Human T-cell lymphotropic virus type 1 (HTLV-1) proposed vaccines ... - BMC Infectious Diseases
Characteristics of included studies
Based on our search, we retrieved 1700 citations. After removing duplicates, a total of 1250 articles were screened based on title and abstract. Furthermore, the hand-searching of other studies revealed 7 studies that met the inclusion criteria and were included after assessing their full texts. Overall, 47 articles were included in this systematic review Most of the included studies investigated the role of protein-based vaccines in developing the HTLV-1 vaccine [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75].
Peptide and protein vaccines
Peptid vaccines were investigated in 26 studies including 16 in-vivo, 3 in-vitro, 2 in-vivo/in-vitro and 5 in-silico studies. All in-vivo studies were animal model with animals such as mouse, rat, rabbit, and monkey. The major protein vaccine constructs assessed in these studies were comprised of Tax peptide in 15 studies [41, 44, 47,48,49, 51, 54,55,56, 63, 64, 66, 67, 73,74,75], Glycoprotein peptide (GP) in 9 studies [33, 35, 38, 48, 49, 58, 66, 72, 75], GAG peptide in 5 studies [47,48,49, 63, 66], POL peptide in 3 studies [47, 63, 66], REX and HBZ peptides each one in 1 study, respectively [47, 63].
Lairmore et al. examined inoculation of chimeric B- and T-cell epitopes of HTLV-1 env-gp46 (SP2 and SP4a) with promiscuous T-cell epitopes (from tetanus toxin and MVF protein) in mice and rabbits. They showed connecting viral peptides with promiscuous epitopes promoted specific helper T-cell responses. MVF-SP2 and SP4a-MVF constructs were efficient to overcome genetic-restricted immunity [58]. Vaccination with T and B cell epitope-based peptide constructed from the conjugation of gp46 (aa 181–210) with a branched polylysine oligomer was examined in rats and rabbits and demonstrated high HTLV-I neutralizing Abs levels. Moreover, the proliferation of T lymphocytes derived from HAM/TSP, ATLL, and asymptomatic carriers was revealed in response to construction including aa194-210 [35].
Sundaram et al. found a multivalent vaccine constructed of three HLA-A ∗ 0201 restricted CTL epitopes (Tax11–19, Tax178–186, and Tax233–241, the numbers after Tax relate to amino acids) that induced cellular immunity in HLA-A ∗ 0201 transgenic mice. Splenocyte lysis response was elicited by Tax11–19 (32%), Tax178–186 (34%), and Tax233–241 (≈6%) epitopes. Results demonstrated that Tax11–19 and Tax178–186 epitopes invoked significant CTL response and IFN-γ release in HHD mice (NSG-HLA-A2/ HHD mutant immunodeficient mice). However, Tax233–241 epitopes elicited IFN-γ release but not a significant CTL response [74]. In another study, they found vaccination chimeric constructs of B-cell epitopes derived from HTLV-1-gp21 in mice and rabbits induced neutralizing antibody response, and inhibition of syncytia formation and virus-mediated cell fusion [72]. Sundaram et al. [73] investigated epitope orientation effects in another study. CTL epitopes Tax11–19 (no. 2), Tax178–186 (no. 3), and Tax306–315 (no. 6) were used to construct 4 multiepitope vaccines with different orientations (construct 236, 632, 326, and 362). IFN-γ release and CTL response investigations demonstrated construct 236 as the most efficient, followed by construct632, against construct362 and 326. Immunity of construct 236 in mice challenging with the HTLV-1 Tax recombinant vaccinia virus showed significant viral load reduction dependent on indicated increased generation of CD8 + T-cell. splenocyte cytolytic response was shown via killing of p40-VV–infected targets by Tax (11-19)- and Tax (178–186)-stimulated splenocytes of 236 immunized mice, against no response from Tax (306–315)-stimulated splenocytes. In-vitro IFN-γ secretion was found highest in Tax (178–186)-stimulated splenocytes (670 pg/mL), followed by Tax (11–19) and Tax (306–315)- stimulated splenocytes (298 and 147 pg/mL, correspondingly) [73]. Immunogenicity investigations of another vaccine comprising three HLA-A*0201-restricted CTL epitopes derived from Tax protein (Tri-Tax) and B-cell env epitope (aa 175–218), showed antibody release against immunogen MVF–175–218 and B-cell epitope in 2/2 of squirrel monkeys. Furthermore, IFN-γ producing cell investigations resulted in three- to sevenfold increase in 2/2 immunized monkeys compared to control monkeys (0/2). Their investigations on mice challenged with HTLV-1-transformed cell lines showed proviral load reduction and strong cell-mediated response as the response [51].
Another study found a novel multi-immunodominant vaccine. The vaccine constructed of sequences of HTLV-1-Tax epitope (11–19 and 178–186) and SP2 and P21 with His-tag or mouse-Fcγ2a fusion (Tax-Env: His and Tax-Env: mFcγ2a, respectively) was examined in BALB/c mice challenging with HTLV-1-MT2 cell line by Shafifar et al. [67]. Higher IFN-γ and IL-12 secretion in "Tax-Env: mFcγ2a" and Higher IL-4 level in "Tax-Env: His" group was indicated, compared to the other group. IFN-γ, IL-12 in the Fc-fusion construct group, and IL-4 levels in the His-tag protein group were negatively correlated to proviral load. "Tax-Env: mFcγ2a" and "Tax-Env: His" demonstrated more Th1 and Th2 immune responses, respectively. They found both constructs with a 50% low proviral load of HTLV-1 and 50% complete protection in challenged mice [67].
In-vivo vaccination regimen of priming with recombinant vaccinia virus expressing whole HTLV-I envelope (gp46 and gp21) or just gp46 as a surface env protein with boosting of entire HTLV-I envelope gene, expressed in a baculovirus non-fusion vector system, demonstrated enhanced anti-env-antibody production. Neutralizing antibody level increment was shown in response to priming with recombinant vaccinia virus expressing only gp46 or with an admission of an adjuvant constructed out of mycobacterial cell wall extract [33].
Encapsulated vaccines and vaccines with adjuvant
Eight studies investigated if adjuvants or encapsulation particles differed in the immune response to HTLV-1 vaccine constructs [30, 38, 39, 48, 49, 55, 56, 66]. PLGA (D, L-lactide-co-glycolide) encapsulation of an HTLV-1 vaccine construct demonstrated high cell-mediated and mucosal immunity [48, 49] and immunization without requiring any boosts and adjuvants, compared with free peptide vaccination [38, 39].
Frangione-Beebe et al. examined a vaccine (MVFMF2) comprising HTLV-1-gp46 (aa 175–218) linked by GPSL turn to MVF (aa 288–302). They demonstrated antibody response in mice and rabbits in the admission of N-acetyl glucosamine-3yl-acetyl-L-alanyl-D-isoglutamine (nor-MDP) adjuvant. They found promoted immunogenicity of MVFMF2 in PLGA-encapsulated form without the need for boosting and adjuvant. Anti-MVFMF2 antibodies, predominantly IgG2 (IgG2a, IgG2b) in mice, recognized HTLV- envelope protein in rabbits (n = 10 out of 12) and mice (n = 9 out of 9). Enhanced reactivity to viral antigens, viral-mediated fusion inhibition, and whole viral preparations recognition were revealed. Interestingly, the construct was not protective efficiently against cell-associated viral challenges in rabbits [38]. Kabiri et al. demonstrated the chimera multiepitope vaccination comprising HTLV-1 Tax, gp21, gp46, and gag (p19) epitopes with PLGA NPs with/without CPG oligodeoxynucleotides (ODN) elevated levels of IgG2a, mucosal IgA, IFN-γ, and IL-10 and decrease in TGF-β1 level in inoculated mice. IgG2a and IgG1 levels didn't have a significant difference in nasal and subcutaneous (SC) deliveries, but IgA level was higher in nasal administration [49]. ISCOMATRIX adjuvant admission demonstrated an increased immune response, compared to monophosphoryl lipid A adjuvant [48]. In line with the previous study [49], intranasal delivery elicited a high mucosal response compared to SC injection inducing a strong cellular-mediated response [48].
Moreover, chitosan (CHT) and trimethyl chitosan (TMC) nanoparticles demonstrated good immunoadjuvant potential in admission with a vaccine comprising env23 and env13, recombinant proteins of gp46. IgG1 and IgG total levels were demonstrated higher than antigen levels in SC injection. IgG2a titer and IgG2a/IgG1 ratio were significantly higher due to nasal delivery of env23 than SC injection. Env23 induced more potent cell-mediated immunity compared with env13 [30].
Furthermore, Schönbach et al. [66] investigated a vaccine comprised of HLA-B*3501 binding HTLV-1-peptides with the admission of C-Ser-(Lys)4 adjuvant. They found seven peptides derived from env-gp46, pol, gag-p19, and tax proteins invoked specific CTL responses in HLA-B*3501 transgenic mice. However, adjuvant-stimulated bulk cultures didn't show a specific CTL response.
Immunization with HLA-A*0201-restricted HTLV-1 Tax-epitope encapsulated with oligomannose-coated liposomes (OML⁄Tax) induced HTLV-1-specific CTL and IFN-γ responses, against no IFN-γ release in only peptide epitope inoculation. Moreover, dendritic cell 48 h exposure to 1 µg/ml of OML⁄Tax invoked increased CD86, MHC-I, MHC-ll, and HLA-A02 expression, in comparison [56].
Vaccination by chimeric peptide comprising HLA-A*0201-restricted HTLV1 Tax-epitope/hepatitis B virus core (HBc) particle induced HTLV-1-specific CD8 + T-cells, antigen-specific IFN-γ reaction, and anti-HBc IgG level in HLA-A*0201-transgenic mice, against only peptide inoculation. Dendritic cell 48 h-exposure to HTLV-1/HBc chimeric particle resulted in CD86, HLA-A02 and TLR4 increased expression in a dose-dependent manner [55].
Totally, studies showed nor-MDP, PLGA, ISCOMATRIX, oligomannose-coated liposomes, chitosan and trimethyl chitosan promoted immunogenicity of vaccines, in comparision with the constructs without adjuvants. However C-Ser-(Lys)4 adjuvant didn't show a specific CTL response.
Vaccines with anti-tumoral effects4 studies in design of in-vivo and in-vitro assessed tumor suppression/regression of their vaccines [41, 44, 53, 54]. Two in-vivo studies used mice and rats in their animal model. Tumor suppression was investigated in a study by Hanabuchi et al. [44]. They examined HTLV-I-infected T-cell line (FPM1-V1AX) inoculated rats. FPM1-V1AX inoculated rats (n = 2) vaccinated with a construct of Tax 180–188 and ISS-ODN adjuvant and showed tumor suppression elicited T cell immunity compared to the control group (n = 2). Moreover, in vivo inoculation of CTLs specific to Tax 180–188 (as a dominant recognized epitope) demonstrated tumor suppression (n = 2), too. Interestingly, equal antitumor effects of CD4 + and CD8 + T Cells were shown in this study as unfractionated T cells.
Furthermore, Fujisawa et al. reported 2 leukemia survival in 5 Tax-peptide vaccinated infected hu-NOG mice with restricted number and growth of infected T cells. Vaccination before infection elicited IL-12 release and Tax-specific CD8 T-cell induction [41]. Helper T lymphocytes (HTLs) reactive with Tax191–205 and Tax305–319 recognized HTLV-1 Tax–expressing T-cell lymphoma cell lines specifically, against Tax152–166 reactive HTLs, in an in-vitro study. This revealed that HTLV-1 + T-cell lymphoma cells naturally expressed these two epitopes on their surface by MHC-ll. Moreover, investigations demonstrated the natural process of these two epitopes by dendritic cells as APCs, pulsed with HTLV-1Tax + tumor lysates [54]. Kobayashi et al. [53] demonstrated an HLA-DR-bound envelope peptide similar to a fragment of human interleukin-9 receptor alpha (IL-9Ra) as an antigen associated with T-cell leukemia/lymphoma. In-vitro investigations demonstrated the induction of specific CD4 helper T lymphocytes, restricted by HLA-DR15 or HLA-DR53, in response to this synthetic peptide. These specific CD4 CTLs recognized and lysed HTLV-1 + , IL-9Ra + T cell lymphoma cells [53]. Furthermore, in-vivo assessment of MHC-I-bound HTLV-1 peptides demonstrated specific CD8 + T cell generation. IFN-γ, IL-10, perforin, MIP-1α, TNF-α, and granzyme B release from specific CD8 + T cells was shown in in-vitro investigations in the presence of MT-2 cell line [60].
Totally, these studies showed tumor suppression and leukemia survival. Main effective epitopes were found Tax 180–188 (with ISS-ODN adjuvant) [44], Tax191–205 and Tax305–319 [41] in these studies. One of the studies showed an HLA-DR-bound envelope peptide similar to a fragment of IL-9Ra as an antigen associated with T-cell leukemia/lymphoma [53].
In-silico investigations
Investigation of designing possible Multi-Epitope Based Vaccine (MEBV) is an important progress in vaccinology as they can evoke both humoral- and cell-mediated immunity [76, 77]. Previous studies predicted engineered multiepitope-based vaccines against HTLV-1 by methodology evaluations such as B- and T-cell epitope prediction, primary, secondary, tertiary, and 3D structures modeling, antigenicity, allergenicity, and solubility prediction, homology modeling, in silico estimation and cloning, molecular dynamics stimulation, and population protection coverage calculations. These studies selected non-toxic and antigenic epitopes to construct vaccines. Antigenicity score of multiepitope vaccines in 4 studies were 0.7840 [75], 0.57 [64], 0.694 [63], and 0.4885 [47] ( at threshold = 0.5, 0.4, 0.4, and 0.4, respectively).
Tariq et al. [75] constructed a 382 amino-acid non-allergenic and non-toxic vaccine from Accessory Protein p12I, gp62, and Protein TAX-1 by selecting Cytotoxic T Lymphocytes, Helper T lymphocyte, and B cell epitopes. One of the criteria of epitopes was generating IFN-γ response. They revealed this construction had no or minimal (< 37%) homology with human proteome. In-silico estimation of the vaccine demonstrated robust IgM, IgG1, IgG2 production and cytokine and interleukin response, and positive expression of the desired protein in silico-cloning. Worldwide population coverage was revealed 95.8% with the highest coverage in India (98%), Unites States (97.14%), and Mexico (95.95%). They revealed a high binding affinity for TLR3 with a binding score of 63.8 kcal/mol and a total of 16 H-bond interactions [75]. Another vaccine predicting HTLV-1 TAX multiepitope protein constructed from CTL and B cell epitopes, Comprises 109 amino acids. All components were found non-toxic but just 3 CTL epitopes were found non-allergenic. Maximum population coverage was revealed in Mexico (90.21%), England (89.88%), and South Africa (81.56%). Strong spontaneous bindings with TLR4 and interactions of T cell epitopes with HLA-A*0201 were indicated [64]. In line with the previous study, A 808 amino-acid vaccine showed interactions with the HLA-A0201. Interactions with HLA-A0701 and HLA-A0301 receptors were demonstrated, too. The vaccine was constructed out of B‐cell, CTL, and HTL epitopes for GAG, POL, ENV, P12, P13, P30, REX, and TAX proteins. The construct was revealed probably be antigenic and non-allergenic. In silico cloning showed expression efficacy. Same as Tariq et al. [75] study Strong interaction was shown with TLR-3 [63]. Moreover, Eight B-cell and T lymphocyte epitopes were selected for 5 proteins including Gag (301–350, 217–205), Tax (142–249), Env (124–209, 354–486), Pol (155–215, 309–409), and Hbz (26–109) proteins to construct 686 amino-acid vaccines. The vaccine was investigated and found immunogenic and non-allergenic. In silico investigations indicated IgM production in initial response and IgG1, IgG2, IgG, and B cell increase in secondary response. The level of cytokines and interleukins, the population of helper and cytotoxic T lymphocytes, macrophages, and dendritic cell production were increased in response. In silico cloning, results demonstrated desired protein expression. The docking analysis demonstrated strong interaction with immune receptors, especially the HLAA*02:01 receptor [47].
Alam et al. [29] predicted 14 epitopes for a vaccine targeting Glycoprotein 62. They found strong interactions of ALQTGITLV and VPSSSTPL epitopes with HLA-A*02:03, and HLA-B*35:01, respectively. Worldwide population coverage was estimated at nearly 70%, less than Tariq et al. [75] and Raza et al. [64] study constructs. The highest coverage in West Africa (87.54%) and Europe (85.87%) was demonstrated [29]. Full characteristics of the studies are available in Table 1.
DNA vaccines
All DNA plasmid vaccines in this literature review were in-vivo animal studies (Table 2). Armand et al., 2000 [32] compared two plasmid vaccines containing the whole HTLV-I envelope gene under the control of the CMV promoter (CMVenv or CMVenvLTR) and human desmin muscle-specific promoter (DesEnv). DesEnv inoculation demonstrated sooner and higher anti-envelope antibody response, compared with CMVenv/LTR vaccination. Consistent with this study, Grange et al. [42] showed single CMVenv or CMVenvLTR could not elicit generating detectable antibody levels. However, boosting with gp62 baculovirus recombinant protein demonstrated detectable HTLV-I-env antibody levels. Kazanji et al. [50] found different results for two immunization regimens. The first regimen was the inoculation of recombinant HTLV-I-env adenovirus or naked DNA plasmid and boosting with Ad5 containing the gp46 gene or with baculovirus-derived recombinant gp46 in WKY rats. No detectable antibodies were found after this regimen compared to the second regimen, priming and boosting with HTLV-I-env gene recombinant vaccinia virus in F-344 rats. CTL response in response to the first regimen was found higher than natural in response to the first regimen, but to the same extent in rats primed with either Ad5-HTLV-I-env or the naked plasmid. There were no changes with boosting. Ohashi et al. [62] found vaccination of F344/N rats with plasmids containing wild-type Tax cDNA driven by the β-actin promoter induced Tax-specific CTLs. But in contrast, no antibody levels were detected. Nakamura et al. [61] demonstrated vaccination of 4 cynomolgus monkeys with the env gene, produced by the Escherichia coli system, elicited a specific Anti-HTLV-I-env humoral response in 2 monkeys. They showed immunity against HTLV-1 producing cell line infection in these 2 monkeys against 2 others which inoculated with low doses of vaccine construct.
Dendritic cell-based vaccine
Dendritic cell-based constructs were suggested as therapeutic vaccines that induced specific CD8-T cells [31, 65, 70] (Table 3). Sagar et al. [65] suggested Tax (11–19) epitope as a potential candidate for the DC-based anti-HTLV-1 vaccine. They reported induction of antigen-specific CD8 T cell in response to Tax (11–19) epitope in presence of dendritic cells (DCs), against no response in DC depletion in an in-vivo HLA-A2/DTR hybrid mice study. They also indicated Freund's adjuvant admission decreased TGF-β and potentiated CD8 T lymphocyte response [65]. A human clinical trial of 3 previously treated ATL patients investigated the therapeutic efficacy of Tax peptide-pulsed dendritic cells with SC injection. Specific CTL responses were elevated. Partial remission was reported in 2 patients in the first 2 months. Complete remission was seen in one of these patients. Remission status maintained 24 and 19 months after injection without requiring any additional chemotherapy. Inconsistently, the third patient showed developed progressive disease slowly, but additional chemotherapy was not needed for 14 months. The first patient showed diarrhea, fever, and dermatitis and the second and third patients showed only fever and dermatitis as not severe adverse effects [70]. Proviral load reduction and Tax-specific CD8 + T cells induction was demonstrated in response to Tax-specific CTL epitope–pulsed DC immunotherapy in infected mice by Ando et al. [31].
Recombinant vaccinia virus
The use of vaccinia virus as a tool for developing vaccines is evident in literature [78]. Previous studies supported the use of this technique to develop vaccines against influenza virus [79], parainfluenza virus [80], and human immunodeficiency virus type 1 (HIV-l) [81]. Regarding HTLV-1, our search identified 8 studies which used vaccinia virus to develop HTLV-1 vaacine [34, 36, 43, 45, 52, 68, 69, 71, 82]. Except three [52, 71, 82], all studies were conducted before 2000 [34, 36, 43, 45, 68, 69]. One of the studies were an in-vitro study performed by Arp et al. [34] and was aimed to express HTLV-1 gp46 envelope protein in a vaccinia virus. All remaining studies were animal studies performed on rabbits [43, 68, 69], mice [36, 71], and monkeys [45, 71]. The most recent study by Sugata et al. showed using a recombinant vaccinia virus (rVV) vaccine expressing HTLV-1 basic leucine zipper (bZIP) factor (HBZ) or Tax induced specific T-cell responses to HBZ and Tax in HTLV-1–infected monkeys [71]. They proposed HBZ157-176 as a candidate peptide for future vaccine developments for this virus while high level of HBZ-specific CTLs were noticeable after inoculation. Two reports by Shida et al. were mainly focused on finding a new site in vaccinia virus for insertion of foreign genes such as HTLV-1 envelope gene [69] and proposing LC16mO as a potential vector [68]. Use of WR-SFB5env constructed vaccine was accompanied by a noticeable immune response. Antibody titers were still recognizable after 2.6 years following the infection [45]. However, these results were in contrast with those published by Hakoda et al. [43]. Compared with controls, rabbits which received WR-SFB5env constructed vaccine were became infected again after receiving an infected HTLV-1 blood (3 out of 3 in control and 2 out of 3 in WR-SFB5env group). In the study by Ford et al. three different construction were developed for assessing the efficacy of rVV vaccine [36]. Depending on the sort of animals used for experiment, vaccination outcomes varied greatly [36]. A combination vaccine therapy using vaccinia virus-derived NYVAC vaccine and a DNA based vaccine has been investigated previously [52]. Administration of a DNA immunogen CMV-env-LTR before immunization with HTLV-1 gag/env NYVAC vaccine showed a full protection among all three inoculated monkeys. Therefore, they suggested live recombinant vector-based vaccine as a potential booster candidate following separate DNA vaccination, as the results showed both humoral and cell-mediated immunity were maintained at its highest level (Table 4).
Other proposed vaccines
Kuo et al. have used a recombinant surface glycoprotein (gp46) attached to the Fc region of human IgG (sRgp46-Fc), which lead to a significant rise in the antibody (Ab) response [57]. Furthermore, the results of this recombinant glycoprotein-based vaccine revealed that the majority of these antibodies recognized HTLV-1-infected cells and inhibited virus fusion to the cells. The robust antagonizing activity of Abs was mostly seen in the N-terminal region of gp46. As an important observation, strong neutrophil response to HTLV-1 infected cells were also reported. The use of attenuated poxvirus vaccine vectors (ALVAC and NYVAC) for immunization of New Zealand White rabbits were described by Franchini et al. [37]. Gp63 was the HTLV-1 envelope protein used in the vaccine construction. Two immunization was done within 1 month, and the results showed full protected rabbits after 5 months of last inoculation.
The use of ATLL patients own peripheral blood mononuclear cells (PBMC) were also suggested to have an immunogen activity against the virus through activating Tax- specific CTLs [46]. Expressing Tax antigen, IL-12, and other stimulatory molecules in a cultured environment with the presence of both HTLV-1 infected cells and the patients' PBMC leads to CD8 + Tax-specific CTL responses. These findings could recommend a future vaccine candidate through the use of these stimulated PBMCs.
In a study by Fujii et al., an anti gp46 antibody was used for a possible induction of passive immunization in two pregnant rats [40]. In their in-vitro investigation, using 5 µg/mL monoclonal antibody of rat origin (LAT-27) completely blocked HTLV-1 infection. Moreover, newborn rats of mothers with pre-infused mentioned antibodies showed complete resistance against HTLV-1 (Table 5).
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