Abstract
Due to the shortcomings of currently available BCG vaccines, new strategies have been considered for the development of alternative vaccines against tuberculosis. Many candidate vaccines are in the pipeline with an aim to replace BCG or boost the effect of BCG for prophylaxis. In addition, therapeutic applications are also considered. In this chapter, the current advances and approaches are explored to develop pre- and postexposure vaccines for tuberculosis.
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1 Immunological Characteristics and Markers for Mycobacterium tuberculosis
Mycobacterium tuberculosis (Mtb) infection in humans has a complex pathology that creates challenges in finding targets of the immune reaction to the pathogen. First, Mtb bacilli enter the lungs in aerosol droplets. During the innate immune response, macrophages ingest the bacteria and recruit other immune cells [1]. Cells such as neutrophils, γδ T cells, NK cells, and CD4+ T cells are activated to control the infection, leading to granuloma formation [2]. A small number of bacilli stay contained in the granuloma and may contribute to disease reactivation later in life [3]. In the majority of cases, CD4+ T cells will control the bacteria from further infection; however, in some cases, the infection can reactivate and develop into an acute, chronic, or extrapulmonary disease [2]. Mtb is efficient in evading the immune response and can be in the latent stage for years before symptoms are expressed [2]. Most people exposed to Mtb do not develop the clinical disease, for reasons that are currently not well understood [4].
The cytokines IL-8, IL-12, IL-17, IFN- γ, TNF- α, TGF-β, and memory T cells have been shown to be active in the immune response against tuberculosis (TB) [5]. While these markers are known to be involved in the immune response, Mtb does not have a known validated immune correlate of protection. Correlates of protection (COP), while complex, are quantitative or qualitative measurements that correlate to adequate levels of protection against a pathogen. These often correlate with the concentration of antibodies produced in response to the specific pathogens [6]. Without a COP, years of study are required to determine if markers are efficacious [4]. With a COP, vaccines could be optimized and explored based on their match with the proven immune response, leading to the licensure of vaccines [7]. Additionally, the COP could help explain some vaccine challenges. For example, the vaccine MVA85A produced a dismal response in phase 2, but in previous clinical trials, the vaccine produced high CD4+ T-cell responses [8]. With a known COP, the vaccine’s immune response could be matched with the standard.
In general, CD4+ T cells play a predominant role in protective immunity against TB, but strategies that boost CD8+ T-cell function have also been shown to enhance vaccine efficacy [8]. Depletion of CD8+ T cells in a nonhuman primate model of TB led to reduced protection in immunized monkeys [8]. Similarly, CD8+ T-cell depletion in Mtb-infected and then antibiotic-treated monkeys led to increased susceptibility to reinfection [8]. These studies indicate the importance of CD8+ T cells in conferring immunity in vaccination or natural infection. Additionally, the human CD8+ CCR7− CD45RA+ effector memory T cells exhibit significant anti-mycobacterial activity [8].
2 Approaches for TB Vaccine Development
There are several approaches for the development of new vaccines against TB, based on our current understanding of immunity against Mtb and the status of the host. These approaches include preventive pre-exposure (for uninfected individuals/infants), preventive postexposure (for latent TB/adolescents and adults), and therapeutic (for active TB) [9, 10]. Pre-exposure vaccines aim to prevent the infection from being established by inducing a more robust protective or faster immune response than BCG [1]. Postexposure vaccines aim to induce either a robust and long-lasting response to prevent disease reactivation or eliminate latent TB by inducing sterilizing immunity so that bacteria are unable to be reactivated later and lead to active TB [1]. The BCG vaccine follows the preventative pre-exposure approach. Vaccines can also be categorized in their biochemical forms: live attenuated, inactivated, adjuvanted protein subunit, and recombinant. Some vaccines have been created also as a boost to BCG [11, 12], and others have used differing modes of administration to boost immune responses [13].
There are currently at least 23 vaccine candidates in clinical trials in humans, as shown in Tables 10.1 and 10.2. Recent developments focus on their biochemical forms: live attenuated, inactivated, subunit, and recombinant vaccine types. Various antigens and adjuvant combinations are being tested in the case of subunit vaccines.
3 Live Attenuated TB Vaccines
Live attenuated vaccines contain whole Mtb in its weakened or altered form [17]. MTBVAC is the only live attenuated vaccine undergoing clinical trials in humans, and currently two trials are recruiting for the vaccine for phase 3 (NCT03767946; NCT03152903) (Table 10.1). MTBVAC, derived from the lineage 4 (L4) of Mtb complex, is designed as a replacement for BCG and as an immunotherapeutic agent [4]. It has been shown to be more attenuated than BCG [18]. In addition to the phase 3 clinical trials with MTBVAC, preclinical studies have been completed with attenuated Mtb belonging to strains L2 (MTBVAC-L2) and L3 (MTBVAC-L3). Vaccinations with MTBVAC, MTBVAC-L2, and MTBVAC-L3 have shown similar or superior protection compared to BCG in immunocompetent mice when the immunized mice were challenged with the three representative strains of Mtb. It appears that the three MTBVAC vaccine candidates could be combined into a polyvaccine to protect against the globally diverse strains of Mtb to provide worldwide protection against TB [18].
The MTBVAC vaccine has also been used as a vector to make a dual TB-human immunodeficiency virus (HIV) vaccine known as MTBVAC.HIVA2auxo [19]. HIV clade-1 A immunogen HIVA was inserted into the parental strain MTBVAC to produce a recombinant strain, which provided similar protective efficacy to the parental MTBVAC strain against Mtb challenge in mice. MTBVAC.HIVA2auxo also showed an increased safety profile in comparison with BCG and MTBVAC [19], showing promise for immunosuppressed individuals at risk of severe infection or death against the pathogen [20].
4 Inactivated TB Vaccines
Inactivated vaccines do not contain any infectious particles and are often considered safer than live vaccines, but their immunogenicity is much weaker and potentially may require multiple doses [20]. Inactivated vaccines have been used for both pre-and postexposure strategies and therapeutic applications [9]. Among the inactivated vaccines is RUTI, which contains detoxified and fragmented Mtb cells in liposomes (Table 10.1). Other inactivated TB vaccines currently in clinical trials include M. vaccae, M. Indicus pranii (MIP), and M. obunese (DAR-901) (Table 10.1).
RUTI, a phase 2b vaccine, has exhibited significant humoral and cellular immune responses against antigens expressed in actively growing and latent bacilli [21]. It has shown efficacy in controlling latent TB in experimental animals, i.e., mice, goats, guinea pigs, and mini pigs [22]. In addition to preventive/prophylactic applications, RUTI, MIP, and M. vaccae are being used as therapeutic vaccines to reduce drug treatment duration for patients with active TB [21, 23,24,25].
Additionally, RUTI has shown vaccine-induced inhibition in mycobacterial counts and a significant shift toward Ly6C− monocyte phenotype in the spleens of immunized mice [26]. Ly6C is an antigen on monocytes that, when elevated, can induce monocyte differentiation to macrophages, dendritic cells, tissue specific macrophages, and other cells [27]. Vaccination of mice with RUTI upregulated the expressions of Ly6C− related mRNA transcripts in splenocytes, producing a monocyte phenotype shift from LyC6+ [26]. Ly6C− monocytes have been shown to have an anti-inflammatory role [28], whereas Ly6C+ monocytes are pro-inflammatory [28]. Therefore, the RUTI vaccine may show a balanced immune response.
5 Subunit TB Vaccines with Adjuvants
Subunit vaccines contain selected parts of the pathogen to produce an appropriate immune response. Such vaccines are usually safer but generally induce less robust immune responses, as compared to attenuated and whole-cell inactivated vaccines [20]. Hence, to increase their efficacies, subunit vaccines are often administered with an appropriate adjuvant [1, 29].
A challenge for this type of vaccine is the required binding to the highly polymorphic major histocompatibility complex (MHC) molecules for antigen recognition by CD4+ T helper and CD8+ T cytotoxic cells [30, 31]. The MHC molecules in humans, also known as human leukocyte antigen (HLA), are divided into three groups, i.e., HLA class I, HLA class II, and HLA class III. HLA class I and HLA class II molecules have antigen presentation functions to CD4+ T helper and CD8+ T cytotoxic cells, respectively. HLA class I molecules are further divided into three categories known as HLA-A, HLA-B, and HLA-C. Similarly, HLA class II molecules are divided into three categories known as HLA-DP, HLA-DQ, and HLA-DR. Antigen−/peptide-based vaccines with differing MHC binding abilities or binding to multiple HLA molecules (promiscuous peptides) will widen the coverage of the target population [32, 33]. The challenge is that MHC molecules are highly polymorphic and the frequency of MHC alleles differs in different populations. To identify appropriate antigens/peptides for vaccine development, databases have been designed based on the HLA allele/haplotype frequency in different populations, such as the Allele Frequency Net Database, which provides allele frequencies from 456 globally distributed populations in 90 countries [34]. Additional databases are available to determine compatibility of T helper lymphocyte and cytotoxic T lymphocyte epitopes to produce robust immune responses [35, 36]. Some databases include binding models based on an allele-specific quantitative structure-activity relationship, a model for human transporter associated with antigen processing, and B cell epitope prediction based on amino acid sequence [37].
Subunit/adjuvanted vaccines, noted as antigen/adjuvant in the literature, are an active area of research due to the wide variety of antigens/peptides and adjuvants (Tables 10.2 and 10.3). Mtb expresses around 4000 proteins [5], which leads to the possibility of selecting a large number of antigens as immune targets (Table 10.4). Common secreted antigenic proteins used in the development of subunit TB vaccines include ESAT-6, CFP10, MPT64, Ag85B, and Ag85A due to their different expression profiles in individuals actively infected with Mtb or individuals with latent TB [5, 75, 76]. Other proteins identified with high immunogenicity include Rv1031, Rv1198, Rv2016, Rv2031c [41, 77], Rv3619c [78], Rv3620c [79], PE35 [80], PPE39 [81], PPE68 [82], Mtb9.8, Mtb32A (Rv0125), Mtb39A (Rv1196) [83], MPT63 (Rv1926c) [84], MPT83 (Rv2873) [32], LppX [85], MPT64 (Rv1980c) [86, 87], and A60 complex [88]. Additionally, a new study showed that Rv0569 increased the release of Th1 cytokines IL-12p40, TNF-α, and IFN- γ [89]. Mtb antigens are expressed at different stages of infection, a challenge for creating a vaccine with adequate/appropriate immune responses against all the stages. Proteins expressed at different timelines include ESAT-6, which is always expressed, and Ag85B, which is expressed early in infection [39]. H56 is an example of a protein fusion and consists of Ag85B, ESAT-6, and Rv660c. This protein fusion stimulates immune responses to antigens expressed at different stages of Mtb infection. A vaccine with H56/CAF01 has shown activation of both innate and adaptive immunity in mice [90, 91]. Additionally, proteins Rv0169, Rv3490, Rv1085c, Rv0563, and Rv3497c are expressed at different stages of the Mtb life cycle and could be promising for a multistage vaccine [92].
Aluminum-based adjuvants are extensively used in vaccines to drive a humoral immune response. Humoral immunity is not considered to have a major role in protection against Mtb, as it is an intracellular pathogen [2]. Therefore, novel adjuvants may be useful to induce protective Th1 responses [89]. Current adjuvants used in Mtb vaccines include IC31, GLA-SE, AS01E, QS21, CFA01, and others (Table 10.5) [5, 101].
The subunit vaccine H4/IC31 (AERAS-404, containing a fusion protein of antigens Ag85B and TB10.4 along with an adjuvant IC31) was studied in adolescents in a high-risk setting for TB to assess its efficacy in decreasing Mtb-specific immune response (an indicator of active TB) in individuals immunized with BCG in neonatal age [102]. The results were compared with BCG revaccination. All the participants had negative results for Mtb-specific immune response as determined by quantifying the concentration of IFN- γ secreted by using the QuantiFERON-TB Gold (QFT) In-Tube assay. QFT conversion, shown by the authors as having a higher risk of progression to TB, was determined in both H4/IC31 vaccinated group and BCG revaccinated group. BCG revaccination reduced the rate of QFT conversion (with an efficacy of 45% and 95% CI 6–68) compared to the H4/IC31 (efficacy of 31%, 95% CI 16–58) [102]. This study renewed interest in revaccination with BCG, which had previously been accepted as having no effect [103, 104].
In a phase 2b clinical trial, the subunit vaccine M72/AS01E (a fusion protein of Mtb32A [Rv0125) and Mtb39A [Rv1196] in the liposome based AS01E) prevented pulmonary TB in adults already infected with Mtb (efficacy of 54%) [105]. When compared with six candidate TB vaccines, i.e., MVA85A, AERAS-402 (a replication-deficient Ad35 vaccine encoding a fusion protein of the Mtb antigens 85A, 85B, and TB10.4), H1/IC31 (a fusion protein of Ag85B-ESAT-6 [H1] formulated with the adjuvant IC31), M72/AS01E, ID93Â +Â GLA-SE (a 93Â kDa fusion protein of Rv3619, Rv1813, Rv3620, and Rv2608 in the adjuvant GLA-SE), and BCG, it was found that M72/AS01E induced higher memory Th1 cytokine-expressing CD4+ T-cell memory responses [106]. The ability of M72/AS01E to induce the highest-memory CD4+ T-cell response demonstrated that it was the best vaccine candidate, because the induction of these cells correlates with protective immunity in TB [106]. In a study reported by Tait et al., M72/AS01E vaccine had an efficacy of 50% against pulmonary tuberculosis in a phase 2B clinical trial after 3Â years of follow-up, a result that represents the first subunit TB vaccine that had significant efficacy against clinical TB [107]. A meta-analysis including 7 studies that involved 4590 participants revealed that vaccine efficacy was 57% with significantly higher abundance of polyfunctional M72-specific CD4+ T cells in the vaccine groups versus the control group. Furthermore, the M72/AS01E vaccine against TB was safe [108].
6 Recombinant TB Vaccines
Recombinant vaccines are produced using techniques of genetic engineering and biotechnology. A piece of DNA encoding an antigenic protein of Mtb is inserted into an appropriate vector to transform either a bacterial, mammalian, or yeast cell. The recombinant vector produces the antigen in large quantities in those cells [109]. Because the recombinant protein can also be purified, the purified protein can be used as a subunit vaccine to stimulate the immune response and avoid some of the potential concerns of other types of vaccines, such as whole-cell vaccines [110].
Recombinant vaccines (Tables 10.2, and 10.3) can be classified based on the type of organism used to express Mtb antigens. These include live mycobacterial, live bacterial, and live viral vaccines. Bacteria such as M. bovis BCG, M. vaccae, and M. smegmatis have been used as live mycobacterial vectors [111,112,113]. M. bovis BCG is commonly used as an expression vector due to its stability, cost-effectiveness, and nonspecific immune stimulation [21, 114, 115]. Lactobacillus lactis has also been used as a vector in the recombinant bacterial vaccine Pnz8149-ag85a/NZ3900. In the preclinical stage, it was able to induce both cellular and antibody responses after mucosal immunization in mice [116]. Many other recombinant bacterial vaccine candidates are in preclinical stages of development and testing (Table 10.3).
Several live viral vector-based vaccines have also entered into clinical trials (Table 10.2). These vaccines have been designed using various viral vectors, i.e., vaccinia Ankara virus (MVA85A/AERAS-485), Adenoviruses (Ad35/AERAS-402, Ad5Ag85A, ChAdOx1.85A, and ChAd3M72), and influenza virus (TB/FLU-04Â L) (Table 10.2). The MVA85A/AERAS-485 is in two phase 2a trials (Table 10.2). One other vaccine is in phase 2a, and five vaccines are currently being evaluated in phase 1 studies (Table 10.2). In general, live viral vector-based vaccines have advantages for safety and ease of production, as compared to whole-cell vaccines, but have the disadvantage of gene expression instability [20].
7 Recombinant Vaccine Candidates Based on M. tuberculosis-Specific Antigens
Many of the above-stated TB vaccine candidates undergoing clinical trials are based on cross-reactive antigens of Mtb. Immunization with these antigens will have the problem of false positivity in tuberculin skin test using purified protein derivative (PPD) of Mtb, as is seen with BCG. Furthermore, because of the cross-reactivity with environmental mycobacteria, these candidate vaccines may face the problem of masking or blocking effects. Hence, such vaccine candidates may not be recommended as booster vaccines in BCG pre-vaccinated individuals [117]. As per the masking hypothesis, early sensitization with environmental mycobacteria leads to some level of protection against TB, which masks the effect of vaccines given later in life due to the presence of cross-reactive antigens. The blocking hypothesis postulates that previous immune responses to cross-reactive antigens, because of sensitization due to exposure to environmental mycobacteria, prevent the taking of a new vaccine by efficient clearance of the new vaccine antigens by preexisting immune responses [117]. The use of Mtb-specific antigens as new TB vaccines may overcome the effects of blocking or masking [75]. Hence, to have TB vaccines better than BCG, researchers are exploring the possibilities of developing new subunit and/or recombinant vaccines based on Mtb-specific antigens [118].
In previous studies, three Mtb-specific regions, known as regions of differences (RDs), were identified using classical molecular and biochemical techniques, but the identification of all Mtb-specific regions was made possible with advances in whole genome sequencing and the comparative genome analysis of Mtb with other mycobacterial genomes [119]. These RDs are deleted/absent in all BCG sub-strains currently being used in different parts of the world [119]. The analysis of Mtb-specific regions for the expression of proteins based on the finding of open reading frames has suggested that these RDs can potentially encode several antigenic proteins [120]. To identify the proteins suitable as TB vaccine candidates, they were first tested for their ability to induce cellular immune responses in vitro with peripheral blood cells obtained from naturally infected animals and humans. Such experiments conducted with cells from humans and cattle identified six antigens that induced potent cellular immune responses, i.e., PE35, PPE68, ESAT-6, CFP10, Rv3619c, and Rv2346c [121, 122]. When tested in animal models of TB, all of these antigens were found to induce Th1 responses when given along with appropriate adjuvants and delivery systems such as DNA vaccine vectors and nonpathogenic mycobacteria, including BCG [123,124,125,126,127]. In animal models like mice and guinea pigs, immunizations with ESAT-6, CFP-10, and Rv3619c resulted in protection against challenges with Mtb [97, 128,129,130].
In humans, a recombinant subunit TB vaccine candidate, GamTBvac, has undergone phase 1 and phase 2 clinical trials. GamTBvac contains three Mtb antigens, i.e., ESAT-6, CFP10, and Ag85A, fused into two chimeric proteins with a dextran-binding domain from Leuconostoc mesenteroides. These fusions are formulated with the adjuvant containing dextran 500 kDa, diethylaminoethyl (DEAE)-dextran 500 kDa, and CpG oligodeoxynucleotides (ODN) [131]. In the phase 1 clinical trial, the safety and immunogenicity of GamTBvac were determined in healthy volunteers who were previously vaccinated with BCG. The GamTBvac achieved an acceptable safety profile and was well tolerated. Furthermore, immunization with GamTBvac resulted in a significant increase in the markers of cellular and humoral immunity, i.e., increased concentration of the protective Th1 cytokine IFN-γ and IgG antibodies. Furthermore, the immune responses were induced to all three antigens included in GamTBvac [131]. The phase 2 clinical trial with GamTBvac was a multicenter, double-blind, randomized, and placebo control study conducted in BCG vaccinated healthy volunteers without Mtb infection. The results showed that the vaccine confirmed an acceptable safety profile. Furthermore, GamTBvac induced antigen-specific interferon-gamma release, Th1 cytokine-expressing CD4+ T cells, and IgG responses [132]. These results support further clinical testing of GamTBvac to demonstrate its ability to protect against clinical TB.
An additional recombinant bacterial vaccine in the preclinical stage and based on Mtb-specific ESAT-6 antigen is L. lactis FnBPA+ (pValac:ESAT-6). When delivered by the mucosal route in mice, this vaccine produced a systemic Th1 cell response (as indicated by significantly increased secretion of IFN-γ by spleen cells) and a significant increase in specific secretory immunoglobulin A production in colon tissue and fecal extracts of the immunized animals [133]. In a booster model in animals preimmunized with BCG, the pValac:ESAT-6 vaccine induced a significant increase in proinflammatory cytokines IL-17, IFN-γ, IL-6, and TNF-α from the spleen cells of immunized mice [44]. Another study was conducted on the same principles by fusing the genes of ESAT-6 and Ag85A and cloning them in the pValac vector to obtain the recombinant L. lactis FnBPA+ (pValac:e6ag85a). When used for oral immunization in mice, this recombinant construct induced significant increases in the concentrations of IFN-γ, TNF-α, and IL-17 cytokines by stimulated spleen cells and significant production of antigen-specific sIgA in the colonic tissues of immunized mice [134]. These findings are novel and interesting because they represent the first successful step toward the development of vaccines for boosting the effect of BCG using the oral route for administration and by employing the recombinant techniques for the expression of an Mtb-specific antigen in the bacterium L. lactis.
8 Routes of Vaccine Delivery
BCG is administered intradermally and results in the induction of strong systemic responses but weak mucosal immune responses [135]. As Mtb is transmitted via the respiratory route, the same route may also be appropriate for the delivery of improved vaccines [136]. The effects of different routes of administration for TB vaccines are not readily discussed in the literature; however, some studies have shown that a route other than intradermal may have a better possibility of success in inducing appropriate immune responses and protection [137]. A comparative analysis of the oral vs. intradermal administration of BCG was evaluated in a small-scale trial in humans, and the results showed that oral BCG produced a stronger mucosal immune response in bronchoalveolar lavage and secretary IgA in nasal washes and tears, whereas intradermal BCG produced a stronger immune response in the blood [138]. In another study, the comparison of intravenous, intradermal, and aerosol delivery of BCG vaccine in rhesus macaques showed that the intravenous administration of BCG was safe, induced significantly more antigen-responsive CD4+ and CD8+ T cells, and afforded better protection against challenge with the highly pathogenic Mtb Erdman strain [27]. Subunit vaccines can also be administered through the subcutaneous, intranasal, edible, and mucosal routes [135]. Nanoparticle-based vaccines have also been explored [2]. Edible-based strategies employ the use of antigens expressed in plants such as carrot, potato, tobacco, and Lemna minor (a species of aquatic freshwater common duckweed or lesser duckweed plant) to activate the immune response [2], and nanoparticle strategies use nanoparticles conjugated with antigens such as Ag85B to increase Th1 responses in lymphoid organs against Mtb [2]. However, an optimal route for Mtb vaccine delivery has yet to be identified. Therefore, more research is needed to identify the route that will induce maximum protection against TB.
9 Conclusion
BCG is currently the only available vaccine against TB in humans. However, BCG has many drawbacks, prompting concerted efforts to develop vaccines better than BCG. Among the approaches being used to develop new TB vaccines, whole-cell mycobacteria, subunit, and recombinant vaccine strategies are being explored. Proteins have been identified, and strategies to develop new vaccine candidates have been expanded. Differing routes of administration are another area of research for new vaccine development. The achievements in the field of developing improved vaccines against TB are quite encouraging with the hope that better TB vaccines for prophylactic and therapeutic applications in humans may become available in the coming years.
References
Fatima S, Kumari A, Das G, Dwivedi VP. Tuberculosis vaccine: a journey from BCG to present. Life Sci. 2020;252:117594. https://doi.org/10.1016/j.lfs.2020.117594.
Yadav J, Verma S, Chaudhary D, Jaiwal PK, Jaiwal R. Tuberculosis: current status, diagnosis, treatment and development of novel vaccines. Curr Pharm Biotechnol. 2019;20:446–58. https://doi.org/10.2174/1389201020666190430114121.
Basaraba RJ, Hunter RL. Pathology of tuberculosis: how the pathology of human tuberculosis informs and directs animal models. Microbiol Spectr. 2017;5. https://doi.org/10.1128/microbiolspec.TBTB2-0029-2016.
Stockdale L, Fletcher H. The future of vaccines for tuberculosis. Clin Chest Med. 2019;40:849–56. https://doi.org/10.1016/j.ccm.2019.07.009.
Zhu B, Dockrell HM, Ottenhoff THM, Evans TG, Zhang Y. Tuberculosis vaccines: opportunities and challenges. Respirology. 2018;23:359–68. https://doi.org/10.1111/resp.13245.
Plotkin SA. Correlates of protection induced by vaccination. Clin Vaccine Immunol. 2010;17(7):1055–6.
Satti I, McShane H. Current approaches toward identifying a correlate of immune protection from tuberculosis. Expert Rev Vaccines. 2019;18:43–59. https://doi.org/10.1080/14760584.2019.1552140.
Bhatt K, Verma S, Ellner JJ, Salgame P. Quest for correlates of protection against tuberculosis. Clin Vaccine Immunol. 2015;22:258–66. Pipeline of vaccines. https://www.tbvi.eu/what-we-do/pipeline-of-vaccines/. Accessed 14 May 2022. https://doi.org/10.1128/cvi.00721-14.
Safar HA, Mustafa AS, McHugh TD. COVID-19 vaccine development: what lessons can we learn from TB? Ann Clin Microbiol Antimicrob. 2020;19(1):56. PMID: 33256750; PMCID: PMC7702199. https://doi.org/10.1186/s12941-020-00402-x.
Gupta N, Garg S, Vedi S, Kunimoto DY, Kumar R, Agrawal B. Future path toward TB vaccine development: boosting BCG or re-educating by a new subunit vaccine. Front Immunol. 2018;9:2371. https://doi.org/10.3389/fimmu.2018.02371.
Kuczkowska K, Copland A, Øverland L, Mathiesen G, Tran AC, Paul MJ, Eijsink VGH, Reljic R. Inactivated lactobacillus plantarum carrying a surface-displayed Ag85B-ESAT-6 fusion antigen as a booster vaccine against Mycobacterium tuberculosis infection. Front Immunol. 2019;10:1588. https://doi.org/10.3389/fimmu.2019.01588.
Platteel ACM, Nieuwenhuizen NE, Domaszewska T, Schürer S, Zedler U, Brinkmann V, Sijts A, Kaufmann SHE. Efficacy testing of H56 cDNA tattoo immunization against tuberculosis in a mouse model. Front Immunol. 2017;8:1744. https://doi.org/10.3389/fimmu.2017.01744.
Bourinbaiar AS, Batbold U, Efremenko Y, Sanjagdorj M, Butov D, Damdinpurev N, Grinishina E, Mijiddorj O, Kovolev M, Baasanjav K, et al. Phase III, placebo-controlled, randomized, double-blind trial of tableted, therapeutic TB vaccine (V7) containing heat-killed M. vaccae administered daily for one month. J Clin Tuberc Other Mycobact Dis. 2019;18:100141. https://doi.org/10.1016/j.jctube.2019.100141.
Gong W, Liang Y, Wu X. The current status, challenges, and future developments of new tuberculosis vaccines. Hum Vaccin Immunother. 2018;14:1697–716. https://doi.org/10.1080/21645515.2018.1458806.
Ahmad F, Umar MS, Khan N, Jamal F, Gupta P, Zubair S, Gupta UD, Owais M. Immunotherapy with 5, 15-DPP mediates macrophage M1 polarization and modulates subsequent Mycobacterium tuberculosis infectivity in rBCG30 immunized mice. Front Immunol. 2021;12:706727. PMID: 34777338; PMCID: PMC8586420. https://doi.org/10.3389/fimmu.2021.706727.
Kaufmann SHE, Dockrell HM, Drager N, Ho MM, McShane H, Neyrolles O, Ottenhoff THM, Patel B, Roordink D, Spertini F, Stenger S, Thole J, Verreck FAW, Williams A, TBVAC2020 Consortium. TBVAC2020: advancing tuberculosis vaccines from discovery to clinical development. Front Immunol. 2017;8:1203. PMID: 29046674; PMCID: PMC5632681. https://doi.org/10.3389/fimmu.2017.01203.
Pérez I, Uranga S, Sayes F, Frigui W, Samper S, Arbués A, Aguiló N, Brosch R, MartÃn C, Gonzalo-Asensio J. Live attenuated TB vaccines representing the three modern Mycobacterium tuberculosis lineages reveal that the euro-American genetic background confers optimal vaccine potential. EBioMedicine. 2020;55:102761. https://doi.org/10.1016/j.ebiom.2020.102761.
Broset E, Saubi N, Guitart N, Aguilo N, Uranga S, Kilpeläinen A, Eto Y, Hanke T, Gonzalo-Asensio J, MartÃn C, et al. MTBVAC-based TB-HIV vaccine is safe, elicits HIV-T cell responses, and protects against Mycobacterium tuberculosis. Mol Ther Methods Clin Dev. 2019;13:253–64.
Vetter V, Denizer G, Friedland LR, Krishnan J, Shapiro M. Understanding modern-day vaccines: what you need to know. Ann Med. 2018;50:110–20. https://doi.org/10.1080/07853890.2017.1407035.
Pennisi M, Russo G, Sgroi G, Bonaccorso A, Parasiliti Palumbo GA, Fichera E, Mitra DK, Walker KB, Cardona PJ, Amat M, et al. Predicting the artificial immunity induced by RUTI® vaccine against tuberculosis using universal immune system simulator (UISS). BMC Bioinformatics. 2019;20:504. https://doi.org/10.1186/s12859-019-3045-5.
Gonzalo-Asensio J, Marinova D, Martin C, Aguilo N. MTBVAC: attenuating the human pathogen of tuberculosis (TB) toward a promising vaccine against the TB epidemic. Front Immunol. 2017;8:1803. https://doi.org/10.3389/fimmu.2017.01803.
Huang CY, Hsieh WY. Efficacy of Mycobacterium vaccae immunotherapy for patients with tuberculosis: a systematic review and meta-analysis. Hum Vaccin Immunother. 2017;13:1960–71. https://doi.org/10.1080/21645515.2017.1335374.
Cardona PJ. The progress of therapeutic vaccination with regard to tuberculosis. Front Microbiol. 2016;7:1536. https://doi.org/10.3389/fmicb.2016.01536.
Talwar GP, Gupta JC, Mustafa AS, Kar HK, Katoch K, Parida SK, Reddi PP, Ahmed N, Saini V, Gupta S. Development of a potent invigorator of immune responses endowed with both preventive and therapeutic properties. Biologics. 2017;11:55–63. PMID: 28496303; PMCID: PMC5422320. https://doi.org/10.2147/BTT.S128308.
Prabowo SA, Painter H, Zelmer A, Smith SG, Seifert K, Amat M, Cardona PJ, Fletcher HA. RUTI vaccination enhances inhibition of mycobacterial growth ex vivo and induces a shift of monocyte phenotype in mice. Front Immunol. 2019;10:894. https://doi.org/10.3389/fimmu.2019.00894.
Teitelbaum R, Schubert W, Gunther L, Kress Y, Macaluso F, Pollard JW, McMurray DN, Bloom BR. The M cell as a portal of entry to the lung for the bacterial pathogen Mycobacterium tuberculosis. Immunity. 1999;10:641–50. https://doi.org/10.1016/s1074-7613(00)80063-1.
Darrah PA, Zeppa JJ, Maiello P, Hackney JA, Wadsworth MH 2nd, Hughes TK, Pokkali S, Swanson PA 2nd, Grant NL, Rodgers MA, et al. Prevention of tuberculosis in macaques after intravenous BCG immunization. Nature. 2020;577:95–102. https://doi.org/10.1038/s41586-019-1817-8.
Safar HA, El-Hashim AZ, Amoudy H, Mustafa AS. Mycobacterium tuberculosis-specific antigen Rv3619c effectively alleviates allergic asthma in mice. Front Pharmacol. 2020;11:532199. PMID: 33101014; PMCID: PMC7546857. https://doi.org/10.3389/fphar.2020.532199.
Mustafa AS. HLA-restricted immune response to mycobacterial antigens: relevance to vaccine design. Hum Immunol. 2000;61(2):166–71. PMID: 10717810. https://doi.org/10.1016/s0198-8859(99)00137-8.
Oyarzun P, Kashyap M, Fica V, Salas-Burgos A, Gonzalez-Galarza FF, McCabe A, Jones AR, Middleton D, Kobe B. A proteome-wide immunoinformatics tool to accelerate T-cell epitope discovery and vaccine design in the context of emerging infectious diseases: an ethnicity-oriented approach. Front Immunol. 2021;12:598778. PMID: 33717077; PMCID: PMC7952308. https://doi.org/10.3389/fimmu.2021.598778.
Mustafa AS. Comparative evaluation of MPT83 (Rv2873) for T helper-1 cell reactivity and identification of HLA-promiscuous peptides in Mycobacterium bovis BCG-vaccinated healthy subjects. Clin Vaccine Immunol. 2011;18(10):1752–9. Epub 2011 Aug 18. PMID: 21852544; PMCID: PMC3187038. https://doi.org/10.1128/CVI.05260-11.
Mustafa AS. Characterization of a cross-reactive, immunodominant and HLA-promiscuous epitope of Mycobacterium tuberculosis-specific major antigenic protein PPE68. PLoS One. 2014;9(8):e103679. PMID: 25136958; PMCID: PMC4138092. https://doi.org/10.1371/journal.pone.0103679.
Gonzalez-Galarza FF, McCabe A, Melo dos Santos EJ, Takeshita L, Ghattaoraya G, Jones AR, Middleton D. Allele frequency net database. Methods Mol Biol. 1802;2018:49–62. https://doi.org/10.1007/978-1-4939-8546-3_4.
Mustafa AS. In silico analysis and experimental validation of Mycobacterium tuberculosis -specific proteins and peptides of Mycobacterium tuberculosis for immunological diagnosis and vaccine development. Med Princ Pract. 2013;22(Suppl 1):43–51. Epub 2013 Aug 31. PMID: 24008694; PMCID: PMC5586813. https://doi.org/10.1159/000354206.
Mustafa AS, Shaban FA. ProPred analysis and experimental evaluation of promiscuous T-cell epitopes of three major secreted antigens of Mycobacterium tuberculosis. Tuberculosis (Edinb). 2006;86(2):115–24. Epub 2005 Jul 21. PMID: 16039905. https://doi.org/10.1016/j.tube.2005.05.001.
Gong W, Pan C, Cheng P, Wang J, Zhao G, Wu X. Peptide-based vaccines for tuberculosis. Front Immunol. 2022;13:830497. PMID: 35173740; PMCID: PMC8841753. https://doi.org/10.3389/fimmu.2022.830497.
Mustafa AS. Immunological characterization of proteins expressed by genes located in Mycobacterium tuberculosis-specific genomic regions encoding the ESAT6-like proteins. Vaccines (Basel). 2021;9(1):27. PMID: 33430286; PMCID: PMC7825740. https://doi.org/10.3390/vaccines9010027.
Asai M, Li Y, Spiropoulos J, Cooley W, Everest D, Robertson BD, Langford PR, Newton SM. A novel biosafety level 2 compliant tuberculosis infection model using a ΔleuDΔpanCD double auxotroph of Mycobacterium tuberculosis H37Rv and galleria mellonella. Virulence. 2020;11:811–24.
Thakur A, Pinto FE, Hansen HS, Andersen P, Christensen D, Janfelt C, Foged C. Intrapulmonary (i.pulmon.) pull immunization with the tuberculosis subunit vaccine candidate H56/CAF01 after intramuscular (i.m.) priming elicits a distinct innate myeloid response and activation of antigen-presenting cells than i.m. or i.pulmon. Prime immunization alone. Front Immunol. 2020;11:803. https://doi.org/10.3389/fimmu.2020.00803.
Counoupas C, Pinto R, Nagalingam G, Britton WJ, Petrovsky N, Triccas JA. Delta inulin-based adjuvants promote the generation of polyfunctional CD4+ T cell responses and protection against Mycobacterium tuberculosis infection. Sci Rep. 2017;7:8582.
Yan YH, Li MC, Liu HC, Xiao TY, Li N, Lou YL, Wan KL. Cellular immunity evaluation of five Mycobacterium tuberculosis recombinant proteins and their compositions. Zhonghua Yu Fang Yi Xue Za Zhi. 2020;54:539–45. https://doi.org/10.3760/cma.j.cn112150-20191119-00872.
Liu X, Peng J, Hu L, Luo Y, Niu H, Bai C, Wang Q, Li F, Yu H, Wang B, et al. A multistage Mycobacterium tuberculosis subunit vaccine LT70 including latency antigen Rv2626c induces long-term protection against tuberculosis. Hum Vaccin Immunother. 2016;12:1670–7. https://doi.org/10.1080/21645515.2016.1141159.
Carvalho Dos Santos C, Rodriguez D, Kanno Issamu A, Cezar De Cerqueira Leite L, Pereira Nascimento I. Recombinant BCG expressing the LTAK63 adjuvant induces increased early and long-term immune responses against Mycobacteria. Hum Vaccin Immunother. 2020;16:673–83. https://doi.org/10.1080/21645515.2019.1669414.
Pereira VB, da Cunha VP, Preisser TM, Souza BM, Turk MZ, De Castro CP, Azevedo M, Miyoshi A. Lactococcus lactis carrying a DNA vaccine coding for the ESAT-6 antigen increases IL-17 cytokine secretion and boosts the BCG vaccine immune response. J Appl Microbiol. 2017;122:1657–62. https://doi.org/10.1111/jam.13449.
Kadir NA, Sarmiento ME, Acosta A, Norazmi MN. Cellular and humoral immunogenicity of recombinant Mycobacterium smegmatis expressing Ag85B epitopes in mice. Int J Mycobacteriol. 2016;5:7–13. https://doi.org/10.1016/j.ijmyco.2015.09.006.
Hall LJ, Clare S, Pickard D, Clark SO, Kelly DL, El Ghany MA, Hale C, Dietrich J, Andersen P, Marsh PD, Dougan G. Characterisation of a live Salmonella vaccine stably expressing the Mycobacterium tuberculosis Ag85B-ESAT6 fusion protein. Vaccine (Basel). 2009;27(49):6894–904. Epub 2009 Sep 13. PMID: 19755145; PMCID: PMC2789253. https://doi.org/10.1016/j.vaccine.2009.09.007.
Mycobrowser Database. Gene Rv3875 (esat-6) in Mycobacterium tuberculosis H37Rv. 2022. https://mycobrowser.epfl.ch/genes/Rv3875. Accessed 26 Jun 2022.
Sali M, Di Sante G, Cascioferro A, Zumbo A, Nicolò C, Donà V, Rocca S, Procoli A, Morandi M, Ria F, Palù G, Fadda G, Manganelli R, Delogu G. Surface expression of MPT64 as a fusion with the PE domain of PE_PGRS33 enhances Mycobacterium bovis BCG protective activity against Mycobacterium tuberculosis in mice. Infect Immun. 2010;78(12):5202–13. Epub 2010 Oct 4. PMID: 20921146; PMCID: PMC2981302. https://doi.org/10.1128/IAI.00267-10.
Wahid AA, Doekhie A, Sartbaeva A, van den Elsen JMH. Ensilication improves the thermal stability of the tuberculosis antigen Ag85b and an Sbi-Ag85b vaccine conjugate. Sci Rep. 2019;9(1):11409. PMID: 31391509; PMCID: PMC6685958. https://doi.org/10.1038/s41598-019-47657-9.
Kim H, Kwon KW, Park J, Kang H, Lee Y, Sohn EJ, Hwang I, Eum SY, Shin SJ. Plant-produced N-glycosylated Ag85A exhibits enhanced vaccine efficacy against Mycobacterium tuberculosis HN878 through balanced multifunctional Th1 T cell immunity. Vaccines (Basel). 2020;8(2):189. PMID: 32325740; PMCID: PMC7349862. https://doi.org/10.3390/vaccines8020189.
Bespyatykh J, Bespiatykh D, Malakhova M, Klimina K, Bespyatykh A, Varizhuk A, Tevyashova A, Nikolenko T, Pozmogova G, Ilina E, Shitikov E. Aureolic acid group of agents as potential antituberculosis drugs. Antibiotics (Basel). 2020;9(10):715. PMID: 33086595; PMCID: PMC7650759. https://doi.org/10.3390/antibiotics9100715.
Mycobrowser Database. Gene Rv1198 (ES6_4, Mtb9.9C) in Mycobacterium tuberculosis H37Rv. 2022. https://mycobrowser.epfl.ch/genes/Rv1198. Accessed 26 Jun 2022.
Mycobrowser Database. Gene Rv2016 in Mycobacterium tuberculosis H37Rv. 2022. https://mycobrowser.epfl.ch/genes/Rv2016. Accessed 26 Jun 2022.
Mycobrowser Database. Gene Rv2031c (acr) in Mycobacterium tuberculosis H37Rv. 2022. https://mycobrowser.epfl.ch/genes/Rv2031c. Accessed 26 Jun 2022.
Mycobrowser Database. Gene Rv3619c (ES6_1, Mtb9.9D) in Mycobacterium tuberculosis H37Rv. 2022. https://mycobrowser.epfl.ch/genes/Rv3619c. Accessed 26 Jun 2022.
Mycobrowser Database. Gene Rv3620c (ES6_10, QILSS) in Mycobacterium tuberculosis H37Rv. 2022. https://mycobrowser.epfl.ch/genes/Rv3620c. Accessed 26 Jun 2022.
Mycobrowser Database. Gene Rv3872 in Mycobacterium tuberculosis H37Rv. 2022. https://mycobrowser.epfl.ch/genes/Rv3872. Accessed 26 Jun 2022.
Mycobrowser Database. Gene Rv2353c in Mycobacterium tuberculosis H37Rv. https://mycobrowser.epfl.ch/genes/Rv2353c. Accessed 26 Jun 2022.
Mycobrowser database. Gene Rv3873 in Mycobacterium tuberculosis H37Rv. 2022. https://mycobrowser.epfl.ch/genes/Rv3873. Accessed 26 Jun 2022.
Liu S, Jia H, Hou S, et al. Recombinant Mtb9.8 of Mycobacterium bovis stimulates TNF-α and IL-1β secretion by RAW264.7 macrophages through activation of NF-κB pathway via TLR2. Sci Rep. 2018;8:1928. https://doi.org/10.1038/s41598-018-20433-x.
Mycobrowser Database. Gene Rv0125 (mtb32a) in Mycobacterium tuberculosis H37Rv. 2022. https://mycobrowser.epfl.ch/genes/Rv0125. Accessed 26 Jun 2022.
Mycobrowser Database. Gene Rv1196 (mtb39a) in Mycobacterium tuberculosis H37Rv. 2022. https://mycobrowser.epfl.ch/genes/Rv1196. Accessed 26 Jun 2022.
Mycobrowser Database. Gene Rv1926c (mpb63) in Mycobacterium tuberculosis H37Rv. 2022. https://mycobrowser.epfl.ch/genes/Rv1926c. Accessed 26 Jun 2022.
Chiliza TE, Pillay M, Pillay B. Identification of unique essential proteins from a Mycobacterium tuberculosis F15/LAM4/KZN phage secretome library. Pathog Dis. 2017;75(1):ftx001. https://doi.org/10.1093/femspd/ftx001.
Mycobrowser Database. Gene Rv2873 (mpb83) in Mycobacterium tuberculosis H37Rv. 2022. https://mycobrowser.epfl.ch/genes/Rv2873. Accessed 26 Jun 2022.
Mycobrowser Database. Gene Rv0569 in Mycobacterium tuberculosis H37Rv. 2022. https://mycobrowser.epfl.ch/genes/Rv0569. Accessed 26 Jun 2022.
Yihao D, Hongyun H, Maodan T. Latency-associated protein Rv2660c of Mycobacterium tuberculosis augments expression of proinflammatory cytokines in human macrophages by interacting with TLR2. Infect Dis (Lond). 2015;47(3):168–77. Epub 2015 Jan 23. https://doi.org/10.3109/00365548.2014.982167.
Mycobrowser Database. Gene Rv0169 (mce1) in Mycobacterium tuberculosis H37Rv. https://mycobrowser.epfl.ch/genes/Rv0169. Accessed 26 Jun 2022.
Mycobrowser Database. Gene Rv3490 in Mycobacterium tuberculosis H37Rv. https://mycobrowser.epfl.ch/genes/Rv3490. Accessed 26 Jun 2022.
Mycobrowser Database. Gene Rv1085c in Mycobacterium tuberculosis H37Rv. https://mycobrowser.epfl.ch/genes/Rv1085c. Accessed 26 Jun 2022.
Mycobrowser Database. Gene Rv0563 in Mycobacterium tuberculosis H37Rv. https://mycobrowser.epfl.ch/genes/Rv0563. Accessed 26 Jun 2022.
Mycobrowser Database. Gene Rv3497c in Mycobacterium tuberculosis H37Rv. https://mycobrowser.epfl.ch/genes/Rv3497c. Accessed 26 Jun 2022.
Sulman S, Shahid S, Khaliq A, Ambreen A, Khan IH, Cooper AM, Akhtar MW. Enhanced serodiagnostic potential of a fusion molecule consisting of Rv1793, Rv2628 and a truncated Rv2608 of Mycobacterium tuberculosis. PLoS One. 2021;16(11):e0258389. PMID: 34767571; PMCID: PMC8589213. https://doi.org/10.1371/journal.pone.0258389.
Mycobrowser Database. Gene Rv2608 in Mycobacterium tuberculosis H37Rv. 2022. https://mycobrowser.epfl.ch/genes/Rv2608. Accessed 26 Jun 2022.
Mustafa AS. Early secreted antigenic target of 6 kda-like proteins of Mycobacterium tuberculosis: diagnostic and vaccine relevance. Int J Mycobacteriol. 2022;11(1):10–5. https://doi.org/10.4103/ijmy.ijmy_232_20.
Liu L, Zhang WJ, Zheng J, Fu H, Chen Q, Zhang Z, Chen X, Zhou B, Feng L, Liu H, et al. Exploration of novel cellular and serological antigen biomarkers in the ORFeome of Mycobacterium tuberculosis. Mol Cell Proteomics. 2014;13:897–906. https://doi.org/10.1074/mcp.M113.032623.
Safar HA, Mustafa AS, El-Hashim A, Amody H. The effect of delivery systems on the induction of T helper 1 cell response to an ESAT6-like protein Rv3619c and identification of its immunodominant peptides. Med Princ Pract. 2022;31(4):359–67.
Ong E, He Y, Yang Z. Epitope promiscuity and population coverage of Mycobacterium tuberculosis protein antigens in current subunit vaccines under development. Infect Genet Evol. 2020;80:104186. https://doi.org/10.1016/j.meegid.2020.104186.
Hanif SN, Al-Attiyah R, Mustafa AS. Species-specific antigenic Mycobacterium tuberculosis proteins tested by delayed-type hypersensitivity response. Int J Tuberc Lung Dis. 2010;14(4):489–94.
Kim A, Hur YG, Gu S, Cho SN. Protective vaccine efficacy of the complete form of PPE39 protein from Mycobacterium tuberculosis Beijing/K strain in mice. Clin Vaccine Immunol. 2014;24:e00219–7. https://doi.org/10.1128/cvi.00219-17.
Mustafa AS, Al-Attiyah R, Hanif SN, Shaban FA. Efficient testing of large pools of Mycobacterium tuberculosis RD1 peptides and identification of major antigens and immunodominant peptides recognized by human Th1 cells. Clin Vaccine Immunol. 2008;15(6):916–24. Epub 2008 Apr 9. PMID: 18400977; PMCID: PMC2446621. https://doi.org/10.1128/CVI.00056-08.
Al-Attiyah R, Mustafa AS, Abal AT, El-Shamy AS, Dalemans W, Skeiky YA. In vitro cellular immune responses to complex and newly defined recombinant antigens of Mycobacterium tuberculosis. Clin Exp Immunol. 2004;138(1):139–44. PMID: 15373916; PMCID: PMC1809193. https://doi.org/10.1111/j.1365-2249.2004.02609.x.
Mustafa AS. Th1 cell reactivity and HLA-DR binding prediction for promiscuous recognition of MPT63 (Rv1926c), a major secreted protein of Mycobacterium tuberculosis. Scand J Immunol. 2009;69(3):213–22. https://doi.org/10.1111/j.1365-3083.2008.02221.x.
Al-Attiyah R, Mustafa AS. Computer-assisted prediction of HLA-DR binding and experimental analysis for human promiscuous Th1-cell peptides in the 24 kDa secreted lipoprotein (LppX) of Mycobacterium tuberculosis. Scand J Immunol. 2004;59(1):16–24. PMID: 14723617. https://doi.org/10.1111/j.0300-9475.2004.01349.x.
Mustafa AS. HLA-promiscuous Th1-cell reactivity of MPT64 (Rv1980c), a major secreted antigen of Mycobacterium tuberculosis, in healthy subjects. Med Princ Pract. 2009;18(5):385–92. Epub 2009 Jul 31. https://doi.org/10.1159/000226293.
Mustafa AS, Shaban F. Mapping of Th1-cell epitope regions of Mycobacterium tuberculosis protein MPT64 (Rv1980c) using synthetic peptides and T-cell lines from M. tuberculosis-infected healthy humans. Med Princ Pract. 2010;19(2):122–8. Epub 2010 Feb 4. PMID: 20134175. https://doi.org/10.1159/000273073.
Hanafiah KM, Arifin N, Sanders PR, Othman N, Garcia ML, Anderson DA. Proteomic analysis of antigen 60 complex of M. bovis bacillus calmette-Guérin reveals presence of extracellular vesicle proteins and predicted functional interactions. Vaccine. 2019;7:80. https://doi.org/10.3390/vaccines7030080.
Kanaparthi KJ, Afroz S, Minhas G, Moitra A, Khan RA, Medikonda J, Naz S, Cholleti SN, Banerjee S, Khan N. Immunogenic profiling of Mycobacterium tuberculosis DosR protein Rv0569 reveals its ability to switch on Th1 based immunity. Immunol Lett. 2022;242:27–36. Epub 2022 Jan 7. PMID: 35007662. https://doi.org/10.1016/j.imlet.2022.01.001.
Moguche AO, Musvosvi M, Penn-Nicholson A, Plumlee CR, Mearns H, Geldenhuys H, Smit E, Abrahams D, Rozot V, Dintwe O, et al. Antigen availability shapes T cell differentiation and function during tuberculosis. Cell Host Microbe. 2017;21:695–706. https://doi.org/10.1016/j.chom.2017.05.012.
Marasini N, Kaminskas LM. Subunit-based mucosal vaccine delivery systems for pulmonary delivery—are they feasible? Drug Dev Ind Pharm. 2019;45:882–94. https://doi.org/10.1080/03639045.2019.1583758.
Madan R, Pandit K, Bhati L, Kumar H, Kumari N, Singh S. Mining the Mycobacterium tuberculosis proteome for identification of potential T-cell epitope based vaccine candidates. Microb Pathog. 2021;157:104996. Epub 2021 May 24. PMID: 34044044. https://doi.org/10.1016/j.micpath.2021.104996.
Mustafa AS. Adjuvants and antigen-delivery systems for subunit vaccines against tuberculosis. Vaccines (Basel). 2021;9(9):972. PMID: 34579209; PMCID: PMC8472090. https://doi.org/10.3390/vaccines9090972.
Qi Y, Fox CB. A two-step orthogonal chromatographic process for purifying the molecular adjuvant QS-21 with high purity and yield. J Chromatogr A. 2021;1635:461705. Epub 2020 Nov 13. PMID: 33234294; PMCID: PMC7770036. https://doi.org/10.1016/j.chroma.2020.461705.
Baldwin SL, Reese VA, Larsen SE, Beebe E, Guderian J, Orr MT, Fox CB, Reed SG, Coler RN. Prophylactic efficacy against Mycobacterium tuberculosis using ID93 and lipid-based adjuvant formulations in the mouse model. PLoS One. 2021;16(3):e0247990. PMID: 33705411; PMCID: PMC7951850. https://doi.org/10.1371/journal.pone.0247990.
Aboutorabian S, Hakimi J, Boudet F, Montano S, Dookie A, Roque C, Ausar SF, Rahman N, Brookes RH. A high ratio of IC31(®) adjuvant to antigen is necessary for H4 TB vaccine immunomodulation. Hum Vaccin Immunother. 2015;11(6):1449–55. PMID: 25997147; PMCID: PMC4514381. https://doi.org/10.1080/21645515.2015.1023970.
Hill DL, Pierson W, Bolland DJ, Mkindi C, Carr EJ, Wang J, Houard S, Wingett SW, Audran R, Wallin EF, Jongo SA, Kamaka K, Zand M, Spertini F, Daubenberger C, Corcoran AE, Linterman MA. The adjuvant GLA-SE promotes human Tfh cell expansion and emergence of public TCRβ clonotypes. J Exp Med. 2019;216(8):1857–73. Epub 2019 Jun 7. PMID: 31175140; PMCID: PMC6683991. https://doi.org/10.1084/jem.20190301.
Tkachuk AP, Gushchin VA, Potapov VD, Demidenko AV, Lunin VG, Gintsburg AL. Multi-subunit BCG booster vaccine GamTBvac: assessment of immunogenicity and protective efficacy in murine and Guinea pig TB models. PLoS One. 2017;12:e0176784. https://doi.org/10.1371/journal.pone.0176784.
Lu J, Guo X, Wang C, Du W, Shen X, Su C, Wu Y, Xu M. Therapeutic effect of subunit vaccine AEC/BC02 on Mycobacterium tuberculosis post-chemotherapy relapse using a latent infection murine model. Vaccines (Basel). 2022;10(5):825. PMID: 35632581; PMCID: PMC9145927. https://doi.org/10.3390/vaccines10050825.
Zheng Y, Bian L, Zhao H, Liu Y, Lu J, Liu D, Zhang K, Song Y, Luo Y, Jiang C, Chen Y, Zhang Y, Kong W. Respiratory syncytial virus F subunit vaccine with AS02 adjuvant elicits balanced, robust humoral and cellular immunity in BALB/c mice. Front Immunol. 2020;11:526965. PMID: 33013922; PMCID: PMC7516270. https://doi.org/10.3389/fimmu.2020.526965.
Agger EM, Rosenkrands I, Hansen J, Brahimi K, Vandahl BS, Aagaard C, Werninghaus K, Kirschning C, Lang R, Christensen D, Theisen M, Follmann F, Andersen P. Cationic liposomes formulated with synthetic mycobacterial cordfactor (CAF01): a versatile adjuvant for vaccines with different immunological requirements. PLoS One. 2008;3(9):e3116. PMID: 18776936; PMCID: PMC2525815. https://doi.org/10.1371/journal.pone.0003116.
Nemes E, Geldenhuys H, Rozot V, Rutkowski KT, Ratangee F, Bilek N, Mabwe S, Makhethe L, Erasmus M, Toefy A, et al. Prevention of M. tuberculosis infection with H4:IC31 vaccine or BCG revaccination. N Engl J Med. 2018;379:138–49. https://doi.org/10.1056/NEJMoa1714021.
Abubakar I, Pimpin L, Ariti C, Beynon R, Mangtani P, Sterne JA, Fine PE, Smith PG, Lipman M, Elliman D, et al. Systematic review and meta-analysis of the current evidence on the duration of protection by bacillus Calmette-Guérin vaccination against tuberculosis. Health Technol Assess. 2013;17:1–372. https://doi.org/10.3310/hta17370.
World Health Organization. BCG vaccine: WHO position paper, February 2018—recommendations. Vaccine. 2018;36:3408–10. https://doi.org/10.1016/j.vaccine.2018.03.009.
White RG, Hanekom WA, Vekemans J, Harris RC. The way forward for tuberculosis vaccines. Lancet Respir Med. 2019;7:204–6. https://doi.org/10.1016/s2213-2600(19)30040-2.
Rodo MJ, Rozot V, Nemes E, Dintwe O, Hatherill M, Little F, Scriba TJ. A comparison of antigen-specific T cell responses induced by six novel tuberculosis vaccine candidates. PLoS Pathog. 2019;15:e1007643. https://doi.org/10.1371/journal.ppat.1007643.
Tait DR, Hatherill M, Van Der Meeren O, et al. Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis. N Engl J Med. 2019;381:2429–39.
Ji Z, Jian M, Chen T, Luo L, Li L, Dai X, Bai R, Ding Z, Bi Y, Wen S, Zhou G, Abi ME, Liu A, Bao F. Immunogenicity and safety of the M72/AS01E candidate vaccine against tuberculosis: a meta-analysis. Front Immunol. 2019;10:2089. PMID: 31552037; PMCID: PMC6735267. https://doi.org/10.3389/fimmu.2019.02089.
Recombinant Vaccine. 2020. https://www.nature.com/subjects/recombinant-vaccine. Accessed May 2022.
Nascimento IP, Leite LC. Recombinant vaccines and the development of new vaccine strategies. Braz J Med Biol Res. 2012;45:1102–11. https://doi.org/10.1590/s0100-879x2012007500142.
Mustafa AS. BCG as a vector for novel recombinant vaccines against infectious diseases and cancers. Vaccines (Basel). 2020;8(4):736. PMID: 33291702; PMCID: PMC7761935. https://doi.org/10.3390/vaccines8040736.
Amoudy HA, Ebrahimi BH, Mustafa AS. Immune responses against Mycobacterium tuberculosis-specific proteins PE35 and CFP10 in mice immunized with recombinant Mycobacterium vaccae. Saudi Med J. 2014;35(4):350–9.
Amoudy HA, Safar HA, Mustafa AS. Development of Escherichia coli and Mycobacterium smegmatis recombinants expressing major Mycobacterium tuberculosis-specific antigenic proteins. Int J Mycobacteriol. 2016;5(Suppl 1):S84–5. Epub 2016 Nov 25. https://doi.org/10.1016/j.ijmyco.2016.10.033.
Da Costa AC, Nogueira SV, Kipnis A, Junqueira-Kipnis AP, Recombinant BCG. Innovations on an old vaccine scope of BCG strains and strategies to improve long-lasting memory. Front Immunol. 2014;5:152. https://doi.org/10.3389/fimmu.2014.00152.
Kilpeläinen A, Saubi N, Guitart N, Olvera A, Hanke T, Brander C, Joseph J. Recombinant BCG expressing HTI prime and recombinant ChAdOx1 boost is safe and elicits HIV-1-specific T-cell responses in BALB/c mice. Vaccine. 2019;7:78. https://doi.org/10.3390/vaccines7030078.
Mancha-Agresti P, de Castro CP, Dos Santos J, Araujo MA, Pereira VB, LeBlanc JG, Leclercq SY, Azevedo V. Recombinant invasive Lactococcus lactis carrying a DNA vaccine coding the Ag85A antigen increases IFN-γ, IL-6, and TNF-Α-α cytokines after intranasal immunization. Front Microbiol. 2017;8:1263. https://doi.org/10.3389/fmicb.2017.01263.
Kaushik A, Ammerman NC, Tyagi S, Saini V, Vervoort I, Lachau-Durand S, Nuermberger E, Andries K. Activity of a long-acting injectable bedaquiline formulation in a paucibacillary mouse model of latent tuberculosis infection. Antimicrob Agents Chemother. 2019;63:e00007–19. https://doi.org/10.1128/aac.00007-19.
Arregui S, Sanz J, Marinova D, MartÃn C, Moreno Y. On the impact of masking and blocking hypotheses for measuring the efficacy of new tuberculosis vaccines. Peer J. 2016;4:e1513. https://doi.org/10.7717/peerj.1513.
Mustafa AS. Plasmid DNA and mycobacteria as antigen delivery systems for Mycobacterium tuberculosis-specific antigens. In: Gupta SK, Lohiya NK, editors. Chapter in molecular medicine: bench to bedside and beyond. Indian Society for the Study of Reproduction and Fertility, University of Rajasthan, Jaipur; 2018. p. 244–52.
Mustafa AS. Mycobacterial gene cloning and expression, comparative genomics, bioinformatics and proteomics in relation to the development of new vaccines and diagnostic reagents. Med Princ Pract. 2005;14:27–34. https://doi.org/10.1159/000086182.
Mustafa AS. Development of new vaccines and diagnostic reagents against tuberculosis. Mol Immunol. 2002;39:113–9.
Mustafa AS, Al-Attiyah R, Hanif SN, Shaban FA. Efficient testing of large pools of Mycobacterium tuberculosis RD1 peptides and identification of major antigens and immunodominant peptides recognized by human Th1 cells. Clin Vaccine Immunol. 2008;15:916–24. https://doi.org/10.1128/CVI.00056-08.
Mustafa AS. In silico analysis and experimental validation of Mycobacterium tuberculosis-specific proteins and peptides of Mycobacterium tuberculosis for immunological diagnosis and vaccine development. Med Princ Pract. 2013;22:43–51. https://doi.org/10.1159/000354206.
Hanif SNM, Al-Attiyah R, Mustafa AS. DNA vaccine constructs expressing Mycobacterium tuberculosis-specific genes induce immune responses. Scand J Immunol. 2010;72:408–15. https://doi.org/10.1111/j.1365-3083.2010.02452.x.
Hanif SN, Al-Attiyah R, Mustafa AS. Cellular immune responses in mice induced by M. tuberculosis PE35-DNA vaccine construct. Scand J Immunol. 2011;74:554–60. https://doi.org/10.1111/j.1365-3083.2011.02604.x.
Shaban K, Amoudy HA, Mustafa AS. Cellular immune responses to recombinant Mycobacterium bovis BCG constructs expressing major antigens of region of difference 1 of Mycobacterium tuberculosis. Clin Vaccine Immunol. 2013;20:1230–7. https://doi.org/10.1128/CVI.00090-12.
Amoudy HA, Ebrahimi BH, Mustafa AS. Immune responses against Mycobacterium tuberculosis-specific proteins PE35 and CFP10 in mice immunized with recombinant Mycobacterium vaccae. Saudi Med J. 2014;35:350–9.
Safar HA, Mustafa AS, Amoudy HA, El-Hashim A. The effect of adjuvants and delivery systems on Th1, Th2, Th17 and Treg cytokine responses in mice immunized with Mycobacterium tuberculosis-specific proteins. PLoS One. 2020;15:e0228381. https://doi.org/10.1371/journal.pone.0228381.
Hanif SNM, Mustafa AS. Humoral immune responses in mice immunized with region of difference DNA vaccine constructs of pUMVC6 and pUMVC7. Int J Mycobacteriol. 2017;6(3):281–8. https://doi.org/10.4103/ijmy.ijmy_98_17.
Ansari MA, Zubair S, Mahmood A, Gupta P, Khan AA, Gupta UD, Arora A, Owais M. RD antigen based nanovaccine imparts long term protection by inducing memory response against experimental murine tuberculosis. PLoS One. 2011;6:e22889. https://doi.org/10.1371/journal.pone.0022889.
Wang C, Lu J, Du W, Wang G, Li X, Shen X, Su C, Yang L, Chen B, Wang J, et al. Ag85b/ESAT6-CFP10 adjuvanted with aluminum/poly-IC effectively protects Guinea pigs from latent Mycobacterium tuberculosis infection. Vaccine. 2019;37:4477–84. https://doi.org/10.1016/j.vaccine.2019.06.078.
Vasina DV, Kleymenov DA, Manuylov VA, Mazunina EP, Koptev EY, Tukhovskaya EA, Murashev AN, Gintsburg AL, Gushchin VA, Tkachuk AP. First-in-human trials of GamTBvac, a recombinant subunit tuberculosis vaccine candidate: safety and immunogenicity assessment. Vaccine. 2019;7:166. https://doi.org/10.3390/vaccines7040166.
Tkachuk AP, Bykonia EN, Popova LI, Kleymenov DA, Semashko MA, Chulanov VP, Fitilev SB, Maksimov SL, Smolyarchuk EA, Manuylov VA, Vasina DV, Gushchin VA, Gintsburg AL. Safety and immunogenicity of the GamTBvac, the recombinant subunit tuberculosis vaccine candidate: a phase II, multi-center, double-blind, randomized, placebo-controlled study. Vaccines (Basel). 2020;8(4):652. PMID: 33153191; PMCID: PMC7712213. https://doi.org/10.3390/vaccines8040652.
Pereira VB, Saraiva TD, Souza BM, Zurita-Turk M, Azevedo MS, De Castro CP, Mancha-Agresti P, Dos Santos JS, Santos AC, Faria AM, et al. Development of a new DNA vaccine based on mycobacterial ESAT-6 antigen delivered by recombinant invasive Lactococcus lactis FnBPA+. Appl Microbiol Biotechnol. 2015;99:1817–26. https://doi.org/10.1007/s00253-014-6285-3.
de Castro CP, Souza BM, Mancha-Agresti P, Pereira VB, Zurita-Turk M, Preisser TM, da Cunha VP, Dos Santos JSC, Leclercq SY, Azevedo V, Miyoshi A. Lactococcus lactis FNBPA+ (pValac:e6ag85a) induces cellular and humoral immune responses after oral immunization of mice. Front Microbiol. 2021;12:676172. PMID: 34093498; PMCID: PMC8173160. https://doi.org/10.3389/fmicb.2021.676172.
Gupta N, Vedi S, Kunimoto DY, Agrawal B, Kumar R. Novel lipopeptides of ESAT-6 induce strong protective immunity against Mycobacterium tuberculosis: routes of immunization and TLR agonists critically impact vaccine’s efficacy. Vaccine. 2016;34:5677–88. https://doi.org/10.1016/j.vaccine.2016.08.075.
Hoft DF, Xia M, Zhang GL, Blazevic A, Tennant J, Kaplan C, Matuschak G, Dube TJ, Hill H, Schlesinger LS, et al. PO and ID BCG vaccination in humans induce distinct mucosal and systemic immune responses and CD4+ T cell transcriptomal molecular signatures. Mucosal Immunol. 2018;11:486–95. https://doi.org/10.1038/mi.2017.67.
Barclay WR, Busey WM, Dalgard DW, Good RC, Janicki BW, Kasik JE, Ribi E, Ulrich CE, Wolinsky E. Protection of monkeys against airborne tuberculosis by aerosol vaccination with bacillus Calmette-Guerin. Am Rev Respir Dis. 1973;107:351–8. https://doi.org/10.1128/iai.2.5.574-582.1970.
Anacker RL, Brehmer W, Barclay WR, Leif WR, Ribi E, Simmons JH, Smith AW. Superiority of intravenously administered BCG and BCG cell walls in protecting rhesus monkeys (Macaca mulatta) against airborne tuberculosis. Z Immunitatsforsch Exp Klin Immunol. 1972;1:363–76. PMID: 4282920.
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Whitlow, E., Mustafa, A.S., Hanif, S.N.M. (2023). Progress in the Development of New Vaccines Against Tuberculosis. In: Christodoulides, M. (eds) Vaccines for Neglected Pathogens: Strategies, Achievements and Challenges . Springer, Cham. https://doi.org/10.1007/978-3-031-24355-4_10
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