Coronavirus (37) South Africa variant of SARS-CoV-2 (a)
The rollout of vaccination against COVID-19 in the UK started from early December last year. Over 32 million people in the UK have received at least one dose of a coronavirus vaccine until now, according to the data from the government website.1 With all the people over-50s and high-risk groups having been offered the first dose,2 the daily number of people tested positive decreased to 3568 from the peak of 81,000.1 The decrease in death toll due to the disease is more significant. Only 13 people who had had a positive test result for COVID-19 died within 28 days of the first positive test.1 So far the figures demonstrated that the UK has successfully lowered the infection rate and suppressed the effect of the disease.1 Whether these improvements are attributed to the national lockdowns or to the vaccination programme, or both, we don’t know.
However, the report of an emerging variant of SARS-CoV-2, the virus that causes COVID-19, from South Africa reminds us to be cautiously optimistic.3 According to the Director of the Rosaline Franklin Institute, the progress of national reopening may be delayed if the South Africa variant has really taken off.4
What is the South Africa variant of SARS-CoV-2? Why should we pay attention to its emergence in the UK? The US Centers for Disease Control and Prevention (CDC) website lists in a table the research studies on the South Africa variant. Let us have a look at the results of these research studies in this and the next blog post.5 You may get some ideas for the reasons of being concerned about the variant.
The South Africa variant of SARS-CoV-2
The South Africa variant of SARS-CoV-2 is also referred to as B.1.351. South Africa authorities named the variant as 20H/501Y.V2 or 501Y.V2, because of a N501Y mutation. Its first emergence can be traced back to July or August 2020 in the Eastern Cape province of South Africa, after the first epidemic wave in the worst-affected Nelson Mandela Bay within the Eastern Cape Province.6 The virus strain later spread across the country and even to other parts of the world, including the UK, via international travel.
The variant is also named VOC-20DEC-02 (Variant of Concern, year 2020, month December, variant 02) by UK authorities. The name is linked with the time when the variant was first sequenced in the UK in December 2020.7 Data up to 7 April showed a total of 533 confirmed cases, detected by PCR, since then.7 The rise in the number of cases is dramatic: there were 44 confirmed cases detected in Wandsworth and Lambeth in South London in a single day last week.3,4 This rises an alarm.
Genomic characteristics of B.1.351
B.1.351 is characterised by nine mutations in the spike gene of SARS-CoV-2, including three (K417N, E484K and N501Y) at important residues in the receptor-binding domain (RBD). B.1.351 also carries mutation D614G. The mutation emerged in late January or early February 2020. Within a few months, D614G mutation replaced the original SARS-CoV-2 strain in China and became the dominant form of the virus circulating globally by June 2020.8
The variant B.1.351 raises concerns because of its increased transmissibility. Moreover, the variant has extensive mutations in the spike gene, which is the major target of neutralizing* antibodies. The mutations in this area may impair the efficacy of the current monoclonal antibody therapies and vaccines which are directed against the spike region of the SARS-CoV-2 virus.
Transmissibility of B.1.351
The Centre for the Mathematical Modelling of Infectious Diseases (CMMID) at the London School of Hygiene & Tropical Medicine (LSHTM) and Stellenbosch University in South Africa estimated that B.1.351 variant is about 50% higher in transmissibility than previously circulating strain. The increase in transmissibility is similar to the variant dominating in the UK nowadays, which is referred to as B.1.1.7.9 Both B.1.351 and B.1.1.7. have mutation D614G. Research studies found that variants with this mutation spread more quickly than viruses without this mutation.10
Mild neutralization by convalescent plasma***
Scientists from Columbia University took plasma from 20 patients recovered from COVID-19 more than one month after documented SARS-CoV-2 infection. They found that most plasma samples (16 out of 20) lost more than 2.5-fold neutralizing activity against B.1.351, compared to the wild type. The loss of plasma neutralizing activity against B.1.351 was found to be largely attributed to the E484K substitution.11
The low neutralizing ability against B.1.351 by the convalescent blood from COVID-19 patients indicates the high possibility of re-infection. The situation was observed in the Novavax vaccine trial in South Africa. The study found that recipients who received the placebo with previous SARS-CoV-2 infection were not protected against a subsequent exposure to B.1.351;12 in Manaus, Brazil, 76% of the population was infected in the first wave of SARS-CoV-2 infection, but the city still suffered with the sweeping second wave of infection due to P.1 variant, which shared most of the substitution mutations including E484K with B.1.351.11 These two examples are sufficient enough to remind us to stay cautious even if we have been infected once before by the initial strain of SARS-CoV-2.
Very low efficacy of monoclonal antibody therapies to B.1.351
The Food and Drug Administration (FDA) of the US has granted the emergency use of 2 combination therapies for COVID-19: bamlanivimab with etesevimab, and REGEN-COVTM (casirivimab with imdevimab). Ingredients of both regimens are monoclonal antibodies (the drug names end with “mab”, which means monoclonal antibody) which bind to non-overlapping epitopes of the spike protein receptor binding domain (RBD) of SARS-CoV-2 and stop the virus from infecting cells. They are allowed for treatment of mild to moderate COVID-19 in adults and paediatric patients (12 years of age and older, weighing at least 40kg), with positive results of direct SARS-CoV-2 viral testing, and at risk of progressing to severe COVID-19 and/or hospitalization.13,14
According to the document from the FDA, the REGEN-COVTM therapy against pseudovirus** expressing all spike protein substitutions found in the B.1.351 lineage, had similar efficacy to the pseudovirus expressing wild type.13 However, the activity of bamlanivimab with etesevimab against pseudovirus expressing B.1.351 mutation substitution was greatly reduced to >45 fold, compare to the pseudovirus expressing wild type.14 This means the therapy with bamlanivimab and etesevimab together has very limited ability to diminish the activity of the variant B.1.351.
In fact, when the activity of the four drugs bamlanivimab, etesevimab, casirivimab, and imdevimab were individually examined against the authentic wild type SARS-CoV-2 virus and its authentic B.1.351 variant, only imdevimab, one of the ingredients of REGEN-COVTM therapy, retained the same activity. The efficacy of each of the other three drugs against B.1.351 variant was completely or markedly abolished, compared with the wild type.11
These findings suggest that antibody treatment of COVID-19 might need to be modified in areas where B.1.351 and related variants are prevalent.
*Neutralization is a process which the vaccine/monoclonal antibody acted against a pathogen, such as virus. A pathogen can be highly neutralized by vaccine/monoclonal antibody, which means its activity can be diminished or abolished by the vaccine/monoclonal antibody, i.e. the vaccine or monoclonal antibody is effective against the pathogen.
**Pseudovirus used in the experiments on SARS-CoV-2 refers to a retrovirus that is genetically engineered to integrate the glycoprotein protein sequence of SARS-CoV-2 (the initial strain or the sequence with mutation(s) found in the SARS-CoV-2 variants) in order to test the efficacy of the drug or vaccine, or to find out the mutation(s) responsible for the change in efficacy of the drug or vaccine. Pseudoviruses are capable of replicating only once, while the SARS-CoV-2 virus and its variants are highly infectious. Therefore, pseudovirus is very much preferred to be used by laboratories which do not meet high biosafety level (BSL) requirements to do testing on the real virus.
***Convalescent serum is taken from the blood from people who have recovered from an illness. The prior infection to the pathogen, which caused the illness, lead to the production of antibodies specific to the pathogen. The convalescent serum therefore could be used as a source of antibodies to help people who are suffering from the same infection.
References
1. https://coronavirus.data.gov.uk/details/vaccinations
2. Covid vaccine: All over-50s and high risk groups offered first dose. BBC new, 13 April, 2021.
3. Covid-19: Vaccination milestone and variant cluster in south London. BBC news, 13 April, 2021.
4. South Africa coronavirus variant: What is the risk? BBC news, 13 April, 2021.
5. SARS-CoV-2 variant classifications and definitions. CDC of the US’s website, updated Mar. 24, 2021. https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html
6. H. Tegally, E. Wilkinson, M.Giovanetti, et al. Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. Medrxiv, December 22, 2020. https://doi.org/10.1101/2020.12.21.20248640
7. Variants of concern or under investigation: data up to 7 April 2021. https://www.gov.uk/government/publications/covid-19-variants-genomically-confirmed-case-numbers/variants-distribution-of-cases-data#Variant2
8. SARS-CoV-2 variants. WHO’s disease outbreak news, 31 December 2020. https://www.who.int/csr/don/31-december-2020-sars-cov2-variants/en/
9. C.A.B. Pearson, T.W. Russell, N.G. Davies, et al. Estimates of severity and transmissibility of novel South Africa SARS-CoV-2 variant 501Y.V2. Paper under peer review. First online: 11-01-2021. Last update: 11-01-2021. https://cmmid.github.io/topics/covid19/sa-novel-variant.html
10. B. Korber, W.M. Fischer, S. Gnanakaran, et al. Tracking changes in SARS-CoV-2 spike: Evidence that D614G increases infectivity of the COVID-19 virus. Cell, 2020 Aug 20;182(4):812-827.e19. doi: 10.1016/j.cell.2020.06.043. Epub 2020 Jul 3.
11. P. Wang, M.S. Nair, L. Liu, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature, 8 March, 2021. doi: 10.1038/s41586-021-03398-2.
12. Novavax COVID-19 vaccine demonstrates 89.3% efficacy in UK Phase 3 trial. Novavax press release, Jan 28, 2021. https://ir.novavax.com/news-releases/news-release-details/novavax-covid-19-vaccine-demonstrates-893-efficacy-uk-phase-3
13. Fact sheet for health care providers’ emergency use authorisation (EUA) of REGEN-COVTM (casirivimab with imdevimab)
14. Fact sheet for health care providers' emergency use authorisation (EUA) of bamlanivimab and etesevimab
The rollout of vaccination against COVID-19 in the UK started from early December last year. Over 32 million people in the UK have received at least one dose of a coronavirus vaccine until now, according to the data from the government website.1 With all the people over-50s and high-risk groups having been offered the first dose,2 the daily number of people tested positive decreased to 3568 from the peak of 81,000.1 The decrease in death toll due to the disease is more significant. Only 13 people who had had a positive test result for COVID-19 died within 28 days of the first positive test.1 So far the figures demonstrated that the UK has successfully lowered the infection rate and suppressed the effect of the disease.1 Whether these improvements are attributed to the national lockdowns or to the vaccination programme, or both, we don’t know.
However, the report of an emerging variant of SARS-CoV-2, the virus that causes COVID-19, from South Africa reminds us to be cautiously optimistic.3 According to the Director of the Rosaline Franklin Institute, the progress of national reopening may be delayed if the South Africa variant has really taken off.4
What is the South Africa variant of SARS-CoV-2? Why should we pay attention to its emergence in the UK? The US Centers for Disease Control and Prevention (CDC) website lists in a table the research studies on the South Africa variant. Let us have a look at the results of these research studies in this and the next blog post.5 You may get some ideas for the reasons of being concerned about the variant.
The South Africa variant of SARS-CoV-2
The South Africa variant of SARS-CoV-2 is also referred to as B.1.351. South Africa authorities named the variant as 20H/501Y.V2 or 501Y.V2, because of a N501Y mutation. Its first emergence can be traced back to July or August 2020 in the Eastern Cape province of South Africa, after the first epidemic wave in the worst-affected Nelson Mandela Bay within the Eastern Cape Province.6 The virus strain later spread across the country and even to other parts of the world, including the UK, via international travel.
The variant is also named VOC-20DEC-02 (Variant of Concern, year 2020, month December, variant 02) by UK authorities. The name is linked with the time when the variant was first sequenced in the UK in December 2020.7 Data up to 7 April showed a total of 533 confirmed cases, detected by PCR, since then.7 The rise in the number of cases is dramatic: there were 44 confirmed cases detected in Wandsworth and Lambeth in South London in a single day last week.3,4 This rises an alarm.
Genomic characteristics of B.1.351
B.1.351 is characterised by nine mutations in the spike gene of SARS-CoV-2, including three (K417N, E484K and N501Y) at important residues in the receptor-binding domain (RBD). B.1.351 also carries mutation D614G. The mutation emerged in late January or early February 2020. Within a few months, D614G mutation replaced the original SARS-CoV-2 strain in China and became the dominant form of the virus circulating globally by June 2020.8
The variant B.1.351 raises concerns because of its increased transmissibility. Moreover, the variant has extensive mutations in the spike gene, which is the major target of neutralizing* antibodies. The mutations in this area may impair the efficacy of the current monoclonal antibody therapies and vaccines which are directed against the spike region of the SARS-CoV-2 virus.
Transmissibility of B.1.351
The Centre for the Mathematical Modelling of Infectious Diseases (CMMID) at the London School of Hygiene & Tropical Medicine (LSHTM) and Stellenbosch University in South Africa estimated that B.1.351 variant is about 50% higher in transmissibility than previously circulating strain. The increase in transmissibility is similar to the variant dominating in the UK nowadays, which is referred to as B.1.1.7.9 Both B.1.351 and B.1.1.7. have mutation D614G. Research studies found that variants with this mutation spread more quickly than viruses without this mutation.10
Mild neutralization by convalescent plasma***
Scientists from Columbia University took plasma from 20 patients recovered from COVID-19 more than one month after documented SARS-CoV-2 infection. They found that most plasma samples (16 out of 20) lost more than 2.5-fold neutralizing activity against B.1.351, compared to the wild type. The loss of plasma neutralizing activity against B.1.351 was found to be largely attributed to the E484K substitution.11
The low neutralizing ability against B.1.351 by the convalescent blood from COVID-19 patients indicates the high possibility of re-infection. The situation was observed in the Novavax vaccine trial in South Africa. The study found that recipients who received the placebo with previous SARS-CoV-2 infection were not protected against a subsequent exposure to B.1.351;12 in Manaus, Brazil, 76% of the population was infected in the first wave of SARS-CoV-2 infection, but the city still suffered with the sweeping second wave of infection due to P.1 variant, which shared most of the substitution mutations including E484K with B.1.351.11 These two examples are sufficient enough to remind us to stay cautious even if we have been infected once before by the initial strain of SARS-CoV-2.
Very low efficacy of monoclonal antibody therapies to B.1.351
The Food and Drug Administration (FDA) of the US has granted the emergency use of 2 combination therapies for COVID-19: bamlanivimab with etesevimab, and REGEN-COVTM (casirivimab with imdevimab). Ingredients of both regimens are monoclonal antibodies (the drug names end with “mab”, which means monoclonal antibody) which bind to non-overlapping epitopes of the spike protein receptor binding domain (RBD) of SARS-CoV-2 and stop the virus from infecting cells. They are allowed for treatment of mild to moderate COVID-19 in adults and paediatric patients (12 years of age and older, weighing at least 40kg), with positive results of direct SARS-CoV-2 viral testing, and at risk of progressing to severe COVID-19 and/or hospitalization.13,14
According to the document from the FDA, the REGEN-COVTM therapy against pseudovirus** expressing all spike protein substitutions found in the B.1.351 lineage, had similar efficacy to the pseudovirus expressing wild type.13 However, the activity of bamlanivimab with etesevimab against pseudovirus expressing B.1.351 mutation substitution was greatly reduced to >45 fold, compare to the pseudovirus expressing wild type.14 This means the therapy with bamlanivimab and etesevimab together has very limited ability to diminish the activity of the variant B.1.351.
In fact, when the activity of the four drugs bamlanivimab, etesevimab, casirivimab, and imdevimab were individually examined against the authentic wild type SARS-CoV-2 virus and its authentic B.1.351 variant, only imdevimab, one of the ingredients of REGEN-COVTM therapy, retained the same activity. The efficacy of each of the other three drugs against B.1.351 variant was completely or markedly abolished, compared with the wild type.11
These findings suggest that antibody treatment of COVID-19 might need to be modified in areas where B.1.351 and related variants are prevalent.
*Neutralization is a process which the vaccine/monoclonal antibody acted against a pathogen, such as virus. A pathogen can be highly neutralized by vaccine/monoclonal antibody, which means its activity can be diminished or abolished by the vaccine/monoclonal antibody, i.e. the vaccine or monoclonal antibody is effective against the pathogen.
**Pseudovirus used in the experiments on SARS-CoV-2 refers to a retrovirus that is genetically engineered to integrate the glycoprotein protein sequence of SARS-CoV-2 (the initial strain or the sequence with mutation(s) found in the SARS-CoV-2 variants) in order to test the efficacy of the drug or vaccine, or to find out the mutation(s) responsible for the change in efficacy of the drug or vaccine. Pseudoviruses are capable of replicating only once, while the SARS-CoV-2 virus and its variants are highly infectious. Therefore, pseudovirus is very much preferred to be used by laboratories which do not meet high biosafety level (BSL) requirements to do testing on the real virus.
***Convalescent serum is taken from the blood from people who have recovered from an illness. The prior infection to the pathogen, which caused the illness, lead to the production of antibodies specific to the pathogen. The convalescent serum therefore could be used as a source of antibodies to help people who are suffering from the same infection.
References
1. https://coronavirus.data.gov.uk/details/vaccinations
2. Covid vaccine: All over-50s and high risk groups offered first dose. BBC new, 13 April, 2021.
3. Covid-19: Vaccination milestone and variant cluster in south London. BBC news, 13 April, 2021.
4. South Africa coronavirus variant: What is the risk? BBC news, 13 April, 2021.
5. SARS-CoV-2 variant classifications and definitions. CDC of the US’s website, updated Mar. 24, 2021. https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html
6. H. Tegally, E. Wilkinson, M.Giovanetti, et al. Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. Medrxiv, December 22, 2020. https://doi.org/10.1101/2020.12.21.20248640
7. Variants of concern or under investigation: data up to 7 April 2021. https://www.gov.uk/government/publications/covid-19-variants-genomically-confirmed-case-numbers/variants-distribution-of-cases-data#Variant2
8. SARS-CoV-2 variants. WHO’s disease outbreak news, 31 December 2020. https://www.who.int/csr/don/31-december-2020-sars-cov2-variants/en/
9. C.A.B. Pearson, T.W. Russell, N.G. Davies, et al. Estimates of severity and transmissibility of novel South Africa SARS-CoV-2 variant 501Y.V2. Paper under peer review. First online: 11-01-2021. Last update: 11-01-2021. https://cmmid.github.io/topics/covid19/sa-novel-variant.html
10. B. Korber, W.M. Fischer, S. Gnanakaran, et al. Tracking changes in SARS-CoV-2 spike: Evidence that D614G increases infectivity of the COVID-19 virus. Cell, 2020 Aug 20;182(4):812-827.e19. doi: 10.1016/j.cell.2020.06.043. Epub 2020 Jul 3.
11. P. Wang, M.S. Nair, L. Liu, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature, 8 March, 2021. doi: 10.1038/s41586-021-03398-2.
12. Novavax COVID-19 vaccine demonstrates 89.3% efficacy in UK Phase 3 trial. Novavax press release, Jan 28, 2021. https://ir.novavax.com/news-releases/news-release-details/novavax-covid-19-vaccine-demonstrates-893-efficacy-uk-phase-3
13. Fact sheet for health care providers’ emergency use authorisation (EUA) of REGEN-COVTM (casirivimab with imdevimab)
14. Fact sheet for health care providers' emergency use authorisation (EUA) of bamlanivimab and etesevimab
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