Since the outbreak of COVID-2019 in December 2019, as of April 2022, according to the World Health Organization (WHO) statistics, there have been more than 500 million confirmed cases worldwide, of which more than 6.1 million died.
In the context of the COVID-19 global pandemic, vaccination has become the key to controlling the spread of the COVID-19 in the population. Existing COVID-19 vaccines mainly include inactivated vaccines, recombinant subunit vaccines, viral vector vaccines, nucleic acid vaccines and virus-like particles (VLPs) vaccines. This article mainly summarizes these five types of COVID-19 vaccines and their characteristics.
New confirmed cases, by date of report
1. Inactivated Vaccines
Inactivated vaccines are vaccines that use physical or chemical methods to kill the virus to lose its infectivity and virulence, but still have immunogenicity and are combined with corresponding adjuvants. It is characterized by good safety, the most complete immunogenicity, rapid early development and mild adverse reactions. However, inactivated vaccines mainly cause humoral immunity, and cellular immunity is rarely detected, so the protection rate of vaccines is relatively low.
Currently, there are mainly two inactivated vaccines against COVID-19 in China: Sinopharm (Beijing) BBIBP-CorV (Vero Cells) and Sinovac CoronaVac. The former is the first COVID-19 vaccine approved for marketing in China, and the data show that its protection rate is 79.34%. Inactivated vaccine is also the most widely used vaccine for clinical prevention. Inactivated vaccines include SARS-COV-2 Vaccine from the Institute of Medical Biology, Chinese Academy of Medical Sciences (IMBCAMS), and Inactivated (Vero Cell) Vaccine is under development.
Schematic diagram of inactivated vaccine preparation principle
Image source: WHO
2. Recombinant Subunit Vaccines
Recombinant subunit vaccines are vaccines that express protective antigen genes in prokaryotic or eukaryotic cells and are made with gene products, i.e. proteins or peptides, and corresponding adjuvants. It is characterized by high purity, good stability and high safety. A three-dose vaccination programme is generally used. Zhifei COVID-19 vaccine is the world's first recombinant COVID-19 vaccine approved for use. The vaccine is made by expressing purified SARS COV-2 S-RBD dimer antigen protein in Chinese Hamsters Ovary (CHO) through genetic engineering, supplemented with Al(OH)3 adjuvant .
A moderate Th1/Th2 mixed-type cellular immune response can be generated after vaccination. The results of phase III clinical trials showed that the overall protective efficacy of the vaccine against all symptoms was 81.43%, and the protective efficacy against severe cases could reach 100%. At present, recombinant subunit vaccines have been vaccinated in some areas, and no serious adverse reactions have been found. The recombinant subunit vaccines under development include SK Bioscience's GBP510 vaccine, WestVac Biopharma's Recombinant COVID-19 Vaccine, and Cinnagen's SpikoGen vaccine.
3. Viral Vector Vaccines
Viral vector vaccines are vaccines that use a viral vector to deliver genetic material coding for a desired antigen into the recipient's host cells. It is characterized by the ability to induce continuous and effective humoral and cellular immune responses. However, the adverse reactions are relatively severe compared with inactivated vaccines, and are not suitable for immunocompromised people. The pre-existing immunity of viral vectors may interfere with the effect of vaccines.
The world's first viral vector vaccine entering clinical trials is the human adenovirus vector COVID-19 vaccine (AD5-NCOV) from China, which was jointly developed by the team of Academician Chen Wei of the Academy of Military Medical Sciences and CanSinoBIO. The vaccine was constructed by cloning the full-length S gene containing tissue-type plasminogen activator signaling peptide gene into replication-deficient human adenovirus type 5 . The mid-term results of phase III clinical trials showed that the protective efficacy of a single dose of vaccine against severe diseases was 96.0% and 91.7% after 14 and 28 days, respectively .
In addition, the existing adenovirus vector vaccines designed by the United Kingdom, Russia and other countries have shown rapid cellular immunity and humoral immunity after inoculation, and clinical data show that they have a high protective power, especially for severe patients, which can reach more than 90%. Currently, adenovirus vector vaccines under development include Sputnik V vaccine from Russia and AD26.cov2.s developed by Janssen–Cilag International NV.
Schematic diagram of Ad5-nCoV structure
Image source: Savina et al. Beni-Suef Univ J Basic Appl Sci (2022) 11:35
4. Nucleic Acid Vaccines
Nucleic acid vaccine is a kind of vaccine that introduces the gene encoding antigen protein (DNA or RNA) into the host cell, uses the expression system of the host cell to synthesize antigen protein and induce the host to produce immune response to the antigen, so as to prevent diseases . Nucleic acid vaccines are divided into DNA vaccines and mRNA vaccines. mRNA vaccine is characterized by short development cycle and flexible design, which can superimpose multiple antigen mRNA to enhance immunity. Moreover, exogenous mRNA itself has antigenicity and does not need adjuvants to enhance immune response. However, mRNA vaccines are unstable and require effective delivery systems (e.g. nanoparticles coated with liposomes) to enter cells and play an antigenic role.
Moderna's COVID-19 vaccine (mRNA-1273) is the first vaccine to enter clinical trials in the world. Phase I and II clinical results showed that this vaccine can rapidly induce neutralizing antibodies and produce TH1-biased T cell immune response. In phase III clinical trials, no safety problems were found except transient local and systemic reactions, and the vaccine effective rate was 94.1%. In addition, the mRNA vaccine developed by Pfizer also produced strong immune effects in the clinical stage. Current mRNA vaccines under development include CSPC mRNA vaccine (SYS6006), CanSinoBIO mRNA vaccine and Moderna's new generation mRNA vaccine (mRNA-1273.214).
LNP-encapsulated mRNA vaccine structure
Image source: Savina et al. Beni-Suef Univ J Basic Appl Sci (2022) 11:35
In addition to mRNA vaccines, DNA vaccines have also been applied to the COVID-19 vaccines. DNA vaccine is to implant the DNA fragment of the target antigen into the plasmid, which is brought into the host cell by the plasmid. The DNA molecule is very stable, it can exist in the host cell for a long time, and continuously generate natural antigens in the body to trigger a sustained and effective immune effect. However, it may also integrate into the chromosome of the host cell causing mutations.
The first DNA vaccine to enter the clinic is INO-4800 produced by Inovio Pharmaceuticals in the United States. Clinical results show that the vaccine can induce a strong S protein specific T cell response and produce neutralizing antibodies. The current research is mainly on the new generation of DNA vaccines from Advaccine.
Schematic diagram of DNA vaccine structure
5. Virus-like Particles (VLPs) Vaccines
Virus-like particles (VLPs) vaccines refer to a class of vaccines with multimeric particles similar to the spatial structure of natural virus particles, which contain hollow particles of one or more structural proteins of a certain virus, without viral nucleic acids that are identical or similar in morphology to true virions. It is characterized by having a three-dimensional structure and composition similar to natural virus particles, which can stimulate the human immune system through a route similar to virus infection, and efficiently induce the human body to produce an immune protection response. Moreover, VLPs vaccine also has an adjuvant effect. It is becoming a hot spot in vaccine research and development. VLPs vaccines under development include Medicago's COVIFENZ® vaccine.
Structural biodiversity of VLP
Image source: EXPERT REVIEW OF VACCINES, 2018. 17(9): p. 833-849.
Another common type of vaccine is attenuated vaccine. An attenuated vaccine is a vaccine created by reducing the virulence of a pathogen, but still keeping it viable (or "live"). Attenuation takes an infectious agent and alters it so that it becomes harmless or less virulent. However, the research and development cycle of attenuated vaccines is long, and it is necessary to consider whether the virulence of the attenuated strains will become stronger. Under the premise of the COVID-19, it is very challenging. Therefore, attenuated vaccines are rarely used in COVID-19 vaccines at present.
As the novel coronavirus continues to mutate, vaccination is more important than ever. Although the data suggest that vaccination does not completely prevent infection, it can reduce the proportion of severe cases. In addition, studies have shown that the level of neutralizing antibodies decreases in patients who recover from COVID-19 seven months after infection, but t-lymphocyte immunity persists. Therefore, cellular immunity induced by T cells should be considered more in the development of the second generation of COVID-19 vaccine.
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 A single dose of an adenovirus-vectored vaccine provides protection against SARS-CoV-2 challenge
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 A tandem-repeat dimeric RBD protein-based covid-19 vaccine zf2001 protects mice and nonhuman primates
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