Expert Review of Vaccines

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ierv20

Dendritic cell vaccine as a potential strategy to

end the COVID-19 pandemic. Why should it be Ex
Vivo?

Jonny Jonny, Terawan Agus Putranto, Enda Cindylosa Sitepu & Raoulian Irfon

To cite this article: Jonny Jonny, Terawan Agus Putranto, Enda Cindylosa Sitepu & Raoulian Irfon
(2022): Dendritic cell vaccine as a potential strategy to end the COVID-19 pandemic. Why should it
be Ex�Vivo?, Expert Review of Vaccines, DOI: 10.1080/14760584.2022.2080658

To link to this article: https://doi.org/10.1080/14760584.2022.2080658

© 2022 The Author(s). Published by Informa

UK Limited, trading as Taylor & Francis
Group.

Published online: 26 May 2022.

Submit your article to this journal

Article views: 5846

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=ierv20
EXPERT REVIEW OF VACCINES
https://doi.org/10.1080/14760584.2022.2080658

REVIEW

Dendritic cell vaccine as a potential strategy to end the COVID-19 pandemic. Why
should it be Ex Vivo?
Jonny Jonny , Terawan Agus Putranto, Enda Cindylosa Sitepu and Raoulian Irfon
Cellcure Center, Gatot Soebroto Central Army Hospital, Jakarta, Indonesia

ABSTRACT ARTICLE HISTORY

Introduction: Developing a safe and efficacious vaccine that can induce broad and long-term immunity Received 29 March 2022
for SARS-CoV-2 infection is the most critical research to date. As the most potent APCs, dendritic cells Accepted 18 May 2022
(DCs) can induce a robust T cell immunity. In addition, DCs also play an essential role in COVID-19
KEYWORDS
pathogenesis, making them a potential vaccination target. However, the DCs-based vaccine with ex vivo
Cell immunotherapy; COVID-
loading has not yet been explored for COVID-19. 19; dendritic cell; SARS-CoV
Areas covered: This review aims to provide the rationale for developing a DCs-based vaccine with ex -2; T cells; vaccination
vivo loading of SARS-CoV-2 antigen. Here, we discuss the role of DCs in immunity and the effect of
SARS-CoV-2 infection on DCs. Then, we propose the mechanism of the DCs-based vaccine in inducing
immunity and highlight the benefits of ex vivo loading of antigen.
Expert opinion: We make the case that an ex vivo loaded DC-based vaccination is appropriate for
COVID-19 prevention.

1. Introduction developed for influenza vaccination in high-risk patients who

COVID-19 (coronavirus infection disease-2019) is a mild to
severe respiratory disease caused by SARS-CoV-2 (Severe
Acute Respiratory Syndrome Coronavirus-2) infection [1]. This
disease is a primary health concern worldwide due to the
pandemic. Although several vaccines have already been
approved for emergency use, herd immunity generally relies
on vaccines [2]. However, recent findings suggest that Variant
of Concerns (VoC) might escape vaccine-induced immunity
hindering its efficacy [3]. In addition, immunity waning raises
the concern for the long-term efficacy of currently available
vaccines [4,5]. Thus, discovering safe and efficacious vaccines
that lead to broader and long-term immunity remains
challenging.
The DCs-based vaccine is one of the promising vaccine
candidates due to the vital role DCs play in the immunity
and pathogenesis of COVID-19 [6]. Ex vivo loading of antigens
to DCs is mainly developed for cancer therapy and chronic
viral infection. Dendritic cell-based vaccine is a novel vaccina­
tion approach. Studies of dendritic cell vaccines in cancer
patients that have been conducted to date show promising
results [7–12]. For example, adding the autologous tumor
lysate-pulsed dendritic cell vaccine to standard therapy for
glioblastoma patients may prolong survival [9]. Other studies
conducted on Wilms tumor patients using autologous dendri­
tic cells incubated with WT1 peptides showed induction of
systemic tumor antigen-specific immune response, increased
infiltration of CD8+ tumor T cells, and increased tumor PD-L1
expression [8]. This method was also developed for HIV-1 and
Hepatitis B [13,14]. Furthermore, DCs-based vaccines were also
respond poorly to traditional vaccines, such as immunocom­
promised and cancer patients [15]. In light of this, this method
might be used for other infections such as SARS-CoV-2.
However, its potential as a COVID-19 vaccine has not been
explored.
This review aims to provide the rationale for developing
a DC-based vaccine with ex vivo loading of SARS-CoV-2 anti­
gen. First, we discuss the role of dendritic cells in immunity
against infection. Then, we review the effects of SARS-CoV-2
infection on dendritic cells. From here, we propose the
mechanism of the DC-based vaccine with ex vivo loading of
antigen in inducing immunity. Finally, we also highlight the
benefits of ex vivo loading of antigen.
2. Dendritic cells in immunity
2.1. Dendritic cell in innate immunity
The human body has a defense system that works during
pathogen attacks. There are two types of immune response:
innate and adaptive immune responses [16]. The innate
immune response is the first line of defense that is activated
instantly within minutes to hours after the pathogen invasion.
However, innate immune responses are generally nonspecific
and unadaptable. Meanwhile, the adaptive immune response
can recognize antigens specifically through diversified somatic
receptors on B cells and T cells. So that, although requiring
a longer time to be acquired, the adaptive immune response
will cause a much faster and more effective response upon
antigen re-encounter [17].

CONTACT Jonny Jonny jonny_army@yahoo.com Cellcure Center, Gatot Soebroto Central Army Hospital, Jakarta, Indonesia
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
2 JONNY ET AL.
Article highlights
● DCs are essential in the innate immune response through the pro­
duction of IFN-1 and immune cells modulation.
● DCs are the most important APCs that activate various T cells
immune responses.
● SARS-CoV-2 can directly infect DCs causing inadequate innate and
adaptive immune response.
● COVID-19 vaccination targeting DCs might result in better outcomes
and potentially causes long-term and broader spectrum immunity.
● Ex vivo loading of antigens is an appropriate approach in manufac­
turing DCs-based vaccines for COVID-19. Because this approach
bypasses the rigorous process of antigen presentation inside the
body, results in high quality and quantity antigen-loaded mature
DCs and has a well-established safety profile.
The innate immune response consists of various modalities:
physical, chemical, and cellular defenses. Physical defense
protects the body from pathogens using epithelial tissue and
mucous membrane [18]. When a pathogen successfully pene­
trates this defense, the cellular component of innate immunity
reacts by destroying the pathogen through phagocytosis. The
primary phagocytic cells are derived from myeloid progenitor
cells, such as monocyte-macrophage cells, neutrophils, baso­
phils, and eosinophils. Meanwhile, Natural Killer (NK) cells are
nonspecific cytotoxic, which destroy cells infected with viruses
or intracellular pathogens [19]. Finally, Dendritic Cells (DCs) are
also an essential cellular component in the innate immune
response, which have phagocytic abilities, produce inflamma­
tory mediators, and present antigen [20] (Figure 1).
The effectiveness of the innate immune response in fight­
ing viral infections depends on the production of IFN-1. IFN-1
suppresses the spread of the virus through the intrinsic anti­
microbial activity of infected cells, promotes antigen presenta­
tion, and induces NK cells activation [21]. Most IFN-1 is
produced by plasmacytoid dendritic cells (pDC) [22]. pDC
recognizes the virus through Toll-Like Receptors (TLR) 7 and
9 [23]. Stimulation of these receptors triggers massive IFN-1
release within 1–3 hours after viral infection, especially the
IFN-α and IFN-β subtypes [24].
In addition to IFN-1, cellular components of innate immu­
nity express other types of inflammatory mediators that are
Figure 1. DCs role in innate and adaptive immune response. Pathogens that pass through the physical barrier (epithelium and mucosa) activate the innate immune
response and adaptive immune response. First, monocytes-macrophages, neutrophils, and DC capture pathogens, then express antigens on cell membranes. next,
DCs as the primary APC migrate to the lymph nodes, where antigens are introduced to T and B cells, thus triggering memory development.
important for cells communication. For example, NK cells
produce IFN-γ that modulates DCs function [25]. IFN-γ triggers
DC maturation, increases MHC I and II expression, triggers
antigen presentation, and boosts Interleukin 2 (IL-2) and
Cluster of Differentiation 80 (CD80) expression, which are
vital in signaling T cell and B cell activation [26,27].
Furthermore, communication between NK and DC is bidirec­
tional, leading to the amplification of pro-inflammatory cyto­
kines [28].
M1 (inflammatory types) macrophages produce a variety of
inflammatory cytokines, including TNF-α [29]. TNF-α produced
by these macrophages mediates DCs maturation and NK cells
activation [30]. In addition, TNF-α plays a role in immunoregu­
lation by limiting the expression of CXR2 receptors and the
TLR7/9-induced gene in pDC [31]. In sepsis, TNF-α decreases
autophagy function and causes DC dysfunction [32]. Taken
together, similar to NK cells, macrophages also modulate
DCs function via TNF-α. Crosstalks between these cells create
a balanced cytokine milieu in the innate immune response.
2.2. Dendritic cell in adaptive immunity
When the innate immune response cannot destroy antigens,
the body activates the adaptive immune response [33]
(Figure 1). Adaptive immunity is antigen-dependent and spe­
cific. It can induce immunological memory that causes a faster
reaction to antigen re-exposure. It is important to note that
recent studies have found that immunological memory can
also occur in innate immunity to a certain extent [34].
However, it remains a fundamental feature of adaptive
immunity.
Adaptive immunity consists of T-cell mediated immunity,
and B-cell mediated immunity [35]. B cells and T cells only
eliminate antigens recognized by their receptors [36]. So, the
key to adaptive immunity is antigen recognition and presenta­
tion by Antigen Presenting Cells (APCs). APCs stimulate the
expression of specific receptors on T cells and B cells.
Compared to other APCs, DCs are more potent in inducing
T cells [37,38]. Therefore, DCs are the most essential APCs that
bridge innate and adaptive immune responses.

There are five types of DC subsets, namely Plasmacytoid
DCs (pDCs), Conventional DCs 1 (cDC1), Conventional DCs 2
(cDC2), Inflammatory DCs, and Langerhans cells [37]. pDC,
cDC1, and cDC2 are present constantly in the body [39].
While Inflammatory DCs are derived from monocyte precur­
sors that differentiate into DCs in the event of infection, tissue
damage, or the production of cytokines and chemokines [37].
Inflammatory DCs are also called Monocyte Derived Dendritic
Cells (MoDCs). Based on the path to access lymphoid organs,
the cDCs consist of two types [40]. First, Resident DCs, derived
from bone marrow precursors within lymphoid organs, do not
pass through peripheral tissues. Second, Migratory DC formed
from precursors in peripheral tissues, after exposure to anti­
gens, will transfer to lymphoid organs to further interact with
T cells to induce adaptive immunity.
Although it has different classifications, phenotypes, and
role specificities, the primary role of DCs is antigen presenta­
tion. Even pDC, whose primary function is to produce IFN-1,
can be diversified into pDC with phenotypes that are able to
stimulate T cells [41]. The DCs will capture pathogenic parti­
cles during an infection, then undergo maturation and
migrate to the local lymph nodes to activate T cells and
B cells [42]. DCs also serves as surveillance cells that continu­
ously take up antigen samples from the environment.
Exogenous antigen uptake is done through endocytosis, pha­
gocytosis, micropinocytosis, and receptor-mediated endocyto­
sis [43]. In addition, TLRs on DCs can recognize parts of
pathogens. For example, TLR3 can recognize the double-
stranded ribonucleic acid (dsRNA), TLR7/8 can recognize sin­
gle-stranded ribonucleic acid (ssRNA), and TLR9 can recognize
5’ – C – phosphate – G – 3’ deoxyribonucleic acid (CpG DNA).
The interaction between pathogen-associated molecular pat­
terns (PAMPS) or danger-associated molecular patterns
(DAMPS) and TLR causes activation of various transcription
factors resulting in DCs maturation [44].
At the time of maturation, DCs undergo morphological
and phenotype changes. Immature DCs have a rounded
shape and high phagocytosis ability but express fewer co-
stimulatory molecules. After interaction with pathogens,
DCs transform their morphology to cells with longer den­
drites and pseudopodia and express more co-stimulatory
molecules such as CD80 and CD86. In addition, mature
DCs have weaker phagocytosis ability but much higher
migratory ability than immature DCs [45].
In the acute phase of infection, especially infections
caused by intracellular viruses or bacteria, some monocyte
cells turn into MoDCs. IFN-γ primarily mediates the forma­
tion of MoDCs [46]. Moreover, MoDCs isolated from periph­
eral blood can differentiate into MoDC outside the body.
This manipulation is done by incubating peripheral blood
mononuclear cells (PBMCs) in the differentiation media such
as GM-CSF and IL-4 [47]. This method is the most widely
used DCs-based vaccine manufacturing.
As the primary APC, DCs have unique capabilities com­
pared to others. DCs can present exogenous antigens through
both MHC-I and MHC-II (cross-presentation). Cross-
presentation can occur through the cytophilic pathway
EXPERT REVIEW OF VACCINES 3
involving the Endoplasmic Reticulum (ER) and the vacuolar
pathway in the endocytic compartment [48,49]. Through the
cytophilic pathway, pathogenic proteins are translocated to
ER. Inside ER, MHC-I binds those proteins to be translocated
back (retrotranslocation) to the cytosol [49]. Antigen presenta­
tion by DCs also involves extracellular vesicles, thus enabling
cross-dressing (peptide-loaded MHC retrieval from dead cells
or cells that have undergone apoptosis) [50].
DCs with peptide-loaded MHC (pMHC) migrate to second­
ary lymphatic organs to activate T cells. The migration of DCs
to the secondary lymphatic organs is regulated by chemokines
C-C Chemokine Ligand (CCL) 19 and 21 secreted by lymphatic
endothelial cells. It also relies on C-C Chemokine Receptor 7
(CCR7) for DCs positioning and initiation of specific immune
responses [51,52]. In secondary lymphoid organs, DCs actively
spread antigens to other DCs through cross-dressing, conse­
quently increasing the number of effective APCs [53]. So that,
T cells priming can still occur even if the donor DCs cannot
directly present the antigen.
T cell priming occurs in secondary lymphoid organs. This
process requires complicated T cell and DC signaling to ensure
contact. After migration to secondary lymphoid organs, DCs
tend to settle, while T cells can scan through hundreds of DCs
by moving from one lymph node to another. Although DCs
are estimated to interact with 5000 T cells per hour, initiation
of T cell response remains highly dependent on the possibility
of T cells encountered by DCs [52,54]. A study in mice found
that it takes at least 85 DCs to initiate T cell priming, so in
order to induce a response, this threshold should be met [55].
In addition to that, T cells priming requires three signals: 1)
Interaction of T Cell Receptors (TCR) with pMHC; 2) Co-
stimulatory signals through the attachment of CD28 with
CD80 and CD86; 3) Cytokines expressed by DCs such as IL-12
[52]. Damage to any of these signals will cause failure to
T priming.
Antigens presented by MHC-I triggers CD8 + T cell
response, while antigens presented by MHC-II triggers
CD4 + T cell response. CD8 + T cells primarily kill host cells
infected with viruses. Therefore, most CD8+ will proliferate
during acute viral infections after exposure to antigens pre­
sented by DCs to assist viral clearance [56]. Meanwhile,
CD4 + T cells differentiate into various sub-types depending
on the cytokines (e.g. Th1, Th2, Tfh, and Th17) [57]. Each sub-
types has a specific function in mediating humoral and cellular
adaptive immunity. Moreover, after interaction with DCs, some
T cells differentiate into T memory cells [52]. DCs are also
essential in germinal center (GC) development by facilitating
T cell follicular helper (Tfh) differentiation and directly migrat­
ing to the light zone of GC [58].
DCs have a vital role in the immune system, as previously
described. The role of DCs begins from innate immunity
through phagocytic abilities, inflammatory mediators produc­
tion, and antigen presentation. DCs are professional APCs that
connect innate and adaptive immune responses. In the adap­
tive immune response, DCs have several advantages in carry­
ing out their function as APCs: 1) DCs are much more potential
than other APCs; 2) Enable various antigen uptake pathways
4 JONNY ET AL.
and can process both endogenic and exogenic pathogens; 3)
The migration of DCs to secondary lymphoid organs and
recruitment of T cells is a very efficient process so that the
probability for the occurrence of T cell priming is very high; 4)
Have cross-presentation capabilities to trigger a wide array of
T cells response; 5) Lastly, Has cross-dressing capability to
allow antigen transfer from other cells and active dissemina­
tion of antigens within secondary lymphatic organs.
3. SARS-CoV-2 infection dysregulate dendritic cell
Viruses that enter the body will try to avoid the immune
response. Some viruses develop ways to escape immune
response by interfering with DCs functions. For example, it
has been suggested that DCs dysregulation plays a vital role in
SARS-CoV-2 immune evasion [6]. DCs dysregulation causes
various abnormalities throughout the innate and adaptive
immune response. In this section, we will highlight some of
the important findings.
3.1. SARS-CoV-2 causes inadequate innate immune
response
SARS-CoV-2 is known to infect cells through the ACE2 receptor
and relies on TMPRSS2 [59]. Several other receptors can be the
entry point of this virus, including CD147, L-SIGN, and DC-SIGN
[60–62]. DCSIGN receptors are widely expressed in DCs and
macrophages, while L-SIGN is mainly expressed in liver sinu­
soid endothelial cells and lymphatic nodes [62]. The presence
of such receptors suggests that this virus can directly infect
DCs. Research on SARS-CoV infected MoDCs proves that these
cells can be infected, but the infection does not cause cell
death [63]. In line with these findings, in vitro research proves
that infected MoDC does not support viral replication [64].
People infected by SARS-CoV-2 experience an increase in
blood serums, pro-inflammatory cytokines, and chemokines
such as TNF, IL-6, IL-8, Macrophage Inflammatory Protein-1-α
(MIP-1), Monocyte Chemoattractant Protein-1 (MCP-1), and
Interferon-inducible Protein-10 (IP-10) [65]. There is a strong
correlation between IP-10 and symptom severity [66]. In addi­
tion, critical patients have an increased inflammatory response
and dysfunctional response related to IFN [67]. Infected DCs
are thought to be the source of these excessive pro-
inflammatory cytokines. Interestingly, a study shows that
macrophages (not DCs) are the source of pro-inflammatory
cytokines when infected with SARS-CoV-2 [64,68]. However,
infected MoDCs express IP-10, resulting in decreased IFN pro­
duction and IFN associated genes [64]. Conflicting results on
this matter still require further exploration, particularly the
immune cells that contribute most to cytokine storms. There
are complex interactions between immune cells that have yet
been explained. Since specific signaling between immune cells
orchestrates innate immunity, it is crucial to identify the
checkpoint that causes this dysfunction. Therefore, there is
still a possibility that MoDC is related to the increase of pro-
inflammatory cytokines.
DCs communicates with NK cells and macrophages in the
induced innate immunity [26,27,30–32]. The myeloid compart­
ment of COVID-19 patients is abnormal. Immature and
dysfunctional monocytes and neutrophils are associated with
the severity of the disease [69]. In studies comparing acute
and convalescent-phase COVID-19 patients, low DCs and
monocyte count values were obtained in the convalescent
phase. Although, the number of T and NK lymphocyte cell
counts was increased. This finding indicates the possibility of
suppressing the production of monocytes, DC, NK, and T cells,
but NK and T cell suppression lasts shorter [70]. As explained
in the previous section, the interaction between NK cells,
macrophages, and DCs is vital in creating a cytokine induction
balance in the innate immune response. Suppression of these
cells creates an imbalance in immunoregulation. Disruptions
in the axiom of communication between these cells may cause
clinical worsening.
There is an IFN-1 response abnormality in COVID-19
patients, as evidenced by the low value of the IFN-1 and IFN-
3 [71]. This finding is likely related to pDCs, the primary source
of IFN-1. A decrease of pDCs is found in patients infected with
SARS-CoV-2 [70]. A timely IFN-1 response is necessary to acti­
vate an effective innate immunity. However, in coronaviruses
infection, there is a delay in innate immunity for the first ten
days in which during this period a steady increase of viral load
occurs [72,73]. Ultimately, delayed IFN-1 response also leads to
the accumulation of pathogenic macrophages that cause pul­
monary infiltration, vascular leakage, and suboptimal T-cell
response [74].
Delayed IFN-1 response might be due to SARS-CoV-2
infected pDC. Protein in SARS-CoV-2 such as ORF9b, Nsp14,
Nsp10, M, and Nsp1 may inhibit IFN-1 production. At the same
time, other proteins such as ORF3a and ORF6 can inhibit the
IFN-1 signaling pathway [72]. Furthermore, congenital
abnormalities (inborn errors) of the IFN-1 related genes,
namely inborn error in TLR-3 and IFN regulatory factor 7
(IRF-7), are found in critical patients [75]. In line with these
findings, pDC as the primary source IFN-1 expresses much IRF-
7 [24,76]. Furthermore, the presence of autoantibodies against
IFN-1 is also found in life-threatening COVID-19 [77]. So that,
people with the IFN-1 genetic disorder become more suscep­
tible to clinical worsening [75].
3.2. SARS-CoV-2 causes adaptive immunity disruption
The adaptive immune response to SARS-CoV-2 relies heavily
on specific T and B lymphocytes. In COVID-19 patients, there is
a tendency for lymphopenia, where the number of CD4 + and
CD8 + T cells were low [78]. Decreased number and fatigue of
T cells are related to high mortality and severe COVID-19 [79–
81]. Low CD4 + T cell counts were also associated with the
longer length of ICU treatment [82]. One reason that might
explain low T cell count is the direct inhibition from cytokines.
For example, increased serum IL-17 is found in critical patients
[67]. IL-17, which Th17 produces, is responsible for T cell
suppression. In addition, direct T cell inhibition from cytokines
such as IL-6, IL-10, or TNF may also contribute [78].
However, another elegant explanation is that the decreased
number and lower DCs maturation causes the lack of optimal
priming of T cells, resulting in delays of T cells movement.
Studies on 32 COVID-19 patients with severe symptoms trea­
ted at Heidelberg University Hospital showed low CD8+ and

myeloid DCs counts of patients’ blood cultures [67]. The study
results to look at the immune system profiles of COVID-19
patients in Prague with peripheral and culture blood isolation
methods showed decreased expression of HLA-DR and DCs
maturation markers such as CD80 and CD86 in all subsets of
DCs [83]. As explained in the previous section, T cell priming
would not have occurred without DCs’ co-stimulatory
molecules.
Lastly, moDC infected with SARS-CoV-2 may cause T cell
death. Research shows increased Tumor Necrosis Factor-
related Apoptosis-Inducing Ligand (TRAIL) activity in MoDCs
of SARS-CoV patients where TRAIL expression is associated
with the amount of SARS-CoV virus [84]. Single-Cell
Sequencing of blood mononuclear cells infected with SARS-
CoV-2 showed a similar thing: increased expression of TRAIL
and its receptors on T cells [85]. TRAIL is a molecule that plays
a role in inducing cellular apoptosis pathways. The bond
between TRAIL and T cells leads to the Death-Inducing
Signaling Complex (DISC) recruitment, resulting in cell death
[86]. Thus, infected DCs can directly affect T cell lymphopenia
due to apoptosis activity through TRAIL.
Abnormalities in the adaptive immune response can also
be caused through other pathways. For example, the SARS-
CoV-2 virus can activate the nuclear factor kappa-light-chain
enhancer of activated B cells (NFkB). Furthermore, NFkB
induces tolerogenic phenotypes, which are immunosuppres­
sive, through the production of IL-10 [87]. Therefore, in a state
of viral infection, suppression of NFkB activity is needed to
increase the activity of the immune response mediated by IFN
[88]. In contrast, there was an increase in the expression of the
Programmed Death-Ligand 1 (PD-L1) program, which plays
a role in inhibiting the adaptive immune response [83].
Failure to change from innate to the adaptive immune
response in SARS-CoV-2 infection led to worsening cases of
COVID-19 infection. Disruption of DCs’ ability to accommodate
such changes is an integral part of the pathogenesis of COVID-
19 (Figure 2). In addition, DCs has an extensive role in the
immune response. Therefore, the COVID-19 vaccination
Figure 2. Immune Response to SARS-COV-2 Infection. SARS-CoV-2 can infect DC mainly via DC-SIGN receptors. Infected DC become dysfunctional, causing
inadequate IFN-1 response, decreased DC maturation, upregulation of pro-inflammatory cytokines, inhibition of adaptive immunity via PD-L1 and NFkB, and
T cell apoptosis via TRAIL. These cause the failure of innate and adaptive immunity.
EXPERT REVIEW OF VACCINES 5
approach that focuses on protecting and improving DCs can
result in faster virus clearance and a better prognosis.
4. Dendritic cell-based vaccine against SARS-CoV-2
There are several reasons to develop DCs-based vaccines for
the prevention of COVID-19. First, SARS-CoV-2 causes DCs
dysfunction, making DCs an appropriate vaccination target
(Figure 3). In addition, stimulation of DCs results in a robust
T cell response [46]. The response of T cells to SARS-CoV-2
lasted longer than the humoral response, which is up to
10 months after infection [89]. Interestingly, research on SARS-
CoV showed that memory T cell responses to the virus could
survive up to 17 years after infection [90]. DCs-based vaccine
might elicit T cell response, which is protective against infec­
tion, this includes formation of memory T cells [46]. Unlike
neutralizing antibody, which is expected to diminish over
time, several findings suggest that T cell responses can be
retained for a long period, even years [89,90]. In this case,
booster doses might only need to be given after a long
time, and might not even be necessary. Hence, DCs-based
vaccine can be a way to acquire long-term immunity.
Second, the DCs-based vaccine also might induce broader
spectrum immunity. Evidence shows that memory T cell
responses remain effective against VoC [91]. DCs-based vac­
cine can elicit such a response. In addition, DCs can trigger the
formation of germinal center (GC) response to form B cells
that can recognize variants [92]. DCs induces GC response in
two ways: converting naïve T cells into follicular helper T cells
and migration of follicular DCs [58]. Thus, DCs-based vaccina­
tion is particularly suitable for fighting viruses with high muta­
tion rates such as SARS-CoV-2.
5. Ex vivo approach: challenges and opportunities
Immunization targeting DCs can be done via ex vivo loading
and in vivo targeting. In the ex vivo loading approach, antigens
are exposed outside the body to DCs isolated from peripheral
6 JONNY ET AL.

Figure 3. DC-based vaccine with ex vivo loading of antigens. Antigen loaded mature DCs are injected back to body, then migrate to secondary lymphoid organ to
induce T cells. DCs are not infected by SARS-CoV-2 so that there’s no immunological dysfunction.

blood monocyte cells and then injected back into the body
[93]. This vaccine is specific and individual. Despite still being
experimental, this approach is also currently being developed
for SARS-CoV-2 vaccination [94]. In contrast, in vivo targeting,
antigen delivery is done by conjugating the desired antigen
with antibodies specific to DCs receptors (e.g. anti-CD40 or
C-type lectin receptor) [95]. Both of these methods have their
respective advantages and disadvantages. However, the ex
vivo loading method is still the primary choice in developing
dendritic cell-based vaccines. Several dendritic cell vaccine
studies that entered the clinical trial employ the ex vivo load­
ing method [7–12,96].
Some studies using ex vivo generated DCs for therapy of
infections are summarized in Table 1. This approach is mostly
developed for chronic infection immunotherapy such as HIV-1,
Hepatitis B, Hepatitis C and HSV [13,14,97–99]. Ex vivo gener­
ated DCs-based vaccine for prevention of viral infection is
deemed unjustifiable due to the high cost of production.
This hinders the progress to understand the full scope of ex
vivo generated DCs in inducing immunity. However, in the
case of COVID-19, the justification to develop this approach
still require a comprehensive cost-benefit analysis. The efficacy
of currently available COVID-19 vaccines are decreasing over­
time, and the emergence of variants are pushing for the

Table 1. Studies of DCs-based vaccines for chronic infections.

Study
(year) Population (N*, Duration) Treatment Result Ref**
Chen et al HBV-infected patients (12 Autologous PMBC Derived DCs Pulsed Suppression of HBV replication, Viral load reduction, HBeAg [14]
(2005) subjects, 1 year) With HbsAg elimination and promotion of HBeAg/anti- HBe transformation
Wang et al Hepatitis B-positive Autologous PMBC DCs No increase in [97]
(2015) Patients with Pulsed With Autologous Irradiated hepatic transaminases, bilirubin, prothrombin time, hepatitis B
Hepatocellular Carcinoma Tumor Stem Cells antigens, or viral DNA
(15 subjects, 8 weeks)
Mekonnen C57BL6 mice (7 subjects, Necrotized DC2.4 cell line expressing Increased the breadth of T-cell responses and enhanced the [108]
et al 2 weeks) HCV NS3 production of IL-2, TNF-α, and IFN-γ by effector memory CD4
(2020) + and CD8 + T cells, induced a greater influx and activation of
cross-presenting CD11c+ CD8α+ DC and necrosis-sensing Clec9A
+ DC in the draining lymph nodes, enhanced clearance of NS3-
positive hepatocytes from the livers
Lu et al Untreated HIV-1-infected Autologous PMBC derived DCs loaded Decreased plasma viral load, prolonged suppression of viral load for [13]
(2004) patients (18 subjects, with autologous aldrithiol- at least 1 year correlated with HIV-1-specifc interleukin-2 or
1 year) 2-inactivated HIV-1 interferon-γ-expressing CD4 + T cells and with HIV-1 gag–specific
perforin-expressing CD8+ effector cells
Surenaud Antiretroviral treated HIV- Autologous PMBC derived IFNα DCs Induced and/or expanded HIV-specific CD8 + T cells producing IFNγ, [98]
et al 1-infected patients (16 loaded with HIV-1 lipopolipeptide perforin, granzyme A and granzyme B, and also CD4 + T cells
(2019) subjects, 24 weeks) secreting IFNγ, IL-2 and IL- 13
Leplina Recurrent HSV-1 infected Autologous PMBC derived DCs loaded Reduction in the recurrence rate and significant enhancement of the [99]
(2016) patients (14 subjects, with HSV-1 recombinant viral inter-recurrent time, induction of an antigen-specific response to
9 months) glycoprotein D (HSV1gD) HCV1gD, reduced mitogenic responsiveness of mono- nuclear
cells
*N = Total number of subjects in the study, **Ref = Reference

discovery of next generation vaccines [4,5]. The potential in
inducing long-term and broad immunity by DCs-based vac­
cine might eliminate the need for frequent booster vaccines,
thus in the long run the total cost of production and distribu­
tion of ex vivo generated DCs vaccine can be comparable to
conventional vaccines. Another aspect that should be consid­
ered is the feasibility of wide distribution due to the fact that
this vaccine production requires a highly trained staff in spe­
cific facilities. However, vaccines made point-of-care such as
hospitals and medical laboratories can be the solution to this
problem [100]. In conclusion, cost and practical limitation of
this approach should not limit the potential benefit (Table 2).
Furthermore, in the context of the SARS-CoV-2 vaccine, the
world is in a race against time [101]. Therefore, the ex vivo
presentation of antigens is currently an appropriate method.
Meanwhile, in vivo DCs targeting still needs to be refined. This
method also has the following advantages:
First, the presentation of antigens outside the body will
bypass DCs antigen presentation process that is key in initiat­
ing the immune response. The process of antigen presentation
in the body is highly complex. Not all antigens that enter the
body are successfully taken up and presented through DCs.
Antigens must meet with DCs directly for the process to occur.
This process is influenced by several factors: availability of
dendritic cells, the presence of PRR (Pathogen Recognition
Receptors), a condition that supports DCs maturation and
differentiation, and activation of antigen processing pathways
through the corresponding compartment [23,43,49].
Deficiency in one of these factors will make the failure of
antigen presentation by DCs. Ex vivo antigen presentation
will cut through such a complicated process.
Second, ex vivo antigen presentation results in a sufficient
number of mature DCs for T cells priming. A study shows that
it takes at least 85 mature DCs to induce T cells response [55].
Moreover, large amounts of antigens are required because the
pMHC only lasts for a short time [40]. Appropriate cytokines
are also needed as maturation signals [43]. When done outside
the body, antigen presentation occurs in a controlled environ­
ment, where the number of DCs, maturation signals, and
antigens are known. In addition, by isolating DCs ex vivo, the
antigen is presented only to the DCs and not other cells. Thus,
this method ensures the development of mature DCs in suffi­
cient quantities for T cells priming.
Third, the ex vivo antigen presentation method produces
high-quality DCs. DCs can be derived from peripheral blood
mononuclear cells when stimulated by IL-4 and GM-CSF
[47,102]. In our study, DCs were obtained by incubation of
peripheral blood mononuclear cells for 5 days within differen­
tiation media [100]. Those DCs are subsequently incubated with
Table 2. Advantages and disadvantages of Ex vivo loading.
Advantages Disadvantages
(1) Bypasses complicated antigen pre­ (1) Relatively high cost (depends on
sentation process. the number of production).
(2) Results in a sufficient number of (2) Require specific facilities for vac­
mature DCs for T cells priming. cine production.
(3) Produces high-quality DCs.
(4) Safe and causes fewer adverse
events.
EXPERT REVIEW OF VACCINES 7
the S-protein of SARS-CoV-2 for 2 days. This process is carefully
controlled, and the quality of the DCs can be checked prior to
administration. High-quality mature DCs can migrate efficiently
to the secondary lymphoid organs, where they initiate the
innate and adaptive immune response to SARS-CoV-2. In addi­
tion, there is evidence that DCs actively spread antigens to
other APCs through cross-dressing [53]. This ability increases
the adequate number of APCs and keeps T cell priming from
occurring even though the donor DCs cannot directly prime
T cells. Whereas in vivo DCs-based vaccination, the quality of
DCs is affected by the difficulty of controlling each individual’s
state of immunity. For example, there is a decrease in the
quality of DCs in people with chronic diseases and the elderly
[103–105]. Furthermore, a DCs-related genetic disorder can
impair DCs’ function [106]. Therefore, in vivo DCs targeting
vaccination in that population might be ineffective.
Fourth, the body can tolerate autologous DCs vaccine with
ex vivo antigen presentation. This method is proved safe from
previous studies and caused only negligible toxicity [7–12].
Side effects are limited to mild local and systemic reactions
such as injection pain, joint pain, and flu-like syndrome. There
are no deaths or life-threatening events related to the auto­
logous DCs vaccine. When an antigen enters the body, the
immune system activates the signaling pathways distinguish­
ing self and non-self [107]. However, autologous DCs are
recognized as a part of the self so that the body can tolerate
the material well without a reaction of foreign body rejection.
6. Conclusion
We have outlined that DCs are the most potent APCs that can
activate a wide array of T-cell immunity. DCs play a crucial role
in innate and adaptive immunity. SARS-CoV-2 can infect DCs
resulting in disruption of innate and adaptive immunity.
Dendritic cell vaccine using ex vivo approach can result in
better clinical outcome.
7. Expert opinion
DCs can activate various T-cells responses and are essential in
T-cells fate determination [38]. In innate immunity, pDCs are
the primary source of IFN-1. Crosstalk between DCs, NK cells,
and macrophages create the cytokine milieu suitable for
innate immune responses. Furthermore, DCs are responsible
for antigen presentation, which is key to adaptive immune
response. T-cells priming by DC is a highly efficient process
orchestrated by various cytokines and chemokines for optimal
cell positioning. On the other hand, SARS-CoV-2 can infect DCs
and causes dysfunction in innate and adaptive immunity [6].
As postulated in this review, this virus can directly infect DCs
resulting in abnormal cytokines production, T-cell depletion
and fatigue, and adaptive immunity inhibition. Therefore, the
vaccination approach by targeting and protecting DCs might
result in faster viral clearance and better clinical outcomes.
Here, we have outlined the rationale to develop DCs-based
vaccine for prevention of COVID-19. Although mainly developed
for treatment of cancer and chronic infections, this method can
also be extended for prevention of SARS-CoV-2 infection [7–
12,96]. Some previous studies show that DCs based vaccine
8 JONNY ET AL.
can induce immunity against viral infection through activation
of T-cells immunity [13,14,98,99,108]. Interestingly, even when
the immune system is compromised such as in HIV infection,
DCs vaccines are still capable to induce T-cell response resulting
in reduction of viral load [13,98]. So that, it is possible that DCs
vaccine will remain effective for people with weaker immunity,
such as children, elderly, and people with chronic illnesses.
DCs are responsible for a wide array of T cell responses,
thus utilizing DCs as vaccine carrier might induce a broad and
long-term immunity for SARS-CoV-2 prevention [46,89,90].
There is also a possibility of induction of GC response by
DCs. Even though the mechanism is still unclear, GCs response
can induce production of antibody with broader neutralization
capacity through clonal evolution [92]. So that, alongside
clinical efficacy, T-cell and GC response elicited by DCs should
be taken into consideration in future studies.
Currently, ex vivo loading is the most feasible method for
DC-based vaccine development. Most of the studies that
entered clinical trial employ this approach [7–12]. There are
several advantages to this approach as previously mentioned.
This method bypasses DCs antigen presentation in a highly
controllable environment so T cells priming can occur. This
approach ensures the generation of a high-quality DCs in
sufficient quantities for T cells priming. Furthermore, ex vivo
loading produces a vaccine with very few adverse reactions
due to its autologous properties.
However, the cost of production of this approach is consider­
ably high, but this depends on the number of productions.
Vaccine production by this method also requires certain facilities,
so wide distribution might not be practical. On the other hand,
the possibility of inducing long-term and broader immunity will
eliminate the need for frequent boosters. So that, the total cost
of production might eventually become cost-effective in com­
parison to conventional vaccine. Production at point-of-care,
such as hospital and medical laboratories, can be the solution
to practical limitation of this approach. In conclusion, this
approach is appropriate for the COVID-19 vaccine, and the safety
profile of this approach should allow clinical study to proceed.
Funding
This paper was funded by Cellcure Center RSPAD Gatot Soebroto.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
ORCID
Jonny Jonny http://orcid.org/0000-0002-8564-7430
Enda Cindylosa Sitepu http://orcid.org/0000-0002-8112-7198
References
1. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients
with Pneumonia in China, 2019. N Engl J Med. 2020;382:727–733.
2. Randolph HE, Barreiro LB. Herd immunity: understanding
COVID-19. Immunity. 2020;52:737–741.
3. Lopez Bernal J, Andrews N, Gower C, et al. Effectiveness of Covid-19
vaccines against the B.1.617.2 (Delta) variant. N Engl J Med.
2021;385:585–594.
4. Sabino EC, Buss LF, Carvalho MPS, et al. Resurgence of COVID-19 in
Manaus, Brazil, despite high seroprevalence. Lancet.
2021;397:452–455.
5. Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2
variants B.1.351 and B.1.1.7. Nature. 2021;593:130–135.
6. Borges RC, Hohmann MS, Borghi SM. Dendritic cells in COVID-19
immunopathogenesis: insights for a possible role in determining
disease outcome. Int Rev Immunol. 2021;40:108–125. 1–2
7. Jiang N, Qiao G, Wang X, et al. Dendritic Cell/Cytokine-Induced
killer cell immunotherapy combined with S-1 in patients with
advanced pancreatic cancer: a prospective study. Clin Cancer Res.
2017;23:5066–5073.
8. Zhang W, Lu X, Cui P, et al. Phase I/II clinical trial of a Wilms’ tumor
1-targeted dendritic cell vaccination-based immunotherapy in
patients with advanced cancer. Cancer Immunol Immunother.
2019;68:121–130.
9. Liau LM, Ashkan K, Tran DD, et al. First results on survival from
a large phase 3 clinical trial of an autologous dendritic cell vaccine
in newly diagnosed glioblastoma. J Transl Med. 2018;16:142.
10. Wang Q-T, Nie Y, Sun S-N, et al. Tumor-associated antigen-based
personalized dendritic cell vaccine in solid tumor patients. Cancer
Immunol Immunother. 2020;69:1375–1387.
11. Bulgarelli J, Tazzari M, Granato AM, et al. Dendritic cell vaccination
in metastatic melanoma turns “Non-T Cell inflamed” Into “T-Cell
inflamed” Tumors. Front Immunol. 2019;10:2353.
12. Lee JM, Lee M-H, Garon E, et al. Phase I Trial of Intratumoral
Injection of CCL21 Gene-Modified dendritic cells in lung cancer
elicits Tumor-Specific immune responses and CD8(+) T-cell
infiltration. Clin Cancer Res. 2017;23:4556–4568.
13. Lu W, Arraes LC, Ferreira WT, et al. Therapeutic dendritic-cell vac­
cine for chronic HIV-1 infection. Nat Med. 2004;10:1359–1365.
14. Chen M, Y-G L, Zhang D-Z, et al. Therapeutic effect of autologous
dendritic cell vaccine on patients with chronic hepatitis B: a clinical
study. World J Gastroenterol. 2005;11:1806–1808.
15. Decker WK, Safdar A. Dendritic cell vaccines for the immunocom­
promised patient: prevention of influenza virus infection. Expert
Rev Vaccines. 2010;9:721–730.
16. Marshall JS, Warrington R, Watson W, et al. An introduction to
immunology and immunopathology. Allergy, Asthma Clin
Immunol. 2018;14:5–14.
17. Varadé J, Magadán S, González-Fernández Á. Human immunology
and immunotherapy: main achievements and challenges. Cell Mol
Immunol. 2021;18:805–828.
18. Stambas J, Lu C, Tripp RA. Innate and adaptive immune responses
in respiratory virus infection: implications for the clinic. Expert Rev
Respir Med. 2020;14:1141–1147.
19. Riera Romo M, Pérez-Martínez D, Castillo Ferrer C. Innate immunity
in vertebrates: an overview. Immunology. 2016 April 05.
2016;148:125–139.
20. Bieber K, Autenrieth SE. Dendritic cell development in infection.
Mol Immunol. 2020;121:111–117.
21. Ivashkiv LB, Donlin LT. Regulation of type I interferon responses.
Nat Rev Immunol. 2014;14:36–49.
22. Mitchell D, Chintala S, Dey M. Plasmacytoid dendritic cell in immu­
nity and cancer. J Neuroimmunol. 2018;322:63–73.
23. Amon L, Lehmann CHK, Baranska A, et al. Transcriptional control of
dendritic cell development and functions. 1st (Amsterdam,
Nedherland: Elsevier Inc) ed. Int. Rev. Cell Mol. Biol. Elsevier Inc.;
2019.
24. Reizis B. Plasmacytoid dendritic cells: development, regulation, and
function. Immunity. 2019;50:37–50.

25. Oth T, Vanderlocht J, Van Elssen CHMJ, et al. Pathogen-
Associated molecular patterns induced crosstalk between den­
dritic cells, T helper cells, and natural killer helper cells can
improve dendritic cell vaccination. Mediators Inflamm. 2016;
2016. 1–12
26. Lee AJ, Ashkar AA. The dual nature of type I and type II interferons.
Front Immunol. 2018. p. 2061. 9
27. Kwon B. IFN-γ in tissue-immune homeostasis and antitumor immu­
nity. Cell Mol Immunol. 2018;15:531–532.
28. Oth T, Habets THPM, Germeraad WTV, et al. Pathogen recognition
by NK cells amplifies the pro-inflammatory cytokine production of
monocyte-derived DC via IFN-γ. BMC Immunol. 2018;19:1–13.
29. Kang S, Kumanogoh A. The spectrum of macrophage activation by
immunometabolism. Int Immunol. 2020;32:467–473.
30. Gupta U, Hira SK, Singh R, et al. Essential role of TNF-α in gamma
c cytokine aided crosstalk between dendritic cells and natural killer
cells in experimental murine lymphoma. Int Immunopharmacol.
2020;78:106031.
31. Kobayashi S, Sakurai T, So T, et al. TNF Receptor–Associated factor 5
limits function of plasmacytoid dendritic cells by controlling IFN
regulatory factor 5 expression. J Immunol. 2019;203:1447–1456.
32. Liu S-Q, Ren C, Yao R-Q, et al. TNF-α-induced protein 8-like 2
negatively regulates the immune function of dendritic cells by
suppressing autophagy via the TAK1/JNK pathway in septic mice.
Cell Death Dis. 2021 12 ;1032.
33. Murphy K, Weaver C. Janeway’s immunobiology. 9th ed. New York
and London: Garland Science : Taylor & Francis Group; 2017.
34. Netea MG, Schlitzer A, Placek K, et al. Innate and adaptive immune
memory: an evolutionary continuum in the hosts response to
pathogens. Cell Host Microbe. 2019;25:13–26.
35. Sun L, Wang X, Saredy J, et al. Innate-adaptive immunity interplay
and redox regulation in immune response. Redox Biol.
2020;37:101759.
36. Normann N, Tietz G, Kühn A, et al. Pathogen-specific antibody
profiles in patients with severe systemic infections. Eur Cells
Mater. 2020;39:171–182.
37. Balan S, Saxena M, Bhardwaj N. Dendritic cell subsets and locations.
1st (Amsterdam, Netherland: Elsevier Inc) ed. Int. Rev. Cell Mol. Biol.
Elsevier Inc. 2019.
38. Constantino J, Gomes C, Falcão A, et al. Dendritic cell-based immu­
notherapy: a basic review and recent advances. Immunol Res.
2017;65:798–810.
39. Collin M, Bigley V. Human dendritic cell subsets: an update.
Immunology. 2018;154:3–20.
40. Villadangos JA, Schnorrer P. Intrinsic and cooperative
antigen-presenting functions of dendritic-cell subsets in vivo. Nat
Rev Immunol. 2007;7:543–555.
41. Alculumbre SG, Saint-André V, Di Domizio J, et al. Diversification of
human plasmacytoid predendritic cells in response to a single
stimulus article. Nat Immunol. 2018;19:63–75.
42. Worbs T, Hammerschmidt SI, Förster R. . Nat. Rev. Immunol. (Berlin,
Germany: Nature Publishing Group); 2017. p. 30–48.
43. Hilligan KL, Ronchese F. Antigen presentation by dendritic cells and
their instruction of CD4+ T helper cell responses. Cell Mol Immunol.
2020;17:587–599.
44. Fitzgerald KA, Kagan JC. Toll-like receptors and the control of
immunity. Cell. 2020;180:1044–1066.
45. Kim MK, Kim J. Properties of immature and mature dendritic cells:
phenotype, morphology, phagocytosis, and migration. RSC Adv.
2019;9:11230–11238.
46. Shin KS, Jeon I, Kim BS, et al. Monocyte-derived dendritic cells
dictate the memory differentiation of CD8+ T cells during acute
infection. Front Immunol. 2019;10:5–7.
47. Gu Y, Zhao X, rong SX. Ex vivo pulsed dendritic cell vaccination
against cancer. Acta Pharmacol Sin. 2020;41:959–969.
48. Blum JS, Wearsch PA, Cresswell P. Pathways of antigen processing.
Annu Rev Immunol. 2013;31:443–473.
49. Roche PA, Cresswell P. . Myeloid Cells Heal Dis A Synth (Wiley
Online Book). 2017;209–223:9781683670667 doi:10.1128/
9781555819194.ch11.
EXPERT REVIEW OF VACCINES 9
50. Lindenbergh MFS, Stoorvogel W. Antigen presentation by extra­
cellular vesicles from professional Antigen-Presenting cells. Annu
Rev Immunol. 2018;36:435–459.
51. Tiberio L, Del Prete A, Schioppa T, et al. Chemokine and chemo­
tactic signals in dendritic cell migration review-article. Cell Mol
Immunol. 2018;15. 15
52. Ugur M, Mueller SN. T cell and dendritic cell interactions in lym­
phoid organs: more than just being in the right place at the right
time. Immunol Rev. 2019;289:115–128.
53. Gurevich I, Feferman T, Milo I, et al. Active dissemination of cellular
antigens by DCs facilitates CD8+ T-cell priming in lymph nodes. Eur
J Immunol. 2017;47:1802–1818.
54. Miller MJ, Hejazi AS, Wei SH, et al. T cell repertoire scanning is
promoted by dynamic dendritic cell behavior and random T cell
motility in the lymph node. Proc Natl Acad Sci U S A.
2004;101:998–1003.
55. Celli S, Day M, Müller AJ, et al. How many dendritic cells are
required to initiate a T-cell response? Blood. 2012;120:3945–3948.
56. Schmidt ME, Varga SM. The CD8 T cell response to respiratory virus
infections. Front Immunol. 2018;9. 10.3389/fimmu.2018.00678
57. Reed J, Wetzel SA. CD4 + T cell differentiation and activation.
Methods Mol Biol. 2018 1803 . p. 335–351.
58. Koutsakos M, Nguyen THO, Kedzierska K. With a little help from
T follicular helper friends: humoral immunity to influenza
vaccination. J Immunol. 2019;202:360–367.
59. Hirano T, Murakami M. COVID-19: a new virus, but a familiar recep­
tor and cytokine release syndrome. Immunity. 2020;52:731–733.
60. Wang K, Chen W, Zhang Z, et al. CD147-spike protein is a novel
route for SARS-CoV-2 infection to host cells. Signal Transduct
Target Ther. 2020;1–10. 5
61. Taefehshokr N, Taefehshokr S, Hemmat N, et al. Covid-19: perspec­
tives on innate immune evasion. Front Immunol. 2020;11:580641.
62. Cai G, Du M, Boss Y, et al. SARS-CoV-2 impairs dendritic cells and
regulates DC-SIGN gene expression in tissues. Int J Mol Sci.
2021;22:1–20.
63. Chu H, Zhou J, Ho-Yin Wong B, et al. Productive replication of
middle East respiratory syndrome coronavirus in
monocyte-derived dendritic cells modulates innate immune
response. Virology. 2014;454–455:197–205.
64. Yang D, Chu H, Hou Y, et al. Attenuated interferon and proinflam­
matory response in SARS-CoV-2-infected human dendritic cells is
associated with viral antagonism of STAT1 phosphorylation. J Infect
Dis. 2020;222:734–745.
65. Chi Y, Ge Y, Wu B, et al. Serum cytokine and chemokine profile in
relation to the severity of coronavirus disease 2019 in China.
J Infect Dis. 2020;222:746–754.
66. Huang C, Wang Y, Li X, et al. Clinical features of patients infected
with 2019 novel coronavirus in Wuhan, China. Lancet.
2020;395:497–506.
67. Tiwari-Heckler S, Rauber C, Longhi MS, et al. Dysregulated host
response in severe acute respiratory syndrome coronavirus
2-Induced critical illness. Open Forum Infect Dis. 2021;8:1–9.
68. Niles MA, Gogesch P, Kronhart S, et al. Macrophages and den­
dritic cells are not the major source of Pro-Inflammatory cyto­
kines upon SARS-CoV-2 infection. Front Immunol. 2021;12:1–12.
69. Schulte-Schrepping J, Reusch N, Paclik D, et al. Severe
COVID-19 is marked by a dysregulated myeloid cell
compartment. Cell. 2020;182:1419–1440.e23.
70. Zhou R, Kkw T, Wong YC, et al. Acute SARS-CoV-2 infection
impairs dendritic cell and T cell responses. Immunity.
2020;53:1–14.
71. Blanco-Melo D, Nilsson-Payant BE, Liu WC, et al. Imbalanced host
response to SARS-CoV-2 drives development of COVID-19. Cell.
2020;181:1036–1045.e9.
72. Ribero MS, Jouvenet N, Dreux M, et al. Interplay between
SARS-CoV-2 and the type I interferon response. PLoS Pathog.
2020;16:1–22.
73. Peiris JSM, Chu CM, Cheng VCC Clinical progression and viral load
in a community outbreak of coronavirus-associated SARS pneumo­
nia: a prospective study , et al. Lancet. , . 2003;361:1767–1772.
10 JONNY ET AL.
74. Channappanavar R, Fehr AR, Vijay R, et al. Dysregulated Type
I interferon and inflammatory Monocyte-Macrophage responses
cause lethal Pneumonia in SARS-CoV-Infected mice. Cell Host
Microbe. 2016;19:181–193.
75. Zhang Q, Liu Z, Moncada-Velez M, et al. Inborn errors of type I IFN
immunity in patients with life-threatening COVID-19. Science (80).
2020;370.
76. Galati D, Zanotta S, Capitelli L, et al. A bird’s eye view on the role of
dendritic cells in SARS-CoV-2 infection: perspectives for immune-
based vaccines. Allergy. 2021: 00. p. 1–11.
77. Bastard P, Rosen LB, Zhang Q, et al. Autoantibodies against type
I IFNs in patients with life-threatening COVID-19. Science (80).
2020;370.
78. Chen Z, John Wherry E. T cell responses in patients with COVID-19.
Nat Rev Immunol. 2020;20:529–536.
79. Du RH, Liang LR, Yang CQ, et al. Predictors of mortality for patients
with COVID-19 pneumonia caused by SARSCoV- 2: a prospective
cohort study. Eur Respir J. 2020;3:55.
80. Xu B, yu FC, lu WANGA, et al. Suppressed T cell-mediated immunity
in patients with COVID-19: a clinical retrospective study in Wuhan,
China. J Infect. 2020;81:e51–e60.
81. Diao B, Wang C, Tan Y, et al. Reduction and functional exhaustion
of T cells in patients with coronavirus disease 2019 (COVID-19).
Front Immunol. 2020. p. 827. 11
82. Chen J, Qi T, Liu L, et al. Clinical progression of patients with
COVID-19 in Shanghai, China. J Infect. 2020;80:e1–e6.
83. Parackova Z, Zentsova I, Bloomfield M. Disharmonic inflammatory
signatures in COVID-19 : augmented neutrophils’ but impaired
monocytes’ and dendritic cells’ responsiveness. Cells. 2020;9. 10
2206
84. Law HKW, Cheung CY, Sia SF, et al. Toll-like receptors, chemokine
receptors and death receptor ligands responses in SARS corona­
virus infected human monocyte derived dendritic cells. BMC
Immunol. 2009;10:1–12.
85. Zhu L, Yang P, Zhao Y, et al. Single-Cell sequencing of peripheral
mononuclear cells reveals distinct immune response landscapes of
COVID-19 and influenza patients. Immunity. 2020;53:685–696.e3.
86. von Karstedt S, Montinaro A, Walczak H. Exploring the TRAILs less
travelled: TRAIL in cancer biology and therapy. Nat Rev Cancer.
2017;17:352–366.
87. Catanzaro M, Fagiani F, Racchi M, et al. Immune response in
COVID-19: addressing a pharmacological challenge by targeting
pathways triggered by SARS-CoV-2. Signal Transduct Target Ther.
2020;5. 10.1038/s41392-020-0191-1
88. DeDiego ML, Nieto-Torres JL, Regla-Nava JA, et al. Inhibition of NF-
B-Mediated inflammation in severe acute respiratory syndrome
Coronavirus-Infected mice increases survival. J Virol.
2014;88:913–924.
89. Jung JH, Rha MS, Sa M, et al. SARS-CoV-2-specific T cell memory is
sustained in COVID-19 convalescent patients for 10 months with
successful development of stem cell-like memory T cells. Nat
Commun. 2021;12:1–12.
90. Le Bert N, Tan AT, Kunasegaran K, et al. SARS-CoV-2-specific T cell
immunity in cases of COVID-19 and SARS, and uninfected controls.
Nature. 2020;584:457–462.
91. Tarke A, Sidney J, Methot N, et al. Impact of SARS-CoV-2 variants on
the total CD4+ and CD8+ T cell reactivity in infected or vaccinated
individuals. Cell Reports Med. 2021;2:100355.
92. Laidlaw BJ, Ellebedy AH. The germinal centre B cell response to
SARS-CoV-2. Nat Rev Immunol. 2022;22:7–18.
93. Sabado RL, Balan S, Bhardwaj N. Dendritic cell-based
immunotherapy. Cell Res. 2017;27:74–95.
94. Martínez L, Malaina I, Salcines-Cuevas D, et al. First computational
design using lambda-superstrings and in vivo validation of
SARS-CoV-2 vaccine. Sci Rep. 2022;12:2–13.
95. Tacken PJ, De Vries IJM, Torensma R, et al. Dendritic-cell immu­
notherapy: from ex vivo loading to in vivo targeting. Nat Rev
Immunol. 2007. p. 790–802. 7
96. Dillman RO, Cornforth AN, Nistor GI, et al. Randomized phase II trial
of autologous dendritic cell vaccines versus autologous tumor cell
vaccines in metastatic melanoma: 5-year follow up and additional
analyses. J Immunother Cancer. 2018;6:19.
97. Wang X, Bayer ME, Chen X, et al. Phase I trial of active specific
immunotherapy with autologous dendritic cells pulsed with
autologous irradiated tumor stem cells in hepatitis B-positive
patients with hepatocellular carcinoma. J Surg Oncol.
2015;111:862–867.
98. Surenaud M, Montes M, Lindestam Arlehamn CS, et al. Anti-HIV
potency of T-cell responses elicited by dendritic cell therapeutic
vaccination. PLoS Pathog. 2019;15:1–21.
99. Leplina O, Starostina N, Zheltova O, et al. Dendritic cell-based
vaccines in treating recurrent herpes labialis: results of pilot clinical
study. Hum Vaccines Immunother. 2016;12:3029–3035.
100. Jonny J. Preventive dendritic cell vaccine, AV-COVID-19, in subjects
not actively infected with COVID-19 [Internet]. Identifier
NCT00103181. cited 2022 Apr 27]. Available from 2022 Apr 27:
https://clinicaltrials.gov/ct2/show/NCT05007496.
101. Khuroo MS, Khuroo M, Khuroo MS, et al. COVID-19 vaccines: a race
against time in the middle of death and devastation! J Clin Exp
Hepatol. 2020;10:610–621.
102. Sung SSJ. Monocyte-derived dendritic cells as antigen-presenting
cells in T-cell proliferation and cytokine production. Methods Mol
Biol. 2019;2020:131–141.
103. Wong C, Goldstein DR. Impact of aging on antigen presentation cell
function of dendritic cells. Curr Opin Immunol. 2013;25:535–541.
104. Zacca ER, Crespo MI, Acland RP, et al. Aging Impairs the ability
of conventional dendritic cells to cross-prime CD8+ T cells upon
stimulation with a TLR7 Ligand. PLoS One. 2015;10:1–20.
105. Li S, Wu J, Zhu S, et al. Disease-associated plasmacytoid dendri­
tic cells. Front Immunol. 2017;8:1–12.
106. Asano T, Immunol S, Asano T, et al. X-linked recessive TLR7 defi­
ciency in ~ 1 % of men under 60 years old with life-threatening
COVID-19. Sci Immunol. 2021;4348:1–31.
107. Forsdyke DR. Lymphocyte repertoire selection and intracellular
self/non-self-discrimination: historical overview. Immunol Cell
Biol. 2015;93:297–304.
108. Mekonnen ZA, Masavuli MG, Yu W, et al. Enhanced T cell responses
induced by a necrotic dendritic cell vaccine, expressing HCV NS3.
Front Microbiol. 2020;11:1–13.