As we move into 2021, we are now hit with the stark reality that Covid-19 is still with us. To date, across the globe more than 2.03 million people have died from COVID-19 and confirmed infections now exceed 90 million. Sadly, the pandemic is still evolving, with new variants of the SARS-CoV-2 virus emerging from the UK, Brazil and South Africa. Effective therapeutic drugs for severe cases and effective vaccines for the healthy people are in urgent need within every country (Zhang et al 2020). In response to the pandemic the scientific community in general has portrayed the development of safe and effective vaccines against the SARS-CoV-2 virus as the perverbial “light at the end of the tunnel”.

As of December 2020, Pfizer-BioNTech’s and Moderna’s SARS-CoV-2 vaccines each have Emergency Use Authorization (EUA) in the USA, for use in individuals age 16 and older. Both Pfizer-BioNTech’s and Moderna’s SARS-CoV-2 vaccines are mRNA vaccines, and are the first of their kind to receive EUA approval in the USA.  

AstraZeneca, Janssen and Novavax each have SARS-CoV-2 vaccines​ in Phase III clinical trials that are based on different vaccine platforms however as the WHO reported, there are 215 COVID-19 vaccine candidates in development (Deborah Pushparajah et al. 2021). Critical to their successful adoption, will be the monitoring of how many people become infected with SARS-CoV-2 even after receiving one of these vaccines. Here, we will explore several of the vaccine platforms begin employed to address the pandemic.

RNA vaccines

Messenger RNA (mRNA) is a sequence of genetic code that our cells use to direct protein production, which is necessary for cellular functions. To produce an RNA vaccine, scientists develop a synthetic version of the virus’ mRNA that is put into a carrier for injection. After delivery by injection,  the cells are instructed to start building the relevant viral protein. The carrier containing the mRNA also enters into dentritic cells and macrophages in the lymph nodes near the injection site, to boost the immune response to the vaccine. For the SARS-CoV-2 vaccine, the encoded sequence is for the SARS-CoV-2 spike protein, which prompts our immune system to generate anti-Spike antibodies, thereby protecting against COVID-19 disease.

mRNA technology is new but not unknown, and has been studied for more than a decade in pre-clinical and toxicology studies for vaccine targets including influenza, Zika and rabies. Advances in mRNA chemistry and the development of safer and more effective carriers have improved the performance of these in terms of stability, safety and efficacy. The real advantage to mRNA vaccines lies in shorter manufacturing times, lower cost per dose and the potential to target multiple infectious agents within the same formulation. These represent the underlying reasons behing the rapid approval of the two mRNA SARS-CoV-2 vaccines from Pfizer-BioNTech and Moderna, both of which display ~95% efficacy. Despite the some challenges with storage and mRNA fragility, mRNA based vaccines technology is proving to be a promising approach for addressing Covid-19.

Fig, 1. mRNA approach to Covid-19 vaccination. Advantages include: safety (non-infectious, non-intergrating), in vivo half-life is controlled through delivery method and chemical modifications of the mRNA. mRNA enters the cells of the muscles resulting in the production of Spike protein and their presentation on the cell surface via MHC I; in addition the mRNA can be presented in the surface of APC cells in the lymph nodes via MHC II. This ensures a strong T-cell and B-cell immune responses, leading to enhanced immunological protection.

Viral vector vaccines

Viral vector vaccines utilize a modified form of a virus to introduce part of the disease-causing virus’ DNA into our cells. The harmless virus transports the code into our cells, which then produce the target protein that then triggers an immune response, priming our immune system to be ready to attack the disease-causing virus during any future exposure.  The first viral vector vaccine, using Adenovirus, was approved for use against Ebola made by Johnson and Johnson on December 19, 2019.

There are two basic types of viral vector vaccines for Covid-19- replicating and non-replicating. Non-replicating require higher doses, but are considered safer. However, when using an Adenovirus vaccine approach, it is important to consider that some individuals within the population have some immunity to human adenovirus; this may partially reduce the effectiveness of a vaccine based on human adenovirus, and therefore some platforms are adopting viruses from other primates including Gorilla Ad (ReiThera) and Chimp Ad (Oxford/AstroZeneca). 

In the case of SARS-CoV-2, Oxford-AstraZeneca have developed the first viral vector vaccine to be approved for use in the UK. Using, a modified form of Chimp Adenovirus (non-replicating) containing DNA encoding the Spike protein, the vaccine triggers the production of the SARS-CoV-2 Spike protein within the cells that take up the Adenovirus.  Viral vector vaccines from other companies such as CanSino Biologics, Gamaleya Research Institute, and Janssen are in late-stage research. They all use adenoviruses as a vector. 

Whole virus vaccines

Another, more traditional vaccine platform involves the use of whole virus particles. The viruses used in these vaccines are either:

1. Inactivated – a version of the virus is inactivated by being exposed to heat, chemicals, or radiation, or 
2. Re-created as Virus-like particles – a version of the virus closely resembling the original virus, is created artificially; however, it does not contain any genetic material, so it is not infectious.   

These vaccines cannot cause the disease but will induce an immune response that will protect against future infection. Some of the most advanced inactivated COVID-19 vaccines in development include Sinovac, Bharat Biotech, and two by Sinopharm. Afluria, Flublok Quadrivalent and Fluvirin are examples of approved virus inactivated vaccines approved for the prevention of influenza.

Protein subunit vaccines

Purified antigenic protein subunits can be used for vaccination. To generate the protein subunit a small piece of the virus’s genetic code is inserted into another cell – perhaps a bacterial, yeast, mammalian, or insect cell. The code instructs a cell to build the virus protein, for example the COVID-19 ‘spike’ protein.  The cells act in essence as factories, producing large quantities of the protein – which is then extracted, purified, and used as the active ingredient in the vaccine. When it is injected, our bodies learn to recognize the viral protein so that they can mount an immune response that protects against future infection.   Some of the SARS-CoV-2 vaccines using this approach include Novavax and the Chinese Academy of Sciences. These vaccines are in phase III clinical trials.

Fig. Summary of vaccine approaches being taken across the globe to combat the spread of Covid-19. It is likely that several approaches will lead to the commercial development of vaccines that will be administered world-wide. 

Final thoughts 

With so many different approaches to the production of Covid-19 vaccines formulations, only time will tell which of these provides the most effective and long lasting protection against SARS-CoV-2 virus and the variant strains that are emerging across the globe.

In our next blog we discuss ways that the efficacy and safety of vaccines developed on these different technology platforms can be monitored using a variety of immunological surveillance tools, and what this could mean for a sustained and worldwide response to Covid-19. 

Dr. Sibtain Ahmed is a scientific writer and a member of FlowMetric’s Business Development team. Sibtain is a skilled a biochemist with experience in the field of biologics, and cell and gene therapy manufacturing, drug discovery, vaccines, and fermentation. Sibtain earned his B.S. in Biology at the University of the Punjab and his Ph.D. from the University of Agriculture Faisalabad. Sibtain did postdoc research at the University of New Mexico and the University of California San Diego. Sibtain’s previous work history includes working at Thermo Fisher Scientific, Hologic, and the Genomics Institute of the Novartis Research Foundation.  Sibtain has authored peer-reviewed articles/book chapters, presented posters, and has given oral talks in
scientific meetings.

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