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The vaccine helps to provoke the immune system and is an efficacious means for disease prevention and treatment. At this particular time of the COVID-19 outbreak, the vaccine for COVID-19 is urgently needed to save tens of thousands of people’s lives. Here we give some basic information on vaccine classification, generation, and application, and make a brief review on the current status of COVID-19 vaccine and tumor vaccine development both in the clinical trial stage and pre-clinical stage.

1. Landscape of vaccines

A vaccine is any substance produced from various pathogenic microorganisms and can spur the body’s immune system to generate antibodies for the prevention, diagnosis, or treatment of diseases when given to the body, including artificial active immunity vaccine, artificial passive immunity vaccine and novel vaccine (Fig. 1). Traditionally, the artificial active immunity vaccines can be divided into three categories: dead vaccines, live vaccines, and toxoid (Fig. 1). Dead vaccines are dead parts or wholes of germ cells, once injected into people or animals, they can trigger mild immune responses, containing pertussis vaccine, typhoid vaccine, meningococcal vaccine, cholera vaccine, etc.; while live vaccines are living parts or all of germ cells, most of them are attenuated to reduce the risk but also provide immunity for the body, such as BCG vaccine, polio vaccine, measles vaccine, plague vaccine, etc.; toxoid is a kind of extracellular toxin treated by formaldehyde, which loses the toxicity but retains the immunogenicity, such as diphtheria toxoid, tetanus toxoid. Considering the long-term required for immune system activation using artificial active immunity, the artificial passive immunity vaccine is designed for rapid disease treatment or emergency prevention, including antitoxin, immunoglobin, cytokine, and monoclonal antibodies.

Besides these two kinds of immunity vaccines, some novel vaccines have been developed or created, such as subunit vaccine, conjugate vaccine, synthetic peptide vaccine, and genetic engineering vaccine (recombinant protein-based vaccines, lipid-based vaccines, polysaccharides-based vaccines, viral vector-based vaccines, and mRNA/DNA vaccines, etc.). However, some of them, such as lipid-based vaccines and polysaccharides-based vaccines, only result in poor immunogenicity. The reasons might be that some antigen structures with adjuvant activity are discarded during vaccine preparation, or some vaccines can only trigger one kind of immune responses, such as cell-mediated or humoral immune responses. Among them, viral vector-based vaccines, and mRNA/DNA vaccines can provoke both humoral and cell-mediated immune responses, which are promising candidates with great potential in the future.

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Figure 1. Classification of Vaccines.

2. Viral vector-based vaccines

Viral vector-based vaccines are vaccines that can deliver specific antigen gene to target cells based on the infection ability of viruses, produce antigens via the nutrition substances in host cells, and then provoke immune responses with the newly synthesized antigens. Compared with the traditional vaccines, viral vector vaccines have a great number of advantages: ①highly efficient in gene transduction; ② mediate specific gene delivery to target cells; ③induce of both humoral and cell-mediated immune responses; ④ better efficacy and safety;⑤ just need low administration dose; ⑥ easy to be applied into large-scale manufacturing; ⑦ possessing widespread potential target diseases, ranging from infectious diseases to cancers. As well, some drawbacks also have been discovered: ① several kinds of vectors mediate gene integration into host genome, which may lead to cancer; ② some hosts may be exposed to antigens prior to the vaccine administration, which may result in the production of neutralizing antibodies (pre-existing immunity) and thus reduce the vaccine efficacy [1].

To date, numerous kinds of viral vectors have been introduced to produce vaccines, such as adeno-associated virus (AAV) vectors (Fig. 2A), adenoviral vectors (Fig. 2B) and lentiviral vectors (Fig. 2C) [2]. Different kinds of viral vectors have their advantages and drawbacks, which are summarized in Table 1.

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Figure 2. Schematics of viral structure and antigens that may stimulate host immune system [2]. (A) AAV viral vector-based vaccines. (B) Adenoviral vector-based vaccines. (C) Lentiviral vector-based vaccines. dsDNA: double-stranded DNA; TLR: toll-like receptor; cGAS: cyclic GMP-AMP synthase; IFN: interferon; APCs: antigen presenting cells; CTL: cytotoxic T lymphocyte; dsRNA: double-stranded RNA; MDA5: melanoma differentiation-associated protein 5; pDC: plasmacytoid dendritic cell; ssRNA: single-stranded RNA.

Table 1. Comparison between Lentivirus, Adenovirus and Adeno-associated virus (AAV) vectors.
Viral vectors Lentivirus Adenovirus AAV
Genome ss RNA ds DNA ss DNA
Integration Yes No No
Packaging Capacity 4kb 5.5kb 2kb
Time to peak expression 72h 36h-72h Cell: 7 days;
Animals: 2 weeks
Sustainable time Stable expression Transient expression > 6 months
Cell Type Most Dividing/Non-Dividing Cells Most Dividing/Non-Dividing Cells Most Dividing/Non-Dividing Cells
Titer 10^8 TU/ml 10^11 PFU/ml 10^12 vg/ml
Animal experiment Low efficiency Lowest efficiency Most suitable
Immune Response Medium High mild

1) AAV vector-based vaccines

Adeno-associated virus (AAV) is a small single strand DNA virus, member of human parvovirus [3, 4], approximately 25nm in diameter and encapsidates a single-stranded DNA genome of 4.7 kilobases (Fig. 3A). The genome consists of two large open reading frames (ORFs) flanked by 145bp inverted terminal repeats (ITR), which are the only cis-acting elements required for AAV genome replication and AAV packaging. The left ORF encodes four replication proteins, Rep40, Rep52, Rep68, and Rep78, in charge of site-specific integration, as well as regulation of AAV capsid formation initiation within the AAV genome, while the right ORF encodes the viral structural proteins, VP1, VP2, and VP3, which interact together to assemble into icosahedral virion shells comprising 60 subunits each (Fig. 3B).

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Figure 3. AAV genome map. (A) The capsid structure of AAV. (B) The positions of the three promoters (p5, p19, p40) as well as the seven protein coding regions of the AAV have been highlighted.


Principle of AAV entry into cells

AAV transduces cells through several stages: ① viral binding to cell surface receptor/coreceptor, ② endocytosis of the virus, ③ intracellular trafficking of the virus through the endosomal compartment, ④ endosomal escape of the virus, ⑤ intracellular trafficking of the virus to the nucleus and nuclear import, ⑥ virion uncoating, ⑦ viral genome conversion from a single-stranded to a double-stranded genome capable of expressing an encoded gene [5-7]. Since AAV has no ability to encode polymerases, AAV is dependent upon cellular polymerase activity to replicate its own genome [8]. The presence of a helper virus such as adenovirus is indispensable for wild-type AAV to facilitate gene expression and replication (Fig. 4A). Without helper virus, expression of Rep68/Rep78 would be restricted owing to Ying Yang 1 (YY1) repression of the P5 promoter, leading to inhibition of AAV genome replication and gene expression, and initiation of AAV chromosome integration (Fig. 4B) [9]. AAV establishes latency by undergoing specifically integration into a genome site, termed as the adeno-associated virus integration site 1 (AAVS1), a 4kb region on chromosome 19 (q13.4).

Picture loading failed. Figure 4. AAV life cycle. (A) AAV can amplify itself with the help of helper virus. (B) AAV establishes latency by undergoing specifically integration into AAVS1 without helper virus.

Immune responses induced by AAV-based vaccine

During the entry of AAV into host cells, AAV virions may uncoat and release their genomes into the endosome, and be recognized by toll like receptor 9 (TLR9) of plasmacytoid dendritic cell (pDC) to provoke innate immune response and produce Interferon (IFN) α/β [10]. This process is dependent on MyD88 signaling, but not the form of transgene or capsid serotype [10]. Besides TLR9, TLR2 dependent cytokine expression was also observed in Kupffer cells [11]. Moreover, some AAV virions are degraded and processed into peptides within proteasomes, and then presented by MHC I of antigen presenting cells (APCs), such as conventional dendritic cells (cDCs), which can be targeted by capsid-specific CD8+ T cells to lyse virally infected cells [12]. In addition to IFNα/β, CD40-CD40L co-stimulation by CD4+ T helper cells, is required for cross-priming of CD8+ T cells against AAV capsid [13]. CD4+ T helper cells is also indispensable to generate memory responses and stimulate B cells to produce antibody against AAV capsid, which is dependent on MyD88 signaling [14].

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Figure 5. Schematic principle of AAV-induced immune responses [15]. IFNAR-1: interferon alpha/beta receptor 1; cDC: conventional dendritic cell; pDC: plasmacytoid dendritic cell; IFN: interferon; TLR: toll-like receptor; MyD88: myeloid differentiation primary response protein (88); MHC: major histocompatibility complex; moDC: monocyte-derived dendritic cell; CD: cluster of differentiation.


AAV serotypes

Over the past decades, numerous AAV serotypes have been identified with variable tropism. To date, 12 AAV serotypes and over 100 AAV variants have been isolated from adenovirus stocks or from human/nonhuman primate tissues. Among them, AAV2, AAV3, AAV5, AAV6 were discovered in human cells, while AAV1, AAV4, AAV7, AAV8, AAV9, AAV10 (AAVrh10), AAV11, AAV12 in nonhuman primate samples [16]. Different serotypes have different tissue tropism, which are summarized in Table 2.

Table 2. AAV serotypes and their respective Tropism.
AAV Serotype Tissue tropism
CNS Retina Lung Liver Pancreas Kidney Heart Muscle

Recombinant AAV

Though wild-type AAV is not associated with human disease, it is naturally defective and requiring helper adenovirus or herpes simplex virus (HSV) coinfection for AAV replication, so recombinant AAV (rAAV) has been developed for gene therapy or vaccines by replacing the viral genome with gene of interest (GOI) to reduce the risk. Traditionally, rAAV vectors used in clinical trials were prepared with a plasmid containing the therapeutic gene flanked by AAV-inverted terminal repeats (ITRs), co-transfected with AAV packaging plasmid pAAV-RC (AAV replication and AAV capsid) and pHelper (AAV helper plasmid) (Fig. 6). The adenovirus helper factors, such as E1A, E1B, E2A, E4 ORF6 and VA RNAs, would be provided by the third helper plasmid. Due to the deletion of Rep and Cap coding regions between the ITRs, rAAV vectors cannot integrate into the genome of host cells, just persist in an episomal form, which significantly reduced their tumorigenicity.

Picture loading failed. Figure 6. The three plasmids co-transfection system of recombinant AAV. pAAV-GOI: an AAV ITR-containing plasmid carrying the gene of interest (GOI); pAAV-RC: an AAV serotype plasmid that carries Rep and Capsid genes; pHelper: an AAV helper plasmid that provides the helper genes isolated from adenovirus.

AAV-based gene therapy

To date, more than 244 clinical trials have been carried out using AAV vectors for gene delivery [17], and promising gene therapy outcomes have been achieved from Phase 1, Phase 2 and Phase 3 trials for a great number of diseases, including lipoprotein lipase deficiency (LPLD) [18], spinal muscular atrophy (SMA) [19], retinal dystrophy [20, 21], cystic fibrosis [22, 23], Duchenne Muscular Dystrophy [24], Hemophilia [25], congestive heart failure [26], Parkinson's disease [27] and Rheumatoid Arthritis [28, 29].

AAV-based vaccine development

But, as a viral vector used for vaccine production, AAV only induces mild immune responses, which is not enough for vaccine to provoke the immune system in host. Several animal studies show that AAV vector-based vaccines can be used to defense HIV-1 [30-32], influenza [33], and papillomavirus [34] and have great potentials in clinical applications. However, AAV vector-based vaccines are rarely applied in clinical trials. Some of the examples are listed in the following Table 3. There are two reasons: ① AAV vectors only cause mild humoral and cellular immunity; ② infectious vaccines transduce a large population of people ranging from children and adolescents, and more safety risks need to be considered. Therefore, compared to the gene therapy with AAV vectors, there is a long way for the clinical applications of AAV vector-based vaccines.

Table 3 - Examples of AAV vector-based vaccines
Disease Vaccine component Status Clinical trials
HIVAAV2Phase INCT00482027
HIVAAV2Phase IINCT00888446
HIVAAV8Phase INCT03374202
HIVAAV1Phase INCT01937455
Stage IV gastric cancerAAV-DC-CTLPhase INCT01637805
Stage IV gastric cancerAAV-DC-CTLPhase INCT02496273

Advantages and disadvantage

AAV viral vector has been developed into a very attractive candidate for gene delivery due to various advantages: ① superior biosafety rating of recombinant AAV after removing most AAV genome elements; ② stable physical properties; ③ broad range of infectivity, AAV has the ability to infect both dividing and quiescent cells in vivo; ④ mediate long term and stable gene expression.

However, there are also some drawbacks for AAV to be used as vaccine vector: ① limited cloning capacity (less than 4.7kb) of the vector, which restricts its use in gene delivery of large genes [35]; ② only inducing mild immunity, restraining the vaccine development; ③ pre-existing immunity and neutralizing antibodies (NAB) against AAV vectors may attenuate the effect of AAV-based gene therapy or vaccines [36].

Optimization strategies

To improve the efficacy of AAV vector for vaccine development, several strategies are adopted: ① assemble and recombine proteins between different viruses, which can produce hybrid rAAVs, such as transcapsidation, which is a process involving the packaging of the ITR from one AAV serotype into the capsid of another serotype, which may determine the tissue tropism of hybrids. ② Recombine, redesign, or introduce random mutations into the capsid protein of AAV by different methods to artificially increase the variance of AAV serotypes, and then screen the appropriate AAV serotypes, including rational design AAV capsid [37], AAV directed evolution [38], point mutation [39], peptide display [40], and DNA shuffling [41]. ③ In combination with other kinds of vaccines.

GeneMedi holds the expertise at AAV production, you can find more information and protocols about AAV on this website:

1) Adenovirus (AdV) vector-based vaccines

Adenovirus (AdV) is a member of the family Adenoviridae, whose name derives from their initial isolation from human adenoids in 1953 [42]. It is a medium sized (90-100nm) and non-enveloped virus with an icosahedral nucleocapsid containing a 36kb double stranded DNA genome (Fig. 7A). Hexon and penton structures form the capsid of AdV, and fiber protein mediates the binding of the virion to the cell surface and is a major determinant of viral tropism. Adenovirus transcription is a two-phase event, early and late, occurring before and after viral DNA replication, respectively (Figure. 7B). The early transcribed regions are E1A, E1B, E2A, E2B, E3, and E4, involved in viral transcription regulation, viral DNA replication, and the suppression of host immune response during infection. The late transcribed genes are L1-L5, encoding viral capsid components (Fig. 7B).

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Figure 7. Schematic of the adenovirus genome and adenovirus-based vectors. (A) Capsid crystal structure. (B) Adenovirus gene map. Top panel: a simplified map of the adenovirus serotype 5 genome showing the early genes (E1–E4) and the region from which the major late transcript is produced. Middle panel: general structure of an early region 1 (E1)-deleted Ad vector. Bottom panel: general structure of a helper-dependent Ad vector [43].


Principle of AdV entry into cells

For most serotypes, adenovirus infection is mediated by the high-affinity binding of the fiber-knob region to a receptor of target cell, named as the coxsackie-Ad receptor (CAR), which mainly determines the viral tropism [44]. Upon attachment, interaction between the penton-base Arg-Gly-Asp (RGD) and cellular αv integrins, which can stimulate actin polymerization, leads to internalisation of the virus into the endosome. Then the endosome acidifies, resulting in disassociation of capsid proteins and transportation of viral DNA into nucleus. Without integration into host genome, adenovirus genome remains in an episomal state, which guarantees the low risk of mutation (Fig. 8). Life cycle of adenovirus is separated by DNA replication process into two distinct phases: the early and late, occurring before and after viral DNA replication, respectively. After the synthesis of viral genome and capsid, they are assembled into viral products, releasing out of cell, and the infected cell starts lysis [45]. To prevent infected cell lysis, recombinant replication deficiency virus has been developed as a gene delivery tool to replace wild-type adenovirus (recombinant AdV in “application” part). Once packaged into a E1-complementing cell line, which provides the E1 products in trans, such as QBI 293A Cells, recombinant viral will be easily propagated. Picture loading failed.
Figure 8. Infection process of adenovirus. CAR receptor-fiber-knob adenovirus interaction and internalization process [46].

Immune responses induced by AdV

The entry of AdV into human body stimulates a wide spectrum of innate cellular responses, which might last a few minutes to hours and result in blood pressure changes, thrombocytopenia, inflammation, and fever [47]. AdV vector in blood activates vascular endothelial cells to release von Willebrand factor (vWF), induces platelets to expose the adhesion molecule P-selectin, and promotes the formation of platelet-leukocyte, ultimately leading to thrombocytopenia and bleeding [48]. Additionally, the hexon component of AdV capsid can bind to coagulation factor X (FX) to activate TLR4 on the surface of splenic macrophages and thereby stimulate NF-κB dependent activation of IL-1β, which may help recruit polymorphonuclear leukocytes to the marginal zone of the spleen and clear virus from the spleen rapidly [49, 50]. Besides binding to coagulation proteins, AdV in blood vessel can also bind to component C3 and natural [51-55]. Antibody-AdV complexes can provoke inflammatory cytokine and chemokine responses in macrophages via the intracellular antibody receptor TRIM21 [56-59].

In addition to innate immune responses in circulation, AdV virions can also be trapped by splenic macrophages (MFs) of the MARCO subset via the binding of fiber knob of the capsid to integrin b3 receptor [60]. This binding process leads to the release of IL-1α and activation of IL-1 receptor, promoting chemokines production and attracting other innate immune cells to kill AdV infected MFs [61]. AdV also activates the NLRP3 inflammasome to recruit proinflammatory caspases and promote IL-1β expression, thereby resulting in necrotic cell death [62]. Cytosolic sensing of AdV DNA via cyclic GMP-AMP synthase (cGAS) binds to stimulator of interferon genes (STING) to promote IRF3 phosphorylation to produce type I IFN [63, 64]. Moreover, AdV DNA is also sensed by the endosomal receptor TLR3, TLR7, and TLR9 to activate MyD88 signaling pathway. Nuclear sensing mechanisms of AdV DNA can also promote or inhibit immunity [65, 66]. These pathways cooperate to regulate the immune responses triggered by AdV vectors.

In the meantime, AdV also provoke highly effective adaptive immune responses, and the mechanism is similar to that of AAV. But contrary to AAV, AdV triggers a particularly strong CD8+ T cell responses, which is facilitated by potent induction of Th1 immunity [67]. Due to the induction of extremely strong immune responses, AdV vectors are a prerequisite vector for vaccine development. Picture loading failed.
Figure 9. Schematic principle of AdV-induced innate immune responses [15]. dsDNA: double-stranded DNA; NLPR3: NACHT, LRR and PYD domains-containing protein 3; ASC: Adaptor Protein Apoptosis-Associated Speck-Like Protein Containing CARD; Pro-casp 1: pro-caspase 1; IFNAR-1: interferon alpha/beta receptor 1; Jak1: Janus kinase 1; Tyk2: tyrosine kinase 2; Stat: signal transducer and activator of transcription; P: phosphoryl group; MDA5: melanoma differentiation-associated protein 5; dsRNA: double-stranded RNA; RIG-I: retinoic acid-inducible gene-I; MAVS: mitochondrial antiviral signaling protein; STING: stimulator of interferon genes; IRF: interferon response factor; cGAS: Cyclic GMP-AMP Synthase; TLR: toll-like receptor; ISG: interferon-stimulated genes; IFN: interferon; MyD88: myeloid differentiation primary response protein (88); NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; ssRNA: single-stranded RNA.


Recombinant AdV

Since wild-type adenovirus is associated with a wide range of illnesses and enlists a variety of immune responses, so recombinant replication deficiency virus has been an attractive vector for gene therapy [68]. To date, there have been many different generations of adenovirus vectors, differing in the extent to which the genome from wild-type adenovirus is attenuated. Based on human adenovirus type 5 (Ad5), recombinant adenovirus (Ad) a replication-defective adenoviral vector system, is widely used for gene delivery in most dividing and non-dividing cells based on its advantages in high transduction efficiency, high level of transgene expression, and broad range of viral tropism [69]. Traditionally, recombinant adenovirus vectors used in gene delivery were prepared with a plasmid containing the transgene flanked by inverted terminal repeats (ITRs), co-transfected with packaging plasmid pAd-BHGlox(delta)E1,3 (Fig. 10). Once packaged into a E1-complementing cell line, such as QBI 293A cells, recombinant viral will be easily propagated. Picture loading failed.
Figure 10. The two plasmids co-transfection system of recombinant adenovirus. pAd-EF1-MCS-CMV-EGFP: an adenovirus ITR-containing plasmid carrying multiple clone sites, which can be cloned into a transgene; pAd-BHGlox(delta)E1,3: a packaging plasmid.

AdV vector-based gene therapy

To date, more than 535 clinical trials have been carried out using adenovirus vectors for gene delivery [17], and promising gene therapy outcomes from recombinant adenovirus have been achieved from clinical trials for a great number of diseases, especially for cancer treatment, such as prostate cancer [70], chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) [71], non-small cell lung cancer (NSCLC) [72], melanoma [73], renal cell carcinoma [74].

AdV vector-based vaccine development

As a viral vector used for vaccine production, AdV induces strong immune responses and show better superiority than other viral vectors. In clinical trials, AdV vector-based vaccines have been used to prevent HIV-1 [75, 76], influenza [77], tuberculosis [78], and solid tumors [79]. Some of examples in clinical trials are listed in Table 4 [80]. However, there are also some reports with discouraging outcomes. For example, Ad5 vector with neutralizing antiserum against HIV contrarily significantly facilitated HIV infection besides the enhanced immune responses [81]. The pre-existing anti-AdV immunity against Ad5 is proved to be another limiting factor for the clinical application of Ad vector-based vaccines [82]. Therefore, although AdV vector exhibits some advantages over AAV vector in vaccine production, there are also some safety hazards and pre-existing anti-AdV immune responses needed for further exploration.

Table 4 - Examples of AdV vector-based vaccines [80]
Target Disease Status Clinical trials
Infectious diseasesHIVPhase I/II


MalariaPhase I/II

MalariaPhase II

Hepatitis C virusPhase I/IINCT02309086
Ebola virusPhase I/IINCT02289027
Ebola virusPhase IINCT02344407
TuberculosisPhase I/IINCT01017536
TuberculosisPhase IINCT01198366
RotavirusPhase IIINCT01305109
CancerColon/breast/lung/head/neck/renalPhase I/II

Colon/breast/lung/head/neck/renalPhase II

ProstatePhase II

LymphomaPhase II

Solid tumor/tissue sarcomaPhase I/II

Leukemia/glioblastomaPhase II

MelanomaPhase I/II

MelanomaPhase IINCT00004025

Advantages and disadvantage

There are many advantages of AdV as a vector for clinical trials: ① well tolerated with no obvious influences on the cell viability after infection; ② great packaging capacity (up to 8kb); ③ broad range of infectivity, from dividing cells to non-dividing cells; ④ high infection efficiency; ⑤ no integration ability into the host genome, remaining epichromosomal in host cells, thus no oncogenicity; ⑥ inducing a wide variety of immune responses, including humoral and cellular immunity. These advantages make AdV as an excellent vector for vaccine development. 

Although adenovirus benefits a great deal of disease prevention, it does present some drawbacks: ① AdV-mediated gene delivery may not sustain for long time, just transient expression; ② pre-existing immunity and neutralizing antibodies (NAB) against AdV vectors might attenuate the preventive effects of AdV vector-based vaccines [83]; ③ despite reduced overall virulence, recombinant Ad5-based vectors exhibit a strong tropism for liver parenchymal cells due to the high expression level of CAR in hepatocytes, which increases hepatotoxicity and limits the clinical use of AdV vectors [84].


Several measures were taken to improve the efficacy of AdV vector for vaccine development: ① modify the fiber protein to alter the tissue tropism and decrease the hepatic toxicity [85]; ② reduce viral vector-derived immune responses by changing virus gene expression, such as deleting E1 and E4 gene of AdV [86]; ③ modify the fiber protein to enhance the transduction of T cells and dendritic cells [87].

Genemedi got a rich experience in adenovirus packaging, you could find more information on

3) Lentiviral vector-based vaccines

Lentivirus (lente-, Latin for "slow") is a genus of retroviruses, medium sized (80-100nm) and enveloped, slightly pleomorphic, spherical with an isometric nucleocapsid containing two copies of positive-sense ssRNA genome (Fig. 11A). Most lentiviral vectors are based on the Human Immunodeficiency Virus (HIV), which causes AIDS, a chronic and deadly diseases in human or other mammalian species [88]. Its DNA genome, transcribed from HIV-1 ssRNA, is approximately 9.7 kb and contains 9 open reading frames (ORFs), which are flanked by 5’ and 3’ long terminal repeats (LTRs), which are required for HIV-1 life cycle, such as reverse transcription, integration, and gene expression (Fig. 11B). Picture loading failed.
Figure 11. Schematic of the lentivirus genome and lentivirus-based vectors. (A) Capsid crystal structure. (B) The viral genome encodes structural, regulatory and accessory genes flanked by LTRs [89]. There are 9 ORFs in lentiviral genome: env and gag responsible for structural proteins; pol for reverse transcriptase and integrase; tat and rev for gene regulatory proteins; vif, vpr, vpu, and nef for viral accessory proteins.


Principle of lentivirus entry into cells

HIV-1 virus enters host cells through binding to the CD4 receptor or a coreceptor (CCR5 or CXCR4) with gp120 protein, thereby anchoring itself onto host cell surface, allowing fusion between the cellular and viral membranes. After entry into the cell, the viral nucleoprotein together with the contents, i.e. the genomic ssRNA, is released into cytoplasm. Then, utilizing the cellular nucleotides as the building blocks, double-stranded DNA is generated from the virus genome ssRNA directed by the HIV-1 reverse transcriptase (RT) in a nucleoprotein complex termed the RTC. Together with other viral proteins, the newly synthesized DNA constitutes an integration-competent nucleoprotein complex, migrating into host cell nucleus and mediating integration of viral DNA into host chromatin. Integrated viral DNA, named as provirus, becomes part of host genome and serves as a transcription template for the synthesis of viral mRNA and genomic RNA. Following the synthesis of viral genomes and proteins, the viral components are assembled together to produce new virions, the virus particles then bud out of host cell and undergo a maturation step to generate infectious HIV-1 (Fig. 12) [90].

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Figure 12. Schematic representation of lentivirus replication [90].

Immune responses induced by lentivirus

Compared to HIV-1 virus, lentiviral vectors elicit weaker IFNα responses from pDC. SsRNA molecules of lentiviral vector in endosomes can be sensed by TLR7, while the reverse-transcribed CpG DNA is sensed by TLR9. TLR7 and TLR9 both contribute to induction of T1 IFN [91, 92] and regulation by mTOR pathway [93]. In addition to innate immune responses, lentiviral vector efficiently transduces APCs, such as MFs and DCs, which significantly facilitates the immune responses against transgene antigen. It was reported that transgene antigen expression in pDCs mainly drives immune responses, while antigen expression in myeloid cells may not obviously provoke immune responses [94, 95]. Furthermore, cell-derived MHC I molecules also helps trigger T cellular immune responses.

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Figure 13. Schematic principle of lentiviral vector-induced innate immune responses [15].


Recombinant lentiviral vector

Since wild-type HIV-1-based lentivirus is associated with destruction of host immune system, especially CD4+ helper T lymphocytes, multiple generations of lentivirus vectors have been designed with enhanced safety features and as attractive vectors for gene therapy and vaccine production. To date, there have been several generations of HIV-1-based lentivirus vectors by deleting the HIV viral envelope and some of the regulatory genes not required during vector production [89]. The recombinant lentiviral vectors in GeneMedi are prepared based on three plasmids co-transfection system: vector plasmid pLV-CMV-MCS-T2A-PURO, envelope expressing plasmid pMD2G, and packaging plasmid pSPAX2 (Fig. 14). Once packaged into 293T, recombinant lentiviral vectors will be easily produced.
Picture loading failed. Figure 14. The three plasmids co-transfection system of recombinant lentivirus. pLV-CMV-MCS-T2A-PURO: a lentivirus LTR-containing plasmid carrying multiple clone sites, which can be cloned into a transgene; pMD2G: envelope VSVG expressing plasmid; pSPAX2: packaging plasmid, containing sequences of gag, pol, tat, and rev.

Lentiviral vector-based gene therapy

To date, more than 236 clinical trials have been carried out using lentivirus vectors for gene delivery [17]. For instance, lentiviral vector-based gene delivery into CD34+ HSCs has been used as an alternative in clinical trials and proved to be effective in treatment of several diseases [96], including β-thalassemia [97], X-linked adrenoleukodystrophy (ALD) [98], metachromatic leukodystrophy [99, 100], and Wiskott-Aldrich Syndrome [101].

Lentiviral vector-based vaccine development

In addition, as a viral vector used for vaccine production, lentiviral vectors can transduce antigen-presenting cells with high efficiency, such as dendritic cells [102], which provides some priority to lentiviral vector-based vaccines. Animal studies demonstrate that lentiviral vector-based vaccines can provoke both CD8+ T-cells and CD4+ T-cell responses and show great defense effects against melanoma by targeting NY-ESO-1 antigen [102, 103], or Melan-A/MART-1 antigen [104]. Besides, lentiviral vector-based HIV vaccines induce Gag-specific T-cell responses [105-107]. Some examples of LV vector-based vaccines are listed in the following Table 5. Although promising outcomes by lentiviral vector-based have been achieved in animal studies, the virulence of lentivirus still raises safety concerns. As the virulence of immunodeficiency virus is species-specific, feline immunodeficiency virus (FIV)-based vectors have been developed [108] to combat HIV-1 and the Herpes simplex virus (HSV) with great potential [109, 110].

Table 5 - Examples of LV vector-based vaccines
Disease Vaccine component Status Clinical trials
LeukemiaLV-mediated genetically engineered AML cellsPhase INCT00718250
ALLLV-mediated IL-12 expression in AML cellsPhase INCT02483312
CD19+ B cell Leukemia and LymphomaARTEMIS™Early Phase 1NCT03895944

Advantages and disadvantages

Recombinant lentiviral vectors have a lot of advantages for vaccine development: ① mediating long-term and stable exogenous gene expression by integrating into the host genome; ② great packaging capacity; ③ highly efficient in transfection in both diving cells to non-dividing cells; ④ low pre-existing immunity. However, lentiviral-mediated gene integration into host genome, which might arouse the risk of tumorigenesis. Additionally, the virulence of lentiviral-derived backbone, i.e. HIV-1, also arouses serious safety concern.


To avoid the virulence of HIV-1, FIV-based viral vectors [108] were discovered and showed great potential for the prevention of HIV-1 and HSV [109, 110]. Moreover, integration-deficient LV vectors are being exploited for vaccine development [111, 112].

4) Comparison of commonly used viral vector-based vaccines

Viral vector-based vaccines can provoke innate and adaptative immune responses in host system besides the transgene antigens, which makes them preferred during vaccine design and development. Nevertheless, the immune responses induced by different viral vectors may have some differences (Table 6). In brief, lentiviral vectors efficiently transduce antigen-presenting cells, but mediate exogenous gene integration into host genome, showing promising prospects as vaccine vectors, especially for the prevention of hematopoietic diseases. Adenoviral vectors induce high immune responses but have pre-existing immunity, exhibiting great promise in vaccine generation and gene therapy against cancers. Whereas, AAV vectors, just inducing mild immune responses and having a large number of serotypes, are the most excellent gene therapy vector but not very suitable to be vaccine vectors (Table 7).

Table 6 - Overview of viral vectors and their immune responses [2]
Viral vector Lentiviral vector Adenoviral vector AAV vector
Virion and genome
Enveloped virus containing capsid and
~10-kb ssRNA genome

Capsid; 36-kb dsDNA genome
Capsid, 5-kb ssDNA genome
(or ~2.5-kb scDNA genome)

Innate immunityStrong IFNα/β response limits transduction
and drives adaptive responses
Potent innate response, including activation of vascular endothelial cells and platelets, inflammatory cytokine production, and macrophage cell death
Comparatively weak and transient innate response; TLR9 signaling promotes CD8+ T cell responses; complement activation and other immunotoxicities seen in some patients receiving high-dose systemic gene transfer

Immunity in human populationLow pre-existing immunityPre-existing immunity to human serotypes
Pre-existing immunity varies
between serotypes and geographic location

In vivo transduction of antigen presenting cells

Use as vaccine carrier
Targeting of dendritic cells for vaccine development
Vaccine and cancer gene therapy applicationsLimited
Adaptive immune responses to vectorNAB formation;
possibly T cell responses to envelope protein

NAB formation;
CD8+ T cell responses to viral gene products (except for high-capacity vectors)

NAB formation;
CD8+ T cell responses to capsid
Adaptive immune responses to transgene productsEfficient inducer of B and T cell responses unless transgene expression is tightly controlled by miRNA and promoter and expression is professional APCs is eliminatedEfficient inducer of CD8+ T cell responses; antibody formation possible
Least efficient inducer of CD8+ T cells compared to Ad and LV; risk of CD8+ T cell and antibody responses highly variable depending on vector design and dose, route of administration, and host factors

Table 7 - Comparison among viral vector-based vaccines
Vector vaccines Lentiviral vector-based vaccines Adenoviral vector-based vaccines AAV vector-based vaccines
Immune responsesMediumHighestMild
Advantages ① mediating long-term and stable exogenous gene expression by integrating into the host genome;

 ② great packaging capacity;

 ③ highly efficient in transfection in both diving cells to non-dividing cells;

 ④ low pre-existing immunity

 ① well tolerated with no obvious influences on the cell viability after infection;

 ② great packaging capacity (up to 8kb);

 ③ broad range of infectivity;

 ④ high infection efficiency;

 ⑤ no integration ability into the host genome;

 ⑥ inducing a wide variety of immune responses.

 ① superior biosafety rating;

 ② stable physical properties;

 ③ broad range of infectivity;

 ④ mediate long term and stable antigen gene expression.
 ① some risk of tumorigenesis;

 ② the virulence of vector backbone may raise some safety concern

 ① inducing transient expression of antigen;

 ② pre-existing immunity and neutralizing antibodies (NAB);

 ③ recombinant Ad5-based vectors may have hepatotoxicity

 ① limited cloning capacity ;

 ② only inducing mild immunity;

 ③ pre-existing immunity and neutralizing antibodies (NAB)

Packaging capacityMediumHighestLowest
Suitable for vaccineSuitableMost suitableNot suitable

GeneMedi provides professional services on viral packaging, you could find more information on the following website:

3. DNA based vaccines

Traditionally, vaccines are prepared with killed or attenuated viruses or bacteria, which might have serious security issues for the development of HIV vaccines. Additionally, vector-based vaccines may induce anti-vector immunity, which might interfere the immune responses provoked by vaccines [113]. Thus, DNA vaccines were first created in 1990 with finding that delivery of recombinant plasmid may allow the expression of exogenous antigen protein [114]. Then, the immune responses [115] and protection against lethal influenza by exogenous plasmid DNA were also discovered [116, 117]. Following these studies, DNA vaccines are demonstrated to be effective for the various diseases, such as infectious diseases, cancers, autoimmune diseases, and allergic diseases.

Generally, the optimized antigen DNA and molecular adjuvant are cloned into plasmid backbone, named as recombinant plasmid. After amplification and purification of the recombinant plasmids, they are delivered into host cells. Utilizing the nutrients and materials of host cells, antigens are transcribed, expressed, and assembled. On the one hand, antigen peptides are recognized and presented on major histocompatibility complex (MHC) class I, while secreted antigen proteins are captured and processed by antigen-presenting cells (APCs) and then presented by MHC class II (MHC II). APCs carrying MHC-antigen peptide complex migrate to lymph node to stimulate T cells and mediate cellular immune response. On the other hand, antigen proteins can be recognized and captured by antigen-specific high affinity immunoglobulins on the B cell surface, then provoke humoral immune response, which is assisted by the pre-activated antigen-specific CD4+ T cells (Fig. 15) [118]. Picture loading failed.
Figure 15. General principles of immune responses induced by DNA vaccines [118]. MHC: major histocompatibility complex.

Compared with the traditional vaccines, the immunogenicity of DNA vaccines is quite weak. To enhance the immunogenicity, several strategies are utilized: ① stronger promoters are adopted for the cloning of recombinant plasmid, such as APC-specific promotors; ② optimize the delivery route, transducing DNA vaccines into antigen-presenting cells (APCs), such as dendritic cells, may significantly promote the cytotoxic responses; ③ optimization of multiple antigen sequences; ④ adjuvants are used to prevent tolerance induction and facilitate the innate immune signals induced by DNA vaccines, including alum, liposome, nanoparticles, cytokines, chemokines and pathogen-recognition receptor (PRR) agonists; ⑤ circumvent potential inhibitory effects of the vector [119].

Although DNA vaccines have not been applied widespread due to their weak immunogenicity, promising outcomes are achieved based on improvements the priming high-level antigen specific antibody responses. Some of them are listed in the following Table 8 [120, 121].

Table 8. Examples of clinical trials using DNA vaccine [121]
Disease Antigen Delivery route Status Outcome Reference
HIVEnV, ReVIntramuscularPhase IAb, CTL, T proliferative, chemokine release was observed[122]
HIVgp120, gp160IntramuscularPhase INo Ab response and cellular response were observed[123]
HIVChAdV63IntramuscularPhase IINo intervention-related serious adverse events[124]
38 cytotoxic T cell epitopes and 16 helper T cell epitopes derived from P. falciparum antigens

ElectroporationPhase Ipoorly immunogenic[125]
AnalHPV-16 E7 fragmentIntramuscularPhase I10/12 patients developed antigen-specific immune responses[126]
B-cell lymphomaIdiotypeIntramuscularPhase I/II
1/12 patient developed T-cell response to autologous Id following initial immunization course; 6/12 patients developed anti-Id responses following booster immunization

Breast carcinomaHER2IntramuscularPhase I
3/8 individuals had enhanced CD4+ T cell responses; 3/5 patients have enhanced HER2 Ab responses

Colorectal cancerCEA fused to T-helper epitopeintradermalPhase IErythema at injection site increased over time[129]
Colorectal cancerCEA (along with HBV surface antigen)IntramuscularPhase I4/17 patients developed Hsp65-specific IL-10 responses[130]
Melanomagp 100 (mouse)IntramuscularPhase I
4/27 patients developed gp100 tetramer+CD8+ cells; 5/27 developed IFNγ+CD8+ responses, one of which was tetramer+

Melanomagp 101 (mouse and human)IntramuscularPhase I6/18 patients developed gp100-specific T cell responses[132]
MelanomaTyrosinase (human and mouse)IntramuscularPhase I7/17 patients developed antigen-specific T-cell responses[133]
MelanomaMART-1IntramuscularPhase INo enhancement in antigen-specific immune responses[134]
MelanomaMART-1 and tyrosinase T-cell epitopesIntra-lymph nodePhase I4/19 patients developed immune responses to MART-1[135]
MelanomaEpitopes from five melanoma antigensIntramuscularPhase I22/31 patients developed antigen-specific T-cell responses[136]
Melanomagp100PMEDPhase INo antigen-specific immune responses detected[137]
MelanomaHLA-B7DNA-containing liposomesPhase I2/22 patients developed enhanced TIL cytotoxicity[138]
MelanomaTyrosinase epitopesIntra-lymph nodePhase I11/26 patients had antigen-specific T-cell responses[115]
NSCLCL523SIntramuscularPhase I1/10 patient developed antigen-specific antibody response[139]

4. RNA based vaccines

Though DNA vaccines avoid the anti-vector immunity, long term existence in cells might produce excessive antigens, which might provoke overactive immune responses and exhaust T cells [140]. Thus, another kind of nucleic acid-based vaccines, RNA vaccines, were developed by directly delivering mRNA into cells for the prevention and therapy of diseases. Without the need to entry into cell nucleus, RNA vaccines mainly function in cytoplasm, which might have higher efficiency in delivery [141].

RNA vaccines can be classified into 2 categories: conventional mRNA-based vaccines and self-amplifying mRNA vaccines (SAM, also termed replicons) (Fig. 9) [142]. Upon entry into cells, conventional RNA vaccines directly generate antigens with nutrients and materials of host cells. On the contrary, SAM vaccines generate antigens by several steps (Fig. 16). SAM can self-replicate in host cells, thus they can mediate high expression levels of antigen. Due to no expression of structural proteins, no virion particle can be produced. Picture loading failed.
Figure 16. Schematic analysis between conventional mRNA-based vaccines and self-amplifying mRNA vaccines [142]. The processes of antigen generation from self-amplifying mRNA vaccines can be divided into four steps: 1) The genomic (+)RNA encodes and generates the nonstructural proteins (nsP1, nsP2, nsP3, nsP4), producing a RNA-dependent RNA-polymerase (RDRP) complex; 2) RDRP utilizes genomic (+)RNA as template to generate genomic (-)RNA; 3)RDRP utilizes genomic (-) RNA as template to produce genomic (+) RNA and subgenomic RNA; 4) Subgenomic RNA is translated into antigen. 5) Conventional mRNA vaccines can be directly translated into antigen.

Besides the common immune responses induced by endogenous antigens, mRNA vaccine can elicit a robust type I IFN response, which facilitates CD8+ T cell cytolytic capacity and promotes eradication of infected cells [143]. However, some adverse effects are also observed. For example, specific single mutations in nsP1 sequence of alphaviruses, such as A533I, induce elevated Type I IFN expression, but decrease the expression level of antigen and vaccine immunity [144, 145]. To improve the efficacy of RNA vaccines, several strategies are applied: ① Modify or optimize the vaccine backbone, such as 5ʹ cap, poly (A) tail, codon optimization; ② Delivery systems (naked mRNA, formulation with liposomes, lipoplexes, polyplexes, particulate carrier-mediated, electroporation, and gene gun [146] ) and route of administration (such as intradermal [147] or intratumor administration [148]); ③ supplementation with small immunomodulatory molecules can also help improve the immune responses provoked by RNA vaccines, such as dexamethasone [149].

As a novel kind of vaccine, RNA vaccines have many advantages: ① Induction of humoral immune responses and cell immune responses; ② Provoke stronger immunity than DNA vaccines; ③ Avoid the anti-vector immunity; ④ Mediate transient expression of antigen; ⑤ No integration into host genome. To date, numerous mRNA vaccines have been translated into clinical trials, and several of them are listed in the following Table 9 [142].

Table 9. Examples of clinical trials using RNA vaccine [142]
Disease Antigen Delivery route Status Outcome Reference
MelanomaNY-ESO-1, MAGE-A3, tyrosinase and TPTEIntravenousPhase IIFNα and strong antigen-specific T-cell responses were induced[150]
Non-small cell lung carcinoma (NSCLC)NY-ESO-1, MAGEC1, MAGEC2, BIRC5, TPBG, and MUC1IntradermalPhase IImproved survival[151]
MelanomaMelan-A, Tyrosinase, gp100, Mage-A1, Mage-A3, and Survivin in 21IntradermalPhase IIVaccines are feasible and safe, and induce immune response[152]
MelanomaMelan-A, Tyrosinase, gp100, Mage-A1, Mage-A3, and Survivin in 22IntradermalPhase I/IIAn increase in antitumor humoral immune response was observed in some patient[153]
Renal cell carcinoma (RCC)Tumor-associated antigens mucin 1(MUC1), carcinoembryonic (CEA), human epidermal growth factor receptor 2 (Her-2/neu), telomerase, survivin, and melanoma-associated antigen 1 (MAGE-A1) IntradermalPhase I/IIInduce CD8+ and CD4+ immune Responses[154]
Renal cell carcinoma (RCC)MUC1, CEA, Her2/neu, telomerase, survivin, MAGE-A1IntradermalPhase I/IIA clear correlation was observed between survival and immunological responses to TAAs[155]
RabiesRabies virus glycoprotein (CV7201)Intradermal or intramuscularPhase IBoostable functional antibodies against a viral antigen was observed when administered with a needle-free device[156]
FluHemagglutinin (HA) proteinsIntramuscularPhase IProtective immunogenicity with acceptable tolerability profiles were induced[157]

5. Vaccines development for COVID-19/SARS-CoV-2

Coronavirus Disease 2019 (COVID-19) is a novel viral pneumonia caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). First discovered in Wuhan, a city in Hubei province of China, COVID-19 has already broken out throughout the world and posed a great threat to the public health, especially in Europe and North America now. Additionally, person-to-person transmission of COVID-19 disease is reported to be extremely rapid [158-160]. To date, more than one million cases were infected with COVID-19 and over 55,000 deaths occurred. Therefore, it is really urgent and noteworthy to develop the vaccines specific to COVID-19/SARS-CoV-2.

Belonging to the Betacoronavirus genus family, SARS-CoV-2 is 60~200nm in diameter and encapsidates a large positive-sense, single-stranded RNA virus (26-32kb) with many spikes on the virus capsid (Fig. 17A). The RNA genome of SARS-CoV-2 encodes several accessory proteins and structural proteins, such as nucleocapsid (N) protein, envelope (E) protein, membrane (M) protein, and spike (S) protein (Fig. 10B). Although the detailed mechanism of SARS-CoV-2 infection has not been clearly illuminated, several studies demonstrated that SARS-CoV-2 enters human cells via utilizing spike (S) protein to bind to the angiotensin converting enzyme (ACE2) on the surface of target cell [161, 162].

Picture loading failed.
Figure 17. SARS-CoV-2 capsid structure and genome map. (A) Three-dimensional structure diagram of SARS-CoV-2. (B) Genome organization of SARS-CoV-2 [158]. ORF: open reading frame. E: envelope. M: membrane. N: nucleocapsid. HR1: heptad repeat 1. HR2: heptad repeat 2. SP: signal peptide. NTD: N-terminal domain. RBD: receptor binding domain. S: spike. S1: subunit 1. S2: subunit 2. TM: transmembrane domain. For more information, see: EMA guidance for COVID-19 vaccine

Since the genome sequences of SARS-CoV were discovered and reported (, a large number of pharmaceutical enterprises and research organizations are sparing all efforts to the vaccine development. Different companies utilize different targets and antigen epitopes. Some of the advances are listed in the following Table 10 (from WHO), and most of them focus on viral vector-based vaccines (replicating or non-replicating viral vector-based vaccines), recombinant protein (Spike), and nucleic acid-based vaccines. To date, two COVID-19 vaccines have entered Phase I clinical testing to assess the safety and potency of vaccines. One is mRNA-1273, was developed by Moderna Therapeutics, encoding a prefusion-stabilized form of Spike (S) protein [163] ( Another vaccine is recombinant protein of SARS-CoV-2 antigen, developed by Chinese Academy of Military Sciences, Institute of Military Medicine. It was predicted that these vaccines can be applied in clinics in a large scale as early as 2021 if they can successfully pass the clinical testing. Although there is a long way for theses vaccines to be applied for prevention and therapy of COVID-19, they indeed bring great hope and light to people all over the world.

Table 10. 52 candidate vaccines in clinical evaluation
COVID-19 Vaccine developer/manufacturer Vaccine platform Type of candidate vaccine Number of doses Timing of doses Route of Adminis-
Clinical Stage
Phase 1 Phase 1/2 Phase 2 Phase 3
Sinovac Inactivated Inactivated 2 0,14 days IM NCT04383574
Study Report
Wuhan Institute of Biological Products/Sinopharm Inactivated Inactivated 2 0,21 days IM ChiCTR2000031809
Interim Report
Beijing Institute of Biological Products/Sinopharm Inactivated Inactivated 2 0,21 days IM ChiCTR2000032459
Study Report
Bharat Biotech Inactivated Whole-Virion Inactivated 2 0, 28 days IM CTRI/2020/07/026300
University of Oxford/AstraZeneca Non-Replicating Viral Vector ChAdOx1-S 2 0,28 days IM PACTR202006922165132
Interim Report
Study Report
CanSino Biological Inc./Beijing Institute of Biotechnology Non-Replicating Viral Vector Adenovirus Type 5 Vector 1 IM ChiCTR2000030906
Study Report
Study Report
Gamaleya Research Institute Non-Replicating Viral Vector Adeno-based (rAd26-S+rAd5-S) 2 0,21 days IM NCT04436471
Study Report
Janssen Pharmaceutical Companies Non-Replicating Viral Vector Adenovirus Type 26 vector 1 2 0 0, 56 days IM NCT04436276
Novavax Protein Subunit Full length recombinant SARS CoV-2 glycoprotein nanoparticle vaccine adjuvanted with Matrix M 2 0,21 days IM NCT04368988
Study Report
(phase 2b)
Anhui Zhifei Longcom Biopharmaceutical/Institute of Microbiology, Chinese Academy of Sciences Protein Subunit Adjuvanted recombinant protein (RBD-Dimer) expressed in CHO cells 3 0, 28, 56 days IM NCT04445194
Moderna/NIAID RNA LNP-encapsulated mRNA 2 0,28 days IM NCT04283461
Interim Report
Final Report
BioNTech/Fosun Pharma/Pfizer RNA 3 LNP-mRNAs 2 0,21 days IM NCT04368728
Study Report
Study Report1
Study Report2
Medicago Inc. VLP Plant-derived VLP adjuvanted with AS03. 2 0, 21 days IM NCT04450004
Inovio Pharmaceuticals/ International Vaccine Institute DNA DNA plasmid vaccine with electroporation 2 0, 28 days ID NCT04447781
Beijing Wantai Biological Pharmacy/ Xiamen University Replicating Viral Vector Intranasal flu-based-RBD 1 IN

West China Hospital, Sichuan University Protein Subunit RBD (baculovirus production expressed in Sf9 cells) 2 or 3 0, 28 days and 0,14, 28 days IM
Curevac RNA mRNA 2 0, 28 days IM NCT04449276
Institute of Medical Biology, Chinese Academy of Medical Sciences Inactivated Inactivated 2 0, 28 days IM NCT04412538
Research Institute for Biological Safety Problems, Rep of Kazakhstan Inactivated Inactivated 2 0, 21 days IM NCT04530357
Shenzhen Kangtai Biological Products Co., Ltd. Inactivated Inactivated 2 IM ChiCTR2000038804
Osaka University/ AnGes/ Takara Bio DNA DNA plasmid vaccine + Adjuvant 2 0, 14 days IM NCT04463472
Cadila Healthcare Limited DNA DNA plasmid vaccine 3 0, 28, 56 days ID CTRI/2020/07/026352
Genexine Consortium DNA DNA Vaccine (GX-19) 2 0, 28 days IM NCT04445389
Kentucky Bioprocessing, Inc Protein Subunit RBD-based 2 0, 21 days IM NCT04473690
Sanofi Pasteur/GSK Protein Subunit S protein (baculovirus production) 2 0, 21 days IM NCT04537208
Biological E Ltd Protein Subunit Adjuvanted protein subunit (RBD) 2 0, 28 days IM CTRI/2020/11/029032
Israel Institute for Biological Research Replicating Viral Vector VSV-S 1 IM NCT04608305
Arcturus/Duke-NUS RNA mRNA IM NCT04480957
SpyBiotech/Serum Institute of India VLP RBD-HBsAg VLPs 2 0, 28 days IM ACTRN12620000817943
Symvivo DNA bacTRL-Spike 1 Oral NCT04334980
Providence Health & Services DNA electroporated S protein plasmid DNA vaccine with or without the combination of electroporated IL- 12p70 plasmid 2 0, 28 days ID NCT04627675
Codagenix/Serum Institute of India Live Attenuated Virus Codon deoptimized live attenuated vaccines 1 or 2 0 or 0,28 days IN NCT04619628
ImmunityBio, Inc. & NantKwest Inc. Non-Replicating Viral Vector hAd5 S+N 2nd Generation Human Adenovirus Type 5 Vector (hAd5) Spike (S) + Nucleocapsid (N) 2 0, 21 days SC NCT04591717
ReiThera/LEUKOCARE/Univercells Non-Replicating Viral Vector Replication defective Simian Adenovirus (GRAd) encoding S 1 IM NCT04528641
CanSino Biological Inc/Institute of Biotechnology, Academy of Military Medical Sciences, PLA of China Non-Replicating Viral Vector Ad5-nCoV 2 0, 28 days IM/mucosal NCT04552366
Vaxart Non-Replicating Viral Vector Ad5 adjuvanted Oral Vaccine platform 2 0, 28 days Oral NCT04563702
Ludwig-Maximilians - University of Munich Non-Replicating Viral Vector MVA-SARS-2-S 2 0, 28 days IM NCT04569383
City of Hope, USA Replicating Viral Vector SARS-CoV-2 S and NP genes inserted into a sMVA vector 2 0, 28 days IM NCT04639466
Clover Biopharmaceuticals Inc./GSK/Dynavax Protein Subunit Native like Trimeric subunit Spike Protein vaccine 2 0, 21 days IM NCT04405908
Vaxine Pty Ltd/Medytox Protein Subunit Recombinant spike protein with Advax™ adjuvant 1 IM NCT04453852
University of Queensland/CSL/Seqirus Protein Subunit Molecular clamp stabilized Spike protein with MF59 adjuvant 2 0, 28 days IM ACTRN12620000674932p
Medigen Vaccine Biologics Corporation/NIAID/Dynavax Protein Subunit S-2P protein + CpG 1018 2 0, 28 days IM NCT04487210
Instituto Finlay de Vacunas, Cuba Protein Subunit rRBD produced in CHO-cell chemically conjugate to tetanus toxoid 2 0, 28 days IM IFV/COR/06
Instituto Finlay de Vacunas, Cuba Protein Subunit RBD + Adjuvant 2 0, 28 days IM IFV/COR/04
FBRI SRC VB VECTOR, Rospotrebnadzor, Koltsovo Protein Subunit Peptide 2 0, 21 days IM NCT04527575
University Hospital Tuebingen Protein Subunit SARS-CoV-2 HLA-DR peptides 1 SC NCT04546841
COVAXX / United Biomedical Inc. Asia Protein Subunit Multitope peptide-based S1-RBD- protein vaccine 2 0, 28 days IM NCT04545749
Chinese Academy of Military Sciences Protein Subunit Subunit expressed in CHO cells 2 or 3 0, 14 days or 0,14, 28 days IM
Merck Sharp & Dohme/IAVI Replicating Viral Vector Replication-competent VSV delivering the SARS-CoV-2 Spike 1 IM NCT04569786
Institute Pasteur/Themis/Univ. of Pittsburg CVR/Merck Sharp & Dohme Replicating Viral Vector Measles-vector based 1 or 2 0, 28 days IM NCT04497298
Imperial College London RNA LNP-nCoVsaRNA 2 IM ISRCTN17072692
People's Liberation Army (PLA) Academy of Military Sciences/Walvax Biotech. RNA mRNA 2 0, 14 or 0, 28 days IM ChiCTR2000034112

Table 11. 162 candidate vaccines in preclinical evaluation
Platform Type of candidate vaccine Developer Coronavirus target Current stage of clinical evaluation/regulatory status- Coronavirus
Same platform for non-Coronavirus candidates
DNA DNA plasmids containing S-gene Biosun Pharmed SARS-CoV2 Pre-Clinical
DNA DNA plasmid vaccine Globe  Biotech Limited, Bangladesh SARS-CoV2 Pre-Clinical
DNA Plasmid DNA, nanostructured RBD National institute of Chemistry, Slovenia SARS-CoV2 Pre-Clinical
DNA DNA, engineered vaccine inserts compatible
with multiple delivery systems
DIOSynVax Ltd / University of Cambridge SARS-CoV-2 and
DNA DNA vaccine Ege University SARS-CoV2 Pre-Clinical
DNA DNA plasmid vaccine RBD&N Scancell/University of Nottingham/ Nottingham Trent University SARS-CoV2 Pre-Clinical
DNA DNA plasmid vaccine S,S1,S2,RBD &N National Research Centre, Egypt SARS-CoV2 Pre-Clinical
DNA DNA with electroporation Karolinska Institute / Cobra Biologics
SARS-CoV2 Pre-Clinical
DNA DNA with electroporation Chula Vaccine Research Center SARS-CoV2 Pre-Clinical
DNA DNA Takis/Applied DNA Sciences/Evvivax SARS-CoV2 Pre-Clinical
DNA Plasmid DNA, Needle-Free Delivery Immunomic Therapeutics, Inc./EpiVax, Inc./PharmaJet SARS-CoV2 Pre-Clinical SARS
DNA DNA vaccine BioNet Asia SARS-CoV2 Pre-Clinical
DNA msDNA vaccine Mediphage Bioceuticals/University of Waterloo SARS-CoV2 Pre-Clinical
DNA DNA vaccine Entos Pharmaceuticals SARS-CoV2 Pre-Clinical
Inactivated Inactivated + Alum Shifa Pharmed SARS-CoV2 Pre-Clinical
Inactivated Inactivated Milad Pharmaceutics Co. SARS-CoV2 Pre-Clinical MMR, IPV
Inactivated Inactivated Zista Kian Azma Co. SARS-CoV2 Pre-Clinical MMR, IPV
Inactivated Inactivated Kocak Farma Ilac ve Kimya San. A.S. SARS-CoV2 Pre-Clinical
Inactivated Egg-based, inactivated, whole chimeric Newcastle Disease Virus (NDV) expressing membrane-anchored pre-fusion-stabilized trimeric SARS-CoV-2 S protein (Hexapro) +
CpG 1018
Institute of Vaccines and Medical Biologicals (IVAC; Vietnam) / Dynavax
SARS-CoV2 Pre-Clinical
Inactivated Egg-based, inactivated, whole chimeric Newcastle Disease Virus (NDV) expressing membrane-anchored pre-fusion-stabilized trimeric SARS-CoV-2 S protein (Hexapro) +
CpG 1018
Government Pharmaceutical Organization (GPO; Thailand) / Dynavax / PATH SARS-CoV2 Pre-Clinical
Inactivated Egg-based, inactivated, whole chimeric Newcastle Disease Virus (NDV) expressing membrane-anchored pre-fusion-stabilized trimeric SARS-CoV-2 S protein (Hexapro) +
CpG 1018
Institute Butantan (Brazil) / Dynavax / PATH SARS-CoV-2 Pre-clinical
Inactivated Inactivated + alum KM Biologics SARS-CoV2 Pre-Clinical JE, Zika
Inactivated Inactivated Selcuk University SARS-CoV2 Pre-Clinical
Inactivated Inactivated Erciyes University SARS-CoV2 Pre-Clinical
Inactivated Inactivated whole virus National Research Centre, Egypt SARS-CoV2 Pre-Clinical
Inactivated Inactivated SARS-CoV2 Pre-Clinical
Inactivated TBD Osaka University/ BIKEN/ NIBIOHN SARS-CoV2 Pre-Clinical
Inactivated Inactivated + CpG 1018 Sinovac/Dynavax SARS-CoV2 Pre-Clinical
Inactivated Inactivated + CpG 1018 Valneva/Dynavax SARS-CoV2 Pre-Clinical
Live Attenuated Virus Codon deoptimized live attenuated vaccines Mehmet Ali Aydinlar University / Acıbadem Labmed Health Services
SARS-CoV2 Pre-Clinical
Live Attenuated Virus Codon deoptimized live attenuated vaccines Indian Immunologicals Ltd/Griffith University SARS-CoV2 Pre-Clinical
Non Replicating Viral Vector Ad 5 vector for intranasal administration University of Helsinki & University of Eastern Finland SARS-CoV2 Pre-Clinical
Non Replicating Viral Vector Adenovirus Type 5 Vector Globe  Biotech Limited, Bangladesh SARS-CoV2 Pre-Clinical
Non-Replicating Viral Vector Sendai virus vector ID Pharma SARS-CoV2 Pre-Clinical
Non-Replicating Viral Vector Adenovirus-based Ankara University SARS-CoV2 Pre-Clinical
Non-Replicating Viral Vector Adeno-associated virus vector (AAVCOVID) Massachusetts Eye and Ear/Massachusetts General Hospital/AveXis SARS-CoV2 Pre-Clinical
Non-Replicating Viral Vector MVA encoded VLP GeoVax/BravoVax SARS-CoV2 Pre-Clinical LASV, EBOV, MARV, HIV
Non-replicating viral vector MVA-S encoded DZIF – German Center for Infection Research/IDT Biologika GmbH SARS-CoV2 Pre-clinical Many
Non-replicating viral vector MVA-S IDIBAPS-Hospital Clinic, Spain SARS-CoV2 Pre-clinical
Non-Replicating Viral Vector Intranasal Ad5 vaccine encoding RBD Altimmune, Inc. SARS-CoV2 IND filed Influenza (NasoVAX), Anthrax
Non-Replicating Viral Vector Adeno5-based Erciyes University SARS-CoV2 Pre-Clinical
Non-Replicating Viral Vector Ad5 S (GREVAX™ platform) Greffex SARS-CoV2 Pre-Clinical MERS
Non-Replicating Viral Vector Oral Ad5 S Stabilitech Biopharma Ltd SARS-CoV2 Pre-Clinical Zika, VZV, HSV-2 and Norovirus
Non-Replicating Viral Vector adenovirus-based  +  HLA-matched peptides Valo Therapeutics Ltd Pan-Corona Pre-Clinical
Non-Replicating Viral Vector Vaxart SARS-CoV2 Pre-Clinical InfA, CHIKV, LASV, NORV; EBOV, RVF, HBV, VEE
Non-Replicating Viral Vector MVA expressing structural proteins Centro Nacional Biotecnología (CNB-CSIC), Spain SARS-CoV2 Pre-Clinical Multiple candidates
Non-Replicating Viral Vector parainfluenza virus 5 (PIV5)-based vaccine
expressing the spike protein
University of Georgia/University of Iowa SARS-CoV2 Pre-Clinical MERS
Non-Replicating Viral Vector Recombinant deactivated rabies virus
containing S1
Bharat Biotech/Thomas Jefferson University SARS-CoV2 Pre-Clinical HeV, NiV, EBOV, LASSA, CCHFV, MERS
Non-Replicating Viral Vector Influenza A H1N1 vector National Research Centre, Egypt SARS-CoV2 Pre-Clinical
Non-Replicating Viral Vector Newcastle disease virus expressing S Icahn School of Medicine at Mount Sinai SARS-CoV2 Pre-Clinical
Protein Subunit Recombinant spike with adjuvant Iran SARS-CoV2 Pre-Clinical Multiple candidates
Protein Subunit Recombinant S protein produced in BEVS Tampere University SARS-CoV2 Pre-Clinical
Protein Subunit RBD protein delivered in mannose-
conjugated chitosan nanoparticle
Ohio State University / Kazakh National Agrarian University SARS-CoV2 Pre-Clinical
Protein Subunit Recombinant spike protein with Essai O/W
1849101 adjuvant
Kazakh National Agrarian University SARS-CoV2 Pre-Clinical
Protein Subunit Peptides Neo7Logic SARS-CoV2 Pre-Clinical
Protein Subunit Recombinant spike protein with Essai O/W
1849101 adjuvant
Kazakh National Agrarian University, Kazakhstan / National Scientific
Center for Especially Dangerous Infections
SARS-CoV2 Pre-Clinical
Protein Subunit Recombinant S protein Max-Planck-Institute of Colloids and Interfaces SARS-CoV2 Pre-Clinical
Protein Subunit RBD protein (baculovirus production) + FAR-
Squalene adjuvant
Farmacológicos Veterinarios SAC (FARVET SAC) / Universidad Peruana
Cayetano Heredia (UPCH)
SARS-CoV2 Pre-Clinical
Protein Subunit Protein Subunit Research Institute for Biological Safety Problems, Rep of Kazakhstan SARS-CoV2 Pre-Clinical
Protein Subunit RBD-protein Mynvax SARS-CoV2 Pre-Clinical
Protein Subunit Recombinant S protein Izmir Biomedicine and Genome Center SARS-CoV2 Pre-Clinical
Protein Subunit Peptide + novel adjuvant Bogazici University SARS-CoV2 Pre-Clinical
Protein Subunit S subunit intranasal liposomal formulation
with GLA/3M052 adjs.
University of Virginia SARS-CoV2 Pre-Clinical
Protein Subunit S-Protein (Subunit) + Adjuvant, E coli based
Helix Biogen Consult, Ogbomoso & Trinity Immonoefficient Laboratory,
Ogbomoso, Oyo State, Nigeria.
SARS-CoV2 Pre-Clinical
Protein Subunit Protein Subunit S,N,M&S1 protein National Research Centre, Egypt SARS-CoV2 Pre-Clinical
Protein Subunit Protein Subunit University of San Martin and CONICET, Argentina SARS-CoV2 Pre-Clinical
Protein Subunit RBD protein fused with Fc of IgG + Adj. Chulalongkorn University/GPO, Thailand SARS-CoV2 Pre-Clinical
Protein Subunit Capsid-like Particle AdaptVac (PREVENT-nCoV consortium) SARS-CoV2 Pre-Clinical
Protein Subunit Drosophila S2 insect cell expression system
ExpreS2ion SARS-CoV2 Pre-Clinical
Protein Subunit Peptide antigens formulated in LNP IMV Inc SARS-CoV2 Pre-Clinical
Protein Subunit S protein WRAIR/USAMRIID SARS-CoV2 Pre-Clinical
Protein Subunit S protein +Adjuvant National Institute of Infectious Disease, Japan/Shionogi/UMN Pharma SARS-CoV2 Pre-Clinical Influenza
Protein Subunit VLP-recombinant protein + Adjuvant Osaka University/ BIKEN/  National Institutes of Biomedical Innovation,
SARS-CoV2 Pre-Clinical
Protein Subunit microneedle arrays S1 subunit Univ. of Pittsburgh SARS-CoV2 Pre-Clinical MERS
Protein Subunit Peptide Vaxil Bio SARS-CoV2 Pre-Clinical
Protein Subunit Peptide Flow Pharma Inc SARS-CoV2 Pre-Clinical Ebola, Marburg, HIV, Zika, Influenza, HPV therapeutic vaccine, BreastCA
Protein Subunit S protein AJ Vaccines SARS-CoV2 Pre-Clinical
Protein Subunit Ii-Key peptide Generex/EpiVax SARS-CoV2 Pre-Clinical Influenza, HIV, SARS-CoV
Protein Subunit S protein EpiVax/Univ. of Georgia SARS-CoV2 Pre-Clinical H7N9
Protein Subunit Protein Subunit EPV-CoV-19 EpiVax SARS-CoV2 Pre-Clinical
Protein Subunit gp-96 backbone Heat Biologics/Univ. Of Miami SARS-CoV2 Pre-Clinical NSCLC, HIV, malaria, Zika
Protein Subunit Subunit vaccine FBRI SRC VB VECTOR, Rospotrebnadzor, Koltsovo SARS-CoV2 Pre-Clinical
Protein Subunit S1 or RBD protein Baylor College of Medicine SARS-CoV2 Pre-Clinical SARS
Protein Subunit Subunit protein, plant produced iBio/CC-Pharming SARS-CoV2 Pre-Clinical
Protein Subunit Recombinant protein, nanoparticles (based
on S-protein and other epitopes)
Saint-Petersburg scientific research institute of vaccines and serums SARS-CoV2 Pre-Clinical
Protein Subunit COVID-19 XWG-03
truncated S (spike) proteins
Innovax/Xiamen Univ./GSK SARS-CoV2 Pre-Clinical HPV
Protein Subunit Adjuvanted microsphere peptide VIDO-InterVac, University of Saskatchewan SARS-CoV2 Pre-Clinical
Protein Subunit Synthetic Long Peptide Vaccine candidate for
S and M proteins
OncoGen SARS-CoV2 Pre-Clinical
Protein Subunit Oral  E. coli-based protein expression system
of S and N proteins
MIGAL Galilee Research Institute SARS-CoV2 Pre-Clinical
Protein Subunit Nanoparticle vaccine LakePharma, Inc. SARS-CoV2 Pre-Clinical
Protein Subunit Plant-based subunit
(RBD-Fc + Adjuvant)
Baiya Phytopharm/ Chula Vaccine Research Center SARS-CoV2 Pre-Clinical
Protein Subunit OMV-based vaccine Quadram Institute Biosciences SARS-CoV2 Pre-Clinical Flu A, plague
Protein Subunit OMV-based vaccine BiOMViS Srl/Univ. of Trento SARS-CoV2 Pre-Clinical
Protein subunit structurally modified spherical particles of
the tobacco mosaic virus (TMV)
Lomonosov Moscow State University SARS-CoV2 Pre-Clinical rubella, rotavirus
Protein Subunit Spike-based University of Alberta SARS-CoV2 Pre-Clinical Hepatitis C
Protein Subunit Recombinant S1-Fc fusion protein AnyGo Technology SARS-CoV2 Pre-Clinical
Protein Subunit Recombinant protein Yisheng Biopharma SARS-CoV2 Pre-Clinical
Protein Subunit Recombinant S protein in IC-BEVS Vabiotech SARS-CoV2 Pre-Clinical
Protein Subunit Orally delivered, heat stable subunit Applied Biotechnology Institute, Inc. SARS-CoV2 Pre-Clinical
Protein Subunit Peptides derived from Spike protein Axon Neuroscience SE SARS-CoV2 Pre-Clinical
Protein Subunit Protein Subunit MOGAM Institute for Biomedical Research, GC Pharma SARS-CoV2 Pre-Clinical
Protein Subunit RBD-based Neovii/Tel Aviv University SARS-CoV2 Pre-Clinical
Protein Subunit Outer Membrane Vesicle (OMV)-subunit Intravacc/Epivax SARS-CoV2 Pre-Clinical
Protein Subunit Outer Membrane Vesicle(OMV)-peptide Intravacc/Epivax SARS-CoV2 Pre-Clinical
Protein Subunit Spike-based (epitope screening) ImmunoPrecise/LiteVax BV SARS-CoV2 Pre-Clinical
Protein Subunit Spiked-based Nanografi Nano Technology, Middle East Technical University, Ankara
SARS-CoV2 Pre-Clinical
Replicating Bacteria Vector Oral Salmonella enteritidis (3934Vac) based
protein expression system of RBD
Farmacológicos Veterinarios SAC (FARVET SAC) / Universidad Peruana
Cayetano Heredia (UPCH)
SARS-CoV2 Pre-Clinical
Replicating Viral Vector Intranasal Newcastle disease virus vector
(rNDV-FARVET) expressing RBD
Farmacológicos Veterinarios SAC (FARVET SAC) / Universidad Peruana
Cayetano Heredia (UPCH)
SARS-CoV2 Pre-Clinical
Replicating Viral Vector YF17D Vector KU Leuven SARS-CoV2 Pre-Clinical
Replicating Viral Vector Measles Vector Cadila Healthcare Limited SARS-CoV2 Pre-Clinical
Replicating Viral Vector Measles Vector FBRI SRC VB VECTOR, Rospotrebnadzor, Koltsovo SARS-CoV2 Pre-Clinical
Replicating Viral Vector Measles Virus (S, N targets) DZIF – German Center for Infection Research/CanVirex AG SARS-CoV2 Pre-clinical Zika, H7N9, CHIKV
Replicating Viral Vector Horsepox vector expressing S protein Tonix Pharma/Southern Research SARS-CoV2 Pre-Clinical Smallpox, monkeypox
Replicating Viral Vector Live viral vectored vaccine based on attenuated influenza virus backbone (intranasal) BiOCAD and IEM SARS-CoV2 Pre-Clinical Influenza
Replicating Viral Vector Recombinant vaccine based on Influenza A virus, for the prevention of COVID-19 (intranasal) FBRI SRC VB VECTOR, Rospotrebnadzor, Koltsovo SARS-CoV2 Pre-Clinical Influenza
Replicating Viral Vector Attenuated Influenza expressing
an antigenic portion of the Spike protein
Fundação Oswaldo Cruz and Instituto Buntantan SARS-CoV2 Pre-Clinical Influenza
Replicating Viral Vector Influenza vector expressing RBD University of Hong Kong SARS-CoV2 Pre-Clinical
Replicating Viral Vector Replicating VSV vector-based DC-targeting University of Manitoba SARS-CoV2 Pre-Clinical
Replicating Viral Vector VSV-S University of Western Ontario SARS-CoV2 Pre-Clinical HIV, MERS
Replicating Viral Vector VSV-S Aurobindo SARS-CoV2 Pre-Clinical
Replicating Viral Vector VSV vector FBRI SRC VB VECTOR, Rospotrebnadzor, Koltsovo SARS-CoV2 Pre-Clinical
Replicating Viral Vector M2-deficient single replication (M2SR)
influenza vector
UW–Madison/FluGen/Bharat Biotech SARS-CoV2 Pre-Clinical influenza
Replicating Viral Vector Newcastle disease virus vector (NDV-SARS-
Intravacc/ Wageningen Bioveterinary Research/Utrecht Univ. SARS-CoV2 Pre-Clinical
Replicating Viral Vector Avian paramyxovirus vector (APMV) The Lancaster University, UK SARS-CoV2 Pre-Clinical
RNA mRNA Providence Therapeutics SARS-CoV2 Pre-Clinical
RNA mRNA Cell Tech Pharmed SARS-CoV2 Pre-Clinical
RNA mRNA ReNAP Co. SARS-CoV2 Pre-Clinical
RNA D614G variant LNP-encapsulated mRNA Globe Biotech Ltd SARS-CoV2 Pre-Clinical
RNA saRNA formulated in a NLC Infectious Disease Research Institute/ Amyris, Inc. SARS-CoV2 Pre-Clinical
RNA LNP-encapsulated mRNA encoding S Max-Planck-Institute of Colloids and Interfaces SARS-CoV2 Pre-Clinical
RNA Self-amplifying RNA Gennova SARS-CoV2 Pre-Clinical
RNA mRNA Selcuk University SARS-CoV2 Pre-Clinical
RNA LNP-mRNA Translate Bio/Sanofi Pasteur SARS-CoV2 Pre-Clinical
RNA LNP-mRNA CanSino Biologics/Precision NanoSystems SARS-CoV2 Pre-Clinical
RNA LNP-encapsulated mRNA  cocktail encoding
Fudan University/ Shanghai JiaoTong University/RNACure Biopharma SARS-CoV2 Pre-Clinical
RNA LNP-encapsulated mRNA encoding RBD Fudan University/ Shanghai JiaoTong University/RNACure Biopharma SARS-CoV2 Pre-Clinical
RNA Replicating Defective SARS-CoV-2 derived
Centro Nacional Biotecnología (CNB-CSIC), Spain SARS-CoV2 Pre-Clinical
RNA LNP-encapsulated mRNA University of Tokyo/ Daiichi-Sankyo SARS-CoV2 Pre-Clinical MERS
RNA Liposome-encapsulated mRNA BIOCAD SARS-CoV2 Pre-Clinical
RNA Several mRNA candidates RNAimmune, Inc. SARS-CoV2 Pre-Clinical
RNA mRNA FBRI SRC VB VECTOR, Rospotrebnadzor, Koltsovo SARS-CoV2 Pre-Clinical
RNA mRNA China CDC/Tongji University/Stermina SARS-CoV2 Pre-Clinical
RNA LNP-mRNA Chula Vaccine Research Center/University of Pennsylvania SARS-CoV2 Pre-Clinical
RNA mRNA in an intranasal delivery system eTheRNA SARS-CoV2 Pre-Clinical
RNA mRNA Greenlight Biosciences SARS-CoV2 Pre-Clinical
RNA mRNA IDIBAPS-Hospital Clinic, Spain SARS-CoV2 Pre-Clinical
T-cell based CD8 T cell peptide targeting (S, M, N) and
(NSPs) SARS-CoV-2 proteins
OSE immunotherapeutics SARS-CoV2 Pre-Clinical
VLP Plant derived VLP Shiraz University SARS-CoV2 Pre-Clinical
VLP VLPs produced in BEVS Tampere University SARS-CoV2 Pre-Clinical
VLP VLP Max Planck Institute for Dynamics of Complex Technical Systems SARS-CoV2 Pre-Clinical
VLP Virus-like particle-based Dendritic Cell(DC)-
targeting vaccine
University of Manitoba SARS-CoV2 Pre-Clinical
VLP VLP Bezmialem Vakif University SARS-CoV2 Pre-Clinical
VLP VLP Middle East Technical University SARS-CoV2 Pre-Clinical
VLP Enveloped Virus-Like Particle (eVLP) VBI Vaccines Inc. SARS-CoV-2,
Pre-Clinical CMV, GBM, Zika
VLP S protein integrated in HIV VLPs IrsiCaixa AIDS Research/IRTA-CReSA/Barcelona Supercomputing
SARS-CoV2 Pre-Clinical
VLP VLP + Adjuvant Mahidol University/ The Government Pharmaceutical Organization
(GPO)/Siriraj Hospital
SARS-CoV2 Pre-Clinical
VLP Virus-like particles,  lentivirus and
baculovirus vehicles
Navarrabiomed, Oncoimmunology group SARS-CoV2 Pre-Clinical
VLP Virus-like particle, based on RBD displayed
on virus-like particles
Saiba GmbH SARS-CoV2 Pre-Clinical
VLP ADDomerTM multiepitope display Imophoron Ltd and Bristol University’s Max Planck Centre SARS-CoV2 Pre-Clinical
VLP Unknown Doherty Institute SARS-CoV2 Pre-Clinical
VLP eVLP ARTES Biotechnology SARS-CoV2 Pre-Clinical malaria
VLP VLPs peptides/whole virus Univ. of Sao Paulo SARS-CoV2 Pre-Clinical

6. Tumor/Cancer vaccines

GeneMedi’s Promise-ORFTM offers the larger collection of ORF/cDNA expression clones of human, mouse, rat and some other species. All ORFs expression clones in viral vectors (lentivirus, AAV and adenovirus) or mammalian expression vectors are sequences-verified. Using our Promise-ORFTM viral-ready expression vectors, you can easily promote your viral vectors packaging, or you can transfect your mammalian cells directly with stronger expression and easier detection.

If you couldn't find your GOI, please check the Custom-made viral production:

Custom-made AAV Production
Custom-made Adenovirus Production
Custom-made Lentivirus Production

Despite several decades’ continuous efforts on tumor therapy with radiation treatment and chemotherapy, serious adverse effects, including nausea, vomiting, physical weakness, mental malaise, sweating, decreased white blood cells and platelets, are really painful and intolerable. Tumor vaccines are vaccines using tumor-specific antigens (TSAs) to provoke the host immune system to specifically eliminate and suppress tumors or cancers, exhibiting promising advantages over traditional radiation and chemotherapy. Several kinds of tumor vaccines are developed for the therapy of tumor as shown in Fig. 18 [164], including nucleic acid vaccines (DNA vaccines and RNA vaccines), protein/peptide vaccines, and cell-based vaccines with tumor antigens.

Picture loading failed.
Figure. 18 Schematic representation of tumor (cancer) vaccines [164].

Nucleic acid-based vaccines can be taken up by APCs and translated into specific antigen to provoke host immune system, such as Tyrosinase Related Protein 1 (TYRP1/gp75) vaccine for the treatment of melanoma [165]. Protein/peptide-based vaccines are tumor specific antigens protein or epitope, which can directly stimulate immune system, such as HSPPC-96 vaccine (Oncophage) for the treatment of melanoma, gastric cancer, renal cell cancer, lymphoma, and pancreatic cancer [166]. Cell-based vaccines are autologous dendritic cells or other immune cells with insertion of tumor antigen genes or transfected with tumor antigens or peptides, such as dendritic cell vaccine, provenge (sipuleucel-T), targeting PAP for the therapy of prostate cancer [167]. A large number of tumor vaccines have been translated into clinics and encouraging therapy outcomes have been achieved (Table 12).

Table 12. Examples of vaccines against tumor
Disease Antigen/target
Vaccine classification

Delivery route Status Outcome References
Prostate cancerPAPDNA vaccineIntravenousPhase IIIImproved survival[167]
Prostate cancerVEGF Receptor 2DNA vaccineOralPhase IVaccine were well-tolerated and T effector was increased[168]
NSCLCMUC1Protein/peptide-based vaccinesIntravenousPhase IIITecemotide might have some adverse events on patients who initially receive concurrent chemoradiotherapy[169]
NSCLCMUC1Protein/peptide-based vaccinesSubcutaneousPhase IIISafe, but adverse events existed[170]
MelanomaHSPPC-96Protein/peptide-based vaccinesIntradermalPhase I/IIFeasible and safe. Modest immune response and anti-tumor activity were observed[171]
Ovarian carcinoma, glioblastoma, pancreatic carcinoma, stomach carcinomaMultiple tumor-associated antigens (TAAs)Tumor cell vaccineIntradermalPhase I/IIAntitumor immune memory and patient survival were improved[172]
Prostate cancerPAPRecombinant adenoviral vector-based vaccineSubcutaneousPhase I/IISafe with no serious vaccine-related adverse events, and anti-PSA T-cell responses were induced[172]
MelanomaIL-2Autologous tumor cell vaccine via Ad vector-mediated IL-2 transfectionIntradermal/subcutaneousPhase ISafe and tolerate[173]
MelanomaMART-1 or gp100Recombinant adenoviral vector-based vaccineIntramuscular/subcutaneousPhase ISafe, but presenting high levels of neutralizing antibody.[174]
MelanomaGM-CSFIrradiated autologous tumor cell vaccine via Ad vector-mediated GM-CSF transfectionIntradermal/subcutaneousPhase IWell tolerated and induce anti-tumor immune response[175]
MelanomaMART-1Autologous dendritic cell vaccine via Ad vector-mediated MART-1 transfectionIntradermalPhase I/IISafe and immunogenic[176]
Solid tumorHER2DNA vaccine and adenoviral vector-based vaccineIntramuscularPhase IWell tolerated and without any serious adverse events[79]
Non-muscle-invasive bladder cancer (NMIBC)IFNα/Syn3Recombinant adenoviral vector-based vaccineIntravesicalPhase IIWell tolerated[177]
Non-muscle-invasive bladder cancer (NMIBC)IFNα2b/Syn4Recombinant adenoviral vector-based vaccineIntravesicalPhase IbPromising drug efficacy was shown[178]
Non-muscle-invasive bladder cancer (NMIBC)IFNα/Syn3Recombinant adenoviral vector-based vaccineIntravesicalPhase IWell tolerated with no dose limiting toxicity[179]
Colorectal cancerCEARecombinant adenoviral vector-based vaccineSubcutaneousPhase I/IISafe and immunogenic[179]
Colorectal cancerCEARecombinant adenoviral vector-based vaccineSubcutaneousPhase IMinimal toxicity[180]
Hepatocellular cancerAFPDNA vaccine and adenoviral vector-based vaccineIntramuscularPhase ISafe and immunogenic[181]
B-cell lymphosarcoma TelomeraseRecombinant adenoviral vector-based vaccineIn femoral bicepsPhase ISafe and prolong the survival time[182]

As is known to all, there are many somatic mutations in tumors varying in different individuals, and more and more highly heterogeneous neoantigens are discovered and identified through next generation sequencing (NGS) technologies. On the basis of tumor mutation profiles, personalized cancer vaccines are designed and developed to activate immune system against cancer by targeting specific epitopes of neoantigens (Fig. 19). Once delivered into the body with adjuvant, personal vaccines provokes host immune responses through the following processes:

① Neoantigen-specific peptides inside personal vaccines are captured and processed by APCs;
② Activated APCs migrate to lymph nodes and present neoantigens to T cells with MHC molecules;
③ Neoantigens are recognized and bound by T cell receptor, thus priming and activating cell immunity;
④ Neoantigen-specific T cells are expanded, migrate and infiltrate to tumor microenvironment;
⑤ Neoantigen-specific T cells kill tumor cells with neoantigens, leading to the release of more antigens, which elicits adaptive immune memory and augments the immune responses.

So far, personal vaccines have achieved encouraging anti-tumor effects in the pre-clinical studies with mouse models and clinical trials. For example, using whole-exome and transcriptome sequencing and mass spectrometry analysis, more than 1300 amino acid changes were identified in MC-38 and TRAMP-C1 murine tumor models, and vaccination with mutated peptides exhibits remarkable and sustainable inhibition of tumor growth [183]. For human melanoma therapy, a neoantigen was discovered via whole exome sequencing and HLA binding prediction algorithm, and dendritic cell vaccine with the neoantigen significantly enhances the T cell immune response to the neoantigen in some patients [184].

Picture loading failed.
Figure 19. Schematic of strategies and principles of personal neoantigen vaccines [164]. (I) Get the tumor specimen from patient and extract the DNA. (II) Characterize the non-synonymous mutations via NGS. (III) Prepare the personal neoantigen vaccine in vitro and deliver the vaccine to patients with adjuvant.

7. Summary

In summary, different kinds of vaccines have their specific advantages and disadvantages (Table 13), and people should select the most suitable vaccines according to their demands. Although nucleic acid-based vaccines need short-term and little cost, DNA-based vaccines provoke mild immune responses, and no available mRNA vaccines have been applied into clinics, which really restrict the application of nucleic acid-based vaccines. Viral vector-based vaccines, especially adenoviral vector-based vaccines, stimulate relatively stronger immune responses, showing unique superiority in vaccine development. However, the COVID-19 is raging across the world now, which makes the vaccines for COVID-19 urgently demanded. At this fierce moment, time is really precious for life, which might give a chance for mRNA vaccine. At the same time, as a kind of effective and efficacious vaccines, viral vector-based vaccines are also promising and with great prospect for COVID-19 vaccine development.

Table 13. Comparison among several kinds of novel vaccines

Vaccine classification

Viral vector-based vaccines DNA vaccine RNA vaccine
Immune responsesInduce humoral and cellular immunityInduce humoral and cellular immunityInduce humoral and cellular immunity
ImmunogenicityVaries with different vectorsWeakWeak
①highly efficient in gene transduction;
② mediate specific gene delivery to target cells;
③induce of both humoral and cell-mediated immune responses;
④ better efficacy and safety;
⑤ just need low administration dose;
⑥ easy to be applied into large-scale manufacturing;
⑦ possessing widespread potential target diseases, ranging from infectious diseases to cancers

① Induction of humoral immune responses and cell immune responses;
② Avoid the anti-vector immunity;
③ Easy to produce in a large scale
① Induction of humoral immune responses and cell immune responses;
② Provoke stronger immunity than DNA vaccines;
③ Avoid the anti-vector immunity;
④ Mediate transient expression of antigen;
⑤ No integration into host genome;
⑥ Easy to produce in a large scale
Pre-existing immunity and neutralizing antibodies (AAV and AdV); tumorigenicity (LV)

Induce weak immunityInduce weak immunity
Suitable timeAAV and LV: long-term stable expression;
AdV: transient
Delivery systemViral vectorNaked nucleic acids, formulation with liposomes, lipoplexes, polyplexes, particulate carrier-mediated, electroporation, and gene gun
Naked nucleic acids, formulation with liposomes, lipoplexes, polyplexes, particulate carrier-mediated, electroporation, and gene gun

Optimization AAV: rational design of capsid;
AdV: modify fiber protein to alter tissue tropism;
LV: develop integration-free vector

① Utilizing stronger promoters;
② Optimize the delivery route;
③ Optimization of multiple antigen sequences;
④ Adjuvants are used to prevent tolerance induction and facilitate the innate immune signals;
⑤ circumvent potential inhibitory effects of the vector

① Modify or optimize the vaccine backbone;
② Optimize the delivery systems and route of administration;
③ supplementation with small immunomodulatory molecules to improve the immune responses
Clinical usageYesNot yetNot yet

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Collection of COVID-19 landscape knowledge base

COVID-19 landscape Knowledge Base

An Insight of comparison between COVID-19 (2019-nCoV disease) and SARS in pathology and pathogenesis
Landscape Coronavirus Disease 2019 test (COVID-19 test) in vitro -- A comparison of PCR vs Immunoassay vs Crispr-Based test

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