The Delta variant explained

29 October 2021


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

Rapid evolution of new SARS-CoV-2 variants
The SARS-CoV-2 virus, responsible for COVID-19 disease, has evolved rapidly in the 20 months since it was first detected in people. The SARS-CoV-2 viruses found in humans are believed to have evolved from the closely related viruses found in captive or farmed animals, such as pangolins, which themselves evolved from the viruses commonly found in free-living horseshoe bats in China, and South-East Asia. (1) 

The variants that have emerged, and rapidly spread, regionally or globally, since mid 2020, have included various lineages, including those called Beta, Alpha, Gamma and Delta. (2) (Figure 1) Each new variant lineage has, to varying degrees, been more successful at transmitting from person to person than other contemporary lineages. Viruses that are sufficiently similar to be considered members of a variant lineage are not identical but share some common distinctive features that are presumed to be necessary for the lineage’s evolutionary success.  We should expect to see continued emergence of new variant lineages in the future.


Figure 1. The proportion of SARS-CoV-2 viruses sequenced from people globally, since August 2020, that have belonged to different evolutionary lineages. The grey shaded area represents the predominance of the founder SARS-CoV-2 lineage prior to early 2021. (2)

What makes the DELTA variant so much more infectious?
New SARS-CoV-2 variants, such as the Delta variant (also known as the B.1.617.2 variant), have mutations in many sites in their genome, which result in changes in multiple SARS-CoV-2 proteins. It appears likely that mutations in the gene for the spike protein make an especially large contribution to the enhanced pathogenicity of these new variants. As shown in Figure 2, the Alpha, Beta and Delta variants all have multiple amino-acid substitutions or deletions in their spike proteins.


Figure 2. Mutant SARS-CoV-2 viruses typically have several mutations which result in amino acid substitutions or deletions in their spike proteins. (2)

The SARS-CoV-2 spike proteins undergo a series of interactions with molecules at the surface of human respiratory cells, which bring about the fusion of the SARS-CoV-2 envelope with the cytoplasmic membrane of the target respiratory cell. (3) (Figure 3.)



Figure 3. A schematic diagram which illustrates the sequential interactions of the SARS-CoV-2 spike protein, first with ACE2, then with the TMPRSS2 enzyme, and then with the furin enzyme, leading to fusion of the SARS-CoV-2 envelope with the cytoplasmic membrane of the respiratory cell, allowing the viral RNA to enter, and thus infect, the target cell. (3)

Recent studies have suggested that a crucial mutation in the genome of Delta variants leads to an amino acid substitution in the portion of the spike protein that is cleaved by furin, an enzyme present in the mucus that coats the surface of respiratory epithelial cells. The mutation (P681R) results in the amino acid proline, being replaced by the amino acid arginine, at position 681 of the spike protein. The presence of arginine, instead of proline, at the furin cleavage site, facilitates the action of furin, which cleaves the spike protein. (4) The tip of the remaining portion of the spike protein is subsequently inserted into the cytoplasmic membrane of the target cell. The truncated spike protein, linking the virus envelope to the cytoplasmic membrane of the target cell, then undergoes conformational changes that lead to virus-cell fusion. The enhanced cleavage of the mutant spike protein by furin appears to approximately double the infectivity of the Delta virus, when compared to the original SARS-CoV-2 viruses that predominated throughout 2020.


Does vaccination provide protection against the Delta virus?
Other mutations, at amino acids 156 to 158 of the spike protein in Delta variants, make the mutant spike protein a less effective target for antibodies, that otherwise would block the attachment of the spike protein to the ACE2 receptor on the surface of respiratory epithelial cells. In consequence, people with antibodies that provide good protection against viruses of the parent lineage may be more susceptible to infection with the Delta mutant. A study of the neutralising activity of serum antibodies from health care workers who had received two doses of the Pfizer vaccine found that their antibodies were slightly less effective at neutralising Delta variant viruses than parent lineage viruses. (5) 

A study of symptomatic COVID-19 cases in England found that two doses of the Pfizer vaccine provided approximately 94 percent protection against the Alpha variant, but only 88 percent protection against the Delta variant. (6) A study of predominantly symptomatic cases, in eight US locations, found that two doses of either the Pfizer or the Moderna vaccine, provided approximately 66 percent protection during a period when the Delta variant was the predominant circulating virus, compared with 91 percent protection during the preceding period. (7)

Conclusions
In summary, the Delta variant, which currently predominates globally, is only the most recent of a succession of SARS-CoV-2 virus lineages, and other variant lineages that are likely to emerge in the near future. 

The success of the Delta variant is likely to be due in part to its enhanced ability to invade human cells, and also to its partial resistance to antibodies, generated either by previous infection with earlier variants, or by vaccination. 

Immunisation with two doses of the Pfizer vaccine does provide a high degree of protection against disease caused by the Delta variant. Further studies are necessary to determine how best to protect against severe or fatal disease caused by the Delta, or other future, variants.

 

References

  1. Lytras S, et al. The animal origin of SARS-CoV-2. Science 2021; 373: 968-70. https://doi.org/10.1126/science.abh0117
  2. Kupferschmidt K. Evolving threat. Science 2021; 373:845-9. https://doi.org/10.1126/science.373.6557.844
  3. Thomas M. How vaccines block COVID-19 infection. A Youtube video available on the RNZCGP website. https://www.rnzcgp.org.nz/GPPulse/Opinion/Jan_2021_update_on_potential_SARS-CoV-2_vaccines.aspx?WebsiteKey=5d6ca365-aa40-4574-8861-3f40caea2dc
  4.  Callaway E. The mutation that helps Delta spread like wildfire. Nature 2021; 596: 472-3. https://doi.org/10.1038/d41586-021-02275-2
  5. Lustig Y, et al. Neutralising capacity against Delta (B.1.617.2) and other variants of concern following Comirnaty (BNT162b2, BioNTech/Pfizer) vaccination in health care workers, Israel. Eurosurveillance 2021; 26(26):pii=2100557.  https://doi.org/10.2807/1560-7917.ES.2021.26.26.2100557
  6.  Bernal JL, et al. Effectiveness of Covid-19 vaccines against the B.1.617.2 (Delta) variant. New England Journal of Medicine 2021;385: 585-94. https://doi.org/10.1056/NEJMoa2108891
  7.  Fowlkes A, et al. Effectiveness of COVID-19 vaccines in preventing SARS-CoV-2 infection among frontline workers before and during B.1.617.2 (Delta) variant predominance – eight US locations, December 2020-August 2021. Morbidity and Mortality Weekly Report 2021;70(34):1167-9. https://www.cdc.gov/mmwr/volumes/70/wr/mm7034e4.htm