The ID93 Tuberculosis Vaccine Candidate Does Not Induce Sensitivity to Purified Protein Derivative

ABSTRACTThe tuberculin skin test (TST) is a simple and inexpensive test to determine whether individuals have been exposed toMycobacterium tuberculosis. This test is not always reliable, however, in people previously immunized with BCG and/or who have been exposed to environmental mycobacterial species due to a reaction to purified protein derivative (PPD) used in the skin test. An issue with BCG, therefore, is that the resulting sensitization to PPD in some individuals compromises the diagnostic use of the skin test. The ability to induce protective immune responses without sensitizing to the tuberculin skin test will be important properties of next-generation tuberculosis (TB) vaccine candidates. We show here that guinea pigs immunized with the candidate TB vaccine ID93/GLA-SE, currently in clinical trials, do not react to intradermal PPD administration. In contrast, positive DTH responses to both ID93 and components thereof were induced in ID93/GLA-SE-immunized animals, indicating robust but specific cellular responses were present in the immunized animals. Noninterference with the TST is an important factor for consideration in the development of a vaccine againstM. tuberculosis.

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Intranasal Vaccination with the Recombinant Listeria monocytogenes ΔactA prfA*Mutant Elicits Robust Systemic and Pulmonary Cellular Responses and Secretory Mucosal IgA

Clinical and Vaccine Immunology ◽

10.1128/cvi.00254-10 ◽

2011 ◽

Vol 18 (4) ◽

pp. 640-646 ◽

Cited By ~ 14

Author(s):

Jin Qiu ◽

Lin Yan ◽

Jianbo Chen ◽

Crystal Y. Chen ◽

Ling Shen ◽

...

Keyword(s):

Listeria Monocytogenes ◽

Immune Responses ◽

Cellular Response ◽

Cellular Responses ◽

Broth Culture ◽

Intravenous Route ◽

Content Type ◽

Vaccine Candidates ◽

Ifn Γ ◽

Subcutaneous Immunization

ABSTRACTWe previously showed that recombinant (r)Listeria monocytogenescarrying ΔactAand a selectedprfA*mutation (r-ListeriaΔactA prfA*) secreted >100-fold more immunogen in broth culture than wild-type r-Listeriaor r-ListeriaΔactAand elicited much greater cellular and humoral immune responses than r-ListeriaΔactAafter intravenous vaccination of mice. Here, we conducted comparative studies evaluating vaccine-elicited immune responses in systemic and mucosal sites after intranasal, intravenous, intraperitoneal, or subcutaneous immunization of mice with r-ListeriaΔactA prfA*vaccine candidates. Intranasal vaccination of mice with r-ListeriaΔactA prfA* vaccine candidates elicited a robust gamma interferon-positive (IFN-γ+) cellular response in systemic sites, although intravenous or intraperitoneal immunization was more efficient. Surprisingly, intranasal vaccination elicited an appreciable pulmonary IFN-γ+cellular response that was nonstatistically higher than the magnitude induced by the intravenous route but was significantly greater than that elicited by subcutaneous immunization. Furthermore, although intranasal r-ListeriaΔactA prfA*delivery induced poor systemic IgG responses, intranasal vaccination elicited appreciable secretory immunogen-specific IgA titers that were similar to or higher in mucosal fluid than those induced by subcutaneous and intravenous immunizations. Thus, intranasal vaccination with r-ListeriaΔactA prfA*appears to be a useful approach for eliciting robust systemic and pulmonary cellular responses and measurable secretory mucosal IgA titers.

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Characterization of the Immune Response of MERS-CoV Vaccine Candidates Derived from Two Different Vectors in Mice

Viruses ◽

10.3390/v12010125 ◽

2020 ◽

Vol 12 (1) ◽

pp. 125 ◽

Cited By ~ 7

Author(s):

Entao Li ◽

Feihu Yan ◽

Pei Huang ◽

Hang Chi ◽

Shengnan Xu ◽

...

Keyword(s):

Immune Responses ◽

Antibody Response ◽

Rabies Virus ◽

Vaccine Development ◽

Vaccine Candidate ◽

Viral Vector ◽

Vaccine Vector ◽

Vaccine Candidates ◽

Cellular Immune Responses ◽

Cellular Immune

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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Evaluation of Gamma Interferon Immune Response Elicited by the Newly Constructed PstS-1(285-374):CFP10 Fusion Protein To Detect Mycobacterium tuberculosis Infection

Clinical and Vaccine Immunology ◽

10.1128/cvi.00726-13 ◽

2014 ◽

Vol 21 (4) ◽

pp. 552-560 ◽

Cited By ~ 9

Author(s):

Leonardo Silva de Araujo ◽

Fernanda Carvalho de Queiroz Mello ◽

Nidai de Bárbara Moreira da Silva ◽

Janaina Aparecida Medeiros Leung ◽

Silvia Maria Almeida Machado ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Tuberculin Skin Test ◽

Skin Test ◽

Positive Tuberculin Skin Test ◽

Gamma Interferon ◽

Preventative Treatment ◽

Mycobacterium Tuberculosis Infection ◽

Content Type ◽

Ifn Γ ◽

First Time

ABSTRACTThe PstS1 antigen is highly immunogenic, principally when combined with CFP10 during both latent and active TB infection. In the present study, a selectedpstS1gene fragment was cloned, fused with CFP10, and expressed inEscherichia coli. The product [PstS-1(285-374):CFP10] was compared to the recombinant fused RD1 (region of deletion 1) protein (ESAT-6:CFP10) in detectingMycobacterium tuberculosisinfection in 108 recent contacts of pulmonary tuberculosis (TB) cases, considering a positive tuberculin skin test (TST) to be the baseline. The release of gamma interferon (IFN-γ) in 22-h whole-blood and 5-day lymphocyte stimulation assays primed with each antigen was determined. All contacts were clinically followed for up to 1 year, and 87% of the tuberculin skin test-positive (TSTpositive) patients accepted preventative treatment. Concerning the IFN-γ response to PstS-1(285-374):CFP10 in the 22-h and 5-day assays, a slight increase in contact-TSTpositivedetection was observed (23/54 and 26/54) compared to the level seen with the RD1 protein (18/54 and 24/54) whereas in the TSTnegativegroup, similarly lower numbers (≤5/48) of responders were achieved for both antigens, except for RD1 in the 5-day assay (8/48). By combining the IFN-γ responders to both antigens in the 5-day assays, slightly higher increases in positivity were found in the TSTpositive(32/54) and TSTnegative(10/48) groups. Two of 12 untreated TSTpositivecontacts progressed to active TB and were concordantly positive in all assays, except for one contact who lacked positivity in the RD1 5-day assay. We demonstrated for the first time that PstS-1(285-374):CFP10 slightly increased contact positivity and detection of active disease progression, suggesting its potential application as a TB infection marker.

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Use of Mycobacterium tuberculosisComplex-Specific Antigen Cocktails for a Skin Test Specific for Tuberculosis

Infection and Immunity ◽

10.1128/iai.66.8.3606-3610.1998 ◽

1998 ◽

Vol 66 (8) ◽

pp. 3606-3610 ◽

Cited By ~ 35

Author(s):

Konstantin Lyashchenko ◽

Claudia Manca ◽

Roberto Colangeli ◽

Anna Heijbel ◽

Alan Williams ◽

...

Keyword(s):

Tuberculin Skin Test ◽

Skin Test ◽

Guinea Pigs ◽

Nontuberculous Mycobacteria ◽

Skin Testing ◽

Specific Antigen ◽

Diagnostic Value ◽

Mycobacterial Species ◽

Diagnostic Specificity ◽

Single Antigen

ABSTRACT The tuberculin skin test currently used to diagnose infection withMycobacterium tuberculosis has poor diagnostic value, especially in geographic areas where the prevalence of tuberculosis is low or where the environmental burden of saprophytic, nontuberculous mycobacteria is high. Inaccuracy of the tuberculin skin test often reflects a low diagnostic specificity due to the presence in tuberculin of antigens shared by many mycobacterial species. Thus, a skin test specific for tuberculosis requires the development of new tuberculins consisting of antigens specific to M. tuberculosis. We have formulated cocktails of two to eight antigens of M. tuberculosis purified from recombinant Escherichia coli. Multiantigen cocktails were evaluated by skin testing guinea pigs sensitized with M. bovis BCG. Reactivity of multiantigen cocktails was greater than that of any single antigen. Cocktail activity increased with the number of antigens in the cocktail even when the same amount of total protein was used for cocktails and for each single antigen. A cocktail of four purified antigens specific for the M. tuberculosis complex elicited skin test responses only in BCG-immunized guinea pigs, not in control animals immunized with M. avium. These findings open the way to designing a multiantigen formulation for a skin test specific for tuberculosis.

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A methyltransferase-defective VSV-based SARS-CoV-2 vaccine candidate provides complete protection against SARS-CoV-2 infection in hamsters

Journal of Virology ◽

10.1128/jvi.00592-21 ◽

2021 ◽

Author(s):

Mijia Lu ◽

Yuexiu Zhang ◽

Piyush Dravid ◽

Anzhong Li ◽

Cong Zeng ◽

...

Keyword(s):

Cell Culture ◽

Immune Responses ◽

Vesicular Stomatitis Virus ◽

Vaccine Candidate ◽

Viral Mrna ◽

S Protein ◽

Vaccine Candidates ◽

Syrian Golden Hamsters ◽

Vesicular Stomatitis ◽

Immunocompromised Mice

The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to dramatic economic and health burdens. Although the worldwide SARS-CoV-2 vaccination campaign has begun, exploration of other vaccine candidates is needed due to the uncertainties of the current approved vaccines such as durability of protection, cross-protection against variant strains, and costs of long-term production, and storage. In this study, we developed a methyltransferase-defective recombinant vesicular stomatitis virus (mtdVSV)-based SARS-CoV-2 vaccine candidate. We generated mtdVSVs expressing SARS-CoV-2 full-length spike (S), S1, or its receptor binding domain (RBD). All these recombinant viruses grew to high titers in mammalian cells despite high attenuation in cell culture. SARS-CoV-2 S protein and its truncations were highly expressed by the mtdVSV vector. These mtdVSV-based vaccine candidates were completely attenuated in both immunocompetent and immunocompromised mice. Among these constructs, mtdVSV-S induced high levels of SARS-CoV-2 specific neutralizing antibodies (NAbs) and Th1-biased T cell immune responses in mice. Syrian golden hamsters immunized with mtdVSV-S triggered SARS-CoV-2 specific NAbs that were higher than convalescent plasma from convalescent COVID-19 patients. In addition, hamsters immunized with mtdVSV-S were completely protected against SARS-CoV-2 replication in lung and nasal turbinate tissues, cytokine storm, and lung pathology. Collectively, our data demonstrate that mtdVSV expressing SARS-CoV-2 S protein is a safe and highly efficacious vaccine candidate against SARS-CoV-2 infection. Significance Viral mRNA cap methyltransferase (MTase) is essential for mRNA stability, protein translation, and innate immune evasion. Thus, viral mRNA cap MTase activity is a novel target for development of live attenuated or live vectored vaccine candidates. Here, we developed a panel of MTase-defective recombinant recombinant vesicular stomatitis virus (mtdVSV)-based SARS-CoV-2 vaccine candidates expressing full-length S, S1, or several versions of the RBD. These mtdVSV-based vaccine candidates grew to high titers in cell culture and were completely attenuated in both immunocompetent and immunocompromised mice. Among these vaccine candidates, mtdVSV-S induces high levels of SARS-CoV-2 specific neutralizing antibody (Nabs) and Th1-biased immune responses in mice. Syrian golden hamsters immunized with mtdVSV-S triggered SARS-CoV-2 specific NAbs that were higher than convalescent plasma from COVID-19 recovered patients. Furthermore, hamsters immunized with mtdVSV-S were completely protected against SARS-CoV-2 challenge. Thus, mtdVSV is a safe and highly effective vector to deliver SARS-CoV-2 vaccine.

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Mantoux Test in Kawasaki Disease

PEDIATRICS ◽

10.1542/peds.98.1.161 ◽

1996 ◽

Vol 98 (1) ◽

pp. 161-161

Author(s):

Alberto Bertotto ◽

Fabrizio Spinozzi ◽

Maurizio Radicioni ◽

Renato Vaccaro

Keyword(s):

Kawasaki Disease ◽

Tuberculin Skin Test ◽

Skin Test ◽

Acute Phase ◽

Mantoux Test ◽

Skin Test Reactivity ◽

Purified Protein Derivative ◽

Characteristic Features ◽

Early Manifestation

Localized erythema at the site of a previous bacillus Calmette-Guérin (BCG) inoculation is a relatively specific and early manifestation of Kawasaki disease (KD),1 and redness and crusting are characteristic features at the site of BCG immunization during the acute phase of the illness.2 With these findings in mind, we evaluated the tuberculin skin test reactivity of children with KD, as determined by a commercially available (Sclavo, Siena, Italy) and intradermally injected (5 TU) purified protein derivative (PPD).

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Induction of Multifunctional Broadly Reactive T Cell Responses by a Plasmodium vivax Circumsporozoite Protein Recombinant Chimera

Infection and Immunity ◽

10.1128/iai.00480-15 ◽

2015 ◽

Vol 83 (9) ◽

pp. 3749-3761 ◽

Cited By ~ 7

Author(s):

Monica Cabrera-Mora ◽

Jairo Andres Fonseca ◽

Balwan Singh ◽

Joseli Oliveira-Ferreira ◽

Josué da Costa Lima-Junior ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Immune Responses ◽

Plasmodium Vivax ◽

Vaccine Candidate ◽

Chimeric Protein ◽

Plasmodium Yoelii ◽

Circumsporozoite Protein ◽

Soluble Form ◽

Content Type

Plasmodium vivaxis the most widespread species ofPlasmodium, causing up to 50% of the malaria cases occurring outside sub-Saharan Africa. An effective vaccine is essential for successful control and potential eradication. A well-characterized vaccine candidate is the circumsporozoite protein (CSP). Preclinical and clinical trials have shown that both antibodies and cellular immune responses have been correlated with protection induced by immunization with CSP. On the basis of our reported approach of developing chimericPlasmodium yoeliiproteins to enhance protective efficacy, we designed PvRMC-CSP, a recombinant chimeric protein based on theP. vivaxCSP (PvCSP). In this engineered protein, regions of the PvCSP predicted to contain human T cell epitopes were genetically fused to an immunodominant B cell epitope derived from the N-terminal region I and to repeat sequences representing the two types of PvCSP repeats. The chimeric protein was expressed in soluble form with high yield. As the immune response to PvCSP has been reported to be genetically restricted in the murine model, we tested the immunogenicity of PvRMC-CSP in groups of six inbred strains of mice. PvRMC-CSP was able to induce robust antibody responses in all the mouse strains tested. Synthetic peptides representing the allelic forms of theP. vivaxCSP were also recognized to a similar extent regardless of the mouse strain. Furthermore, the immunization regimen induced high frequencies of multifunctional CD4+and CD8+PvRMC-CSP-specific T cells. The depth and breadth of the immune responses elicited suggest that immunization with PvRMC-CSP can circumvent the genetic restriction of the immune response toP. vivaxCSP. Interestingly, PvRMC-CSP was also recognized by naturally acquired antibodies from individuals living in areas where malaria is endemic. These features make PvRMC-CSP a promising vaccine candidate for further development.

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The Interplay of Disease Modifying Anti Rheumatic Drugs and Tuberculin Skin Test

Current Clinical Pharmacology ◽

10.2174/1574884715999201231201538 ◽

2020 ◽

Vol 15 ◽

Author(s):

Zia Abdullah ◽

Arvind Kumar ◽

M. A. Khan ◽

Uma Kumar ◽

Surabhi Vyas ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Tuberculin Skin Test ◽

Skin Test ◽

Steroid Use ◽

Purified Protein Derivative ◽

Disease Modifying

Objective:: The study was conducted to determine whether synthetic disease modifying Anti Rheumatic drugs (DMARDs) suppresses the latency of Tuberculosis (TB) infection in Rheumatoid Arthritis (RA) patients along with other variables. Methods:: This was done through Tuberculin Skin Test (TST) using Purified protein derivative (PPD) in cohort of RA Patients. The TST was taken positive when induration post PPD injection was  5mm and negative or anergic when it was < 5mm. We included 100 patients (N = 100). Results:: The prevalence of positive TST was 36%, while 64% presented a negative result. Negative TST was significantly associated with steroid usage (39.4%, 95% CI: 28.4%-51.4%). Anergic (TST negative) and non-anergic (TST positive) patients were separated in groups, and a new analysis was done with elaboration on DMARDs used. Conclusion:: Steroid use and not treatment with methotrexate or other DMARDs was associated with TST negativity and thus TST should be interpreted with caution especially before starting biologicals.

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