With input from Dr Monica Vasudev

1254: South Africa and United Kingdom Variants 

South African Variant of SARS-CoV-2 [Excerpts from https://www.sciencemediacentre.org/]

Two individuals in the UK who had returned from South Africa had a SARS-CoV-2 variant from South Africa. 

• Dr Julian Tang, Honorary Associate Professor/Clinical Virologist, University of Leicester: 
• UK B.1.1.7 (variant) virus is spreading across South/Southeast England.
• A new variant ‘501.V2’ from South Africa has been detected in some COVID-19 cases in the UK. 
• The South African variant ‘501.V2’ has N501Y, E484K and K417N mutations in the S protein. In this, it shares the N501Y mutation with the UK variant; however, the other two mutations are not there in the UK variant.  The South African variant does not carry the 69-70del mutation, as seen in the UK variant.
• The spread of this variant appears to be focused in the south and southeast regions of South Africa, and has shown higher viral loads diagnostic swabs. This could possibly make it more transmissible via aerosols produced during breathing and talking, etc.
• Studies being done in South Africa are evaluating whether it causes more severe disease, whether it targets young people specifically (or is it a behavioural effect), and whether the COVID-19 vaccines being developed will be effective against it.
• It has been suggested that the South African variant may be mediating a faster spreading second wave in South Africa that may be bigger than the first wave.
• Prof Jonathan Ball, Professor of Molecular Virology, University of Nottingham: The mutation that has surfaced in Africa has been seen before.
• Dr Andrew Preston, Reader in Microbial Pathogenesis, University of Bath: The South African variant is different from the UK variant, but both the variants contain an unusually high number of mutations compared to other SARS-CoV-2 lineages.  Some of these mutations alter the S protein. Both contain the N501Y mutation but the same holds true for several other variants that do not appear to have increased transmission. The scenario is therefore complex.
• The UK has used genomics throughout the pandemic and thus was able to detect the new variant early during its rise.  In countries that lack this capacity, it is possible that these variants are already in circulation, but are unidentified as of now.  This could signal a particularly dangerous phase of this pandemic, making the effective roll out of the vaccines even more time-critical.
• Prof Lawrence Young, Professor of Molecular Oncology, Warwick Medical School: The South African virus variant has several spike mutations and emerged in a major metropolitan area in South Africa following the first wave of the epidemic. It then spread to multiple locations within two other neighboring provinces. The variant has rapidly spread and has become the dominant variant in the Eastern and Western Cape provinces.  The variant has 3 mutations at key sites in the receptor binding domain (K417N, E484K and N501Y) of the spike gene.  Two of these (E484K and N501Y) are within the receptor-binding motif (RBM),the principal functional motif that forms the interface with the human ACE2 receptor.  The N501Y mutation is the same as that noted in the UK virus variant. It is still not clearly known as to what these changes mean for the infectiousness of the variant virus and its impact on disease severity.
• Variants of SARS-CoV-2 have been there since the pandemic began and occur as a result of the natural process by which viruses develop and adapt to their hosts as they replicate.  Most of these mutations do not affect the behavior of the virus but occasionally they can improve the ability of the virus to infect or become more resistant to the body’s immune response. 
• Several thousands of these mutations have already been identified in isolates of the virus with around 4000 spike mutations identified in different viruses from around the world. 
• The UK and South African virus variants have changes in the spike gene consistent with the possibility that they are more infectious. 
• The standard measures to restrict transmission (hands, face, space) will continue to prevent infection with this variant.  Besides improved surveillance (testing, tracing and isolating) and speeding up the roll out of the vaccine, these measures will prevent transmission of this variant and any others that may arise later.  Stricter levels of restriction across the country are inevitable.  It is essential that everything possible is done to prevent the South African variant from spreading to the UK population.  Quarantine measures and restricting travel from and to South Africa are needed.

UK variant [Excerpts from https://www.nationalgeographic.com/]

1. In early December, cases of COVID-19 were reported to rise in Kent, England. Nick Loman, a part of the COVID-19 Genomics Consortium U.K., and his colleagues evaluated how the coronavirus was mutating. By looking at these slightly different viruses, they could roughly track the outbreak’s spread through the community.
2. For SARS-CoV-2, these mutations develop at a pace of one or two every month.
3. In the Kent cases, there was a large cluster that was considerably different, with a total of 23 mutations arising without prior notice and faster than expected.
4. A follow-up investigation by Public Health England revealed that the variant, known as B.1.1.7 or 501Y.V1, began to thrive at a time when cases were surging in Kent and other parts of southeastern England. Retroactive tracing through a database of samples linked B.1.1.7 to patients as early as September 20. By mid-November, the variant accounted for around 20-30% of cases in London and a region east of the city. Three weeks later, it amounted to nearly 60%. On December 23, U.K. scientists announced that a separate SARS-CoV-2 variant reported in South Africa had been detected in two people in England.
5. One possible hypothesis for their origin involves chronically ill patients treated with experimental therapies such as convalescent plasma. In such long illnesses, the virus gets more chances to replicate, increasing the odds for mutations. The consistent use of the therapies, may put more pressure on the virus to evolve.
6. Some of these people who are chronically infected have some big shifts in the virus.
7. Some are immune-suppressed. Some of them have had convalescent plasma. Some of them have had remdesivir.
8. If this suspected origin story proves to be true, it could have implications for treatment.
9. If new-wave medicines like antivirals and antibody therapy contributed to the development of viral variants, it will serve as a reminder for the medical community that we need to use these treatment options judiciously.
10. While mutations tend to edit the genetic code, they don’t always lead to outward changes in a germ or organism. It could be understood as the virus entering a dressing room and coming out with a new outfit, rather than the normal circumstances where it would only change its hat.
11. Of the 23 mutations in the UK variant, 17 are at positions in the genome that alter the building blocks making up the virus’ proteins, as described in a recent COVID-19 Genomics Consortium report from Loman and his colleagues. The consortium stated that such a large shift is “unprecedented” for the COVID-19 pandemic. Eight of the changes are in the region that encodes for the spike protein.
12. It could make the virus more contagious. Increase in cases could mean more hospitalizations and deaths.
13. Laboratory experiments suggest that one of the observed deletions that eliminates two building blocks in the spike—H69 and V70—may increase the viral infectiousness by two-fold.
14. Other research suggests that another mutation—N501Y—increases the spike protein’s binding capability. This one also independently surfaced in the South African variant (501Y.V2), which was first detected in October.
15. On December 18, the U.K.’s advisory panel for emerging respiratory outbreaks released a preliminary assessment of the variant. Their modeling suggests that the variant might account for up to 70% greater transmission.
16. Some of the spread could originate from human behaviour.
17. A case report of a 45-year-old immunocompromised man, infected for around five months before succumbing, reported “accelerated viral evolution.” Most of the mutations occurred in the spike protein, including changes present in both variants under investigation in the U.K. and South Africa.
18. After a year of closely tracking these mutations, scientists know that most don’t do anything worth noticing. Some are even harmful to the virus’s ability to multiply. One mutation—D614G—increases coronavirus replication and infectivity while it also makes the virus more vulnerable to neutralization by antibodies.
19. The idea is similar to HIV patients developing resistance to treatment after taking incomplete drug courses.
20. Convalescent plasma has large differences in potency between doses due to natural variation between the wide spectrum of antibodies produced by the immune systems of the donors. In a preprint, scientists noted mutation of the virus after a patient received three treatments of convalescent plasma starting at day 63 of their illness. Two of the viral mutations developed in genes that code for the spike protein. Something similar was noted inside a 65-year-old cancer patient who survived after 105 days with the virus. One of the mutations recently identified in the South African variant—N439K—may allow the virus to bypass monoclonal antibody drugs, suggested a preprint released by the COVID-19 Genomics Consortium in November.
21. Enhanced genomic testing is the reason why scientists in the U.K. are able to act so fast and warn others as B.1.1.7 slowly started to trickle into Denmark, The Netherlands, Italy, Belgium, Hong Kong, and Australia—and how they just discovered two cases of the variant linked to South Africa.

Dr KK Aggarwal

President CMAAO, HCFI and Past National President IMA