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Current HIV Research, 2019, 17, 1-10
1
REVIEW ARTICLE
Updated Studies on the Development of HIV Therapeutic Vaccine
Mona Sadat Larijani, Amitis Ramezani and Seyed Mehdi Sadat*
Hepatitis, AIDS, and Bloodborne diseases Department, Pasteur Institute of Iran, Tehran, Iran
ARTICLE HISTORY
Abstract: Background: Among the various types of pharmaceuticals, vaccines have a special place.
However, in the case of HIV, nearly after 40 years of its discovery, an effective vaccine still is not
available. The reason lies in several facts mainly the variability and smartness of HIV as well as the
complexity of the interaction between HIV and immune responses. A robust, effective, and longterm immunity is undoubtedly what a successful preventive vaccine should induce in order to prevent the infection of HIV. Failure of human trials to this end has led to the idea of developing therapeutic vaccines with the purpose of curing already infected patients by boosting their immune responses against the virus. Nevertheless, the exceptional ability of the virus to escape the immune
system based on the genetically diverse envelope and variable protein products has made it difficult
to achieve an efficient therapeutic vaccine.
Received: April 10, 2019
Revised: May 29, 2019
Accepted: May 30, 2019
Objective: We aimed at studying and comparing different approaches to HIV therapeutic vaccines.
DOI:
10.2174/1570162X17666190618160608
Methods: In this review, we summarized the human trials undergoing on HIV therapeutic vaccination which are registered in the U.S. clinical trial database (clinicaltrials.gov). These attempts are divided into different tables, according to the type of formulation and implication in order to classify
and compare their results.
Result/Conclusion: Among several methods applied in studied clinical trials which are mainly divided into DNA, Protein, Peptide, Viral vectors, and Dendritic cell-based vaccines, protein vaccine
strategy is based on Tat protein-induced anti-Tat Abs in 79% HIV patients. However, the studies
need to be continued to achieve a durable efficient immune response against HIV-1.
Keywords: HIV, vaccine, therapeutic, clinical trials.
1. INTRODUCTION
The human immunodeficiency virus (HIV) has affected
76.1 million people for nearly four decades from whom 35
million are dead. It was estimated that 36.7 million individuals were living with HIV with 56% accessing antiretroviral
therapy (ART) in June 2017 [1, 2]. ART has resulted in depletion of mortality and also had a significant effect on the
patients quality of life in the past decade; however, its global
coverage is 55% which declines to 16-35% in low- or middle-income parts of Africa [3]. Despite the fact of a substantial impact on the virus life cycle, ART is unable to eradicate
the virus and subsequently cure the infected individuals.
Even with no viral detectable levels in the blood, HIV remains dormant among multiple host organs [4]. The initial
aim of the HIV vaccine was based on prevention of infection. Failure of primary studies motivated the idea of creating therapeutic vaccines with the purpose of cure.
*Address correspondence to this author at the No: 69. Pasteur Ave, Hepatitis and HIV Department, Pasteur Institute of Iran, Tehran, Iran;
Tel: + 98 (21) 66969291; E-mail: mehdi_sadat@pasteur.ac.ir
1570-162X/19 $58.00+.00
Clinical trials of HIV vaccine candidates mainly ended
with unsatisfying results [5, 6]. Among them, RV-144 was
the only trial which demonstrated 31.2 percent efficacy in
Thailand. [7]. It was a combination of ALVAC-­‐HIV (canarypox vector) as a prime vaccine and AIDSVAX gp120
(from HIV subtypes B and E) vaccine as a boost [8]. The
summary of these attempts is shown in Table 1 [9].
Therefore, much research to approach a therapeutic vaccine has been conducted along with the preventive strategies
to overcome HIV obstacles. These difficulties include lack of
an ideal animal model, reduced funding for HIV vaccine, and
specifically the virus characteristics which pose huge challenges towards any achievements above all [8, 15].
Moreover, due to the intense sensitivity of vaccine products, the number of participants in these kinds of clinical
trials is normally greater than in non-vaccine drug trials. In
addition, testing these vaccines is time-consuming and requires enough cost resource which should be provided by
manufacturers. The successful development of an effective
HIV therapeutic vaccine needs many different candidates to
be studied simultaneously among different populations
worldwide [16, 17]. When the infection occurs by the virus,
© 2019 Bentham Science Publishers
2 Current HIV Research, 2019, Vol. 17, No. 2
Table 1.
Larijani et al.
Late-stage HIV-1 clinical trials.
Date
Trial
Vaccine Structure
Result
Targeting Population
Ref.
2013
HVTN 505
DNA/rAd5
No efficacy
Transgender women &
MSM/USA
[10]
2009
RV144
ALVAC/gp120
31.2 efficacy
Normal individuals/ Thailand
[11]
2007
STEP
Ad5
No efficacy
high-riskwomen
& MSM/ America + Australia
[12]
2003
VAX004
gp120 protein
No efficacy
2003
Vax003
gp120 protein
No efficacy
a burst of viremia appears and HIV specific CD8+ and CD4+
T cells are created as a response to the viremia and the viral
load decreases due to T-cell mediated responses and antibodies can be tracked six months after infection [18, 19]. Nevertheless, this virus is able to escape both immune recognition
arms based on the genetically diverse envelope and variable
protein products that manipulate the cell cycle. As a result,
the viral load increases and the immune system fails to progress [20-22].
A successful therapeutic vaccine must trigger proper host
immune responses which often causes expression of broadly
neutralizing antibodies through traditional strategies [23]. In
the case of HIV, humoral immunity has not been sufficient
due to the virus features in viral immune evasion. Consequently, cell-mediated immune responses seem to be necessary in order to limit the infection, although an ideal vaccine
should be able to elicit both arms of immunity [24-26].
Different strategies implied in order to achieve a way to
cure the HIV suffering population which are shown in Fig.
(1). Here we summarized the clinical trials toward an HIV
therapeutic vaccine according to the records in the U.S. National Library of Medicine (clinicaltrials.gov). These attempts are divided into different tables according to the type
of formulation and implication in order to classify and compare their results [27-29].
DNA, peptide, protein, and viral vaccines are normally
based on bioinformatic studies to obtain immunogenic conserved regions. DC vaccines are mostly autologous cells
loaded with the favourite antigen.
2. DENDRITIC CELL-BASED VACCINES
One of the most promising methods used to induce an
immune response against antigens is dendritic cell (DCs)
therapy. A summary of trials based on this method is shown
in Table 2. These professional antigen presenting cells
(APCs) are able to activate T cell which is an essential step
in pathogen-specific immune activity in both innate and
adaptive pathways [30, 31]. To achieve this aim, antigens are
targeted to the DCs through different strategies. Most of the
studies have been conducted on autologous DCs which are
obtained from patients, loaded by ideal antigens often derived from plasma sample and followed by giving back to
high-riskwomen
& MSM/US & Europe
IV drug users/ Thailand
[13]
[14]
the same person [32]. There were some differences including
DC maturation, antigen selection, and in vivo or ex vivo targeting among conducted studies [33, 34]. AGS-004, the trial
which developed the phase IIb, was based on autologous
DCs co-electroporated with patient’s derived HIV-1 RNA
encoding three or four HIV-1 antigens and also CD40L. This
study aimed at testing the safety and activity of AGS-004
successfully ART-treated patients infected with HIV-1 in
combination with ART following by ART interruption. This
immunotherapeutic agent was successful in the induction of
HIV-specific effector and memory CD8 T-cell responses,
however, there was no detectable antiviral effect after its
administration in comparison to placebo recipients [35].
The next trial based on DCs which completed phase I and
II was autologous HIV-1 ApB DC vaccine with the aim of
safety and antiviral activity evaluation of a therapeutic vaccine. It was derived from autologous dendritic cells loaded
with autologous HIV-1 infected apoptotic cells. Although the
vaccine was safe, well tolerated, and induced T-cell activation and cytolysis, including HIV-1–infected cells, it did not
prevent viral rebound during treatment interruption [36].
Dendritic cell vaccine (DCV-2) was performed to study
the efficacy of a therapeutic HIV vaccine composed of
autologous myeloid dendritic cells (MD-DC) pulsed ex vivo
with high doses of heat-inactivated autologous HIV-1, in
HIV-1 infected patients at a very early stage of the disease
(CD4 > 450 x 106 /L). Significant depletion in plasma viral
load was observed in immunized recipients associated with a
consistent increase in HIV-1 specific T cell responses suggesting that HIV-1 specific immune responses were elicited
by therapeutic DC vaccines which can greatly change plasma
viral load set point after cART interruption in infected patients treated at early stages [38].
In the other study, dendritic cells loaded with HIV-1
lipopeptides were applied and completed phase I to determine whether the administration of a dendritic cell vaccine
is an effective and safe treatment for HIV-1 infected individuals. Ex vivo generated DCs were loaded by HIV-1
lipopeptides and an Analytical Treatment Interruption
(ATI) was conducted on the vaccine recipients at week 24.
The regimen was well-tolerated and elicited polyfunctional
HIV-specific responses but virus rebound was observed
after 14 days [34].
Updated Studies on Development
Current HIV Research, 2019, Vol. 17, No. 2
3
Fig. (1). Schematic view of different vaccine strategies against HIV-1 in clinical trials.
Table 2.
Dendritic Cell-based vaccines.
Trial
AGS-004 (personalized
therapeutic vaccine utilizing
Phase
IIb
Registry Identifier
Result
Status
Last Update
Ref.
NCT00672191
no antiviral effect was observed
after the administration when
compared with placebo despite
induction of HIV-specific effector/memory CD8 T-cell
responses
completed
2013
[35]
NCT00510497
It did not prevent viral rebound
during treatment interruption,
despite a significant decrease in
viral load
completed
2016
[36]
completed
2014
[37]
completed
2017
[38]
patient-derived dendritic
cells and HIV antigens)
Autologous HIV-1 ApB DC
Vaccine
I/II
Dendritic cell vaccine (DCV2)
I/II
NCT00402142
significant depletion in plasma
viral load associated with a
consistent increase in HIV-1–
specific T cell responses
Dendritic cells loaded with
HIV-1 lipopeptides
I
NCT00796770
polyfunctional HIV-specific
responses were elicited
3. PROTEIN-BASED VACCINES
Recombinant proteins strategy provides us to target immune responses exactly against favourite protective antigens
(Table 3). There are different expression systems with several advantages which lead to the production of a large
amount of desirable proteins depending on the required features [39].
Over the past decades, attempts toward an HIV therapeutic vaccine included almost all virus products specifically
inner proteins, with the purpose of eliciting cellular immunity directly to the virus proteins including Gag, the structural unit of HIV, RT, Int and Pol, the catalytic units, regulatory viral products Trans-Activator of Transcription (TAT),
and regulatory factors (Nef, vif, Vpu,Vpr). However, no
practical approach has yet been achieved to deliver effective
treatment. Some studies aimed at a single antigen targeting
whereas some set their goal at a multi-frame protein vaccine
[40-42].
4 Current HIV Research, 2019, Vol. 17, No. 2
Table 3.
Larijani et al.
Protein-based vaccines.
Trial
Phase
Registry Identifier
Result
Status
Last Update
Ref.
GSK Biologicals HIV Vaccine
732462 (p24-RT-Nef-p17
fusion protein vaccine)
IIb
NCT01218113
Safe but failed to show a significant reduction of HIV-1 VL
completed
2018
[43]
completed
2016
[44]
Tat protein vaccine
II
NCT01513135
Safe and immunogenic, a significant reduction of blood
proviral DNA was observed
after week 72
Tat Oyi (protein-based vaccine)
I/II
NCT01793818
Safe and Successful in HIV
RNA & DNA reduction
Not recruiting
2016
[45]
TUTI-16 (synthetic HIV-1 Tat
epitope vaccine)
I/II
NCT01335191
safe and immunogenic but had
no effect on controlling HIV
rebound after ART termination
completed
2013
[46]
One of these multi-antigenic designs was GSK Biological
HIV Vaccine designed to assess the efficacy and safety of
fusion protein (p24-RT-Nef-p17) on viral load reduction in
antiretroviral therapy (ART)-naive HIV-1 infected adults
after 48 weeks follow up [43]. This recombinant fusion protein (F4) containing four HIV-1 clade B antigens, induced
F4-specific CD4+ T-cell responses and had a clinically acceptable safety profile, but had no effect on HIV-1 viral load
reduction, CD4+ T-cells count, ART initiation delay, nor on
HIV-1 related clinical events prevention.
The other study based on protein vaccine that only targeted one HIV protein was placebo-controlled clinical trial,
Tat protein vaccine, with the aim of immunogenicity and the
safety assessment of a therapeutic, recombinant, biologically
active HIV-1 Tat vaccine in HIV-1 infected volunteers who
were anti-Tat antibody negative with chronically suppressed
HIV-1 infection as indicated by a HIV-1 plasma viremia <
400 copies/ml, and a CD4+ T cell count ≥ 200 cells/µl. The
results after 48 weeks showed that Tat vaccination was safe,
immunogenic, and also capable of reducing impairment of
immune system which persisted despite HAART in treated
individuals and was able to induce anti-Tat Abs in most patients (79%) suggesting that Tat immunization represents an
effective pathogenesis-driven intervention to increase
HAART efficacy [44].
cine, which was designed to activate anti-Tat antibodies that
block the circulating Tat function. The participants in this
randomized double-blind dose-escalating study were asymptomatic treatment-naïve HIV-1 infected subjects. The surprising result was reported as a highly significant reduction
of HIV-1 viral load in the lowest vaccine dose group (p <
0.01) but not at the higher doses suggesting that an anti-Tat
antibody response below the limit of detection inhibited HIV
viral load at this dose. However, this effect was aborted at
higher vaccine doses by adjuvant induced cytokines components in TUTI-16. In order to clarify its immunogenicity/activation, the team performed an open-label immunogenicity study among healthy, HIV uninfected individuals
and ART-controlled HIV-infected subjects. The final data
showed healthy HIV negative subjects developed antibody
responses, ART-controlled HIV infected subjects had similarly robust antibody responses, and finally, adjuvantinduced increases of HIV viral load did not happen in the
presence of ART. Despite these facts, anti-Tat epitope vaccination of ART-controlled HIV-infected subjects was impotent in controlling HIV rebound after ART cessation [46].
4. PEPTIDE-BASED VACCINES
Tat has been also targeted in another study termed Tat
Oyi, a synthetic protein of 101 amino acid residues, with the
aim of extracellular Tat neutralization which might help the
cellular immune response to eliminate HIV-1 infected cells.
This double-blinded trial was carried out on long-term HIV1 infected volunteers whose viral loads were suppressed by
antiretroviral therapy (cART) for at least one year. At the
end of following up for Tat Oyi has been introduced as the
first therapeutic vaccine to show success in regard to both
HIV RNA and DNA in phase II clinical trial with the potency to reduce HIV DNA and the number of HIV infected
cells in peripheral blood. The investigators concluded that
applying this vaccine with cART may provide a method of
control of HIV infection [45].
Peptide-based vaccines have generally been applied to
target immune response directly against the most immunogenic and/or conserved domain of the target protein. Table 4
can show the attempts of these methods. The immune responses can be elicited against naturally subimmunodominant epitopes [47-49]. What is more, several
strains and different stages of the life cycle can be targeted
by the use of a multi-epitope approach. Recently, production
of peptides has become simple, fast and easily reproducible.
It is also cost-effective according to recent approaches to
solid phase peptide synthesis (SPPS). Moreover, these kinds
of vaccines are typically soluble in water and durable under
simple storage conditions. Another advantage of peptide
antigens is that they are less likely to induce autoimmune
responses or allergic or due to their lack of redundant factors
[48, 50, 51].
The third clinical trial based on Tat protein, termed
TUTI-16, was a synthetic universal HIV-1 Tat epitope vac-
Vacc-4x, a peptide-based vaccine, was designed to induce and maintain cellular immune responses against HIV
Updated Studies on Development
Table 4.
Current HIV Research, 2019, Vol. 17, No. 2
5
Peptide-based vaccines.
Trial
Phase
Registry Identifier
Result
Status
Last Update
Ref.
Vacc-4x
II
NCT00659789
Induction of CD4 and CD8, reduction of VL,
One sever adverse event
completed
2017
[52]
VAC-3S
I/II
NCT01549119
Safe and immunogenic
Reduction of HIV blood reservoir
completed
2015
[53]
completed
2014
[54]
completed
2013
[55]
completed
2012
[56]
Vacc-C5
I/II
NCT01627678
safely induced marginal immune
responses, whereas markedly
increased Vacc-C5-induced regulatory T cell
AFO-18
I
NCT01141205
Safe and showed few CD8 T cell
responses
HIV-v
I
NCT01071031
composing of four synthetic HIV peptides. These peptides
included conserved regions on the HIV-1 Gag p24 capsid
protein, Vac-10: amino acids 186-204, Vac–11: amino acids
273-293, Vac-12: amino acids 288-308, and Vac–13: amino
acids 359-378. They contained multiple CD4 and CD8 cell
epitopes which correspond to improve human leukocyte antigen (HLA) binding and presentation. It was performed on
virologically suppressed on cART patients as a multinational
double-blind study. A significant difference in viral load was
observed at the primary and secondary endpoints (week 48
and week 52) between Vacc-4X and placebo groups. It is to
say that although HIV viral load increased in both groups
after cART interruption, the placebo recipients showed
3times higher titers than vaccinated individuals. Finally, it
was evaluated immunogenic and effective in inducing proliferative responses in both CD4 and CD8 T-cell populations
beside one reported serious adverse event [52].
Vac-3s had the purpose of evaluating the safety and immunogenicity of a highly conserved and specific motif called
3S located in the gp41 HIV-1 protein. This region was chosen based on its highly pathogenic motif which can induce
expression of NKp44L. It is the cellular ligand of NKp44, an
activating NK receptor, making uninfected CD4 + T cells
sensitive to NK lysis. This study was done on HIV-1 infected patients under ART who had undetectable viral loads.
VAC-3S at the end of phase I was reported a safe and immunogenic HIV immunotherapy. The induction of anti-3S antibodies was correlated with an increase in CD4/CD8 ratio and
decrease in total HIV blood reservoir [53].
Another peptide-based vaccine trial, Vacc-C5 was a single heterodimeric peptide-based corresponding to the C5
domain on gp120 and the outer region of gp41 (C5/gp41732744
). The vaccine was intended to develop a non-neutralizing
antibody against C5 region and applied to HIV patients on
ART with 26 weeks follow up. As a result, anti-Vacc-C5
antibody levels seemed to decrease in comparison with preexisting levels. Despite this, there was a significant increase
in Vacc-C5-specific CD8+ T cell proliferative responses
after the first booster period; however, they were reduced
after the second. In contrast, Vacc-C5-induced regulatory T
cell increased after completed vaccination [54].
AFO-18, a therapeutic HIV vaccine concept was based
on peptides representing 15 HLA- conserved CD8 T cell
epitopes, three CD4 T-helper cell epitopes, and supertyperestricted subdominant. Safety and immunogenicity were
assessed in untreated HIV-1-infected individuals in this
phase I clinical trial. The study showed that therapeutic immunization was safe and feasible. They also achieved the
possibility to redirect T cell immunity with CAF01adjuvanted HIV-1 peptide vaccine at the course of untreated
HIV-1 infection in some patients. However, vaccine-induced
HIV-1 T cell responses to CD8 T cell epitopes were detected
relatively few against HIV-1 [55].
HIV-v vaccine targeted conserved immune reactive domains in Nef, Rev, Vif, and Vpr. The purpose of this study
was to assess the safety and efficiency of a single dose vaccination in HIV positive patients who were not under antiretroviral therapy. This peptide-based therapeutic vaccine
was reported well tolerated and IgG responses were elicited
up to 75% of volunteers by adjuvanted formulations. Moreover, cellular responses in 45% of tested volunteers were elicited at the high adjuvanted dose. 1 log reduction of viral
loads was seen in the responding subjects compared to placebo recipients and non-responders. No changes in CD4
count were seen [56].
5. DNA-BASED VACCINES
DNA vaccines, also known as plasmids, are composed of
small pieces of DNA which have some potential advantages
over traditional vaccine approaches. Different DNA vaccine
trials are summarized in Table 5. Antigen-encoding DNA
plasmid has the potency to induce both humoral and cellular
immune response against viruses [57-59]. The expression of
the inserted gene of interest can be controlled under a strong
mammalian promoter which can be located on a plasmid
backbone of bacterial DNA. When the target cells are transfected with DNA vaccines, the translated encoded proteins
will be in the context of self-major histocompatibility complex (MHC) [28, 58, 60].
Ad26 was a combined phase I and IIa Study using an
Adenovirus type 26 vector as a prime and MVA (Modified
6 Current HIV Research, 2019, Vol. 17, No. 2
Table 5.
Larijani et al.
DNA vaccines.
Trial
Phase
Registry Identifier
Result
Status
Last Update
Ref.
Ad26.Mos.HIV + MVA-Mosaic
II
NCT02919306
Not reported
completed
2018
[9]
MAG pDNA vaccine +/- IL-12
I
NCT01266616
Elicited CD4+ but not
CD8+ T-cell responses to
multiple HIV-1 antigens.
completed
2015
[61]
PENNVAX-B (Gag, Pol, Env) +
electroporation
I
NCT01082692
Strong induction of CD8 T
cell responses
completed
2012
[62]
Phase
Registry Identifier
Result
Status
Last Update
Ref.
NCT01712425
Safe and immunogenic, able
to shift pre-existing immune
response to conserved encoded genes
completed
2016
[72]
Recruiting
2017
[73]
completed
2017
[74]
completed
2012
[75]
Table 6.
Viral vector vaccine.
Trial
ChAdV63.HIVcons +
MVA.HIVconsv (viral vector
vaccines
I
HIVAX (lentiviral vector-based
therapeutic vaccine)
I
NCT01428596
Safe, elicited strong CD4 and CD8 T cell responses, over-­‐
came the pre-­‐existing im-­‐
mune responses
JS7 DNA + MVA62B (DNA +
viral vector vaccines)
I
NCT01378156
Successful in eliciting CD8 responses with no sign of exhaustion
rMVA-HIV + rFPV-HIV (viral
vector vaccines) in young adults
I
NCT00107549
Vaccinia Ankara) as a boost in HIV-1 Infected adults with
acute HIV Infection on ART. Gag, Pol, and Env were inserted in the mosaic vectors to elicit immune responses.
MAG (multi-antigen) HIV DNA vaccine encoded HIV-1
Gag, Pol, Nef, Tat, Vif, and Envelope with or without interleukin-12 (IL-12). This DNA vaccine was composed of two
vaccine plasmids: ProfectusVax DNA Plasmid (HIV-1
gag/pol) and ProfectusVax DNA Plasmid (HIV-1 nef/tat/vif,
env) which was testified in HIV-1-infected patients on
antiretroviral therapy by electroporation delivery (EP) in
combination with intramuscular injection (IM-EP).
There was an increase in CD4+ T cells expressing IL-2 in
response to Gag and Pol and also interferon-γ responses to
Gag, Pol, and Env at week 14 in the low-dose IL-12 arm
compared to placebo users. The overall increase in the IL-2
expressing CD4+ T-cell responses to any antigen was also
higher in the low-dose IL-12 arm in comparison with placebo. Nevertheless, cytokine responses by CD8 T cells to
HIV antigens did not increase in any vaccine arms [61].
A similar therapeutic vaccine, PENNVAX-B including
plasmids targeting the gag, pol, and env proteins of HIV-1,
was given to HIV-1 infected individuals whose viral load
was undetectable on a HAART regimen via electroporation
(EP). They used this way due to the fact that animal studies
had shown that this kind of delivery method increases the
immune response to the vaccine. The vaccine was evaluated
safe and well-tolerated and showed significant specific T-cell
responses against at least one of the three vaccine antigens
(Gag, Pol, or Env) following vaccination (75%). Furthermore, 50% of subjects had sharp vaccine-induced responses
to at least 2 of the 3 antigens. The more important result was
that CD8+T-cells induction was predominant. This feature is
considered to be essential in clearing chronic viral infections
and an important measure of a functional therapeutic vaccine
[62].
6. VIRAL VECTOR-BASED VACCINES
The vectors selection is dependent on some factors including nature of the illness, absence of pre-existing vectorspecific immunity, and tissue tropism [63]. Viral vectors are
strong tools for vaccine development gene therapy (Table 6).
This stems from viruses’ ability to infect cells. There are
some main viral vector features which have had a substantial
impact on different vaccine studies as high efficiency in gene
transduction; highly specific targeting in gene delivery, enhancement of cellular immunity, induction of immune responses, and significant immunogenicity without an adjuvant
[64, 65].
Recombinant viral vectors facilitate the way of therapeutic vaccine production since they induce a robust cytotoxic T
Updated Studies on Development
Table 7.
Current HIV Research, 2019, Vol. 17, No. 2
7
Undergoing trial based on viral vectors.
Trial
Phase
Identifier Status
Last Update
Ref.
DC-HIV04
Comparison of Dendritic Cell-Based Therapeutic
Vaccine Strategies for HIV Functional Cure
I
NCT03758625 recruiting
2018
[9]
GCHT01
I
NCT01428596 Active
2019
[9]
GTU-MultiHIV B-clade + MVA HIV-B(DNA +
viral vector vaccines)
II
NCT02972450
Not yet
recruiting
2018
[9]
THV01 (lentiviral vector-based therapeutic vaccine
I/II
NCT02054286
Active
2019
[9]
Ad26.Mos4.HIV + MVA-Mosaic or clade C
gp140 + mosaic gp140
I
NCT03307915
Recruiting
2019
[9]
lymphocyte (CTL) response via intracellular antigen expression leading to the elimination of virus-infected cells [66,
67]. Despite their advantages, they are accompanied by
safety concerns such as stable expression of the interesting
gene which is achieved via viral integration mechanisms and
can lead to cancer. The other possible obstacle to the clinical
usage of viral vectors is the presence of pre-existing immunity against the viral vector due to previous exposure to the
virus and neutralizing antibodies development which reduces
vaccine efficacy [68, 69]. Adenovirus and Vaccinia virus are
the most widely applied vectors due to their potency in inducing a robust immune response, specifically including
CTL, to the expressed foreign antigens [70, 71].
ChAd-MVA.HIVconsv-BCN01 was a study based on
HIV conserved genes by assembling 14 conserved regions of
the HIV-1 products into one chimeric protein. This gene was
inserted into two non-replicating vaccine vectors including
ChAdV63, an attenuated chimpanzee adenovirus serotype 63
and MVA, a modified vaccinia virus Ankara in recently
HIV-1 infected subjects with early viral suppression 6
months after initiation HAART. T cell specific responses
were observed among all participants. Moreover, Pol and RT
were the most immunogenic antigens among chosen conserved regions. Finally, they reported that it was a safe strategy to change pre-existing immune response towards vaccine-encoded conserved regions [72].
The other clinical trial based on viral vectors is HIVAX
on subjects receiving stable highly active antiretroviral therapy (HAART) due to the last update on clinical trials.
HIVAX is a patented replication-defective lentiviral vector
vaccine which is capable of stimulating both antibody and
cellular immune responses in primate models. As they
claimed, this product has overcome some obstacles specially
vaccine-induced or pre-existing immunity to other viral vectors. The main results from phase I clinical trial was its
safety and ability to elicit strong CD8 T cell responses in
recipients [73].
GV-TH-01, a DNA prime-Modified Vaccinia Ankara
(MVA) boost vaccine was evaluated in HIV infected subjects on ART in term of safety and ability to elicit CD8 T
cell responses. Both DNA and MVA contained clade B Gag,
Pol, and Env, and produced immunogenic virus-like particles. Eight of 9 vaccines had CD8+ T able to be stimulated
by Gag peptides prior to vaccination. Vaccination caused to
boost these responses and also elicited former undetected
CD8+ responses as well. Moreover, elicited T cells did not
show signs of exhaustion. However, the vaccination process
did not achieve a reduction in virus re-emerged and viral
reservoirs in all participants during phase I [74].
Modified vaccinia Ankara in combination with Fowlpox
virus was used in another study. The purpose of rMVA-HIV
+ rFPV-HIV phase I trial was defined as determining the
safety of two recombinant HIV vaccines, rFPV-HIV
(env/gag + tat/rev/nef-RT and rMVA-HIV (env/gag +
tat/rev/nef-RT, in HIV infected young adults on stable antiHIV treatment. They reported that this vaccination led to a
modest transient increase in latently infected CD4+ T cells
decay. However, this study lacked from small sample size
and placebo group [75].
In addition to the mentioned viral vector trials, there are
some studies undergoing different strategies with the same
main goal to control HIV viral replication. Furthermore,
Lentiviruses, Adenoviruses, and Modified Vaccine Virus are
being investigated which means researchers still hope to
make use of these natural tools to achieve a therapeutic HIV
vaccine in the future in combination with HAART or without
the need of that if possible. Table 7 shows these trials briefly.
CONCLUSION
A preventative or therapeutic vaccine has not been reported although nearly 40 years have passed since HIV-1
discovery. Significant technological and conceptual approaches have been applied to elicit CD8+ T-cell responses
and eradication of the virus from the host cells. Consequently, these trials have provided important and crucial
insights into the potential correlates of immune system recovery protection which has been missing for many years.
However, these results have been limited and not durable
after interruption. HIV-1, as a highly mutable virus, has
rapid replication and lack of proofreading in reverse transcriptase activity [76, 77]. From an old point of view, vaccination has been applied to prevent infectious disease using
organisms which express stable antigenic structures that can
elicit special antibodies. To this aim, HIV-1 virus has been
greatly investigated by vaccine researchers with a variety of
8 Current HIV Research, 2019, Vol. 17, No. 2
targets although no effective prophylactic vaccine has been
reported yet [78, 79].
There are still many different methods applied at the
same time worldwide to help HIV suffering patients. Despite
the successes of anti-retroviral therapy (ART), a globally
protective or therapeutic vaccine stays the easiest and the
most effective approach to stop the HIV epidemic. The great
knowledge achieved by the HIV clinical trials in the last
decades has provided hopeful opportunities for the design of
therapeutics. Nevertheless, defining the correlates of spontaneous HIV control and protection from infection has led to
many steps closer to better control of the disease globally.
Although practical vaccine design approaches against HIV
have failed, emerging therapeutics and correlate-inspired
vaccines are powerful to revolutionize the fight against HIV
[80-82]. By looking at the results from completed studies, it
is clear that they have mainly failed to elicit long term and
durable immune responses specifically CTLs which are the
key arm of host immunity to eradicate HIV from infected
cells. The other obstacle which has been most challenging in
different trials is the prevention of viral rebound during
treatment interruption since one of the main goals of a therapeutic vaccine is eliminating the need for ART. Scientists
who attempt to design vaccines against other pathogens will
rarely encounter the difficulties that HIV imposes [80].
Among all the discussed studies above, cellular immune responses are mostly achieved. However, virus rebounding is
observed after interruption.
One of the protein strategies which showed a great advance in viral reduction among clinical trials was Tat protein-based vaccine. Tat has been targeted in three completed
clinical trials and led to induce anti-Tat Abs in 79% HIV
patients which sounds great among all attempts which seem
to be continued in future trials, too [44, 45] Apart from difficulties toward defeat HIV-1 including the virus characteristics and lack of funding, the importance of this issue must
pose renewed efforts in researching community to obtain a
final vaccine formulation against the virus. There is no doubt
that novel ideas and technologies will be needed to develop
new strategies [79].
Larijani et al.
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