A primer on potential SARS-CoV-2 vaccines

By Dr Mark Thomas, Associate Professor in Infectious Diseases, University of Auckland

24 April 2020

A safe, effective vaccine is essential for New Zealand’s strategy of long-term control of the COVID-19 epidemic. In the absence of widespread community spread, very few people in New Zealand will be immune to SARS-CoV-2 infection (the virus that causes COVID-19) and almost everyone will be susceptible to infection. A successful immunisation programme will remove that risk. The overwhelming majority of people infected with SARS-CoV-2 recover from illness and eliminate the infection (1), clearly indicating that protective immune responses are the usual result of infection. While it appears that the immune responses following severe disease are a little stronger than those following mild or asymptomatic infection (1), it is likely that any immune responses will prime the immune system to produce very effective responses to subsequent episodes of infection.

Studies of SARS-CoV-2, and the closely related viruses responsible for SARS and MERS, have shown that spike proteins, projecting from the surface of these viruses, bind to receptor molecules on the surface of respiratory epithelial cells, initiating viral entry into these cells, followed by viral replication (2). Infection with SARS-CoV-2 results in antibodies which bind to various regions of the spike proteins, including the region which binds to the ACE2 receptor. When SARS-CoV-2 is incubated with these antibodies, the virus is “neutralised” - it is unable to enter and infect respiratory epithelial cells (3). The spike proteins, and a range of other SARS-CoV-2 proteins, are potential vaccine antigens.

Figure 1. A schematic representation showing a SARS-CoV-2 virus with spike proteins projecting out of the viral surface (A), a virus attached to an ACE2 receptor on the surface of a respiratory epithelial cell (B), antibody to the viral spike protein stimulated either by natural infection or by vaccination (C), and a virus coated with antibody bound to the viral spike proteins which prevents the virus attaching to, and infecting, a respiratory epithelial cell (D).

Potential SARS-CoV-2 vaccines, their similarity to currently used vaccines, their potential risks, and prospective vaccines currently under development, are discussed below (4).

1. Live attenuated SARS-CoV-2 virus
This method involves genetic modification of the SARS-CoV-2 virus to create a strain able to replicate in people but is very much less pathogenic. The attenuated virus is then used a live vaccine. This strategy is comparable to that used for the measles, mumps and rubella vaccine, and the previously used oral poliomyelitis vaccine. The risks include severe disease if the vaccine is inadvertently administered to immuno-compromised people, or if, following administration, the virus reverts to full virulence. Codagenix in collaboration with the Serum Institute of India is working to develop a live attenuated vaccine. 

2. Inactivated SARS-CoV-2 virus
This method involves growth of large volumes of SARS-CoV-2 virus, reliably inactivating the cultured virus, and then vaccinating with whole inactivated virus. This strategy is comparable to that used for the hepatitis A vaccine, and the currently used IM poliomyelitis vaccine. Its risks include the possibility that some batches of vaccine are incompletely inactivated and therefore can cause infection in recipients.

3. Live genetically modified vector virus containing the gene coding for a SARS-CoV-2 protein
This method involves inserting the gene for a SARS-CoV-2 protein (e.g. the spike protein) into non-pathogenic vector virus. Replication of this genetically modified virus in the vaccinated person results in generation of large amounts of hybrid viruses, which have the SARS-CoV-2 protein on their surface. This strategy is comparable to that used for a highly effective Ebola vaccine. Its risks include the possibility that some vaccinated people may have pre-existing immunity to the vector virus that limits viral replication and hence exposure to the SARS-CoV-2 protein. Johnson and Johnson and Sanofi are working to develop live vector virus vaccines.

4. SARS-CoV-2 protein vaccines 
This method involves inserting the gene for a SARS-CoV-2 protein into a virus, bacterium, or yeast, culturing large amounts of the genetically modified microbe, and purifying the SARS-CoV-2 protein that has been secreted into the culture medium. The purified SARS-CoV-2 protein is then used in the vaccine. This strategy is comparable to that used for the current Hepatitis B virus and Human Papilloma virus vaccines. This appears to be one of the safest vaccine strategies. A large number of companies and research institutes (e.g iBio, ExpresS2ion, Baylor College of Medicine, University of Queensland) are working to develop recombinant protein vaccines.

5. DNA or RNA SARS-CoV-2 vaccines
These methods involve preparation of either DNA or RNA coding for a SARS-CoV-2 protein. The DNA or RNA is administered as an IM injection, and taken up by local cells, resulting in synthesis of the SARS-CoV-2 protein. There are no DNA or RNA vaccines in current use. An RNA vaccine developed by a company called Moderna, in collaboration with the Vaccine Research Centre at the National Institutes of Health in the US, is in early clinical trials.

While some vaccine candidates have recently entered initial trials, it is unlikely that any vaccine will be demonstrated to be effective and safe, and be able to be produced in sufficient volumes for global administration, until some time in 2021 at the earliest.(5)

References

  1. To KK-W, et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infectious Diseases March 23, 2020. https://doi.org/10.1016/S1473-3099(20)30196-1
  2. Letko M, et al. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nature Microbiology 2020;5:562-9.  https://doi.org/10.1038/s41564-020-0688-y
  3. Okba NMA, et al. Severe acute respiratory syndrome coronavirus 2-specific antibody responses in coronavirus disease 2019 patients. Emerging Infectious Diseases 2020;26(7).(accessed 21/04/2020) https://doi.org/10.3201/eid2607.200841
  4. Amanat F, & Krammer F. SARS-CoV-2 vaccines: status report. Immunity 2020;52:583-9. https://doi.org/10.1016/j.immuni.2020.03.007
  5. Lurie N, et al. Developing Covid-19 vaccines at pandemic speed. New England Journal of Medicine March 30, 2020. https://doi:10.1056/NEJMp200563