SARSCoV2 variants of concern : Omicron BA.4 – BA.5

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What are recombinants and how are they formed?

Viruses naturally evolve and are continuously changing as a result of genetic selection.[181] They can undergo minor genetic changes through mutation, as well as major genetic changes through recombination.[181]

Mutation occurs when an error is incorporated in the viral genome, and recombination occurs when two viruses infect the same host cell and exchange genetic information, creating a novel virus. Recombinants can emerge when more than one variant infects the same person (or animal) at the same time (‘co-infection’) – this allows the variants to interact during replication, mixing their genetic material and forming new combinations.[173]

Genetic recombination is a common evolutionary mechanism among coronaviruses and is thought to be critical for coronavirus diversity and the emergence of SARS-CoV-2, MERS-CoV, SARS-CoV, and other zoonotic coronaviruses.[182] Genetic recombination events occur often in natural reservoirs, leading to the emergence of new viruses.

The possibility for coronaviruses to transmit between species makes the emergence of novel viruses a particular threat to human and animal health.[183] Recombination allows viruses to overcome selective pressure and adapt to new hosts and environments.[184] Many recombinants will never be spread, but some do. I

t has been recently proposed that the prototype Omicron variant B.1.1.529 may have been generated by genomic recombination of two early SARS-CoV-2 lineages in the spike protein Coding Sequence.[184]

Recombinant events become more likely when case numbers are higher.[185] Liu et al (2022) note that the rapid and extensive spread of SARS-CoV-2 in humans has contributed additional mutational variability in this genome, increasing opportunities for future recombination.[184] The frequency of creation of recombinants between two variants depends on the duration of their co-circulation,  the time until viral clearance, and  the number of people exposed to both viruses.[186]

Collaborations between scientists are essential to verify possible new variants. For example, a supposed Delta-Omicron recombinant found in January in Cyprus turned out to be likely due to laboratory contamination.[187]

Of note, several of the emerging recombinants have been referred to as Deltacron, however this term is also being widely used in popular press as an umbrella term referring to any Delta/Omicron recombinants.  ‘Deltacron’ is a non-scientific and simplistic term because there are many possible recombinants of various parts of Omicron and Delta genomes (i.e. different versions of Deltacron). Having two variants recombine does not necessarily mean they will share the most severe or concerning features of each variant.

The WHO continues to closely monitor and assess the public health risk associated with recombinant variants, alongside other SARS-CoV-2 variants, and will provide updates as further evidence becomes available.[6]  The Pango dynamic nomenclature system gives recombinant viruses a two-letter abbreviation starting with X.

Three SARS-CoV-2 recombinant variants with evidence of person-to-person transmission have been reported: XD (AY.4/BA.1 recombinant, where AY.4 is Delta), XE (BA.1/BA.2 recombinant) and XF (another AY.4/BA.1 recombinant). XE was first reported in New Zealand on 23 April 2022.[188]

The latest sequencing data from ESR had not found any of the other known recombinant variants, or an original recombination variant, in New Zealand. The significance of the existing recombinants, and potential future recombinants is not yet known.

Table 5 below outlines the recombinant lineages designated by Pangolin which are currently being monitored by the UKHSA as part of horizon scanning.[3] These recombinants are XD, XE, and XF.

Table 5: Recombinant lineages XD, XE and XF

Recombinant lineageParentsGenomic featuresGeographic distribution and prevalenceCharacteristics/ possible impact
XEOmicron BA.1 and Omicron BA.2XE contains BA.1 mutations for NSP1-6 and BA.2 mutations for the remainder of the genome. It also has three mutations that are not present in BA.1 or BA.2 sequences: NSP3 C3241T and V1069I, and NSP12 C14599T.[1]  XE has predominantly been isolated and sequenced in the UK, with the first case detected on 19 January 2022. [3, 7]  The total number of XE cases identified in England as of 05 April 2022 was 1,125 cases (1,179 for whole UK).[1] Cases are geographically distributed across England (mostly in London and East and South East England) and increasing in number.[1] XE shows evidence of community transmission within England, although it represents <1% of total sequenced cases at April 5th. [1] XE was first reported in New Zealand on 23 April 2022.[188]The most recent UKHSA analysis, using data up to 30 March 2022, found XE has a growth rate 12.6% above that of BA.2.[1] UKHSA notes this estimate has not remained consistent as new data have been added and cannot be interpreted as an accurate estimate of growth advantage.[1] WHO stated on 5 April that XE has been estimated at having a ~10% transmission advantage compared to BA.2, however this finding requires further confirmation.[189]      
XD  [185]Delta and Omicron BA.1The XD recombinant lineage is a Delta AY.4 genome that has acquired an Omicron BA.1 spike sequence (nucleotide positions 21,643 to 25,581).  XD contains the unique mutation NSP2: E172D.[3]       XD is present in several European countries but as of 1 April it had not been detected in the UK.[1] The earliest collection date for XD samples is January 2022. UKHSA reported that total of 68 XD samples in GISAID met the XD definition on 01 April, of which 66  were from France, one from the Netherlands, and one from Belgium.[1]  The WHO weekly epidemiological report of 29 March stated that no new evidence indicates that XD is associated with higher transmissibility or more severe outcomes.[6] XD, which has an Omicron S gene incorporated into a Delta genome, is present primarily in France but has not been detected in the UK. Whilst the total number of genomes is still small, it has been designated on the basis that data published from France suggests that it may be biologically distinct.[1]  
XFDelta and Omicron BA.1The XF lineage is a recombinant of Delta and BA.1 with a break point near the end of NSP3 (nucleotide 5,386).  In the UK, 39 sequences samples have been identified and validated as part of the XF lineage since 7 January 2022.[3] XF caused a small cluster in the UK but has not been detected since mid- February.[3] There is currently no evidence for XF samples from non-UK countries on GISAID.Given the lack of evidence for recent UK samples from this lineage it is thought unlikely to be associated with sustained community growth.[3]

The UKHSA has also noted a BA.1/BA.2 recombinant (with unique mutation C3583T) as a signal currently under monitoring and investigation.[1]

Table 1: Overview of SARS-CoV-2 variants of public health interest

Table updated: 24 April 2022

Pango lineage WHO labelUKHSA label UKHSA designation Earliest documented samples Distribution
B.1.1.7 Alpha V-20DEC-01 (previously VOC-20DEC-01) Variant (previously a variant of concern)United Kingdom, Sep-2020 [6] Detected in UK in past 12 weeks as at 8 April.[1]
B.1.617.2 and sub-lineages Delta V-21APR-02 (previously VOC-21APR-02)Variant (previously a variant of concern) India, Oct-2020 [6]Detected in UK in past 12 weeks as at 8 April.[1]
B.1.1.529/BA.1Omicron VOC-21NOV-01 Variant of concern  Detected in UK in past 12 weeks as at 8 April.[1]  
B.1.1.529/BA.2 Omicron VOC-22JAN-01Variant of concern (previously a variant under investigation) Detected in UK in past 12 weeks as at 8 April.[1]
AY.4.2 V-21OCT-01 (previously VUI-21OCT-01) Variant (previously a variant under investigation) – *AY.4.2 is a sub-lineage within Delta that has been assigned as a distinct variant by UKHSA.  Detected in UK in past 12 weeks as at 8 April.[1]
B.1.640 – – Signal in monitoring (previously Variant in monitoring) Multiple countries, Sep-2021 [6]Detected in UK in past 12 weeks as at 8 April.[1]  
BA.3 – – Signal in monitoring (previously Variant in monitoring)  Detected in UK in past 12 weeks as at 8 April.[1]
 Delta and Omicron recombinant lineages (UK)– Signal in monitoring (previously Variant in monitoring) United Kingdom, Feb-2022 [6] Detected in UK in past 12 weeks as at 8 April.[1]
B.1.351 Beta V-20DEC-02Unclear designation (Variant or Variant of concern) South Africa, May-2020 [6]Detected in GISAID, but not in the UK, in the past 12 weeks  as at 8 April.[1]  
P.1 Removed from UKHSA listRemoved from UKHSA listBrazil, Nov-2020 [6]    
B.1.621 Mu V-21JUL-01 (previously VUI-21JUL-01)Variant (previously Variant under Investigation) Colombia, Jan-2021 [6] Detected in GISAID, but not in the UK, in the past 12 weeks  as at 8 April.[1]  
 AY.119.2/BA.1.1 Recombinant Signal under monitoring  Detected in GISAID, but not in the UK, in the past 12 weeks  as at 8 April.[1]  
 XD Recombinant (Delta x BA.1) V-22APR-01 Variant (previously signal under monitoring) France, Jan-2022 [6]Detected in GISAID, but not in the UK, in the past 12 weeks  as at 8 April.[1]  
XE Recombinant (BA.1 x BA.2) V-22APR-02VariantFirst case detected on 19 January 2022. [3, 7]Detected in UK in past 12 weeks as at 8 April.[1]  
B.1.617.3 V-21APR-03Variant Detected in UK in past 12 weeks as at 8 April.[1]  
BA.1/BA.2 Recombinant (with unique mutation C3583T)  Signal in monitoring Detected in UK in past 12 weeks as at 8 April.[1]
XF Recombinant  Signal in monitoring Detected in UK in past 12 weeks as at 8 April.[1]  
B.1.1.529/ BA.4Omicron sub-lineage BA.4V-22APR-03Variant Detected in UK in past 12 weeks as at 8 April.[1]
B.1.1.529/ BA.5Omicron sub-lineage BA.5V-22APR-04Variant Detected in UK in past 12 weeks as at 8 April.[1]

Omicron Overview

Like other variants, the Omicron variant (B.1.1.529) comprises a number of lineages and sub-lineages.[8] This includes BA.1, BA.2, BA.3, BA.4, BA.5 and descendent lineages, as well as BA.1/BA.2 circulating recombinant forms such as XE.[5] There are a large number of mutations differentiating Omicron variants from other known SARS-CoV-2 lineages.[9] BA.2 and BA.3 are evolutionarily linked to BA.1[9] and BA.4 and BA.5 are evolutionarily linked to BA.2.[1]

The Omicron variant was first detected in November 2021 and was associated with a rapid resurgence of COVID-19 cases in South Africa.[9] The Omicron variant carries over 30 mutations in the spike glycoprotein and has spread rapidly even in regions with high levels of population immunity.[9] Within three days of the first genome being uploaded, the WHO had designated it as the fifth variant of concern of SARS-CoV-2 (Omicron, B.1.1.529).[9] Within three weeks the variant had been identified in 87 countries.[9]

In early December 2021, Pango announced it was designating two genetically distinct sub-lineages of B.1.1.529 as BA.1 (B.1.1.529.1) and BA.2 (B.1.1.529.2)[10]: BA.1 for the original globally distributed lineage, and BA.2 for the new outlier lineage. The prefix BA was then an alias for B.1.1.529.[10] BA.2 was designated a variant under investigation (VUI) by UKHSA on 21 January 2022. UKHSA’s latest BA.2 risk assessment was published on 23 March 2022. [11] BA.2 contains 29 mutations in the spike protein and a deletion at 25-27. Some of the mutations in the spike protein are shared with BA.1.[12] 

Definitive differentiation of BA.1 from BA.2 requires whole genome sequencing (WGS). However, as the Omicron genome (lineage BA.1) contains the spike deletion at position 69-70 which is associated with S-gene target failure (SGTF) in some widely used PCR tests, SGTF patterns can be used to assess the spread of Omicron lineage BA.1. The BA.2 genome generally is S-gene target positive, but as of 30 March 2022, the UKHSA reported that 0.16% of BA.2 samples sequenced had the deletion at position 69-70.[1]

Omicron sub-lineage BA.3 is currently very rare. It has the SGTF deletion (Δ69-70) so can be detected using PCR tests that detect SGTF. There is little data on BA.3. BA.3 is a sub-lineage of Omicron (B.1.1.529). Preliminary investigation suggests that BA.3 has no specific mutations in the spike protein, but is a combination of the mutations found in BA.1 and BA.2.[13] Similar to BA.1, BA.3 has the SGTF deletion (Δ69-70) which means it can be detected using PCR tests that detect SGTF, such as Thermo Fisher’s TaqPath and does not present the same issues as BA.2 discussed above in relation to PCR tests. (link) BA.3 is currently very rare, as of 24 January 2022, 85 sequences in the BA.3 lineage have been detected since the lineage was identified (link) and it is most commonly reported in Poland, South Africa and UK (link). 

Two new variants within the Omicron lineage have been recently identified and named BA.4 and BA.5. These were classified by the VTG on 6 April 2022 as V-22APR-03 and V-22APR-04, respectively.[1] On 12 April 2022, WHO announced that BA.4 and BA.5 had been added to their list of variants for monitoring. Monitoring is needed to understand any effects of their mutations and whether these will they assist the virus in evading the immune system in people with natural or vaccine-induced immunity. At this stage it is unknown what effect on transmissibility or severity of disease these mutations have.

Prevalence of Omicron and its sub-lineages 

The highly transmissible Omicron variant continues to be the dominant variant circulating globally, and has rapidly replaced all other circulating variants in almost all countries in which it has been reported.[14] The WHO Weekly Epidemiological Update on 20 April noted that Omicron accounted for 99.5% of the 313 715 sequences uploaded to GISAID in the most recent 30-day period (16 March-14 April 2022). The remaining sequences were Delta (<0.1%) or sequences not assigned to a Pango lineage (0.4%).[15] However, the WHO notes these trends should be interpreted with due consideration of the limitations of surveillance systems.[15]

BA.1 was responsible for the initial Omicron surge and is now being replaced by BA.2 globally.[4]

  • WHO has previously reported that the prevalence of BA.2 among sequenced Omicron cases globally submitted to GISAID has been steadily increasing, and that as of 22 February 2022, 18 countries have reported a predominance of BA.2 (>50%).[16] WHO notes significant differences between regions, with the South-East Asia Region reporting the highest prevalence of BA.2 among Omicron sequences (44.7%) and the Region of the Americas reporting the lowest prevalence (1%), though this is likely to be affected by the capacity to conduct widespread whole genome sequencing in many countries.[17]
  • According to the UKHSA, in England between 27 March to 3 April 2022, 88.5% of sequenced genomes were Omicron lineage BA.2 (VOC-22JAN-01), 11% were Omicron BA.1 (VOC-21NOV-01), and 0.5% were other variants.[1] 
  • CDC projections for the week ending 9 April 2022, estimated that 100% of lineages in the United States are Omicron, with the predominant Omicron lineage continuing to be BA.2.[18] The national proportion of BA.2 was projected to be 85.9% [18] (up from 53.9% at 1 April [19]), BA.1.1 13.1%, and BA.1 and BA.3 1.0% combined.[18]

New signals

The  risk of clinically significant emerging variants is considered to  be high, according to the WHO.[6] The WHO has expressed concern that during recent months, some countries have significantly reduced SARS-CoV-2 testing. They caution that unless robust surveillance systems are retained, countries may lose the ability to accurately interpret epidemiological trends, implement the appropriate measures necessary to reduce transmission and monitor and assess the evolution of the virus.[14]

Table 4: BA.4 and BA.5

Variant Genomic features Geographic distribution and prevalence Characteristics/ possible impact 
BA.4 BA.4 shares all mutations and deletions with the BA.2 lineage except the following: S: 69/70 deletion, NSP4: L438F reverted to WT (wild type), S:L452R, F486V, Q493 (WT), ORF 6: D61 (WT), ORF 7b: L11F and N: P151S.[1]  BA.4 has been found in multiple countries, with the highest prevalence in South Africa where the first known sample was collected on the 10 Jan 2022.[1] For samples sequenced and identified in GISAID between 10 Jan 2022 and 30 March 2022, prevalence was reported as following: South Africa (45 genomes), Denmark (3), Botswana (2), England (1) and Scotland (1). [1] Media have reported that BA.4 and BA.5 are rapidly growing in South Africa (link). In Gauteng there has been informal reporting of approximately 60% of COVID-19 cases being BA.4 as at the 1 April 2022.(link)Although the number of cases is relatively low, the geographic spread indicates that the variant is successfully transmitting.[1] In an informal report from Gauteng, BA.4 was observed to have a 0.09 per day growth rate, similar to BA.2.(link)   The mutation on the spike (69/70 deletion) is associated with S-gene target failure. This will have implications for detection. [1]    Spike L452R has been associated with in increased infectivity and increased cell fusion.[179] Mutations to L442R spike protein in BA.4 have been seen other variants including Delta, Epsilon, Kappa and BA.5. This mutation appeared to play a role in the increased spread of Delta. There are concerns BA.4 variant could have the immune evading properties of BA.2 and the increased transmissibility of Delta.(link)
BA.5 Shares all the same mutations/deletions as BA.4 except the following:   M: D3N; ORF 7b: L11 (WT);  N: P151 (WT);  synonymous SNPs: A27038G, and C27889T.[1]Between 25 Feb 2022 and 25 Mar 2022, 27 sequences of the BA.5 lineage were reported.[1] All BA.5 cases were from South Africa. This is most prominent in KwaZulu-Natal, where informal reporting suggests 55% of COVID-19 cases were reported as BA.5. (link)Due to the similarities in mutations, BA.5 has similar implications to BA.4.  BA.5 does not have the geographic spread of BA.4 at this stage.[1] It does have a similar observed growth rate of 0.11 in the location of primary focus. This is comparable to growth rates seen in BA.4 and BA.2.

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