Novel variants of SARS-CoV-2 may change the rates of transmissibility and severity of COVID-19 symptoms experienced. While vaccines appear to offer some level of protection against the emerging variants, reduced efficacy has been consistently observed against the South African variant. Continued surveillance is the best approach to understanding the extent of change in these variants, and to preparing new strategies to overcome them. Furthermore, experts agree that the current global roll out of the vaccines should not be delayed by the emergence of these new variants as the protection offered far outweighs the risks of a potential decrease in efficacy.
The origin of virus variants – is the SARS-CoV-2 virus unusual?
Virus variants arise from mutations in the viral genome and are natural by-products of viral replication.1 A mutation is a particular change in the genetic sequence of a virus compared with an accepted ‘standard’ sequence. Viruses which express such mutations are known as variants. Variants may simultaneously express numerous mutations, such as the 2020 SARS-CoV-2 variants arising in the UK and South Africa.2
The average mutation rate of SARS-CoV-2 remains low and steady, and is much slower than other RNA viruses such as influenza viruses. Unlike coronaviruses, influenza viruses (which cause the flu) are prone to changes through processes called antigenic drift and antigenic shift.3,4
Antigenic drift refers to the accumulation of genetic mutations that cause an alteration in the surface of the virus (the mutated antigen ‘drifts’ from the original conformation). This is one of the main reasons why a novel flu vaccine is required every year. Antigenic shift occurs when segments from the genome of two different viruses combine to make a novel strain. Coronaviruses are not prone to undergo antigenic drift or shift.4,5
Despite this, SARS-CoV-2 variants have started spreading rapidly across the world, and many more are expected to develop. Mutations are part of natural evolution and, although a mutation may change the virulence of the virus or how it is transmitted, only those that are selectively advantageous will spread to the higher frequencies.1
The SARS-CoV-2 variant containing the D614G mutation quickly spread around the world.
For example, the variant containing the D614G mutation has become the wild-type (predominant) form of SARS-CoV-2 worldwide since mid-2020. The mutation likely increased the affinity of the virus to bind to the human receptor ACE2, resulting in higher infectivity and transmission rates.6 Variants can also become extinct due to natural selection. For instance, in June 2020, a concerning SARS-CoV-2 variant thought to present a decreased sensitivity to the immune response was detected in mink in the Netherlands and Denmark. However, this variant was declared extinct just a few months later and is no longer in circulation.7
Currently, there are three variants of concern, which are named based on the country where they were first identified. The UK (B.1.1.7), South African (B.1.351) and Brazilian (P.1) variants have mutations which are thought to make them more transmissible. There are also early data to suggest that the UK variant is associated with a higher mortality risk than the wild-type SARS-CoV-2.8 The mutations in these variants lead to small changes in the structure of the spike protein, which is the protein used by the virus to enter human cells. The spike protein is also a part of the structure of the virus where neutralising antibodies bind to block the SARS-CoV-2 infection. Consequently, these mutations can affect SARS-CoV-2 in an advantageous or disadvantageous way.9-13
Current SARS-CoV-2 variants of concern.
Implications of the emerging SARS-CoV-2 variants on the efficacy of the COVID-19 vaccines
Most current COVID-19 vaccines induce the immune system to develop an antibody and T-cell response against the spike protein of SARS-CoV-2. In this way, the immune system of someone who has been vaccinated and subsequently exposed to the virus will recognise the spike protein. The immune response to neutralise binding and block the infection will then be initiated. Since the mutations may alter the local structure of the spike protein, there is a risk that they might compromise the immune response developed by natural infection or by vaccines.14,15
The binding of neutralising antibodies to a virus variant may differ from their binding to the original virus.
One way to assess whether current vaccines work against the emerging variants is to expose blood samples from individuals who have been vaccinated against, or previously contracted, COVID-19 to new variants in vitro. In doing so, scientists can determine the relative ability of the participants’ antibodies to neutralise the novel variant compared with the original or ‘wild-type’ virus.16,17
Example of an assay to determine the ability of previously developed neutralising antibodies against the original virus to neutralise a SARS-CoV-2 variant.
The in vitro studies only probe the capacity of antibodies to neutralise variants in the laboratory, and not the wider effects of other components of the immune response such as T-cell activation. T cells work to activate different parts of the immune system or directly kill invading substances such as viruses and bacteria, and have been shown to play a key role in the immune response to SARS-CoV-2.18-20 For further information on how the immune response induced by vaccines is evaluated, please click here.
It is also possible to analyse how vaccines perform against the new variants by determining the efficacy of the vaccine in a specific group of those who have become infected with one of the SARS-CoV-2 new variants in the context of the clinical trials.
Once researchers understand how the immune response induced by a vaccine correlates to vaccine efficacy against the new variants, it will be easier to accurately determine the efficacy from neutralisation assays alone.
Strategies to overcome vaccine escape
Vaccine escape is the term used to describe the process of a virus mutating to form a variant that evades the immune response induced by vaccination. This process is rare, but occurrence depends on factors such as therapeutic targets and viral mutation rates.21
As explained above, in the case of SARS-CoV-2, the mutation rate is slow; however, as the virus is so widespread, numerous variants have developed. Novel variants may reduce the capacity of the antibodies to neutralise the virus in individuals who have previously contracted, or had a vaccination against, COVID-19. In fact, a decrease in the neutralisation power of previously developed antibodies against the South African variant has been consistently observed.22,23
Nevertheless, vaccines allow for multitudes of different antibodies and T cells to be produced against numerous parts of the spike protein,5,24 and, as such, it is expected that a certain level of protection should still be maintained. To ensure a maximum level of protection, strategies have been devised to overcome a decrease in vaccine efficacy:
- The vaccine administration regimen can be modified to increase the overall immune response and, ideally, provide more protection against new variants (e.g. an additional booster vaccine dose can be considered)
- Optimisation of the original vaccine such as the development of a new version with an updated spike protein is also possible; however, while the direct changes to the vaccine can be performed relatively quickly, further steps will be required to ensure the quality, safety and perhaps effectiveness of the new vaccine(s)
To determine whether either of these approaches are required, surveillance data on emerging variants are collected to ensure that the best vaccine strategy is being employed.
Although it seems reasonable to expect that new SARS-CoV-2 variants will emerge over time, experts agree that it is essential that current vaccines continue to be administered to as many people as possible. This is because the protection offered by the vaccines is greater than the risk of vaccine escape from potential new variants.
Evidence suggests that the available COVID-19 vaccines may still produce a protective immune response against the new variants identified to date, however the level of efficacy especially against severe disease is yet to be defined.25 Tests to analyse the entirety of the immune response, including the T-cell response, will improve scientists’ understanding of the effect of the variants on vaccine efficacy. Changes to the vaccine can be made to target novel variants and will likely be needed as new variants will begin to become dominant amongst the viruses that are circulating.
Collaboration between regulatory authorities and government investment globally will be essential to achieving efficient roll-out if such new vaccines are deemed to be necessary as part of our ongoing efforts to bring an end to the pandemic.
Implications of the emerging SARS-CoV-2 variants on the efficacy of the COVID-19 monoclonal antibodies
While vaccines train the immune system to fight a future infection, monoclonal antibodies mimic naturally developed antibodies to immediately neutralise SARS-CoV-2 infection. The mutations in the emerging variants of SARS-CoV-2 may induce some escape from these therapeutic interventions. However, when two complementary monoclonal antibodies are combined into one therapeutic intervention, the risk of the combination losing efficacy is considerably diminished as the virus would have to mutate in multiple distinct locations to escape the action of both antibodies.26,27 As for the vaccines, continued surveillance of SARS-CoV-2 is the best approach to ensure their success.
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- Davies NG, et al. Estimated transmissibility and severity of novel SARS-CoV-2 Variant of Concern 202012/01 in England [online ahead of print December 26, 2020] Available at: https://doi.org/10.1101/2020.12.24.20248822 (Accessed January 2021)
- Duchene S, et al. Temporal signal and the phylodynamic threshold of SARS-CoV-2. Virus Evolution. 2020;6:veaa061
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- Baric RS. Emergence of a Highly Fit SARS-CoV-2 Variant. N Engl J Med. 2020;383:2684–2686
- Burkholz A, et al. Paired SARS CoV-2 spike protein mutations observed during ongoing SARS-CoV-2 viral transfer from humans to minks and back to humans [online ahead of print December 29, 2020]. Available at: https://doi.org/10.1101/2020.12.22.424003 (Accessed January 2021)
- Iacobucci G. Covid-19: New UK variant may be linked to increased death rate, early data indicate. BMJ. 2021;372:n230. Available at: https://doi.org/10.1136/bmj.n230 (Accessed January 2021)
- Kemp SA, et al. Recurrent emergence and transmission of a SARS-CoV-2 Spike deletion H69/V7 [online ahead of print January 12, 2021]. Available at: https://doi.org/10.1101/2020.12.14.422555 (Accessed January 2021)
- Abdool Karim SS. Presented at CAPRISA Ministerial Briefing; December 18, 2020; South Africa. Available at: https://moien.lu/wp-content/uploads/2020/12/488618010-Full-Presentation-by-SSAK-18-Dec.pdf (Accessed January 2021)
- Voloch CM, et al. We identified a novel circulating lineage of SARS-CoV-2 in the state of Rio de Janeiro Brazil originated from B.1.1.28 lineage [online ahead of print December 26, 2020]. Available at: https://doi.org/10.1101/2020.12.23.20248598 (Accessed January 2021)
- Greaney AJ, et al. Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies [online ahead of print January 04, 2021]. Available at: https://doi.org/10.1101/2020.12.31.425021 (Accessed January 2021)
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- Sahin U, et al. COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses. Nature. 2020; 586:594-599. Available at: https://doi.org/10.1038/s41586-020-2814-7 (Accessed January 2021)
- World Health Organisation, Guidelines on clinical evaluation of vaccines: regulatory expectations. 2016. Available at: https://www.who.int/biologicals/BS2287_Clinical_guidelines_final_LINE_NOs_20_July_2016.pdf (Accessed January 2021)
- Jeyanathan M, et al. Immunological considerations for COVID-19 vaccine strategies. Nat Rev Immunol. 2020;20:615-632 (2020). Available at: https://doi.org/10.1038/s41577-020-00434-6 (Accessed January 2021)
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- McMahan C, et al. Correlates of protection against SARS-CoV-2 in rhesus macaques. Nature. 2020. Available at: https://doi.org/10.1038/s41586-020-03041-6 (Accessed January 2021)
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- Wu K, et al. mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants. bioRxiv. 2021. Available at: https://doi.org/10.1101/2021.01.25.427948 (Accessed February 2021)
- Xi X, et al. Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K, and N501Y variants by BNT162b2 vaccine-elicited sera. BioRxiv. 2021. Available at: https://doi.org/10.1101/2021.01.27.427998 (Accessed February 2021)
- Sekine T, et al. Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19. Cell. 2020;183:158-168
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