Human T-cell lymphotropic virus type 1 (HTLV-1) proposed vaccines: a systematic review of preclinical and clinical studies
BMC Infectious Diseases volume 23, Article number: 320 (2023)
Numerous vaccination research experiments have been conducted on non-primate hosts to prevent or control HTLV-1 infection. Therefore, reviewing recent advancements for status assessment and strategic planning of future preventative actions to reduce HTLV-1 infection and its consequences would be essential.
MEDLINE, Scopus, Web of Science, and Clinicaltrials.gov were searched from each database's inception through March 27, 2022. All original articles focusing on developing an HTLV-1 vaccine candidate were included.
A total of 47 studies were included. They used a variety of approaches to develop the HTLV-1 vaccine, including DNA-based, dendritic-cell-based, peptide/protein-based, and recombinant vaccinia virus approaches. The majority of the research that was included utilized Tax, Glycoprotein (GP), GAG, POL, REX, and HBZ as their main peptides in order to develop the vaccine. The immunization used in dendritic cell-based investigations, which were more recently published, was accomplished by an activated CD-8 T-cell response. Although there hasn't been much attention lately on this form of the vaccine, the initial attempts to develop an HTLV-1 immunization depended on recombinant vaccinia virus, and the majority of results seem positive and effective for this type of vaccine. Few studies were conducted on humans. Most of the studies were experimental studies using animal models. Adenovirus, Cytomegalovirus (CMV), vaccinia, baculovirus, hepatitis B, measles, and pox were the most commonly used vectors.
This systematic review reported recent progression in the development of HTLV-1 vaccines to identify candidates with the most promising preventive and therapeutic effects.
Human T-cell lymphotropic virus type 1 (HTLV-1) is a member of the Deltaretrovirus genus. The number of infected individuals is currently estimated at approximately 5–10 million globally [1,2,3]. The main endemic areas are Japan, sub-Saharan Africa, South America, the Caribbean area, Iran, Romania, and Melanesia [4,5,6]. HTLV-1 is capable of inducing or strongly associated with several serious medical conditions such as adult T-cell leukemia/lymphoma (ATLL), HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and a variety of inflammatory processes, including uveitis and dermatitis [1, 7]. Furthermore, evidence suggests HTLV-1 links to bronchitis, Sjögren’s syndrome, rheumatoid arthritis, fibromyalgia, and ulcerative colitis . Although only 3–5% of seropositive individuals develop ATLL throughout their life, consequences can enormously impact the individual. Although there are less aggressive forms of ATLL such as the smoldering form, ATLL is frequently considered a highly aggressive poor prognosis form of non-Hodgkin's lymphoma accompanied by generalized lymphadenopathy, skin lesions, hepatosplenomegaly, and hypercalcemia. HAM/TSP characterized by an insidious onset of progressive weakness of lower limbs, urinary/bowel dysfunction, and lumbar pain affects approximately 0.25–3.7% of HTLV-1 carriers based on ethnic susceptibility [1, 9,10,11,12]. Notably, High previous load appears to be a risk factor for developing both ATL and HAM/TSP in infected HTLV-1 individuals [2, 13, 14].
Upon direct contact via cell-containing body fluids, including blood, breast milk, and semen, the transmission of HTLV-1 is possible . In addition, the main risk factors among these transmission routes include but are not limited to the exposure time (e.g., duration of breastfeeding), HTLV-1 provincial load in blood or milk, and HLA compatibility. At the molecular level, transmission is described by binding to receptors like glucose transporter 1 (Glut-1), neuropilin-1 (NRP-1), and heparan sulfate proteoglycans (HSPG) [16,17,18,19]. To raise the number of infected cells, HTLV-1 alters the immunophenotypic features of infected cells and then uses the combined action of HTLV-1 bZIP factor and Tax to inhibit apoptosis and induce proliferation .
Since the detection and isolation of HTLV-1 by Robert C. Gallo et al. in 1980 , no proven measure to cure HTLV-1 infection nor any effective therapeutic management to alter the poor prognosis of patients with ATL has been announced . Moreover, the clinical management of HAM/TSP is still challenging and particularly unsatisfactory . Additionally, underestimation of the total number of infected individuals is not improbable due to a lack of data [4, 6]. Accordingly, the implantation of preventive measures such as screening or vaccination to lessen the cumulative burden of this pathogenic agent is considered crucial [22, 23]. Currently, there are several suggested preventive measures namely antenatal screening and screening of blood and organ donors [24,25,26,27]. However, there is debate about the cost-effectiveness of these measures mainly based on the heterogeneity of endemicity of infection in different geographical areas [22, 28]. The production of an efficacious safe vaccine would prevent the transmission of HTLV-1 and in case of a reduction in proviral load in infected individuals can even lead to less probability to develop HTLV-1 linked diseases.
Numerous vaccine research studies including recombinant peptide or protein, naked DNA, and antibodies have been carried out, mostly on non-primate hosts. Therefore, an evaluation of recent progress in this field would be beneficial for status assessment and strategic planning of future preventive measures to diminish HTLV-1 infection and its outcomes. Taking these into consideration, we aimed to systematically review developed HTLV-1 vaccines by appraising the available literature.
This study is reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
We have searched Medline (through PubMed), Scopus, and Web of Science until March 27, 2022. The following keywords were searched to retrieve relevant studies: (((("Human T-lymphotropic virus 1"[Mesh]) OR (Human T-lymphotropic virus 1[Title/Abstract])) OR (Human T lymphotropic virus 1[Title/Abstract])) OR (HTLV*[Title/Abstract])) AND ((((("Vaccines"[Mesh]) OR (vaccines [Title/Abstract])) OR (vaccin*[Title/Abstract])))). Studies not identified by the above databases were included by evaluating the reference sections of relevant studies (A full list of search query used for each database is available in Supplementary material Table 2).
Study selection and data extraction
We have included randomized clinical trials, observational studies (cross-sectional, case–control, or cohort), case series/reports, and congress and conference abstracts as a source of grey literature. The following criteria were used as our inclusion criteria; original research articles focusing on developing a HTLV-1 vaccine candidate, whether using an experimental animal model, a human-based model, or in-vitro studies investigating HTLV-1 vaccine development. The title and abstract of the studies were assessed based on the inclusion criteria after duplicate papers were removed. Finally, a thorough screening of the full texts took place. The selection was carried out independently by the two authors. Two researchers independently extracted the following data: author, year, country, type of study, number of participants (if applicable), host, vaccine type, vaccine, construct, vaccine dose, vector, route of administration, prescribed number, adjuvant, laboratory method, and study’s main findings. A third reviewer resolved disagreements.
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 . 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 .
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 . 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 . Sundaram et al.  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) . 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 .
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. . 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 .
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 .
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 . 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 . ISCOMATRIX adjuvant admission demonstrated an increased immune response, compared to monophosphoryl lipid A adjuvant . In line with the previous study , intranasal delivery elicited a high mucosal response compared to SC injection inducing a strong cellular-mediated response .
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 .
Furthermore, Schönbach et al.  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 .
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 .
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. . 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 . 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 . Kobayashi et al.  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 . 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 .
Totally, these studies showed tumor suppression and leukemia survival. Main effective epitopes were found Tax 180–188 (with ISS-ODN adjuvant) , Tax191–205 and Tax305–319  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 .
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 , 0.57 , 0.694 , and 0.4885  ( at threshold = 0.5, 0.4, 0.4, and 0.4, respectively).
Tariq et al.  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 . 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 . 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.  study Strong interaction was shown with TLR-3 . 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 .
Alam et al.  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.  and Raza et al.  study constructs. The highest coverage in West Africa (87.54%) and Europe (85.87%) was demonstrated . Full characteristics of the studies are available in Table 1.
All DNA plasmid vaccines in this literature review were in-vivo animal studies (Table 2). Armand et al., 2000  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.  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.  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.  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.  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.  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 . 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 . 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. .
Recombinant vaccinia virus
The use of vaccinia virus as a tool for developing vaccines is evident in literature . Previous studies supported the use of this technique to develop vaccines against influenza virus , parainfluenza virus , and human immunodeficiency virus type 1 (HIV-l) . 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.  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 . 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  and proposing LC16mO as a potential vector . 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 . However, these results were in contrast with those published by Hakoda et al. . 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 . Depending on the sort of animals used for experiment, vaccination outcomes varied greatly . A combination vaccine therapy using vaccinia virus-derived NYVAC vaccine and a DNA based vaccine has been investigated previously . 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 . 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. . 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 . 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 . 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).
This is, to the best of our knowledge, the most comprehensive systematic review that thoroughly reviewed the available evidence regarding multiple efforts to create a well-developed vaccine against HTLV-1. In this paper, we reviewed the findings from 47 studies which used several different methods to design the aforementioned vaccine, including peptide/protein, DNA-based, dendritic-cells-based, and recombinant vaccinia virus. Most of the included studies were peptide or protein based experimental models, which mostly used Tax, Glycoprotein (GP), GAG, POL, REX, and HBZ as their peptides to develop the vaccine. Dendritic cell-based studies were more recently published and achieved their immunization through an activated CD-8 response. The first attempts to create an HTLV-1 vaccination relied on recombinant vaccinia virus and most results sound positive and efficacious, albeit there hasn't been much focus regarding this type of vaccine lately. Most of the studies were experimental studies performed on animal models, although few investigations were done on humans. CMV, vaccinia, baculovirus, hepatitis B, measles, pox, E. coli, and adenovirus were among the most commonly used vectors in the studies (Fig. 1).
In addition to our predefined database search, we also systematically searched the Cochrane library (CENTRAL) to gather recent progression and future perspectives regarding the evaluation of the HTLV-1 vaccine in clinical trials. The most recent randomized controlled study protocol by Suehiro et al. is registered in the Japan Registry of Clinical Trials and aims to evaluate the effectiveness of autologous dendritic cell vaccine therapy in adult T-Cell Leukemia/Lymphoma (ATLL) patients. The main population were pre-treated ATLL patients and positive for any of HLA-A*0201, *2402, *1101, or *0207. The three times with a two-week interval at a dose of 5.0 × 106 cells vaccine will be subcutaneously injected and patients’ progression-free survival, the vaccine safety and effectiveness will be reported. Moreover, another protocol submitted by Suehiro et al. was aimed at studying the effectiveness of autologous dendritic cell vaccine pulsed with Tax peptides in ATLL patients. However, this study was terminated. A few other protocols were available, but none of them reported their results. Therefore, the authors of this systematic review urge further investigation into the potential use of these suggested vaccines to prevent and treat HTLV-1 infection in humans based on their efficacy in animal models.
Previous reviews are also available in the literature regarding developing an efficacious HTLV-1 vaccine [83,84,85,86]. The most recent study by Santana et al. systematically reviewed the last 35 years efforts for developing HTLV-1 vaccine . In their study, 25 articles were included, out of which 19 were peptide based, and 6 were viral vector-based vaccines. The authors focused on including only the articles with strong evidence and excluded those articles which discussed new strategies to develop HTLV-1 vaccine. In our article, we also included recent advances in developing HTLV-1 vaccine which includes but not limited to dendritic cell-based vaccines, recombinant vaccines, and use of ATLL patients own PBMCs. Furthermore, we discussed in-vitro investigation in addition to animal and human models.
Our study has several limitations. First, due to the heterogeneous results and methodology of each study, meta-analysis was not carried out and the result section was presented in narrative form. Second, because the number of studies evaluating the effects of the proposed HTLV-1 vaccine in humans was insufficient, the applicability of the efficacy of the experimental animal models is unknown. Finally, little information was available regarding the comparison of the effects of the different proposed vaccine types to each other.
In conclusion, this systematic review summarized recent assessments of HTLV-1 vaccine candidates. There are numerous constructs with potential immunogenicity investigated in in-silico, in-vitro, and in vivo studies. Cell-mediated immunity, tumor suppression, leukemia regression, and humoral response with antibody secretion were reported in reviewed studies. HTLV-1-Tax epitopes (especially 11–19 and 178–186) and gp46 and gp21 were the most used epitopes in different immunogen vaccines. Some dendritic-cell-based and Tax epitope (180–188)-based vaccines showed reducing risk of the development of ATL in vivo. Although human clinical trials for HTLV-1 vaccines remain rare yet, a 3-individual-human trial showed the therapeutic efficacy of autologous dendritic cells for ATL patients. Recent in silico studies predicted the highest immunogenic T- and B-cell epitopes for efficient HTLV-1 vaccine. Further wet lab and in vitro investigations are required to authorize their vaccines. Elevated cell immunity appeared to be associated with Tax-specific CTL responses and protection from illness. Encapsulation of the vaccine with some nanoparticles (such as PLGA) showed the same immunity without the need for adjuvants or boosting. This study will address the essential need for a potential HTLV-1 vaccine to prevent and or treat ATLL and other HTLV-1 immune-related disorders. It is difficult to determine which approach is the most promising for developing an HTLV-1 vaccine, as each approach has its own advantages and disadvantages. Additionally, each approach may work differently in different populations and may have different safety and efficacy profiles. However, some of the approaches that have shown promising results in preclinical studies include the use of peptide vaccines, virus-like particle (VLP) and adenoviral vector vaccines encoding HTLV-1 proteins. These approaches have been shown to induce strong immune responses against HTLV-1 in animal models. It is important to note that while preclinical studies are promising, the safety and efficacy of these approaches in humans is not well known. Further clinical trials are needed to determine the safety and effectiveness of HTLV-1 vaccines in humans.
Availability of data and materials
Data sharing is available by contacting corresponding author.
Human T-cell lymphotropic virus type 1
Adult T-cell leukemia/lymphoma
HTLV-1-associated myelopathy/tropical spastic paraparesis
Cytotoxic T Lymphocytes
Tumor necrosis factor
Human leukocyte antigen
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This study was funded by Alborz University of Medical Sciences. Grant No. 82-5747.
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Seighali, N., Shafiee, A., Rafiee, M.A. et al. Human T-cell lymphotropic virus type 1 (HTLV-1) proposed vaccines: a systematic review of preclinical and clinical studies. BMC Infect Dis 23, 320 (2023). https://doi.org/10.1186/s12879-023-08289-7