Immunotherapy Advances, 2021, Vol. 1, No.

1, 1–16
doi:10.1093/immadv/ltaa007
Advance Access Publication Date: 25 November 2020
Review

Review

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Recent advances in immunotherapies
against infectious diseases
Dharanidharan Ramamurthy1, Trishana Nundalall1, Sanele Cingo1,
Neelakshi Mungra1, Maryam Karaan1, Krupa Naran1,† and Stefan Barth1,2,†,*,
1
Medical Biotechnology and Immunotherapy Research Unit, Institute of Infectious Disease and Molecular
Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa and 2Cancer
Biotechnology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of
Cape Town, Cape Town, South Africa
†
These authors contributed equally to this work.
*Correspondence: Stefan Barth, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular
Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town 7700, South Africa. Tel: +27-21-406-6938; Email: stefan.
[email protected]

Received 15 October 2020; Revised 10 November 2020; Accepted 19 November 2020

Summary
Immunotherapies are disease management strategies that target or manipulate components of the
immune system. Infectious diseases pose a significant threat to human health as evidenced by coun-
tries continuing to grapple with several emerging and re-emerging diseases, the most recent global
health threat being the SARS-CoV2 pandemic. As such, various immunotherapeutic approaches are
increasingly being investigated as alternative therapies for infectious diseases, resulting in significant
advances towards the uncovering of pathogen–host immunity interactions. Novel and innovative
therapeutic strategies are necessary to overcome the challenges typically faced by existing infec-
tious disease prevention and control methods such as lack of adequate efficacy, drug toxicity, and the
emergence of drug resistance. As evidenced by recent developments and success of pharmaceuticals
such as monoclonal antibodies (mAbs), immunotherapies already show abundant promise to over-
come such limitations while also advancing the frontiers of medicine. In this review, we summarize

Abbreviations: AMA 1: Apical membrane antigen 1; BCG: Bacillus Calmette-Guérin; bNAbs: Broadly neutralizing antibodies; CAR: Chimeric
antigen receptor; cART: Combination antiretroviral therapy; CMV: Cytomegalovirus; CTLA4: Cytotoxic T-lymphocyte-associated pro-
tein 4; Cz: Cruzipai; E or Env: Envelope protei; EBOV: Ebola virus; GM-CSF: Granulocyte-macrophage colony-stimulating factor; gp120:
Glycoprotein 120; HIV: Human immunodeficiency virus; HLA: Human leukocyte antigen; HpHb: Haptoglobin-hemoglobin receptor; iNKT:
Invariant natural killer T-cells; mAbs: Monoclonal antibodies; MAIT: Mucosal-associated invariant T-cells; MHC: Major histocompatibility
complex; MRSA: Methicillin-resistant S. aureus; MSP: Merozoite surface protein; Mtb: Mycobacterium tuberculosis; NK: Natural killer; NKT:
Natural killer T-cells; PD1: Programmed cell death protein 1; PD-L1: Programmed cell death 1 ligand 1; pDNA: Plasmid DNA; prM: Pre-
membrane protein; rhIL-2: Recombinant human interleukin-2; rPV: Recombinant protein-based vaccines; S: Spike protein; TB: Tuberculosis;
TIM3: T-cell immunoglobulin and mucin domain-containing protein 3; TLR4: Toll-like receptor 4; TNF-α: Tumor necrosis factor-α; ZIKV:
Zika virus.

© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Immunology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://
creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium,
1
provided the original work is properly cited. For commercial re-use, please contact [email protected]
2 Immunotherapy Advances, 2021, Vol. 1, No. 1

some of the most notable inroads made to combat infectious disease, over mainly the last 5 years,
through the use of immunotherapies such as vaccines, mAb-based therapies, T-cell-based therapies,
manipulation of cytokine levels, and checkpoint inhibition. While its most general applications are
founded in cancer treatment, advances made towards the curative treatment of human immuno-
deficiency virus, tuberculosis, malaria, zika virus and, most recently COVID-19, reinforce the role of
immunotherapeutic strategies in the broader field of disease control. Ultimately, the comprehensive
specificity, safety, and cost of immunotherapeutics will impact its widespread implementation.

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Keywords: immunotherapy, infectious disease, vaccine, checkpoint inhibition, T-cells

Introduction (iii) antibody-dependent cellular cytotoxicity, which in-

volves the Fc region of the antibody helping to recruit
Immunotherapies manipulate components of the immune
constituents of cell-mediated immunity [such as natural
system to target and eliminate pathogens or diseased
killer (NK) cells, monocytes, and macrophages], and
host cells to offer protection against disease or alleviate
(iv) by complement-dependent cytotoxicity arising from
symptoms. Based on their mechanism of action, they are
the activation of the complement cascade after binding
classified as passive immunotherapies which employ con-
to the target structure. Antibody conjugates use the
stituents produced ex vivo (immune cells or recombinant
targeting domain of a mAb fused to a toxic payload,
antibody derivatives) that are administered to patients,
such as small molecules or apoptosis-inducing toxins
and active immunotherapies which trigger components
to target disease-associated antigens. Once bound to its
of the host immunological memory using virulence fac-
target, they are internalized and release their payload,
tors that activate effectors (T-cells or humoral response)
triggering cell death while aiming at minimal damage to
[1]. Over the decades, several approaches have been de-
healthy tissues [2]. Bi-specific antibodies containing two
scribed and successfully employed, the most prominent
binding domains, in general, one specific for an antigen
among which have been summarized in Fig. 1 [2].
the other for an effector cell, have also been developed.
Vaccines represent the oldest and most successful
By interfering with multiple surface receptors/ligands,
form of immunotherapy [3]. They may confer protection
bispecific antibodies can affect molecules involved in cell
through two broad means: (i) immunological memory
proliferation or inflammatory processes, bring targets
through the administration of immunogens to induce
into close proximity to support protein complexation in
clonal proliferation of antigen-specific lymphocytes, al-
the clotting cascade or recruit immune cells to the dis-
lowing the host immune system to respond more rapidly
eased site circumventing major histocompatibility com-
and effectively against pathogens that it has previously
plex (MHC) engagement [2, 6].
encountered [4], and (ii) conferring passive protection,
One of the most notable immunotherapies of recent
post-infection, through the delivering neutralizing agents
times has been checkpoint blockade therapy which in-
such as antibodies binding to e.g. bacterial antigens/
volves the use of mAbs to disrupt the interaction between
toxins [2]. The success of immunization programs over
immune inhibitory receptor-ligand pairs. Immune check-
the years has contributed to the near or complete eradi-
points are cellular processes that prevent the host immunity
cation of communicable diseases such as smallpox and
from attacking otherwise healthy cells indiscriminately.
polio. In the last three decades, scientific advances have
Blocking disease-associated abnormal immune check-
impacted the establishment of new vaccine platforms
point activation restores normal immune system func-
using recombinant antibodies, nucleic acid-based vac-
tion, thus permitting enhanced immune responses against
cines and improving adjuvants [3].
upregulated ligands. Prominent checkpoint blockade
Monoclonal antibodies (mAbs) have been approved
mAbs target cytotoxic T-lymphocyte-associated protein
for therapeutic use since 1986 and currently have the
4 (CTLA4), programmed cell death 1 ligand 1 (PD-L1),
most widespread applications among immunotherapies
programmed cell death protein 1 (PD1), T-cell immuno-
[2, 5]. mAbs rely on the specificity and selectivity of anti-
globulin, and mucin domain-containing protein 3 (TIM3)
bodies to their antigen and exert their function through
and OX40, which prevent T-cell inhibition and promote
the following mechanisms: (i) by binding to cell surface
effector T-cell activation. Numerous drugs using these
receptors and inducing a signaling cascade, leading to
checkpoint inhibitors have been approved by the U.S
cell death, (ii) the interference of ligand–receptor inter-
Food and Drug Administration for intervention against
actions necessary for continued cell growth or viability,
Immunotherapy Advances, 2021, Vol. 1, No. 13

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Figure 1. Immunotherapeutic advances employed against infectious disease. Most prominent types of immunotherapies de-
scribed fall under three major categories, namely: (A) T-cell engineering strategies that use genetically modified patient-derived
T-cells which are transiently cultured in vitro to express CARs. Such CAR T-cells provides a non-major histocompatibility complex
driven recognition of abnormal cells and thus aid in enhanced targeting and elimination of diseased cells. The activity of native
4 Immunotherapy Advances, 2021, Vol. 1, No. 1

various cancers since their first regulatory approval in immunotherapy, published over mainly the last 5 years.
2011. Their use in combination with other treatments Among the vast repertoire of information available, this
has reported promising outcomes against human im- has allowed us to narrow the viral pathogens discussed
munodeficiency virus (HIV), tuberculosis (TB), and mal- to Ebola, HIV, Zika virus, and SARS-CoV-2. Similarly,
aria and are further described in the sections ‘Checkpoint we have limited the antibacterial therapeutics pre-
inhibition’ and ‘Checkpoint blockade’ [7, 8]. sented, mostly to TB, with Pseudomonas aeruginosa and
Cytokines are soluble proteins that mediate intercel- Staphylococcus aureus being specifically mentioned to

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lular communication for a variety of biological processes highlight the importance of immunotherapy in circum-
including cell proliferation, inflammation, immunity, venting drug resistance in such pathogens. Finally, the
angiogenesis, wound healing, and repair. Cytokines me- antiparasitic therapies have been limited to immunother-
diate signaling fundamental to both disease spread and apies against malaria, leishmaniasis, and trypanosomiasis
control and have been approved for therapeutic use since which are public health threats in Sub-Saharan Africa
1986 [7]. Their use is infectious disease immunotherapy and Latin America. Fungal pathogen affects a small
have been exemplified in the section ‘Cytokine therapy’ population of immunocompromised individuals such as
and in Fig. 3. patients with HIV and was thus considered beyond the
A recently approved immunotherapeutic approach in- scope of this review [2].
volves enhancing T-cell function via a chimeric antigen re-
ceptor (CAR) [9]. CAR-T-cells are engineered to express a Immunotherapies of viral disease
recombinant receptor, usually incorporating a T-cell speci-
Vaccines
ficity determining antibody derivative binding to a specific
receptor expressed on targeted cells fused to a transmem- Nucleic acid vaccines include mRNA or plasmid DNA
brane signaling domain, thus allowing MHC-independent (pDNA) vaccines [10]. Alphavirus genomes are com-
T-cell activation. CAR T-cell therapy is a form of adoptive monly modified into mRNA vaccines where the genes
cell therapy, which involves isolating a patient’s peripheral encoding for structural proteins are replaced with genes
blood T-cells, modifying it to express a CAR ex vivo, then encoding target antigens while conserving the RNA rep-
administering the CAR-T-cells into the patient. As many lication machinery. mRNA vaccines utilize the host’s cel-
first-generation CARs were anergic, subsequent modi- lular machinery to amplify the antigen-encoded RNA and
fications allowed engineering of not only targeting and post-translationally modify the resulting antigens, thereby
transmembrane signaling domains such as a CD3 chain mimicking natural infection [10]. The innate immune
but also by incorporation of a co-stimulatory receptor-like response is therefore stimulated, and the adaptive im-
CD28. The third- and fourth-generation CARs were de- mune system is activated. There are currently no licensed
veloped with the addition of a second co-stimulatory mol- RNA vaccines for human application, however, clinical
ecule and an inducible gene to express pro-inflammatory trials are currently underway to develop mRNA vac-
or pro-proliferative cytokines, respectively [2]. cines expressing the pre-membrane (prM) and envelope
In the present review, using examples of diseases that (E) proteins of the Zika virus (ZIKV) (NCT04064905;
have had the most significant burden and impact on NCT03014089) [11, 12]. Shortly after the discovery of
human health in the last decade, we aim to illustrate the the SARS-CoV-2 genome, an mRNA vaccine encoding
advances made and the relevance of the most important the stabilized perfusion SARS-CoV-2 spike protein en-
immunotherapeutic strategies employed, from litera- tered clinical trial (NCT04283461) [13]. During phase
ture on research in the field of infectious disease and I and II, all participants developed anti-SARS-CoV-2

lymphocytes such as T-cells and natural killer (NK) cells can be enhanced through multiple ways as illustrated in panel B. (B)
Activation of lymphocytes is accomplished through approaches such as vaccinations, that trigger immune memory response to
combat invading pathogens. Checkpoint inhibition therapy aims at overcoming inhibitory signals (such as PD-1 or PD-L1) and en-
hances recognition of abnormal or diseased cells. Checkpoint inhibition also counteracts regulatory T-cells (Treg) that may dampen
host cytotoxic T cell responses to infections. Bispecific monoclonal antibodies (BsmAbs) can bind to 2 targets: an antigen on a
diseased cell and an antigen on an immune effector like a cytotoxic T-cell (e.g. the CD3 antigen), thus bringing a cytotoxic T-cell in
proximity to the cell that requires elimination. Administering proinflammatory cytokines serves to increase the immune activa-
tion of patients’ T-cells. (C) Antibody/ligand-based therapies make use of monoclonal antibodies (mAbs) or ligands that function
through controlled modulation of other immune system components such as lymphocytes. Such approaches include checkpoint
inhibition, BsmAbs, and cytokines. Additionally, therapeutic mAbs are used to neutralize antigen that contribute to pathogenesis
such as host or pathogen surface antigens, toxins etc. Appropriately modified mAbs may also be conjugated with agents such a
small molecule toxins for their targeted delivery.
Immunotherapy Advances, 2021, Vol. 1, No. 15

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Figure 2. Immunotherapy for viral diseases. (A) Zika virus E trimers bind to entry receptors found in clathrin coated pits of target
cells during the initial stages of viral infection. Monoclonal antibodies ZK2E10, ZIKV117, ZIKV195, and ZIKV190 bind to the entry
receptors preventing viral binding and infection. ZIKV-195 crosslinks E protein preventing the formation of E trimers needed for
viral entry. ZIKV-SigN-36 binds to the E protein resulting in the formation of aggregates which prevents viral entry. (B) IL-6 secreted
6 Immunotherapy Advances, 2021, Vol. 1, No. 1

immune responses without developing trial-limiting side Antibody-based therapies

effects [14]. The vaccine has subsequently progressed to To address the lack of clinically approved targeted
phase III (NCT04470427) and is currently under inves- therapy for ZIKV, antibody-based therapies have been
tigation for its efficacy against COVID-19. DNA vac- developed. ZIKV-195, a potent human mAb that binds
cines are primarily based on pDNA backbones encoding to the E protein protected mice against a lethal strain
for viral antigen with an inserted eukaryotic expression of the ZIKV [16]. Other notable E-protein-specific
cassette [15]. Upon in vivo cellular uptake, the vaccine- mAbs (Fig. 2D) include ZIKV-117, ZKA190, and the

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induced high-capacity target gene expression, initiating bispecific antibody FIT-1, which is using paratopes of
an antigen-specific immune response [10]. Although there two E-protein-specific mAbs, ZKA190, and ZKA185,
are currently no licensed human DNA vaccines, there are was shown to retain the potency of the parental anti-
several ongoing clinical trials (Supplementary Table S1). bodies while simultaneously preventing the generation of
Viral vaccines use recombinant viral-based vectors, resistant mutant strains [16–20].
either in live attenuated or in non-replicative forms to Passive immunization has proven to be a feas-
express a target antigen [10]. There are numerous viral ible treatment approach for the Ebola virus (EBOV)
vector vaccines in clinical trials, including an adenovirus- (Fig. 2B). A mAb cocktail containing the glycoprotein
based vaccine for ZIKV (NCT03356561) and two viral trimer-specific Abs FVM04 and CA45 was able to neu-
vaccines in phase III for SARS-CoV-2 [15]. The former tralize various EBOV strains and conferred complete
is based on a type 5 adenovirus expressing SARS-CoV-2 protection in non-human primates [21]. Furthermore,
spike (S) protein (NCT04341389) and the latter, ex- FVM04 improved the potency and breadth of the
pressing the same protein, is based on a chimpanzee ZMappTM antibody cocktail composed the glycoprotein-
adenoviral vector (ISRCTN89951424). specific paratopes c2G4, c4G7, and c13C6, which ori-
Recombinant protein-based vaccines (rPV) consist of ginally failed to meet the targets in humans when [21,
immunogenic proteins from target pathogens. The lack of 22]. MBP134, which is composed of two broadly neu-
pathogenic genetic material and the absence of live patho- tralizing antibodies (bNAbs) that binds to the base
gens make rPVs safer than other vaccine platforms [10]. subdomain of the glycoprotein was shown to be effective
It may also be the platform of choice for rapid production against EBOV, was further modified to improve efficacy
such as in the case of an emerging epidemic. Many rPV and engage NK cells [23]. Promising antibody mono-
comprise recombinant-virus subunits derived from viral therapy includes anti-EBOV mAb (M318) which neu-
capsids that can self-assemble into viral-like particles [10]. tralized EBOV and induced antibody-dependent cellular
Viral-like particles maintain their original conformation cytotoxicity, and EBOV-520, which neutralized EBOV in
by displaying high numbers of antigen epitopes, thereby animal models [24, 25].
preserving viral immunogenicity, allowing crosslinking of Individuals with SARS-CoV2 possess activated
B-cell receptors on B-cell surfaces while also permitting macrophages and T-cells which produce IL-6, eventu-
uptake into antigen-presenting cells. When self-assembly ally resulting in a cytokine storm [26]. The anti-IL-6
is not possible, target antigens are expressed as chi- mAb, Tocilizumab, has shown promise in clinical
meric proteins [10]. There are multiple rPV undergoing studies, demonstrating efficacy in patients presenting
pre-clinical and clinical evaluation for the prevention of with cytokine storm (Fig. 2A). Although it may reduce
SARS-CoV-2 (Supplementary Table S1).

by SARS-CoV-2 activated T-cells contributes to the pathogenesis related to cytokine storms during infection. Tocilizumab binds to
IL-6 preventing activation of IL-6 receptor, reducing inflammation resulting from the cytokine storm. SARS-CoV-2 binding to ACE2
receptor induces viral entry into target cells. Monoclonal antibodies CB6, H4, and B38 bind to ACE2 prevent viral binding and
entry. (C) Attachment of Ebola virus to the surface of macrophages is the first step of viral infection. Monoclonal antibodies M138,
CA45, mb144, and FVM04 specific for Ebola glycoproteins (GP) bind to the GP and prevent their interaction with macrophages
thus preventing infection. Monoclonal antibody M1382-mediated antibody-dependent cellular cytotoxicity through the recruitment
of NK-cells which degranulate and activate death signaling by binding to death receptors expressed on the cell membranes of
Ebola-infected macrophages. (D) The first step of HIV infection is the binding of GP120 to CD4 receptor on target cells. CD4-specific
monoclonal antibodies Leronlimab, Ibalizumab, and UB-421 bind to CD4 receptor on T-cells prevent viral GP120 from binding to
the receptor, thus prevent viral entry and infection. GP120-specific antibodies VRC07, VRC01, 3BNC117, VRC26.25, CAP256, and
PGDM1400 bind to GP120 on the viral envelop and prevent GP120 from binding to CD4 thus prevent viral entry into target cells.
CD8 and GP120 bi-specific antibodies bind to CD8 with one arm and GP120 with the second arm bringing HIV into close proximity
of cytotoxic T-cells, enhancing their capacity to target and kill the virus. (E) Dual CD4 and HIV E protein-specific CD8 CAR-T-cell binds
to both CD4 and E proteins on CD4 infected T-cells, inducing cell death of the infected T-cell. The expression of C46 on the surface of
the CAR-T-cell prevent the CAR T-cell itself from being infected by the HIV virus.
Immunotherapy Advances, 2021, Vol. 1, No. 17

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Figure 3. A: (i) Mycobacterium tuberculosis can induce the expression of ligands for PD-1, CTLA-4, TIM3, and LAG3 on the sur-
faces of infected macrophages, thereby inhibiting T-cell activation. Using mAb targeting either receptors on the T-cell or ligands on
antigen-presenting cells (APC) can disrupt the interaction between receptors and ligands, resulting in T-cell activation. (ii) Invariant
natural killer T-cells recognize mycobacterial lipids presented by CD1d on APCs and subsequently secrete cytokines to mediate
an immune response. (iii) Various cytokines (IL-2; IFN-γ; TNF-α; GM-CSF) are involved in the Th1 response to Mtb infection, and
8 Immunotherapy Advances, 2021, Vol. 1, No. 1

the necessity mechanical ventilation for infected people suppression was not sustained, and relapse occurred fol-
or prevent their death, conclusive results from ongoing lowing rapid clearance of the antibody from serum [36,
trials are awaited [27–29]. CB6, a human mAb that binds 37]. Modifications were then made to VRC01, generating
to the SARS-CoV-2 receptor binding domain, inhibited VRC01-LS, as well as other mAbs to extend the serum
the infection in rhesus monkeys, showing promise for half-life [38]. The efficacy of the bNAbs was further im-
human application [30]. Furthermore, another study de- proved by use in combination therapy. 3BNC117 used in
scribed two antibodies, B38 and H4, which both bind to combination with 10–1074 was well tolerated in healthy

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the receptor-binding domain, and thus neutralize SARS- adults and achieved prolonged viral suppression in some
CoV-2 in mice by preventing the interaction between the patients [39]. The combination therapy further potenti-
virus and the cell receptor thus blocking uptake [31]. ated increased HIV group-specific antigen CD8+ T-cell
Despite the efforts made to curb the overwhelming response and increased the CD4+ T-cell response [38].
effects of the HIV/AIDS epidemic, the disease burden These strides to combat HIV have shown promise but
remains substantial [32]. The use of combination anti- would require further development before realizing clin-
retroviral therapy (cART) has reduced transmission of ical application.
the virus, the progression toward AIDS, and reduced
viremia to below the limit of detection by standard test
CAR T-cell immunotherapy
methods [31]. cART is, however, not curative and re-
quires lifelong sustenance. Cessation of cART results Some of the very first CAR T-cells developed for HIV en-
in a rapid relapse in viremia, but lifetime use of cART velope protein (Env)-targeted treatment were generated
is costly and may lead to drug-related toxicity empha- by replacing the extracellular T cell receptor domain by
sizing the need for safer, long-lasting treatments [10]. CD4 (CD4-CAR). While the CAR treatment was safe and
Antibody-based therapies targeting epitopes exclusive to feasible in clinical trials, it failed to reduce viral burden
diseased cells or foreign pathogens have shown promise permanently [40].
(Fig. 2C). Ibalizumab, a CD4-directed mouse-derived Second-generation CARs containing an intracellular
recombinant humanized mAb received Food and Drug CD28 domain exhibited higher cytokine production and
Administration approval for the treatment of multi-drug- better control over HIV replication in vitro but were sus-
resistant HIV-1 in adults [33]. Another CD4-directed ceptible to HIV infection. To overcome this, CD4-CARs
humanized mAb, UB-421, was able to maintain viral sup- were equipped with a viral fusion inhibitor or small
pression in the absence of ART in phase II clinical trial hairpin RNAs which degrade viral RNA and knock down
[34]. Rather than neutralizing multi-drug-resistant HIV-1 CCR5, an HIV-1 co-receptor [39]. Both strategies ren-
strains, bNAbs binding to the CD4 binding region or the dered the CD4-CARs resistant to infection and provided
V3 loop, have demonstrated a broader depth of anti- persistent control of infection in animal models. Several
viral activity by neutralizing myriads of HIV-1 strains. other editing techniques have been used to knock out
Promising anti-HIV-1 bNAbs include VRC01, 3BNC117, CCR5 including zinc finger nucleases (NCT00842634;
and 10–1074 [35]. VRC01 was well tolerated as a mono- NCT01044654; NCT01252641), transcription acti-
therapy in adults and new-born infants; however, viral vators and CRISPR-Cas9. Novel second-generation

this effect can be supplemented by systemically administered cytokines. (iv) The novel M72/AS01E vaccine consists of an im-
munogenic fusion protein (M72) derived from two Mtb antigens (Mtb32 and Mtb39) in the AS01E adjuvant. Upon application,
the vaccine mounts humoral (B-cell) and cell-mediated (T-cell) responses, conferring protection against active TB infection. B: (i)
The bispecific mAb, MEDI3902, targets two P. aeruginosa virulence factors, part of the type-3 secretion system (PcrV) and the Psl
exopolysaccharide. Binding to PcrV prevents cytotoxicity while binding to Psl favors complement-dependent opsonophagocytic
killing by host effector cells. (ii) Synthetic immunobiotiocs involve the application of polymyxin B (antibiotic) conjugated to anti-
genic epitopes. Polymyxin B attaches to the cell surface of Gram-negative bacteria while the antigenic epitopes recruit antibodies
in human serum, thereby re-engaging components of the immune system (complement system and antibody-dependent cellular
cytotoxicity) against the pathogen. C: (i) Various mAbs can be used to target the S. aureus alpha-toxin, resulting in a protective
strategy against the alpha-toxin-mediated killing of host immune cells. (ii) DSTA4637S, an antibody-antibiotic conjugate, specific-
ally binds to the cell surface of S. aureus, followed by opsonophagocytosis of the conjugate, resulting in the intracellular delivery
of the antibiotic to S. aureus within the host cell, ensuring more effective antibiotic bactericidal effects. (iii) The combination of anti-
microbial sonodynamic therapy with anti-virulence immunotherapy involves the use of toxin-neutralizing antibodies on the sur-
face of a nanovesicle, which is simultaneously loaded with sonosensitizers [meso-tetrakis (4-sulfonatophenyl) porphyrin (TPPS)]
that produce reactive oxygen species capable of inducing bacterial cell death upon ultrasound activation.
Immunotherapy Advances, 2021, Vol. 1, No. 19

CARs targeting the HIV CD4 binding site or glyco- CMV since they also stimulated cytokine release, the pro-
protein 120 (gp120) antigens were designed based on liferation of effectors and the suppression of viral repli-
single-chain variable fragments derived from Env-specific cation [41].
bNAbs [39]. While these CARs demonstrated specific Aside from engineering CARs, T-cells can also be ma-
killing of HIV infected cells, their antiviral efficacy was nipulated in different ways and used for adoptive cell
highly variable and strain-dependent. This was improved transfer. In Zika virus models, a study generated CD4+
by combining second-generation glycan CARs, targeting and CD8+ ZIKV-specific T-cell in clinically relevant num-

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variable glycans regions on the surface of HIV with bers ex vivo. These T-cells expressed Th1 type cytokines
CCR5 ablation, enabling superior control of viral repli- and successfully killed human leukocyte antigen (HLA)-
cation over the CAR alone. First-generation anti-gp120 matched ZIKV-infected monocytes. Epitope mapping re-
CARs, efficiently stimulated activation, and cytokine se- vealed that these T-cells bound to multiple novel HLA
cretion mediating lysis of Env-expressing HIV-1 infected class I and class II epitopes on the NS1 antigen [42]. NS1
CD4 T-cells in vitro [39]. Third-generation gp120-specific is essential to viral replication and immune evasion. This
CARs had superior lysis over CD4 CARs and remained study provided a proof-of-concept for T-cell therapy as
uninfected upon interaction with the cell-free virus. a potential treatment strategy against ZIKV infections.
Furthermore, the CAR-induced cytolysis of reactivated
HIV reservoirs isolated from infected patients [39]. The Immunotherapies of bacterial infections
main drawback of this approach is viral escape mutants
which render the therapy inefficient. To improve treat- Vaccines
ment efficacy, bi- and tri-specific CARs targeting up to Mycobacterium tuberculosis (Mtb) is the etiological agent
three HIV antigens were designed. Two bi-specific CARs of TB and the leading cause of infectious disease-related
comprising a CD4 domain fused to gp120 or a carbohy- deaths [44]. While Bacillus Calmette-Guérin (BCG), the
drate recognition domain C-type human lectin that binds only approved TB vaccine, provides consistent protection
to conserved glycans on Env, showed superior suppres- against severe extrapulmonary forms of pediatric TB, it
sive activity compared to CD4-CAR [39]. Recently, CAR confers limited protection against pulmonary TB in adults
T-cells with three functionally distinct HIV Env-binding [45]. Furthermore, despite its widespread administration
domains were engineered to express two distinct CARs as a TB vaccine, its failure to prevent active TB infection
on the same T-cell or one CAR with two targeting elem- emphasizes the need for novel strategies. An effective TB
ents. Targets included gp120 CD4 binding site, a CD4- vaccine should ideally provide greater protective efficacy
induced gp120 epitope and C46 peptide or C34-CXCR4 than BCG and prevent disease thereby disrupting Mtb
[41]. C46 peptide and C34-CXCR4 inhibit viral fusion transmission [44]. Unfortunately, many of the TB vac-
preventing infection of the CAR T-cell [42]. Bi- and tri- cines developed in the past have failed to achieve this.
specific CARs were able to prevent HIV infection of the Notably, the MVA85A vaccine failed to improve the
CARs while efficiently killing other HIV-positive cells protective efficacy of BCG in infants and HIV-1-infected
in humanized mouse models as noted in Fig. 2 [43]. adults [46, 47]. Several novel vaccine candidates are cur-
There are currently two human clinical trials trying to rently advancing through or have recently completed
eradicate the latent HIV reservoir; one is a bNAb-based clinical trials, with variable success (Supplementary Table
CAR T-cell therapy (NCT03240328); the other a CD4- S2). In a recent three year analysis of a prevention-of-
CAR T-cell therapy in conjunction with CCR5 ablation disease study, the M72:AS01E subunit vaccine (Fig. 3A),
(NCT03617198). composed of the immunogenic fusion protein (M72) de-
In addition to HIV, two cytomegalovirus (CMV)- rived from two Mtb antigens and the GlaxoSmithKline
specific CARs were recently described. One CAR, based adjuvant AS01E, displayed a 49.7% efficacy in inducing
on a 21E9 glycoprotein subunit H targeting antibody, protection against TB disease in HIV-negative individuals
had superior activity in all functional tests. Surprisingly, it with latent TB infection, showing evident promise for
had 10-fold less binding affinity compared to other CARs this vaccine (NCT01755598) [48]. The limited success
targeting the same protein suggesting affinity not to be achieved in clinical trials investigating vaccines against
the main determinant of effectiveness. The 21E9-CAR infections caused by antibiotic-resistant P. aeruginosa
however binds to a unique epitope suggested to be more and S. aureus (Supplementary Table S2) is partly attrib-
accessible [41]. While the CAR showed only modest uted to suboptimal study designs that disregard the het-
CD8+ T-cell killing of CMV-infected cells it provided erogeneity of patients, hospital epidemiology, specific
support as a potential candidate for immunotherapy of bacterial strains, and disease progression, highlighting
10 Immunotherapy Advances, 2021, Vol. 1, No. 1

the need for detailed characterization of these parameters mycobacterial loads and fatalities [59, 60]. Similarly,
to ensure meaningful results [49]. Tezera et al. (2020) demonstrate that the inhibition
of PD-1 (in a 3D cell culture model of human TB) ac-
Monoclonal antibody therapy celerates Mtb growth via excessive tumor necrosis
factor-alpha (TNF-α) secretion [61]. Additionally, in
mAbs are being reconsidered for the treatment of bac-
vitro blockade of the PD-1/PD-L1 pathway, may result
terial infections [50]. Antibodies play an important role
in enhanced production of IFN-γ, however, this may
in immunomodulation during TB, evidenced by antibody

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be insufficient to restore the proliferative potential of
profiles during latent TB infection which show enhanced
Mtb-specific CD4+ T-cells [57]. The development of
Fc-mediated immune effector function and drive macro-
checkpoint blockade-associated TB and atypical Mtb
phage destruction of intracellular pathogens, highlighting
infections in patients receiving anti-PD-1/PD-L1 mAbs
the protective role of these antibodies [51]. However, to
as cancer therapy support these findings [59, 62]. The
date, the development of protective mAbs against Mtb
role of TIM3 has also been evaluated in chronic Mtb
has failed. In contrast, several engineered mAbs for
infection; wherein functionally impaired TIM3+ T-cells
P. aeruginosa and S. aureus have progressed to clinical
co-expressed other inhibitory receptors while accumu-
trials (Supplementary Table S2). MEDI3902 (AstraZeneca
lating during infection [63]. Notably, the treatment
PLC), a bispecific IgG1 antibody targeting the PcrV pro-
of chronically infected mice with anti-TIM3 mAb im-
tein (host cell cytotoxicity) and Psl exopolysaccharide
proved T-cell function and achieved better control of
(colonization and tissue adherence) of P. aeruginosa
the bacterial load [62]. Furthermore, LAG3 is prom-
(Fig. 3B), is under development for the prevention of
ulgated as a more superior target than PD-1, since
pneumonia in high-risk patients (NCT02696902) [52].
inhibiting its action activates T-cells and abrogates the
Furthermore, the targets are conserved across global iso-
suppressive activity induced by regulatory T-cells [64].
lates of P. aeruginosa and may mediate broad coverage
In summary, immune checkpoint expression in TB may
[53]. AR-301 (Aridis Pharmaceuticals), a mAb with
be regarded as a physiological response to persistent
alpha-toxin (virulence factor) neutralizing capability
Mtb pathogen, and its inhibition could potentially en-
(Fig. 3C), conferred protection against alpha toxin-
hance infection and pathology, as observed in PD-1 in-
mediated host cell damage when administered as ad-
hibition in knockout mice, cellular, and epidemiological
junctive treatment to patients with methicillin-resistant
studies. The decision to implement immune checkpoint
S. aureus (MRSA) pneumonia (NCT03816956) [54].
inhibition for TB treatment will therefore, most likely
Furthermore, MEDI4893 (AstraZeneca PLC), a novel,
depend on various aspects such as the host (immuno-
long-acting mAb targeting alpha-toxin (Fig. 3C) pro-
competence and HIV status), as well as specific myco-
vided effective immunoprophylaxis against S. aureus
bacterial factors (Mtb strain and drug resistance) [65].
disease in addition to sustaining serum levels after intra-
venous administration to healthy individuals and is cur-
rently in phase II clinical trial (NCT02296320) [55]. T-cell-based immunotherapies
With the need to develop more effective therapeutic
Checkpoint inhibition interventions for TB (with or without HIV coinfection),
While immune checkpoint inhibitors have revolu- the relevance and applicability of T-cell-based immuno-
tionized cancer therapeutics, varied outcomes exist therapies are being actively investigated. Unconventional
regarding their efficacy in the management of TB. T-cells [natural killer T-cells (NKT), mucosal-associated
Despite the protective roles of CD4+ and CD8+ T-cells invariant T-cells (MAIT), γδ T-cells, and HLA-E-restricted
in the containment of Mtb, increasing evidence sug- T-cells] – a heterogeneous group of T lymphocytes that
gests their progressive dysfunction in patients with ac- are not limited to antigen recognition via the classical
tive TB infection, often resulting from the expression MHC – could be instrumental candidates in the develop-
of inhibitory receptors (PD-1, CTLA-4, LAG3, and ment of TB-directed T-cell-based therapies [66]. Invariant
TIM3) causing T-cell exhaustion [56, 57]. While mAbs NKT (iNKT) cells can recognize several lipids associated
targeting PD-1 and its ligand (PD-L1) have been shown with the mycobacterial cell and produce different cyto-
to restore tumor-specific T-cell function, it remains un- kines (IFN-γ, IL-4, IL-17A, and IL-21) that can mount
clear whether this would be advantageous in the treat- an immune response against Mtb (Fig. 3A) [65]. The po-
ment of human TB [58, 59]. For instance, Mtb-infected tential of iNKT cells is being investigated in phase I and
PD-1 knockout mice are dramatically susceptible to II clinical trials for TB patients concurrently presenting
new TB infections, which are characterized by higher with malignant solid tumors (NCT03551795).
Immunotherapy Advances, 2021, Vol. 1, No. 111

Cytokine therapy pipeline of notable anti-malarial vaccines in develop-

With a better understanding of their contributing roles ment are listed in a review by Philips et al. [73]. A re-
in important biological processes, various cytokines cent review further elaborates on progress made in
are being manipulated to alter diseased states (Fig. 3A) subunit-based vaccines for malaria [70]. Vaccines can
[2]. A preclinical in vivo study demonstrated how a be a useful tool against zoonotic transmission as sev-
novel albumin-fused granulocyte-macrophage colony- eral licensed vaccines for dogs have shown high efficacy
stimulating factor (GM-CSF) enhanced its biostability against canine leishmaniasis [74]. Combinations vaccin-

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and increased the dendritic cell populations responsible ation therapy strategies are proving to be effective to
for inducing a potent immune response against Mtb [67]. treat parasitic disease by improving drug efficacy with
Furthermore, adjunctive immunotherapy using recom- a reduced dose. Recombinant Tc24 C4 antigen formu-
binant human interleukin-2 (rhIL-2) is under clinical as- lated with a toll-like receptor 4 (TLR4) agonist EC6020
sessment in multi-drug-resistant TB patients, aiming to exhibited synergism with benznidazole (one of the two
improve treatment efficiency and shortening treatment chemotherapeutic agents used to treat Chagas disease),
course (NCT03069534). to abrogate parasite load in mice through the induction
of a balanced Th1/Th2 response and the antigen-specific
release of IFN-γ and IL-4 [75]. The development of nu-
Emerging technologies against bacterial
cleic acid-based vaccines can complement peptide vac-
pathogens
cines especially to circumvent the limitations the latter
Several new technologies are emerging against bacterial possess. Such vaccines can elicit both innate and adaptive
infections. Antibody-antibiotic conjugates promote the responses and would be beneficial to add to the vaccine
targeted delivery of the antibiotics while ensuring the compendium. Several mRNA vaccines against malaria,
maintenance of its bactericidal properties (Fig. 3C). leishmaniasis, and toxoplasmosis are presently under
DSTA4637S (Genentech), an anti-S. aureus antibody- investigation [76]. Treatment of Trypanosoma cruzi
antibiotic conjugates consisting of a mAb directed through DNA-based immunization using cruzipain (Cz)-
against S. aureus-specific wall-teichoic acids linked to an encoding plasmid with GM-CSF was shown to induce
antibiotic showed favorable safety and pharmacokinetic a Th1 response through IgG2a production in mice and
profiles in phase I clinical trial (NCT03162250) [68]. promote survival in a mouse infection study [77].
A recent proof-of-concept study combined antimicro-
bial sonodynamic therapy with anti-virulence immuno- Monoclonal antibodies
therapy, in the form of a nanocapturer (Fig. 3C). These
are composed of a neutralizing antibody on the surface Antibodies characterized by the humoral immune re-
nanovesicles loaded with sonosensitizers that produce re- sponse of volunteers enrolled in clinical trials have
active oxygen species upon ultrasound activation, thereby led to the identification of potent mAbs such as mAbs
killing the bacteria and accelerating virulence clearance 2530, 2544, 2586, and 2587 against P. falciparum
to eradicate MRSA in mice [69]. Furthermore, synthetic transmission-blocking vaccine candidate Pfs25 [78].
immunobiotics (Fig. 3B), consisting of polymyxin B (an Transmission-blocking vaccines aim to break the loop
antibiotic that attaches to the surface of Gram-negative of vector to host transmission by targeting the sexual
bacteria) conjugated to antibody-recruiting antigenic stage of P. falciparum, limiting infected host to vector
epitopes to induce a targeted immune response, are under parasite spread or by blocking the transmission of pre-
investigation [70]. These studies are promising for future erythrocytic P. falciparum from Anopheles mosquito to
treatment strategies for bacterial infections. humans [77]. Similarly, Fab binding of the mAbs 311 and
317, derived from human donors enrolled in an RTS,S/
Immunotherapies of parasitic disease AS01B clinical trial, to P. falciparum circumsporozoite
protein inhibits in vivo parasite development in C57BL/6
Vaccines mice [8]. mAbs such as humABAMA1 and humAB10.1–
The first and only human vaccine in use against a parasitic 10.3, derived from semi-immune donors against the
disease is RTS,S/AS01 (Mosquirix, GlaxoSmithKline) merozoite antigens Apical Membrane Antigen 1 (AMA1)
that showed limited efficacy (<50%) against Plasmodium and Merozoite Surface Protein 10 (MSP10), respect-
falciparum among children. The vaccine was piloted in ively, have shown promising in vitro inhibition of P. fal-
Ghana, Kenya, and Malawi in 2019 [71, 72]. Several sub- ciparum [79, 80]. The role of opsonizing antibodies is
unit and irradiated sporozoite vaccines against malaria another area of research as recently demonstrated in
are currently under development and a comprehensive vitro by the use of an MSP1 subunit antigen to induce
12 Immunotherapy Advances, 2021, Vol. 1, No. 1

opsonization-driven neutrophilic respiratory burst re- chemotherapeutics including efficacy, toxicity, and the
sponse to merozoites [81]. looming challenge of drug resistance [73, 84]. As with
most therapies for any disease, it has become increas-
Checkpoint blockade ingly evident that a multi-faceted approach for the treat-
ment of various infectious diseases is required. Future
Blocking of the PD1/PD-L1 interaction using mAbs was
pre-clinical and clinical studies would have to incorp-
shown to have therapeutic potential in mice to treat
orate the best combinatorial strategies that will result in
malaria and leishmaniasis. The mAbs used against PD1

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optimal patient outcomes. This may include a combin-
receptor-targeted CD4+ lymphocytes and PD-L1 in den-
ation of immunotherapeutic approaches together with
dritic cells in both diseases and the studies highlight the
traditional treatment options to ensure sterilization of
therapeutic potential of such antibodies [8, 82]. PD-L2
a disease like TB, which is defined by mycobacteria at
on the other hand plays a protective role in malarial in-
varying states of replication, or malaria, which requires
fections through inhibition of PD1/PD-L1 interaction
control measures on multiple levels to prevent infection
and mediating Th1 immunity. Multimeric PDL2 fused
and spread [73, 85]. The advantage of such an approach
with the Fc region of immunoglobulin (PDL2–Fc) has
that prioritizes optimal clinical outcomes encourages the
been shown to reduce infections in mice infected with
development of therapeutics that have a high degree of
lethal or cerebral malaria [8].
specificity and selectivity and advances medicine to an
Antibody conjugates era of precision medicine [84, 86].
While it might be intuitive that such advances might
One of the most direct evidence of infectious disease
come at a high cost, technological breakthroughs such as
benefiting from cancer immunotherapy can be illustrated
the use of phage display libraries for large-scale antibody
using the example of MacGregor and colleagues who
fragment screening, improvements in molecular methods
demonstrated receptor-dependent internalization and
to fine-tune and improve antibody longevity and potency
killing of Trypanosoma brucei using human haptoglobin-
(thereby reducing the required dosage), identification
hemoglobin receptor (HpHbR) mAbs conjugated to a
of suitable hosts of expression, and optimization of cell
pyrrolobenzodiazepine toxin in vitro [83].
culture conditions have all lead to decreasing costs of
mAb-based therapies which have now have become com-
Future directions and conclusions parable to the cost of essential chemotherapeutics over
Despite the diversity of strategies in existence, besides the last three decades, with concurrent improvements
vaccines, approved immunotherapies for human use in their safety and efficacy. These have in turn spurred
against infectious disease trail behind those available to the regulatory approval and increased use of therapeutic
treat different cancers. Nevertheless, immunotherapies antibodies thus overcoming multiple factors that previ-
of infectious diseases have benefited from advances in ously discouraged their wider use [74, 84]. Novel vac-
cancer immunotherapy. For example, insights into im- cine platforms such as the use of DNA, mRNA, and viral
mune evasion mechanisms exhibited by disease cells vector vaccines provide alternative approaches that may
have led to the exploration of the role of checkpoint in- lead to rapid and cheaper vaccine development pipelines,
hibition and T-cell exhaustion, which are in turn used overcoming the limitations previously posed by peptide-
as predictive markers of immune suppression to evolve based vaccines [33, 76, 84]. The parallel development of
treatment strategies and improve patient responses [8]. targeted delivery and improvements in vehicle technolo-
Drug and vaccine development against infectious disease gies show the potential to overcome the drug safety issues
are ongoing efforts that are perplexed in large part by that stem from systemic immunotherapy administration,
multivariate factors such as diversity of pathogenic spe- expanding options that would be available for experi-
cies causing disease, the clinical manifestation of the dis- mental interventions. Immunotherapeutic advances are
ease in different forms, the array of surface antigens that hence increasingly becoming appealing options for infec-
they express to circumvent host immunity and the various tious disease treatment.
survival mechanisms (such as latency) they have evolved. State-of-the-art therapies such as CAR T-cell ther-
Such facets challenge both the development and the ef- apies are still very expensive treatment options costing
ficacy of broad range vaccines and immunotherapeutic several hundred thousand dollars per patient and year,
strategies employed against them [10, 70]. in large part due to the approach having a complex pro-
Immune-based approaches are particularly promising cess of development before delivery and administration
and aim to overcome limitations posed by conventional to the patient. This limits the broad applicability of this
Immunotherapy Advances, 2021, Vol. 1, No. 113

approach to be used in resource-limited or poor settings, Supplementary material

while also limiting their access due to economic dispar- Supplementary data are available at Immunotherapy Advances
ities [87]. An ideal immunotherapeutic strategy would online.
employ a means that can be easily manufactured, trans-
ported and administered easily (including e.g. subcuta-
neous or oral routes) with minimal numbers of doses to Acknowledgements
individuals, aiming to confer long-lasting protection that
The Editor-in-Chief and editorial team would like to thank the

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ensures maximum benefit with low costs and off-target handling editor, Adriana Bonomo, and the following reviewers,
effects. Achieving prolonged biological activity to confer Paul Elkington and Herbert Guedes, for their contribution to
protection while also having to ensure reduced costs for the publication of this article. All figures were designed by the
equitable access will be a recurring theme that will con- authors and illustrated by Alison Schroeer.
tinue to push the limits and applicability of immunother-
apies. Recombinant peptides such as vaccines, mAbs, and Funding
antibody conjugates seem like ideal candidates that may The authors would like to thank for in part support and funding
accomplish all such goals in the future. Making such a of S.B. by the National Research Foundation of South Africa
generalization however would mean skimming over the (Grant Number 47904).
complexities of the underlying diverse biological mech-
anisms that contribute to disease progression such as Author contributions
factors contributing to host and pathogen heterogeneity,
D.R. contributed to the development of the article and authored
limitations in technology platforms and study models the section on antiparasitic immunotherapies; T.N. and S.C. au-
available; all of which are active areas of exploration and thored the section on antiviral immunotherapies. N.M. and
yet to be thoroughly understood. M.K. contributed to the writing of immunotherapies for bac-
The importance of vaccines and the need for novel terial infections. K.N. and S.B. directly and substantially contrib-
therapeutic approaches to combat communicable disease uted through their critical intellectual input.
is especially evidenced in recent times by the emergence
of the SARS-CoV-2 pandemic and the subsequent, un- Conflict of interest
precedented clinical development of approximately a The authors of this review article declare that they have no con-
hundred vaccine candidates, and the repurposing of ex- flicts of interest to disclose.
isting approved therapeutics such as the IL-6 inhibiting
mAbs, Siltuximab, and Tocilizumab [88]. Access to Data availability
prophylactic and therapeutic medication is still unfortu-
No new data were generated or analysed in support of this
nately very much affected by socio-economic differences.
research.
This is quite evident from how middle- and low-income
countries bear the heaviest burden of infectious disease.
Furthermore, low-income and indigenous populations in References
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