations derived from this construct were evaluated. Initial studies revealed that a single intramuscular (i.m.) injection of 106 infectious units (i.u.) of HSV:gp120 amplicon particles (HSV:gp120) elicited Env-specific cellular and humoral immune responses. A potent, CD8+-T-cell-mediated response to an H-2Dd-restricted peptide from gp120 (RGPGRAFVTI) was measured by a gamma interferon ELISPOT and was confirmed by standard cytotoxic-T-lymphocyte assays. Immunoglobulin G enzyme-linked immunosorbent assay analysis showed the induction of a strong, Env-specific antibody response. An i.m. or an intradermal administration of HSV:gp120 at the tail base elicited a more potent cellular immune response than did an intraperitoneal (i.p.) inoculation, although an i.p. introduction generated a stronger humoral response. The immune response to HSV:gp120 was durable, with robust cellular and humoral responses persisting at 171 days after a single 106-i.u. inoculation. The immune response to HSV:gp120 was also found to be dose dependent: as few as 104 i.u. elicited a strong T-cell response. Finally, HSV:gp120 elicited significant Env-specific cellular immune responses even in animals that had been previously infected with wild-type HSV-1. Taken together, these data strongly support the use of helper-free HSV-1 amplicon particles as vaccine delivery vectors.
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Son, Wonrak, Nayoung Kim, Minhoon Lee, Euni Sim, Donghyun Song, Chiho Yu, YoungJo Song, et al. "The effective immunization of plasmid DNA vaccine targeted for smallpox virus." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 167.32. http://dx.doi.org/10.4049/jimmunol.204.supp.167.32.
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Abstract Smallpox, caused by variola virus, could be a bio-terrorism agent although eradicated from the WHO program in the 1980s. DNA vaccine is a third generation vaccine system which contains DNA sequence with specific antigen codes that activates the immune system. DNA vaccines show great potential in inducing immune response with strong triggered-humoral, and cellular immunity. DNA vaccines have emerged as an attractive approach for infectious disease because of rapid manufacture, fast adaptation to newly emerging pathogens and high stability at ambient temperatures. However, since the potency of naked DNA vaccines is limited to immune efficacy, adjuvant incorporation could be a good option to increase the immune response. Several different compound-composed adjuvants are developed to help DNA vaccine efficacy. In other aspects, for inducing a more effective immune response, global vaccine manufacturer focused on targeting dendritic cell (DC) through the DC-specific surface protein, DEC-205. In this study, with plasmid construction modification, we developed a DNA vaccine vector that have effective antigen expression and confirmed immunogenicity against smallpox. For enhancing in vivo immune responses, we screened various adjuvant strategies and observed effective DNA vaccination response with various adjuvant studies and time-pointed reaction. Also, we tested the enhancement of immune response using DNA vaccine containing the smallpox antigen fused with DEC-205 and revealed a th1–th2 cellular immune response. Our results propose how to regulate modified-DNA immunization efficacy within DC targeting stimulation and adjuvant strategy against DNA vaccine development.
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Lee, Min Ja, Hyundong Jo, So Hui Park, Mi-Kyeong Ko, Su-Mi Kim, Byounghan Kim, and Jong-Hyeon Park. "Advanced Foot-And-Mouth Disease Vaccine Platform for Stimulation of Simultaneous Cellular and Humoral Immune Responses." Vaccines 8, no. 2 (May 28, 2020): 254. http://dx.doi.org/10.3390/vaccines8020254.
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Currently available commercial foot-and-mouth disease (FMD) vaccines have various limitations, such as the slow induction and short-term maintenance of antibody titers. Therefore, a novel FMD vaccine that can rapidly induce high neutralizing antibody titers to protect the host in early stages of an FMD virus infection, maintain high antibody titers for long periods after one vaccination dose, and confer full protection against clinical symptoms by simultaneously stimulating cellular and humoral immunity is needed. Here, we developed immunopotent FMD vaccine strains A-3A and A-HSP70, which elicit strong initial cellular immune response and induce humoral immune response, including long-lasting memory response. We purified the antigen (inactivated virus) derived from these immunopotent vaccine strains, and evaluated the immunogenicity and efficacy of the vaccines containing these antigens in mice and pigs. The immunopotent vaccine strains A-3A and A-HSP70 demonstrated superior immunogenicity compared with the A strain (backbone strain) in mice. The oil emulsion-free vaccine containing A-3A and A-HSP70 antigens effectively induced early, mid-term, and long-term immunity in mice and pigs by eliciting robust cellular and humoral immune responses through the activation of co-stimulatory molecules and the secretion of proinflammatory cytokines. We successfully derived an innovative FMD vaccine formulation to create more effective FMD vaccines.
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Kong, Wing-pui, Ling Xu, Konrad Stadler, Jeffrey B. Ulmer, Sergio Abrignani, Rino Rappuoli, and Gary J. Nabel. "Modulation of the Immune Response to the Severe Acute Respiratory Syndrome Spike Glycoprotein by Gene-Based and Inactivated Virus Immunization." Journal of Virology 79, no. 22 (November 15, 2005): 13915–23. http://dx.doi.org/10.1128/jvi.79.22.13915-13923.2005.
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ABSTRACT Although the initial isolates of the severe acute respiratory syndrome (SARS) coronavirus (CoV) are sensitive to neutralization by antibodies through their spike (S) glycoprotein, variants of S have since been identified that are resistant to such inhibition. Optimal vaccine strategies would therefore make use of additional determinants of immune recognition, either through cellular or expanded, cross-reactive humoral immunity. Here, the cellular and humoral immune responses elicited by different combinations of gene-based and inactivated viral particles with various adjuvants have been assessed. The T-cell response was altered by different prime-boost immunizations, with the optimal CD8 immunity induced by DNA priming and replication-defective adenoviral vector boosting. The humoral immune response was enhanced most effectively through the use of inactivated virus with adjuvants, either MF59 or alum, and was associated with stimulation of the CD4 but not the CD8 response. The use of inactivated SARS virus with MF59 enhanced the CD4 and antibody response even after gene-based vaccination. Because both cellular and humoral immune responses are generated by gene-based vaccination and inactivated viral boosting, this strategy may prove useful in the generation of SARS-CoV vaccines.
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Starostina, E. V., S. V. Sharabrin, A. P. Rudometov, V. R. Litvinova, M. B. Borgoyakova, S. I. Bazhan, A. A. Ilyichev, and L. I. Karpenko. "Immune response against DNA- and mRNA vaccines encoding artificial influenza virus immunogens." Russian Journal of Immunology 25, no. 3 (September 20, 2022): 321–26. http://dx.doi.org/10.46235/1028-7221-1103-ira.
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Constant antigenic drift of circulating influenza viruses leads to inefficiency of seasonal influenza vaccines, thus requiring annual re-design of these vaccines. Therefore, the development of a universal influenza vaccine is of particular relevance. A promising line of research in this area is to design the immunogens consisting of conserved protein fragments from different influenza viral strains. The aim of this work was to assess immunogenicity of DNA vaccines and mRNA vaccines encoding artificial antigens consisting of conserved hemagglutinin stem fragments and conserved M2 protein. We have obtained DNA vaccine constructs encoding artificial immunogens AgH1, AgH3, and AgM2, which contained conserved fragments of the hemagglutinin stalk from the two subtypes of influenza A H1N1 and H3N2, and conserved M2 protein. These DNA vaccines were used as templates for the synthesis of mRNA vaccines. To assess immunogenicity of the obtained constructs, BALB/c mice were immunized with DNA and mRNA vaccines by i/m administration. Assessment of the humoral immune response was carried out by ELISA, using influenza viruses A/Aichi/2/68(H3N2), A/California/07/2009 as antigens and the ULTRIX vaccine containing purified antigens of H1N1 and H3N2 influenza viruses. T cell immune response was assessed using two methods: intracellular cytokine staining (ICS) and ELISpot. ICS was performed to determine CD8+ and CD4+T-lymphocytes producing IFN. ELISpot was carried out using the mouse IFN ELISpot kit (BD). A peptide mixture which included composition of the target antigens, was used for cell stimulation. The results showed that the designed DNA vaccine constructs induce virus-specific humoral and cellular responses in immunized BALB/c mice. Intramuscular administration of the naked mRNA vaccine constructs induced a weak humoral immune response, thus suggesting a need for further work to improve the delivery approaches.
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Tornyos, G., Melinda Kovács, M. Rusvai, P. Horn, J. Fodor, and F. Kovács. "Effect of dietary fumonisin b1 on certain immune parameters of weaned pigs." Acta Veterinaria Hungarica 51, no. 2 (March 1, 2003): 171–79. http://dx.doi.org/10.1556/avet.51.2003.2.5.
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Only few data are available on the effect of fumonisins on the immune response. The aim of the present study was to examine whether dietary fumonisin B1 (FB1) has any effect on the humoral and cellular immune response in weaned pigs, depending on the dose and the time of toxin exposure. Fusarium moniliforme fungal culture was added to the experimental animals' diet to ensure an FB1 intake of 1, 5 and 10 ppm (first experiment) or 100 mg per animal per day (second experiment). The control animals were fed a toxin-free diet. In order to determine the immune response, the animals were vaccinated against Aujeszky's disease with inactivated vaccine (Aujespig K, Phylaxia-Sanofi, Budapest, Hungary). Specific and nonspecific in vitro cellular immune response was measured by the lymphocyte stimulation test (LST) induced by PHA-P, Con A, LPS and inactivated suspension of the Aujeszky's disease virus. Humoral immune response, e.g. specific antibody titre, was measured by the virus neutralisation (VN) test. None of the immunological parameters examined showed significant differences between groups. It could be concluded that fumonisin B1 had no significant effect on the humoral and cellular specific and nonspecific immune response when fed in a high dose (100 mg/animal/day for 8 days) or in a low concentration even for a longer period (1, 5 and 10 ppm for 3-4 months).
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Lundstrom, Kenneth. "Self-Amplifying RNA Viruses as RNA Vaccines." International Journal of Molecular Sciences 21, no. 14 (July 20, 2020): 5130. http://dx.doi.org/10.3390/ijms21145130.
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Single-stranded RNA viruses such as alphaviruses, flaviviruses, measles viruses and rhabdoviruses are characterized by their capacity of highly efficient self-amplification of RNA in host cells, which make them attractive vehicles for vaccine development. Particularly, alphaviruses and flaviviruses can be administered as recombinant particles, layered DNA/RNA plasmid vectors carrying the RNA replicon and even RNA replicon molecules. Self-amplifying RNA viral vectors have been used for high level expression of viral and tumor antigens, which in immunization studies have elicited strong cellular and humoral immune responses in animal models. Vaccination has provided protection against challenges with lethal doses of viral pathogens and tumor cells. Moreover, clinical trials have demonstrated safe application of RNA viral vectors and even promising results in rhabdovirus-based phase III trials on an Ebola virus vaccine. Preclinical and clinical applications of self-amplifying RNA viral vectors have proven efficient for vaccine development and due to the presence of RNA replicons, amplification of RNA in host cells will generate superior immune responses with significantly reduced amounts of RNA delivered. The need for novel and efficient vaccines has become even more evident due to the global COVID-19 pandemic, which has further highlighted the urgency in challenging emerging diseases.
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Wang, Shen, Cheng Zhang, Bo Liang, Weiqi Wang, Na Feng, Yongkun Zhao, Tiecheng Wang, et al. "Characterization of Immune Response Diversity in Rodents Vaccinated with a Vesicular Stomatitis Virus Vectored COVID-19 Vaccine." Viruses 14, no. 6 (May 24, 2022): 1127. http://dx.doi.org/10.3390/v14061127.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as the prime challenge facing public health safety since 2019. Correspondingly, coronavirus disease 2019 (COVID-19) vaccines have been developed and administered worldwide, varying in design strategies, delivery routes, immunogenicity and protective efficacy. Here, a replication-competent vesicular stomatitis virus (VSV) vectored recombinant COVID-19 vaccine was constructed and evaluated in BALB/c mice and Syrian golden hamsters. In BALB/c mice, intramuscular (i.m.) inoculation of recombinant vaccine induced significantly higher humoral immune response than that of the intranasal (i.n.) inoculation group. Analyses of cellular immunity revealed that a Th1-biased cellular immune response was induced in i.n. inoculation group while both Th1 and Th2 T cells were activated in i.m. inoculation group. In golden hamsters, i.n. inoculation of the recombinant vaccine triggered robust humoral immune response and conferred prominent protective efficacy post-SARS-CoV-2 challenge, indicating a better protective immunity in the i.n. inoculation group than that of the i.m. inoculation group. This study provides an effective i.n.-delivered recombinant COVID-19 vaccine candidate and elucidates a route-dependent manner of this vaccine candidate in two most frequently applied small animal models. Moreover, the golden hamster is presented as an economical and convenient small animal model that precisely reflects the immune response and protective efficacy induced by replication-competent COVID-19 vaccine candidates in other SARS-CoV-2 susceptible animals and human beings, especially in the exploration of i.n. immunization.
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Murtaza, Asad, Haroon Afzal, Thu-Dung Doan, Guan-Ming Ke, and Li-Ting Cheng. "Flagellin Improves the Immune Response of an Infectious Bursal Disease Virus (IBDV) Subunit Vaccine." Vaccines 10, no. 11 (October 22, 2022): 1780. http://dx.doi.org/10.3390/vaccines10111780.
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Flagellin activates the immune system through Toll-like receptor 5 (TLR5) and can work as an adjuvant for subunit vaccines. In this study, we tested the adjuvancy of two different N-terminal fragments of flagellin, (1) FliC99, residues 1–99, and (2) FliC176, residues 1–176, to incorporate larger areas of the hotspot region for potentially higher levels of TLR5 activation and immune response. A truncated version of the VP2 protein (name tVP2, residues 199–356) of the Infectious bursal disease virus (IBDV) was genetically linked to the flagellin constructs, and the immune response was evaluated in chickens. Results showed that both chimeric antigen–adjuvant constructs increased humoral (total IgG titers), cellular and cytokine immune response (IL-4, IFN-γ). The resulting antibody also successfully neutralized IBDV. We conclude that the N-terminus of flagellin can act as an immune activator to enhance vaccine efficacy.
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Chen, Keyan, Kui Zhao, Wenqi He, Wei Gao, Chuanbo Zhao, Li Wang, Wei Pan, Deguang Song, Chengli Wang, and Feng Gao. "Comparative Evaluation of Two Hemagglutinating Encephalomyelitis Coronavirus Vaccine Candidates in Mice." Clinical and Vaccine Immunology 19, no. 7 (April 18, 2012): 1102–9. http://dx.doi.org/10.1128/cvi.05716-12.
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ABSTRACTPorcine hemagglutinating encephalomyelitis (PHE) is caused by the coronavirus hemagglutinating encephalomyelitis virus (PHE-CoV), and the recent, rapid spread of PHE-CoV in piglets from many countries emphasizes the urgent need for a PHE-CoV vaccine. Here we use a murine model for evaluation of the induction of humoral and cellular immune responses by inactivated and PHE-CoV DNA vaccines in order to define the immune correlates for protection against PHE-CoV. The inactivated vaccine was composed of purified PHE-CoV and aluminum hydroxide gel (alum), which was chosen as an adjuvant because of its long history of safety for human use. The PHE-CoV DNA vaccine was constructed by subcloning the S1 gene of PHE-CoV into the pVAX1 vector to create the recombinant plasmid pV-S1. Our results showed that the inactivated PHE-CoV vaccine (IPV) elicited a high level of humoral immunity, resulting in good protection efficacy against PHE-CoV challenge. The IPV induced the IgG1 subclass of serum antibodies and expression of the cytokine interleukin-4 (IL-4), suggesting that the IPV generated a predominantly Th2-type immune response. The DNA vaccine was found to mediate primarily a cellular immune response with high levels of IgG2a and the cytokines IL-2 and gamma interferon (IFN-γ). However, mice that were vaccinated twice with the DNA vaccine and boosted with the IPV could mount a sufficient neutralizing antibody response against live PHE-CoV, with little variation in IgG1 and IgG2a levels, and showed high levels of IL-2 and IL-4. This response may activate both B and T cells to mount a specific humoral and cellular immune response that could, in turn, elicit a phagocyte-mediated defense against PHE-CoV infections to achieve viral clearance.
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Perciani, Catia T., Walter Jaoko, Sharon Walmsley, Bashir Farah, Salaheddin M. Mahmud, Mario Ostrowski, Omu Anzala, KAVI-ICR Team, and Kelly S. MacDonald. "Protocol of a randomised controlled trial characterising the immune responses induced by varicella-zoster virus (VZV) vaccination in healthy Kenyan women: setting the stage for a potential VZV-based HIV vaccine." BMJ Open 7, no. 9 (September 2017): e017391. http://dx.doi.org/10.1136/bmjopen-2017-017391.
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IntroductionA protective HIV vaccine would be expected to induce durable effector immune responses at the mucosa, restricting HIV infection at its portal of entry. We hypothesise that use of varicella-zoster virus (VZV) as an HIV delivery vector could generate sustained and robust tissue-based immunity against HIV antigens to provide long-term protection against HIV. Given that HIV uniquely targets immune-activated T cells, the development of human vaccines against HIV must also involve a specific examination of the safety of the vector. Thus, we aim to evaluate the effects of VZV vaccination on the recipients’ immune activation state, and on VZV-specific circulating humoral and cellular responses in addition to those at the cervical and rectal mucosa.Methods and analysisThis open-label, randomised, longitudinal crossover study includes healthy Kenyan VZV-seropositive women at low risk for HIV infection. Participants receive a single dose of a commercial live-attenuated VZVOkavaccine at either week 0 (n=22) or at week 12 (n=22) of the study and are followed for 48 and 36 weeks postvaccination, respectively. The primary outcome is the change on cervical CD4+T-cell immune activation measured by the coexpression of CD38 and HLA-DR 12 weeks postvaccination compared with the baseline (prevaccination). Secondary analyses include postvaccination changes in VZV-specific mucosal and systemic humoral and cellular immune responses, changes in cytokine and chemokine measures, study acceptability and feasibility of mucosal sampling and a longitudinal assessment of the bacterial community composition of the mucosa.Ethics and disseminationThe study has ethical approval from Kenyatta National Hospital/University of Nairobi Ethics and Research Committee, the University of Toronto Research Ethics Board and by Kenyan Pharmacy and Poisons Board. Results will be presented at conferences, disseminated to participants and stakeholders as well as published in peer-reviewed journals.Trial registration numberNCT02514018. Pre-results.
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Aberle, Judith H., Stephan W. Aberle, Regina M. Kofler, and Christian W. Mandl. "Humoral and Cellular Immune Response to RNA Immunization with Flavivirus Replicons Derived from Tick-Borne Encephalitis Virus." Journal of Virology 79, no. 24 (December 15, 2005): 15107–13. http://dx.doi.org/10.1128/jvi.79.24.15107-15113.2005.
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ABSTRACT A new vaccination principle against flaviviruses, based on a tick-borne encephalitis virus (TBEV) self-replicating noninfectious RNA vaccine that produces subviral particles, has recently been introduced (R. M. Kofler, J. H. Aberle, S. W. Aberle, S. L. Allison, F. X. Heinz, and C. W. Mandl, Proc. Natl. Acad. Sci. USA 7:1951-1956, 2004). In this study, we evaluated the potential of the self-replicating RNA vaccine in mice in comparison to those of live, attenuated vaccines and a formalin-inactivated whole-virus vaccine (ImmunInject). For this purpose, mice were immunized using gene gun-mediated application of the RNA vaccine and tested for CD8+ T-cell responses, long-term duration, neutralizing capacity, and isotype profile of specific antibodies and protection against lethal virus challenge. We demonstrate that the self-replicating RNA vaccine induced a broad-based, humoral and cellular (Th1 and CD8+ T-cell response) immune response comparable to that induced by live vaccines and that it protected mice from challenge. Even a single immunization with 1 μg of the replicon induced a long-lasting antibody response, characterized by high neutralizing antibody titers, which were sustained for at least 1 year. Nevertheless, it was possible to boost this response further by a second injection with the RNA vaccine, even in the presence of a concomitant CD8+ T-cell response. In this way it was possible to induce a balanced humoral and cellular immune response, similar to infection-induced immunity but without the safety hazards of infectious agents. The results also demonstrate the value of TBEV replicon RNA for inducing protective long-lasting antiviral responses.
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Yan, Banadyga, Zhao, Zhao, Schiffman, Huang, Li, et al. "Peste des Petits Ruminants Virus-Like Particles Induce a Potent Humoral and Cellular Immune Response in Goats." Viruses 11, no. 10 (October 5, 2019): 918. http://dx.doi.org/10.3390/v11100918.
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Peste des petits ruminants is a highly contagious acute or subacute disease of small ruminants caused by the peste des petits ruminants virus (PPRV), and it is responsible for significant economic losses in animal husbandry. Vaccination represents the most effective means of controlling this disease, with virus-like particle (VLP) vaccines offering promising vaccine candidates. In this study, a PPRV VLP-based vaccine was developed using a baculovirus expression system, allowing for the simultaneous expression of the PPRV matrix (M), hemagglutinin (H), fusion (F) and nucleocapsid (N) proteins in insect cells. Immunization of mice and goats with PPRV VLPs elicited a robust neutralization response and a potent cellular immune response. Mouse studies demonstrated that VLPs induced a more robust IFN-γ response in CD4+ and CD8+ T cells than PPRV Nigeria 75/1 and recruited and/or activated more B cells and dendritic cells in inguinal lymph nodes. In addition, PPRV VLPs induced a strong Th1 class response in mice, as indicated by a high IgG2a to IgG1 ratio. Goat studies demonstrated that PPRV VLPs can induce the production of antibodies specific for F and H proteins and can also stimulate the production of virus neutralizing antibodies to the same magnitude as the PPRV Nigeria 75/1 vaccine. Higher amounts of IFN-γ in VLP-immunized animal serum suggested that VLPs also elicited a cellular immune response in goats. These results demonstrated that VLPs elicit a potent immune response against PPRV infection in small ruminants, making PPRV VLPs a potential candidate for PPRV vaccine development.
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Li, Entao, Feihu Yan, Pei Huang, Hang Chi, Shengnan Xu, Guohua Li, Chuanyu Liu, et al. "Characterization of the Immune Response of MERS-CoV Vaccine Candidates Derived from Two Different Vectors in Mice." Viruses 12, no. 1 (January 20, 2020): 125. http://dx.doi.org/10.3390/v12010125.
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Middle East respiratory syndrome (MERS) is an acute, high-mortality-rate, severe infectious disease caused by an emerging MERS coronavirus (MERS-CoV) that causes severe respiratory diseases. The continuous spread and great pandemic potential of MERS-CoV make it necessarily important to develop effective vaccines. We previously demonstrated that the application of Gram-positive enhancer matrix (GEM) particles as a bacterial vector displaying the MERS-CoV receptor-binding domain (RBD) is a very promising MERS vaccine candidate that is capable of producing potential neutralization antibodies. We have also used the rabies virus (RV) as a viral vector to design a recombinant vaccine by expressing the MERS-CoV S1 (spike) protein on the surface of the RV. In this study, we compared the immunological efficacy of the vaccine candidates in BALB/c mice in terms of the levels of humoral and cellular immune responses. The results show that the rabies virus vector-based vaccine can induce remarkably earlier antibody response and higher levels of cellular immunity than the GEM particles vector. However, the GEM particles vector-based vaccine candidate can induce remarkably higher antibody response, even at a very low dose of 1 µg. These results indicate that vaccines constructed using different vaccine vector platforms for the same pathogen have different rates and trends in humoral and cellular immune responses in the same animal model. This discovery not only provides more alternative vaccine development platforms for MERS-CoV vaccine development, but also provides a theoretical basis for our future selection of vaccine vector platforms for other specific pathogens.
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Sultana, Sharmin, Shahina Tabassum, Afzalun Nessa, and Munira Jahan. "Antibody Responses In Bangladeshi Children Following Measles Vaccination." Bangladesh Journal of Medical Microbiology 10, no. 1 (February 13, 2017): 13–17. http://dx.doi.org/10.3329/bjmm.v10i1.31447.
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Measles is a highly contagious vaccine preventable viral disease which mainly affects children. Infection with wild measles virus induces an immune response that provides life long protection. Measles has been targeted for global eradication. In Bangladesh, there is insufficient data about the antibody responses in children following measles vaccination. In the present study, the antibody response of a single dose of measles vaccine was investigated among 77 children of different age groups. The humoral immune response immunoglobin IgG (IgG) was detected by a commercial Enzyme-linked Immunosorbent Assay (ELISA). Among the study population, detectable antibody titer was observed in 75.3% children while 24.7% showed detectable titers. The mean antibody concentration was highest (2.75 ± 1.10 IU/ml) in the 13-24 months age group, decreased gradually with age, and was lowest (0.77 ± 0.13 IU/ml) in the 85-96 months age group. Thereafter, the mean antibody concentration gradually increased again in the 97-108 months (1.20 ± 0.13 IU/ml) and in the 109-120 months (1.45 ± 0.13 IU/ml) age groups. The mean antibody titer was statistically significant in relation to age (p<0.01) but not to gender (p<0.95). This study showed that around 25% children remained antibody negative indicating challenges ahead for eradication of measles from Bangladesh.Bangladesh J Med Microbiol 2016; 10 (1): 13-17
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Jensen, Kara, Rafiq Nabi, Koen K. A. Van Rompay, Spencer Robichaux, Jeffrey D. Lifson, Michael Piatak, William R. Jacobs, et al. "Vaccine-Elicited Mucosal and Systemic Antibody Responses Are Associated with Reduced Simian Immunodeficiency Viremia in Infant Rhesus Macaques." Journal of Virology 90, no. 16 (June 1, 2016): 7285–302. http://dx.doi.org/10.1128/jvi.00481-16.
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ABSTRACTDespite significant progress in reducing peripartum mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) with antiretroviral therapy (ART), continued access to ART throughout the breastfeeding period is still a limiting factor, and breast milk exposure to HIV accounts for up to 44% of MTCT. As abstinence from breastfeeding is not recommended, alternative means are needed to prevent MTCT of HIV. We have previously shown that oral vaccination at birth with live attenuatedMycobacterium tuberculosisstrains expressing simian immunodeficiency virus (SIV) genes safely induces persistent SIV-specific cellular and humoral immune responses both systemically and at the oral and intestinal mucosa. Here, we tested the ability of oralM. tuberculosisvaccine strains expressing SIV Env and Gag proteins, followed by systemic heterologous (MVA-SIV Env/Gag/Pol) boosting, to protect neonatal macaques against oral SIV challenge. While vaccination did not protect infant macaques against oral SIV acquisition, a subset of immunized animals had significantly lower peak viremia which inversely correlated with prechallenge SIV Env-specific salivary and intestinal IgA responses and higher-avidity SIV Env-specific IgG in plasma. These controller animals also maintained CD4+T cell populations better and showed reduced tissue pathology compared to noncontroller animals. We show that infants vaccinated at birth can develop vaccine-induced SIV-specific IgA and IgG antibodies and cellular immune responses within weeks of life. Our data further suggest that affinity maturation of vaccine-induced plasma antibodies and induction of mucosal IgA responses at potential SIV entry sites are associated with better control of viral replication, thereby likely reducing SIV morbidity.IMPORTANCEDespite significant progress in reducing peripartum MTCT of HIV with ART, continued access to ART throughout the breastfeeding period is still a limiting factor. Breast milk exposure to HIV accounts for up to 44% of MTCT. Alternative measures, in addition to ART, are needed to achieve the goal of an AIDS-free generation. Pediatric HIV vaccines constitute a core component of such efforts. The results of our pediatric vaccine study highlight the potential importance of vaccine-elicited mucosal Env-specific IgA responses in combination with high-avidity systemic Env-specific IgG in protection against oral SIV transmission and control of viral replication in infant macaques. The induction of potent mucosal IgA antibodies by our vaccine is remarkable considering the age-dependent development of mucosal IgA responses postbirth. A deeper understanding of postnatal immune development may inform the design of improved vaccine strategies to enhance systemic and mucosal SIV/HIV antibody responses.
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Qiao, Yongbo, Shuang Li, Shenghui Jin, Yi Pan, Yuhua Shi, Wei Kong, and Yaming Shan. "A self-assembling nanoparticle vaccine targeting the conserved epitope of influenza virus hemagglutinin stem elicits a cross-protective immune response." Nanoscale 14, no. 8 (2022): 3250–60. http://dx.doi.org/10.1039/d1nr08460g.
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A schematic overview showing nanoparticle preparation, BALB/c mice immunization, and viral challenge. Humoral and cellular immune responses were determined after three immunizations, and protective effects were evaluated after the challenge.
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Bang, Yoo-Jin, Yun-Hee Kim, Yu-Sun Lee, Jae-Yong Kim, Hyo-Jung Park, Hae-Li Ko, Sang-In Park, Kyung-Ah Hwang, Hun Kim, and Jae-Hwan Nam. "Development of inactivated subunit influenza vaccine endowing with IgA induction and protection against heterologous strain." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 245.11. http://dx.doi.org/10.4049/jimmunol.204.supp.245.11.
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Abstract Vaccination is known to be the best way to prevent and control seasonal influenza infections. Among the various available influenza vaccines, an inactivated vaccine shows improved protective effects associated with greater safety. However, since the influenza virus is continuously evolving, its response to inactivated vaccines becomes increasingly difficult to predict, leading to complete or partial loss of protection against the virus. In addition, immunogenicity is lower than other types and Th2-biased immune responses have been reported. In this study, we have investigated the role of the single-stranded RNA (ssRNA) adjuvant derived from the intergenic region of internal ribosome entry site of Cricket Paralysis virus in seasonal inactivated subunit influenza vaccine (ISIV). We found that the ssRNA adjuvant stimulated balanced cellular (indicated by IgG2a, IFN-γ, IL-2, and TNF-α) and humoral (indicated by IgG1 and HI) responses, along with mucosal (indicated by IgA) immune response. Moreover, the ssRNA adjuvant formulated ISIV enhanced viral clearance and improved lung pathology after homologous and even heterologous influenza virus infections. The proportion of memory CD4+ and CD8+ T cells, important for long term immunity, was also observed to increase. Therefore, the ssRNA adjuvant formulated ISIV is effective in inducing humoral and cellular immune responses, cross protection, and long-term immunity.
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Masalova, Olga V., Ekaterina I. Lesnova, Sergey M. Andreev, Nadezhda N. Shershakova, Vyacheslav V. Kozlov, Kristina Yu Permyakova, Natalia A. Demidova, et al. "Adjuvant effect of dispersed fullerene C60 on the immune response to constructs harboring amino acid and nucleotide sequences of hepatitis C virus nonstructural NS5B protein." Problems of Virology 67, no. 6 (February 7, 2023): 516–26. http://dx.doi.org/10.36233/0507-4088-149.
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Introduction. A vaccine against hepatitis C has not yet been developed. Recombinant proteins and plasmids encoding hepatitis C virus (HCV) proteins, the components of candidate vaccines, induce a weak immune response and require the use of adjuvants.
The aim of the work was to study the adjuvant action of an aqueous solution of fullerene C60 during immunization of mice with HCV recombinant protein NS5B (rNS5B) that is an RNA-dependent RNA polymerase, or with NS5B-encoding pcNS5B plasmid.
Materials and methods. An aqueous solution of dispersed fullerene (dnC60) was obtained by ultrafiltration. C57BL/6 mice were immunized with rNS5B subcutaneously, pcNS5B intramuscularly mixed with different doses of dnC60 three times, then the humoral and cellular response to HCV was evaluated.
Results. Mice immunization with rNS5B in a mixture with dnC60 at doses of 250 g/mouse significantly induced humoral response: a dose-dependent increase in IgG1 antibody titers was 720 times higher than in the absence of fullerene. There was no increase in the cellular response to rNS5B when administered with dnC60. The humoral response to DNA immunization was weak in mice of all groups receiving pcNS5B. The cellular response was suppressed when the plasmid was injected in a mixture with dnC60.
Conclusions. Dispersed fullerene dnC60 is a promising adjuvant for increasing the immunostimulating activity of weakly immunogenic proteins including surface and other HCV proteins, important for a protective response. Further research is needed to enhance the ability of dnC60 to boost the cellular immune response to the components of the candidate vaccine.
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Probst, Peter, John B. Grigg, Emily A. Hemann, Yueh-Ming Loo, Megan L. Knoll, Renee Ireton, Michael J. Gale, Shawn P. Iadonato, and Kristin M. Bedard. "Small molecule agonists of IRF3 activation function as influenza vaccine adjuvants by modulating the humoral and cellular anti-viral immune response." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 76.2. http://dx.doi.org/10.4049/jimmunol.196.supp.76.2.
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Abstract We have identified a panel of small molecule immunomodulators that activate IRF3 and induce innate immune signaling to drive an antigen-specific protective immune response against viral infections. Our lead adjuvant candidate, KIN1148, binds to retinoic acid inducible gene-I (RIG-I) and induces RIG-I signaling to drive IRF3 activation. Studies using the H1N1 influenza virus challenge model demonstrate that immunization with monovalent influenza split vaccine (SV) and KIN1148 is dose sparing and protects mice against a lethal H1N1 A/California/04/2009 challenge. The SV-H1N1/KIN1148 adjuvant system induces functional antibodies neutralizing viral infectivity and inhibiting influenza hemagglutinin-mediated blood agglutination. SV-H1N1/KIN1148 prime/boost immunizations mediate a strong influenza-specific Th2 response and enhance the production of the immunoregulatory cytokine IL-10 by lung and draining lymph-node-derived T cells from challenged mice. In addition, prime immunization with SV-H1N1/KIN1148 alone provides protection against a 10xLD50 H1N1 challenge by reducing the viral load in the lungs of infected mice. Passive transfer experiments suggest that the protection after prime immunization is at least partially mediated by a cellular immune component. In summary, the KIN1148 split vaccine adjuvant system controls influenza virus infection by boosting the production of functional antibodies, reducing viral load, and inducing a Th2-type immune response. The induction of Th2 and immunoregulatory cytokines by KIN1148-adjuvanted SV might be beneficial to ameliorate the immunopathogenesis of an immune response to highly pathogenic avian influenza virus in infected individuals.
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Walsh, E. E. "Humoral, Mucosal, and Cellular Immune Response to Topical Immunization with a Subunit Respiratory Syncytial Virus Vaccine." Journal of Infectious Diseases 170, no. 2 (August 1, 1994): 345–50. http://dx.doi.org/10.1093/infdis/170.2.345.
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Jin, Yanwen, Cheng Cao, Ping Li, Xuan Liu, Wei Huang, Chufang Li, and Qingjun Ma. "Boosting Immune Response to Hepatitis B DNA Vaccine by Coadministration of Prothymosin α-Expressing Plasmid." Clinical Diagnostic Laboratory Immunology 12, no. 12 (December 2005): 1364–69. http://dx.doi.org/10.1128/cdli.12.12.1364-1369.2005.
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ABSTRACT DNA vaccines induce protective humoral and cell-mediated immune responses in several animal models. However, compared to conventional vaccines, DNA vaccines usually induce poor antibody responses. In this study, we report that coadministration of a hepatitis B virus (HBV) DNA vaccine with prothymosin α as an adjuvant improves antibody responses to HBV S antigen. We also observed higher seroconversion rates and higher antibody titers. Prothymosin α appears to increase the number and affinity of hepatitis B surface antigen-specific, gamma interferon-secreting T cells and to enhance cellular immune response to the PreS2S DNA vaccine. Interestingly, administering the DNA separately from the prothymosin α plasmid abrogated the enhancement of DNA vaccine potency. The results suggest that prothymosin α may be a promising adjuvant for DNA vaccines.
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Grazhdantseva, A. A., D. V. Antonets, L. I. Karpenko, E. V. Starostina, M. B. Borgoyakova, and G. V. Kochneva. "INDUCTION OF T-CELL IMMUNE RESPONSE BY A RECOMBINANT STRAIN OF VACCINIA VIRUS EXPRESSING A CASSETTE OF STRUCTURAL PROTEIN'S GENES OF MARBURG VIRUS." http://eng.biomos.ru/conference/articles.htm 1, no. 19 (2021): 174–76. http://dx.doi.org/10.37747/2312-640x-2021-19-174-176.
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The constructed recombinant strain MVA-GP-VP40-MARV, in addition to the induction of humoral immunity, also forms specific cellular immunity to the Marburg virus, and therefore can be considered as a promising vaccine against Marburg fever.
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Zhang, Xiao-Lian, Yushan Ren, Miao Lin, and Yuanqin Min. "CpG-E1E2 glycosylation-mutants of Hepatitis C Virus enhance specific cellular immune response and neutralizing antibodes (113.14)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 113.14. http://dx.doi.org/10.4049/jimmunol.188.supp.113.14.
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Abstract Hepatitis C virus (HCV) infects 170 million people world wide, and about 80% of the infected individuals develop chronic hepatitis with a risk of progression to cirrhosis and hepatocellular carcinoma. In contrast to hepatitis A and B virus, there is no vaccine for HCV. Thus, the development of an idea vaccine against hepatitis C remains a high prority goal. N-linked glycosylation of viral proteins have been implicated in immunicity. HCV neucleocapsids consist of two highly glycosylated envelop protein E1 and E2, in which the E1 contains 5 N-linked glycans and the E2 has 11 N-glycosylation sites. These oligose chains are essential for correct folding, assemble, and antigenic variation of virus and important for inducing immune response. In this study, the effects of the N-linked glycosylation of HCV E1-E2 fusion protein, a naturally poor immunogen, on the induction of specific immune response were examined. Different E1E2 glycosylation mutants were constructed into pVAX -1 and were used as DNA vaccine. We found that some fusion E1E2 mutants and CpG-E1E2 mutants could enhance much higher specific cellular and humoral reesponses than the wild type of E1E2 in the immunized BALB/c mice. Specific mutants were determined and could be as a HCV candidcate vaccine for its higher induction of specific cellular and neutralizing antibody immune responses.
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Yu, Hong, Lorne A. Babiuk, and Sylvia van Drunen Littel-van den Hurk. "Priming with CpG-enriched plasmid and boosting with protein formulated with CpG oligodeoxynucleotides and Quil A induces strong cellular and humoral immune responses to hepatitis C virus NS3." Journal of General Virology 85, no. 6 (June 1, 2004): 1533–43. http://dx.doi.org/10.1099/vir.0.79821-0.
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Cell-mediated immune responses to hepatitis C virus (HCV) proteins play a key role in recovery from infection. The NS3 protein of HCV is of special interest, since it is one of the most conserved proteins and NS3-specific immune responses are stronger and more frequently observed in patients resolving the infection than in chronically infected patients. Since these characteristics make NS3 an attractive vaccine candidate, the objective of this study was to optimize NS3-specific immune responses. Results from this group first demonstrated that a plasmid enriched with 24 CpG motifs (pBISIA24-NS3) tends to induce the strongest and most consistent Th1-biased immune response. Subsequently, it was shown that NS3 formulated with CpG oligodeoxynucleotide and Quil A (rNS3+CpG+Quil A) adjuvants induces a balanced immune response in mice, whereas rNS3 combined with either CpG or Quil A elicits a Th2-biased response. To further enhance NS3-specific cell-mediated immune responses, a vaccination regime consisting of priming with pBISIA24-NS3, followed by boosting with rNS3+CpG+Quil A, was explored in mice and pigs. When compared to immunization with rNS3+CpG+Quil A, this regime shifted the immune response to a Th1-type response and, accordingly, enhanced MHC I-restricted killing by cytotoxic T lymphocytes in mice. Although immunization with pBISIA24-NS3 also induced a Th1-biased response, including cytotoxicity in the mice, the humoral response was significantly lower than that induced by the DNA prime–protein boost regime. These results demonstrate the advantage of a DNA prime–protein boost approach in inducing a strong NS3-specific cell-mediated, as well as humoral, immune response, in both inbred laboratory and outbred large animal species.
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Hassett, Daniel E., Jie Zhang, Mark Slifka, and J. Lindsay Whitton. "Immune Responses following Neonatal DNA Vaccination Are Long-Lived, Abundant, and Qualitatively Similar to Those Induced by Conventional Immunization." Journal of Virology 74, no. 6 (March 15, 2000): 2620–27. http://dx.doi.org/10.1128/jvi.74.6.2620-2627.2000.
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ABSTRACT Virus infections are devastating to neonates, and the induction of active antiviral immunity in this age group is an important goal. Here, we show that a single neonatal DNA vaccination induces cellular and humoral immune responses which are maintained for a significant part of the animal's life span. We employ a sensitive technique which permits the first demonstration and quantitation, directly ex vivo, of virus-specific CD8+ T cells induced by DNA immunization. One year postvaccination, antigen-specific CD8+ T cells were readily detectable and constituted 0.5 to 1% of all CD8+ T cells. By several criteria—including cytokine production, perforin content, development of lytic ability, and protective capacity—DNA vaccine-induced CD8+ memory T cells were indistinguishable from memory cells induced by immunization with a conventional (live-virus) vaccine. Analyses of long-term humoral immune responses revealed that, in contrast to the strong immunoglobulin G2a (IgG2a) skewing of the humoral response seen after conventional vaccination, IgG1 and IgG2a levels were similar in DNA-vaccinated neonatal and adult animals, indicating a balanced T helper response. Collectively, these results show that a single DNA vaccination within hours or days of birth can induce long-lasting CD8+ T- and B-cell responses; there is no need for secondary immunization (boosting). Furthermore, the observed immune responses induced in neonates and in adults are indistinguishable by several criteria, including protection against virus challenge.
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Atabani, Sowsan, Gary Landucci, Michael W. Steward, Hilton Whittle, Jeremiah G. Tilles, and Donald N. Forthal. "Sex-Associated Differences in the Antibody-Dependent Cellular Cytotoxicity Antibody Response to Measles Vaccines." Clinical Diagnostic Laboratory Immunology 7, no. 1 (January 1, 2000): 111–13. http://dx.doi.org/10.1128/cdli.7.1.111-113.2000.
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ABSTRACT In some countries, excessive non-measles-related mortality has been observed among female recipients of high-titer measles vaccines. We determined if differences in the immune response to measles vaccines underlie the excessive female mortality by measuring the measles virus (MV)-specific antibody-dependent cellular cytotoxicity (ADCC) antibody response in 65 3-year-old Gambian children immunized with Edmonston-Zagreb medium-titer (EZ) or Schwarz standard vaccines during infancy. Among the 20 females and 22 males with undetectable anti-MV antibodies at the time of immunization, females had significantly lower ADCC than males (median cytotoxicities of 1/100 serum dilutions = 8.4 and 12%, respectively; P = 0.04). This sex-associated difference was present only among the six female and seven male recipients of EZ vaccine (median cytotoxicities = 5.1 and 19.0%, respectively;P = 0.02). There were no significant sex-associated differences in neutralizing antibody activity. Decreased ADCC antibody activity may contribute to the lower survival rate observed in females receiving high-titer measles vaccination.
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Lukacs, Nicholas W., and Carrie-Anne Malinczak. "Harnessing Cellular Immunity for Vaccination against Respiratory Viruses." Vaccines 8, no. 4 (December 21, 2020): 783. http://dx.doi.org/10.3390/vaccines8040783.
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Severe respiratory viral infections, such as influenza, metapneumovirus (HMPV), respiratory syncytial virus (RSV), rhinovirus (RV), and coronaviruses, including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), cause significant mortality and morbidity worldwide. These viruses have been identified as important causative agents of acute respiratory disease in infants, the elderly, and immunocompromised individuals. Clinical signs of infection range from mild upper respiratory illness to more serious lower respiratory illness, including bronchiolitis and pneumonia. Additionally, these illnesses can have long-lasting impact on patient health well beyond resolution of the viral infection. Aside from influenza, there are currently no licensed vaccines against these viruses. However, several research groups have tested various vaccine candidates, including those that utilize attenuated virus, virus-like particles (VLPs), protein subunits, and nanoparticles, as well as recent RNA vaccines, with several of these approaches showing promise. Historically, vaccine candidates have advanced, dependent upon the ability to activate the humoral immune response, specifically leading to strong B cell responses and neutralizing antibody production. More recently, it has been recognized that the cellular immune response is also critical in proper resolution of viral infection and protection against detrimental immunopathology associated with severe disease and therefore, must also be considered when analyzing the efficacy and safety of vaccine candidates. These candidates would ideally result in robust CD4+ and CD8+ T cell responses as well as high-affinity neutralizing antibody. This review will aim to summarize established and new approaches that are being examined to harness the cellular immune response during respiratory viral vaccination.
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Li, Hai, Hu Ren, Yangzi Zhou, Yan Zhang, Lei Cao, and Wenbo Xu. "HRSV prefusion-F protein with Adju-Phos adjuvant induces long-lasting Th2-biased immunity in mice." PLOS ONE 17, no. 1 (January 31, 2022): e0262231. http://dx.doi.org/10.1371/journal.pone.0262231.
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The development of human respiratory syncytial virus (hRSV) vaccine has been hampered by the risk of enhanced respiratory disease (ERD) which was induced by highly skewed toward Th2 immune response. In our previous study, we expressed the recombinant pre-F protein using Escherichia coli BL21, called RBF. To verify if the RBF protein could cause ERD, we tested the immunogenicity and safety of RBF with a commercial alum adjuvant (GMP-grade Adju-Phos). RBF alone and RBF/Adju-Phos elicited long-lasting protective antibodies and a cellular immune response in mice after three immunizations. Unfortunately, compared with the mice in RBF group, mice in RBF/Adju-Phos generated a serious Th2 humoral immune response that elicited Th2-mediated lung pathology. From the IL-4+:IFNγ+ ratio, there was also a robust Th2 cellullar immunologic response in the RBF/Adju-Phos group. This study demonstrates that it may not be enough for RBF to increase the titer of neutralizing antibodies. A balanced immune response must be induced for hRSV vaccine safety.
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Spiri, Andrea M., Marilisa Novacco, Marina L. Meli, Martina Stirn, Barbara Riond, Jonathan E. Fogle, Felicitas S. Boretti, Imogen Herbert, Margaret J. Hosie, and Regina Hofmann-Lehmann. "Modified-Live Feline Calicivirus Vaccination Elicits Cellular Immunity against a Current Feline Calicivirus Field Strain in an Experimental Feline Challenge Study." Viruses 13, no. 9 (August 31, 2021): 1736. http://dx.doi.org/10.3390/v13091736.
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Feline calicivirus (FCV) is a common cat virus associated with oral ulcerations and virulent-systemic disease. Efficacious FCV vaccines protect against severe disease but not against infection. The high genetic diversity of FCV poses a challenge in vaccine design. Protection against FCV has been related to humoral and cellular immunity; the latter has not been studied in detail. This study investigates the cellular and humoral immune response of specified pathogen-free (SPF) cats after modified-live FCV F9 vaccinations and two heterologous FCV challenges by the analysis of lymphocyte subsets, cytokine mRNA transcription levels, interferon (IFN)-γ release assays in peripheral blood mononuclear cells (PBMCs), anti-FCV antibodies, and neutralisation activity. Vaccinated cats developed a Th1 cytokine response after vaccination. Vaccination resulted in antibodies with neutralising activity against the vaccine but not the challenge viruses. Remarkably, IFN-γ-releasing PBMCs were detected in vaccinated cats upon stimulation with the vaccine strain and the first heterologous FCV challenge strain. After the first experimental infection, the mRNA transcription levels of perforin, granzyme B, INF-γ, and antiviral factor MX1 and the number of IFN-γ-releasing PBMCs when stimulated with the first challenge virus were higher in vaccinated cats compared to control cats. The first FCV challenge induced crossneutralising antibodies in all cats against the second challenge virus. Before the second challenge, vaccinated cats had a higher number of IFN-γ-releasing PBMCs when stimulated with the second challenge virus than control cats. After the second FCV challenge, there were less significant differences detected between the groups regarding lymphocyte subsets and cytokine mRNA transcription levels. In conclusion, modified-live FCV vaccination induced cellular but not humoral crossimmunity in SPF cats; innate immune mechanisms, secretory and membranolytic pathways, and IFN-γ-releasing PBMCs seem to be important in the host immune defence against FCV.
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Wong, Pamela T., Peter H. Goff, Jessica J. O’Konek, Jeffrey J. Landers, Katarzyna W. Janczak, Pascale R. Leroueil, Peter Palese, and James R. Baker. "Combined nanoemulsion and RIG-I agonist adjuvants-activation of diverse pathways for a broad spectrum influenza vaccine." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 145.11. http://dx.doi.org/10.4049/jimmunol.196.supp.145.11.
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Abstract Current influenza vaccines are limited by low immunogenicity, short duration of protection, and narrow cross-strain efficacy. Broad-based cellular immune responses and mucosal immunity are key to an effective vaccine. However, most single adjuvants exhibit only some of these qualities. Here we combine two adjuvants, an oil-in-water nanoemulsion (NE), and a synthetic RNA from Sendai virus (IVT DI), each individually shown to elicit protective immunity to influenza via distinct mechanisms. Intranasal (IN) immunization with NE and influenza hemagglutinin induces mucosal and systemic antibodies, activates NF-κB via TLR signaling, and induces a balanced TH1/TH2/TH17 cellular response. NE is also an antigen carrier, facilitating cellular uptake and processing. IVT DI activates the RIG-I receptor inducing type-I interferon and TH1 immunity. We sought to determine if combining the complementary properties of NE and IVT DI improves the strength of the immune response and affords new activities not seen with the single adjuvants. Combined adjuvant was evaluated with inactivated H1N1 virus (PR8) as antigen. While IN coadmin of NE and IVT DI did not improve humoral responses in mice, cellular recall responses were much enhanced relative to either adjuvant alone. Separate sequential admin of NE and IVT DI (2 wks apart) resulted in very high humoral and mucosal antibody responses and increased cytokine production. Interestingly, the cytokine pattern for sequential vs. coadmin of NE and IVT DI was distinct. Notably, both methods elicited a TH17 response not seen with IVT DI alone. Combining complementary adjuvants may be a promising approach for generating a broader, more optimal immune response for influenza when used with diverse HA antigens.
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Dasari, Vijayendra, Corey Smith, Jie Zhong, Gillian Scott, William Rawlinson, and Rajiv Khanna. "Recombinant glycoprotein B vaccine formulation with Toll-like receptor 9 agonist and immune-stimulating complex induces specific immunity against multiple strains of cytomegalovirus." Journal of General Virology 92, no. 5 (May 1, 2011): 1021–31. http://dx.doi.org/10.1099/vir.0.029413-0.
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Natural human cytomegalovirus (CMV) infection is characterized by a strain-specific neutralizing antibody response. This is particularly relevant in clinical settings such as transplantation and pregnancy where reinfection with heterologous strains occurs and the immune system does not mount an effective response against the infecting strain due to underlying immunosuppression. There is an emerging argument that a CMV vaccine that induces high titres of cross-neutralizing antibodies will be more effective in protecting individuals from infection with antigenically different CMV strains. In addition, induction of cell-mediated immunity offers the additional advantage of targeting virus-infected cells. This study presents a novel formulation of a CMV vaccine that, by combining recombinant soluble gB protein with a Toll-like receptor 9 agonist (CpG ODN1826) and immune-stimulating complexes (AbISCO 100), was able to elicit strong polyfunctional CMV-specific cellular and cross-neutralizing humoral immune responses. These data demonstrated that prime–boost immunization of human leukocyte antigen (HLA)-A2 mice with gB protein in combination with CpG ODN1826 and AbISCO 100 induced long-lasting CMV-specific CD4+ and CD8+ T-cell and humoral responses. Furthermore, these responses neutralized infection with multiple strains of CMV expressing different gB genotypes and afforded protection against challenge with recombinant vaccinia virus encoding the gB protein. These observations argue that this novel vaccine strategy, if applied to humans, should facilitate the generation of a robust, pluripotent immune response, which may be more effective in preventing infection with multiple strains of CMV.
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Pleyer, Christopher, Kerry J. Laing, Mir Ali, Christopher L. McClurkan, Susan Soto, Inhye E. Ahn, Pia Nierman, et al. "Effect of Bruton Tyrosine Kinase Inhibitor on Serologic and Cellular Immune Responses to Recombinant Zoster Vaccine." Blood 138, Supplement 1 (November 5, 2021): 1556. http://dx.doi.org/10.1182/blood-2021-148539.
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Abstract Introduction The recombinant zoster vaccine (RZV) is effective in preventing herpes zoster reactivation in the general population. We previously showed that patients with chronic lymphocytic leukemia (CLL), particularly those receiving Bruton tyrosine kinase inhibitors (BTKis), have decreased humoral immune responses following vaccination. The impact of vaccination on cellular immune responses in CLL patients is not well characterized. Understanding the effect of humoral and cellular immunity in CLL patients who are treatment naïve or receiving BTKis can inform vaccination strategies in this immunosuppressed patient population. Methods In this phase II open-label study (NCT03702231), patients with CLL who were either treatment naïve (TN) or receiving a BTKi (ibrutinib or acalabrutinib) received 2 doses of RZV via intramuscular injection at baseline and 3 months. Subjects were followed for 6 months and assessed for serologic response at 3 and 6 months. Serologic response was defined as a ≥ four-fold rise in anti-glycoprotein E (anti-gE) IgG serum titer at the 6 month timepoint. Cellular immune response was assessed by intracellular cytokine staining and flow cytometric analysis of gE-specific CD4+ T cells expressing upregulation of ≥2 effector molecules (interferon-γ, interleukin-2, tumor necrosis factor-α, and/or CD40 ligand). Cellular response was defined as ≥ two-fold rise over baseline and ≥320 net gE-specific CD4(2+) cells per million CD4+ T cells. Descriptive statistics were used to report vaccine response rates. Mann-Whitney test and Fisher's exact test were used to compare titers and response rates between different groups. Spearman r was used to measure the correlation between vaccine responses and clinical characteristics. All subjects completed an adverse event (AE) diary documenting any local (injection site) or systemic AE that started within 7 days after receiving the first and second vaccine dose. Results 106 subjects had serologic response assessment at 6 months. Baseline characteristics are shown in Table 1. The serologic response rate to RZV was significantly higher in the TN cohort (76.8%, 95% CI, 64.2-85.9; n = 56) compared to patients receiving a BTKi (40.0%, 95% CI,27.6-53.8; n = 50; P = .0002). Cellular vaccine response was assessed in 94 subjects at 6 months. Similarly, the rate of cellular immunity was significantly higher in the TN cohort (69.4%, 95% CI,55.5-80.5; n = 49) compared to patients treated with a BTKi (40.0%, 95% CI,27.0-54.5; n = 45, P = .0067). Paired serologic and cellular responses were available in 93 subjects. 68.5% (95% CI,55.3-79.3; n = 54) of subjects with a serologic response also had a positive cellular immune response, whereas 35.9% (95% CI,22.7-51.6; n = 39) of subjects attained a cellular immune response in absence of a serologic response (P = .0029) (Figure 1). Among subjects with a negative serologic response and a positive cellular immune response, 42.9% were TN (n = 6) and 57.1% (n = 8) received a BTKi. There was no difference in serologic or cellular responses between patients treated with ibrutinib and acalabrutinib (P > 0.05). Serologic antibody titers and T cell responder frequencies were weakly positively correlated (r = 0.26; 95%CI .05-.44; P = .0127). Serologic titers and T cell responses were not correlated with age, beta-2 microglobulin, absolute lymphocyte count, absolute peripheral blood CD19+, CD3+, CD4+ or CD8+ counts or serum immunoglobulin levels (IgA, IgG, IgM) (all P > 0.05). The most frequent local and systemic AEs were injection site pain (98.3%), injection site reaction (97.4%), headache (51.7%), and generalized myalgias (51.7%). Most AEs were grade 1-2 and all AEs resolved or returned to baseline within 7 days of vaccine administration. Conclusions RZV is safe in CLL patients and can induce both humoral and cellular immune responses. BTKi treatment was associated with impaired serologic and cellular vaccine responses compared to TN patients. Although BTKi therapy may inherently decrease vaccine immunogenicity, TN CLL patients could be more immunocompetent because of less advanced disease, thereby permitting more effective immune responses. The majority of patients with a positive antibody response also developed virus-specific T cells following vaccination. Approximately one third of patients without a positive serologic response developed virus reactive T cells. Figure 1 Figure 1. Disclosures Laing: Curevo Vaccine: Consultancy; MaxHealth LLC: Consultancy. Wiestner: Acerta Pharma: Research Funding; Pharmacyclics LLC: Research Funding; Merck: Research Funding; Nurix: Research Funding; Verastem: Research Funding; Genmab: Research Funding. Koelle: Merck: Research Funding; Curevo Vaccine: Other: Scientific Advisory Board ; MaxHealth LLC: Other: Scientific Advisory Board ; Oxford Immunotec: Research Funding; Sensei Biotherapeutics: Research Funding; Sanofi Pasteur: Research Funding. Sun: Genmab: Research Funding.
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Huang, Y., L. A. Babiuk, and S. van Drunen Littel-van den Hurk. "Immunization with a bovine herpesvirus 1 glycoprotein B DNA vaccine induces cytotoxic T-lymphocyte responses in mice and cattle." Journal of General Virology 86, no. 4 (April 1, 2005): 887–98. http://dx.doi.org/10.1099/vir.0.80533-0.
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Virus-specific cytotoxic T lymphocytes (CTLs) are considered to be important in protection against and recovery from viral infections. In this study, several approaches to induce cytotoxicity against bovine herpesvirus 1 (BHV-1) were evaluated. Vaccination of C57BL/6 mice with BHV-1 induced a strong humoral, but no CTL, response, which may be due to downregulation of major histocompatibility complex class I molecules. In contrast, vaccinia virus expressing glycoprotein B (gB) elicited a weaker antibody response, but strong cytotoxicity, in mice. As an approach to inducing both strong humoral and cellular immune responses, a plasmid vector was then used to express gB. Both antibody and CTL responses were induced by the plasmid encoding gB in C57BL/6 and C3H mice, regardless of the type of vector backbone. This demonstrated that DNA immunization induces a broad-based immune response to BHV-1 gB. Interestingly, removal of the membrane anchor, which resulted in secretion of gB from transfected cells, did not result in reduced cytotoxicity. Here, it is shown that, compared with the cell-associated counterpart, plasmid-encoded secreted protein may induce enhanced immune responses in cattle. Therefore, calves were immunized intradermally with pMASIAtgB, a plasmid encoding the secreted form of gB (tgB), using a needle-free injection system. This demonstrated that pMASIAtgB elicited both humoral responses and activated gamma interferon-secreting CD8+ CTLs, suggesting that a DNA vaccine expressing tgB induces a CTL response in the natural host of BHV-1.
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Lobby, Jenna L., Shamika Danzy, Anice Lowen, and Jacob E. Kohlmeier. "Impact of pre-existing immunity on the development of de novo virus-specific TRM following live attenuated influenza vaccination." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 126.41. http://dx.doi.org/10.4049/jimmunol.208.supp.126.41.
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Abstract Live attenuated influenza vaccine (LAIV) elicits both humoral and cellular immune memory in children, but its efficacy is limited in adults. We hypothesize that pre-existing immunity from past infections and/or immunizations prevents the attenuated vaccine from establishing an immune response. To determine if we can overcome this limitation by increasing the antigenic distance of the vaccine strain from previous circulating seasonal strains, we generated a series of drifted LAIVs with successive mutations in the HA protein, allowing for increasing levels of escape from pre-existing antibody. We also inserted a CD8+ T cell epitope from the Sendai virus nucleoprotein (SeV-NP) as a readout for generation of a de novo TRM response following immunization. Surprisingly, we were unable to identify SeV-NP+ CD8+ TRM following LAIV immunization in PR8-immune mice, even with LAIV strains that can fully escape pre-existing antibody. As these data suggested a role for cell-mediated immunity in limiting LAIV efficacy, we investigated several scenarios to assess the impact of pre-existing LAIV-specific TRM in the upper and lower respiratory tract. Ultimately, we found that deletion of the immunodominant influenza NP366–374 epitope was sufficient to escape pre-existing CD8+ TRM and to establish de novo CD8+ TRM. Combined, these studies demonstrate that both pre-existing humoral and cellular immunity can limit the effectiveness of LAIV, thereby informing future design of vaccine vectors against respiratory pathogens. Supported by grants from NIH (F31 HL156639-01, R35 HL150803)
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Pogodina, E. A., A. V. Lobov, P. I. Ivanova, V. I. Kazey, and I. Zh Shubina. "Induction of anti-SARS-CoV-2 immune reactions in immune compromised patients." Russian Journal of Biotherapy 20, no. 4 (December 1, 2021): 18–25. http://dx.doi.org/10.17650/1726-9784-2021-20-4-18-25.
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The aim of the review is studying the immune response to the new coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus in different populations, including those with immunosuppression due to concomitant diseases or immunosuppressive therapy.The role of T cells in building up the anti-COVID-19 immunity is of special interest, particularly, when comparing T cell and antibody based immunity. A number of studies are focused on the effectiveness of T-cell immunity against SARS-CoV-2 infection, as well as on the resistance to re-infection. The decreased immunity associated with such illnesses as autoimmune diseases, non-autoimmune inflammations, and the effect of immunosuppressive drugs and obviously, different cancers increase the susceptibility to SARS-CoV-2 and COVID-19 development, and exacerbate the course of the disease.Several studies showed that patients with cancer are at risk of impaired immune response associated with a malignant neoplasm. The inefficient immune response was also shown in cancer patients receiving immunomodulatory therapy. However, some studies registered the specific immunogenicity after vaccination in patients with concomitant immunosuppression.Methotrexate is a folate antimetabolite. The drug can be used both in high doses as an antimetabolite in the antitumor therapy, and in low doses as an immunosuppressive agent in patients with autoimmune diseases. Therefore, the review also discusses a study that evaluated the humoral and cellular immune response to the BNT162b2 (PfizerBioNTech) anti-COVID-19 vaccine in patients receiving methotrexate. The rate of antibody production was lower in patients receiving methotrexate, though the level of T-cell response was similar in all groups studied.The review discussed immune compromised patients with cancer and hematological malignancies and patients living with HIV who had COVID-19. Most studies reported no significant differences of COVID-19 outcomes between major population and the patients with suppressed immune system.Hereby, the cell and humoral immune response in immune compromised patients is possible, however, additional studies are required to confirm these data.