22 March, 2021

A Guide to the Current Global COVID-19 Vaccine Landscape

Sharat J. Vayttaden, PhD, University of Texas

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On 31st December 2019, the WHO China Country Office was informed of cases of pneumonia of unknown etiology detected in Wuhan City, Hubei Province of China (WHO 2020). On 12th January China shared the sequence of the novel coronavirus (WHO 2020a). The first case of this novel coronavirus outside China was recorded in Thailand on 13th January 2020 (WHO 2020d). On March 11th 2020 WHO declared COVID-19 as a pandemic (Cucinotta and Vanelli 2020). China approved the CanSino Biologics vaccine candidate for military use on 25th June 2020 (Reuters 2020a). While Russia announced approval of its Sputnik V vaccine for emergency use on 11th August 2020 (Burki 2020). On 2nd December 2020, the Medicines and Healthcare products Regulatory Agency of United Kingdom gave temporary regulatory approval for the Pfizer–BioNTech COVID‑19 vaccine (MHRA 2020a). The Food and Drug Administration of the United States granted an Emergency Use Authorization for the Pfizer–BioNTech vaccine on 11th December 2020 (FDA 2020). The most striking feature of the global COVID-19 vaccine R&D landscape was not just the unprecedented rapidity with which vaccine development occurred but also the range of vaccine technology platforms that were/are being evaluated (Figure 1). This article tries to summarize the COVID-19 vaccine landscape as of March 13th 2021.

Approved COVID-19 Vaccines

Currently, there are 13 COVID-19 vaccines approved for use at least in one or more countries (Table 1) spanning four vaccine platforms – inactivated virus, non-replicating viral vector, protein subunit and RNA vaccines. World Health Organization has an article on different COVID-19 vaccines (WHO 2021). The US Department of Health and Human Services also has written about different vaccine types not just limited to COVID-19 (HHS 2021).

Inactivated virus vaccines

Vaccines from Bharat Biotech, Chumakov Center, Sinopharm, Sinovac (Jonathan Corum 2021f), and Wuhan Institute of Biological Products all use an inactivated/killed SARS-CoV-2 virus as the immunogen. Because it has only killed Coronavirus these vaccines cannot cause COVID-19 in people. Using inactivated pathogens to make vaccines is a long established technique. The injected Salk polio vaccine (Bandyopadhyay et al. 2015), Hepatitis A vaccines like HAVRIX, VAQTA, AVAXIM, Healive, Aimugen, Weisairuian and Veraxim (Shouval 2019) use an inactivated virus as an immunogen.

How does it work?

Inactivated virus vaccines teach the immune system to make antibodies against SARS-CoV-2. The antibodies attach to viral proteins. Large stocks of SARS-CoV-2 are grown in cells and then the viral particles are treated with a chemical to inactivate the virus. The inactivated coronaviruses can no longer replicate, but usually their proteins remain intact. These inactivated virus particles are then mixed with compounds used to boost an immune response. The cell eventually destroys the inactivated virus from the vaccine, leaving no permanent trace.

Non-replicating viral vector vaccines

Vaccines from AstraZeneca (Jonathan Corum 2021d), CanSino, Gamaleya Institute(Jonathan Corum 2021a) and Johnson & Johnson (Jonathan Corum 2021c), all use a non-replicating cold causing virus that introduces SARS-CoV-2 DNA to produce spike proteins as immunogen. Because these vaccines do not have Coronavirus, they cannot cause COVID-19 in people. The technology to use modified cold causing virus as a vaccine against other viral diseases was used in developing the vaccine against Ebola by Johnson & Johnson (Custers et al. 2020).

How does it work?

Non-replicating cold viruses are modified to include the gene of the SARS-CoV-2 spike protein. When these modified cold viruses are injected into the body, they enter the cell and introduce its DNA into the nucleus of the cell. No new cold viruses are formed, but the cells of the body can use the introduced DNA to make the SARS-CoV-2 spike protein. The immune system reacts strongly to the presence of the non-replicating cold virus. It sees the SARS-CoV-2 spike protein and makes antibodies against it. The DNA from the cold virus does not integrate with the human DNA since the cold virus does not have the enzymatic machinery to do so and it is eventually destroyed by the cell, leaving no permanent trace.

Protein subunit vaccines

Vaccines from VECTOR Institute and Anhui Zhifei Longcom Biopharmaceutical use parts of the SARS-CoV-2 spike protein as the immunogen. Because it has only Coronavirus protein parts and not the whole virus, these vaccines cannot cause COVID-19 in people. Using protein subunits to make vaccines is a stable technology and has been used to make Hepatitis A vaccines like Recombivax HB, Engerix-B, Heplisav-B, and GenHevac B (Li et al. 2017).

How does it work?

Protein subunit vaccines contain smaller parts of the SARS-CoV-2 proteins. The Anhui Zhifei Longcom Biopharmaceutical vaccine contains the receptor binding domain of the spike protein while the vaccine from VECTOR institute has subunits that cover more parts of the spike protein (Pollet et al. 2021). When these subunits are injected into the body, the immune system reacts to the presence of SARS-CoV-2 protein parts and makes antibodies against it. The protein from the vaccine is eventually destroyed by the cell, leaving no permanent trace. These protein fragments are incapable of causing COVID-19, but the antibodies that they elicit are capable of attaching to the viral proteins encountered on any subsequent SARS-CoV-2 exposure.

RNA vaccines

Vaccines from Moderna (Jonathan Corum 2021b) and Pfizer/BioNTech (Jonathan Corum 2021e) are RNA vaccines. They have the messenger RNA (mRNA) to build the spike protein of SARS-CoV-2. The mRNA from the vaccine is very fragile and is enveloped in lipid nanoparticles. These do not have molecular machinery like reverse transcriptase enzymes and primers that are required for making DNA from RNA. Therefore, post injection the mRNA from the vaccine is eventually destroyed by the cell, leaving no permanent trace.

How does it work?

mRNA SARS-CoV-2 vaccines contain the message required by the cells to make the spike protein. When the vaccine is injected into the body, lipid nanoparticles deliver the mRNA into the cytoplasm of the cells. This mRNA is “read” by the cells to produce spike proteins. The immune system reacts to the presence of SARS-CoV-2 proteins and makes antibodies against it. These proteins are incapable of causing COVID-19, but the antibodies that they elicit are capable of attaching to the viral proteins encountered on any subsequent SARS-CoV-2 exposure.

COVID-19 Vaccines in Human Trials

There are 84 COVID-19 vaccine candidates that have made it into human trials (Table 2) spanning eight different vaccine platforms as detailed in Figure 1. Presence of a candidate in the list does not indicate that it is still under active development.

Future Challenges

The COVID-19 pandemic sped up the licensing of promising vaccine formulations. Despite these advances the eradication of SARS-CoV-2 might prove challenging, owing to reservoirs in animal species (Abdel-Moneim and Abdelwhab 2020), incomplete reach of vaccines in the general populace and the rise of variants(WHO 2020b). It is highly likely that we are heading to seasonal SARS-CoV-2 vaccines like the flu shots based on the dominant strains. Due to multiple dominant variants, vaccines may need to incorporate more than one strain when in development. Vaccine platforms like the mRNA vaccine are well suited for modified vaccination, as different mRNAs containing variant proteins can be rapidly synthesized.