Table 1.

Application, utility, and dual-use potential of different vaccine approaches. Presentation of leading COVID-19 vaccine candidates based on the WHO Draft landscape of COVID-19 candidate vaccines as of 9 Jan 2021[30].

Approach	Description and COVID-19 use	Utility for tackling emerging diseases	Estimated dual-use potential
Platform approaches
Virally vectored vaccines	Antigen is inserted into genome of well-defined, non-pathogenic, usually replication-defective viral vectors, such as adenovirus (Ad), inducing expression in vaccine recipient’s cells [7] Manufactured in mammalian cell culture. -Oxford/AstraZeneca, ChAdOx1, phase 3, licensed -CanSino, Ad5, phase 3 -Janssen/J&J, Ad26, phase 3	High: -Multiple virally vectored vaccines have been licensed, e.g. for Ebola and Dengue fever[8] -Induction of both robust humoral and cellular immune responses[9] -Potential for single-dose regimen[10], [11] -Potential for large scale manufacturing; likely achievable if use of suspension cell culture system -Limitations: -Pre-existing anti-vector immunity[12], [13] -Induction of anti-vector immunity limits reusability of vectors[14]	Relatively high: -Creation of chimeric viruses for evasion of pre-existing anti-vector immunity[15] -Potential for further research into how to engineer viral immune evasion -Increases number of people with access to viral engineering knowledge and tools
mRNA vaccines	Antigen is encoded as messenger RNA, synthesised in cell-free in vitro transcription process, and formulated, e.g. with lipid nanoparticle (LNP) coat, to prevent degradation and improve cell entry. mRNA induces expression of the antigen in vaccine recipient’s cells for induction of an immune response.[7] -Pfizer/BioNTech, LNP-mRNA, phase 3, licensed -Moderna/NIAID, LNP-mRNA, phase 3, licensed -Curevac, LNP-mRNA, phase 3	High: -No licensed mRNA vaccine to date, but early phase 3 reports for COVID-19 promising[16], [17] -Promising neutralising antibody levels in immunogenicity trials, but induction of robust cellular responses still in question[6] -Very high speed of development -Future potential for high speed of manufacturing, scalable manufacturing likely -High flexibility of expressed antigen[18] -Limitations: -Efficacy (potency with regard to protection from disease/infection) needs to be confirmed and no large scale manufacturing experience to date[6] -Subzero cold-chain requirement[19]	Low: -No viral/organism engineering involved -Might increase accessibility to synthesis of DNA/RNA which encodes viral proteins
Self-amplifying RNA vaccines	Similar to mRNA vaccines, RNA replicon based on the alphavirus genome mediates amplification of the antigen-encoding mRNA within the recipient’s cells. -Arcturus Therapeutics, LNP-saRNA, phase 2 -Imperial College, LNP-saRNA, phase 1	Medium-High: -Similar properties to mRNA vaccines -No clinical safety/immunogenicity data yet -Prospect of inducing robust immune response at very low vaccine dose, promising low-cost and scalable manufacturing[20] - Limitation: - Need for clinical data and manufacturing of long replicon-containing RNA has yet to be shown at scale[18] - Anti-vector immunity against replicon proteins may limit reusability[6]	Low(-Medium): -No viral/organism engineering involved -Might increase accessibility to synthesis of DNA/RNA which encodes viral proteins -Study of and work on viral replicons might inform how to amplify viral replication
DNA vaccines	Antigen is encoded as DNA plasmid, synthesised in cell-free in vitro transcription process, and injected to induce expression of the antigen in vaccine recipient’s cells. Cell uptake may be improved by electroporation.[7] -Inovio, DNA + electropo., phase 2/3 -Osaka/AnGes/Takara, DNA + adjuvant, phase 2/3 -Cadila, DNA, phase 3 -Genexine, DNA, phase 1/2	Medium: -Only DNA vaccines for veterinary use have been licensed to date[18] -Share many properties of mRNA vaccines -Additional limitation: DNA needs to be delivered to cell nuclei for expression, potential reliance on electroporation device for administration, potential safety risk of genomic integration[7]	Low: -No viral engineering involved -Might increase accessibility to synthesis of DNA which encodes viral proteins -Research into how to deliver DNA into nucleus and genome; however, the key driver for this is gene therapy
Recombinant protein expression platform	Antigen gene inserted into the expression system for protein production, e.g. insect baculovirus-mediated insertion into insect cell lines, modified to exhibit human glycosylation patterns; resulting proteins may be administered as virus-like particles (VLPs) or with adjuvant.[18] -Novavax, baculovirus-produced glycoprotein + adjuvant, phase 3 -Anhui Zhifei Longcom/IM, mammalian cell-produced RBD-Dimer + adjuvant, phase 3 -Kentucky Bioprocessing, plant-produced RBD protein subunit, phase 1/2	Medium-High: -Good track record of recombinant protein vaccines, including several baculovirus-insect cell-based vaccines having been licensed[18] -Recombinant proteins and adjuvants induce good humoral immune responses -Administration as virus-like particles (VLPs) (protein mixed with preformed VLPs or are engineered self-assemble into VLPs in case of the ADDomer system) has may induce strong and lasting humoral responses[21] -VLP vaccines may have high thermostability[18] - Limitations: - Complex development and manufacturing compared to other platforms;[18]	Low-Medium: -Protein engineering-based approach, hence seems largely safe -Some risk associated with potential for production of toxins -Involves limited amount of viral engineering, e.g. of insect or plant virus -Might somewhat contribute to routine of modifying viruses -Investigation of and work on viral capsid structure to inform VLP vaccines may increase insight into viral engineering
Traditional approaches
Inactivated virus vaccines	Exposure of virulent virus to heat or chemical agents, for example, formalin or β-propiolactone, to “inactivate” the virus, to prevent infectivity while retaining immunogenicity.[5], [22] Virus for vaccination may be grown in embryonated chicken eggs or cell lines.[23] -Bharat Biotech, inactivated SARS-CoV-2, phase 3, licensed -Sinopharm, inactivated SARS-CoV-2, phase 3 -Sinovac, inactivated SARS-CoV-2, phase 3	Medium: -Traditional approach, lots of experience with technology, e.g. for large scale manufacturing -Usually good immunogenicity -Usually require multiple doses[22] -Fast response during COVID-19 pandemic supports usefulness during pandemic - Limitations: - Requirement of viral samples for vaccine development and manufacturing, need for high containment facilities - Likely won’t be able to keep up with speed of development and probability of licensing of more platform-like approaches in future pandemics	Medium: -Requires very little understanding of viral pathogenesis and modification -Biosafety risk from culturing large batches of replication-competent, pathogenic virus before inactivation -Creates knowledge and facilities forculture of pathogenic viruses
Live attenuated virus vaccine (empirical attenuation through serial passaging)	Classic empirical approach: Serial passaging of virus, e.g. through cells, for loss of virulence. Virus for vaccination may be grown in embryonated chicken eggs or cell lines.[23] -None in clinical development for COVID-19	Low: -Lots of experience with empirical approach -Potent immunogenicity -Risk of reversion to virulence[24] -Limitation: Not platform-like, each vaccine needs to be optimised and tested independently	Low-Medium: -Requires very little understanding of viral pathogenesis and modification -Creates knowledge and facilities for culture of attenuated virus
Live attenuated virus vaccines (rational attenuation)	Rational attenuation approach: Based on viral engineering, e.g. synonymous codon replacement[25] -Codagenix/Serum Institute of India, synonymous codon de-optimised SARS-CoV-2, phase 1	-Limited experience with rational attenuation approach to date -Potentially reduced risk of virulence reversion -Limitation: Not platform-like, each vaccine needs to be optimised and tested independently	Medium-High: -Generates tools for precise insertion of many mutations[26] -May create knowledge on enhancing virulence -Increases number of people with access to viral engineering knowledge and tools