Thread by @vipintukur

Will the newly identified sub-lineages of #Delta may initiate a new wave of #Covid19 in India? What impact the increasing prevalence of the Delta-D clade would have on global #COVID burden?

My write-up deliberating on these issues in @TheWireScience 👇 science.thewire.in/the-sciences/a…

#Delta variant and its extended family: How much do we need to worry?

During the first few months of the #pandemic, the evolution of the virus was relatively predictable, with substitutions accumulating at a fixed pace: 1 substitution every second week 2/

In contrast, the 2nd year of the #pandemic is punctuated by the emergence of several #variants that bore evidence of dramatic evolution 3/

In the past few months, the focus has shifted to the #Delta &has been detected in at least 119 countries. Its current global prevalence: 15% 4/
outbreak.info/situation-repo…

Evolution of key #VOCs: Most variants have displayed minor “blips”, i.e., they increased in frequency rapidly in one location, yet this increase in frequency was also followed by a rapid decay 5/

Only two variants- #Alpha & #Delta, displayed a more dramatic global pattern, increasing dramatically in frequency over most of the globe 6/

#Alpha does not have substitutions that are associated w/ immune evasion (except for NTD del), which was in line w/ the timeline during which Alpha began to spread. The global population was not vaxxed, thus Abs-evasion substitutions bore no selective advantage for the virus 7/

In contrast to Alpha, the spread of the #Delta variant is currently occurring at a very different landscape, with an increase in immunized & recovered individuals, thus Abs-evasion substitutions may confer a significant advantage 8/

All the VOCs have 3 key features:
1-Most have a higher proportion of non-synonymous (NS) substitutions
2-These NS substitutions are most often predominantly in the Spike
3- The NS substitutions are mostly located in the NTD & RBD, many of which are ass w/ escape from NAbs 9/

All VOCs bear an AA replacement at either position 203, 204, or 205 of the N protein, often combined. N has a crucial role in evasion from the cell’s innate immune resp, & AA replacements at this region may increase replication capacity of the virus 10/
biorxiv.org/content/10.110…

#Delta genome has 13 mutations that produce alterations in the AA sequences of the proteins it encodes. It has key mutations in the gene encoding the ‘Spike’ causing the substitutions D614G, T478K, P681R & L452R, which are known to affect the transmissibility & immune escape 11/

Interestingly, the delta does not have N501Y substitution which is an integral part of all other key VOCs like Alfa, Beta, & Gamma and is known to enhance the transmission capability of these variants 12/

The #L452R confers a stronger affinity of S protein for #ACE2 receptor & decreased recognition capability of immune system. The #P681R may boost cell-level infectivity by facilitating cleavage of S precursor protein to the active S1/S2 configuration 13/
virologyj.biomedcentral.com/articles/10.11…

#Delta is not only different from all other VOCs in its ability to transmit more vigorously but its evolution is also different. Most VOCs are characterized by long branches leading to their emergence, with an excess of NS substitutions occurring in the S & N proteins 14/

In contrast, the #Delta variant lacks the ‘signature’ long branch and is characterized by a ‘step-wise' evolutionary process that is ongoing. 15/

#Delta is not only having a shorter incubation period but also have a shorter latent period. Meaning?
People infected w/ delta test +ve more quickly on exposure than earlier strain. It also triggers symptoms in a host much faster w/ fewer presymptomatic transmission events 16/

Infected individuals shed much more virus & can start infections w/ smaller viral particle numbers. It also binds & replicates faster, creates a higher viral load (~1000 times higher) than those in the earlier strain infections on the day when viruses were first detected 17/

Overall, the time difference stayed the same but with a much higher viral load. That's terrible and explains near-vertical waves seen in India & many other countries. If people get symptoms, they isolate & cannot act as ‘asymptomatic’ spreaders 18/
virological.org/t/viral-infect…

Together w/ shorter incubation periods, it might explain steep upward & downward slopes of Delta waves in India. So, it means Delta seems to burn bright but for a short duration, meaning cases explode near-vertically, but also, without too much effort, collapse as forcefully 18/

It is very unusual for a virus to change so much that it spreads this much faster than original strain. There is no precedent in virology history. The original Wuhan virus had a Ro of ~2 (which was enough to cause a huge pandemic), and the Delta variant has a Ro of ~6. 19/

More importantly for vaccines, the original virus took ~6-7 days for symptomatic #COVID19, whereas #Delta has sped that up to ~ 4 days. That’s a big difference for our immune system’s defences. 20/

Going back to April 2020, we said a fundamental aspect of this viral infection was that it took 6-7 days for #COVID19 (mostly nasal), and around 2 weeks for severe pneumonia (lung disease and hospitalization) 21/

Those two-time windows are consistent with the immune system having a substantial amount of time to stop the virus, both for stopping any symptoms (1st-time window) and for stopping pneumonia and hospitalizations (2nd-time window). But that is different now 22/

We predicted that #vaccines would probably be successful against #COVID19. And they have been. Vaccines have done their job incredibly well against the original coronavirus & well against many #VOCs 23/

But the Delta being this much faster & more transmissible is almost like a new virus. If the virus is ~2-3 days faster (4 days), that is a much harder task of the T cells & B cells to stop virus fast enough to prevent symptoms (and transmission)....... 24/

That means it is a variant with more burden on the NAbs to stop upfront. For a virus so fast, it causes disease in 4 days, it is much more likely to primarily require Abs to prevent symptoms (& transmission).....25/

The T cells & B cells can jump in to help and probably have an effect by 6-7 days, but probably not 4 days. This is the reason why even the most potent vaccines are struggling ag delta, particularly to protect against infection and symptomatic disease..by @profshanecrotty 26/

@profshanecrotty As a result, the Delta variant has a significant impact on the VE of current vaccines. In a new study by Mayo Clinic, the VE of #Pfizer vaccine went down considerably ag infection (from 76% ag Alfa to 42% ag Delta)... 27/
medrxiv.org/content/10.110…

.....however, both #Pfizer & #Moderna mRNA vaccines retained their high vaccine effectiveness (VE) against hospitalization & death.. 28/

Coming to the Delta family. #AY1 variant is also known as the ‘#DeltaPlus variant’ characterized by #B16172 variant acquiring another mutation, #K417N which is also found in #Beta variant. In India, all the sub-lineages (particularly, AY1 & AY2) are referred as “Delta Plus” 29/

#AY1 & #AY2 sub-lineages of the #Delta variant have traded higher transmissibility for greater immune evasion potential, compared to the delta. In fact, both sub-lineages are unlikely to be more transmissible than the delta itself 30/
livemint.com/news/india/cov…

All the three sub-lineages of the Delta variant (AY.1, AY.2 and AY.3) are now labelled as VOCs by both the #CDC and the #WHO, and they continue to be monitored within the original Delta category 31/

Acc to CDC's COVID Data Tracker, the original Delta is estimated to account for 83.4% of all COVID infections in the US. While the estimated prevalence for AY.1 (0.1%) and AY.2 (0.8%) remain small, AY.3 accounts for an estimated 9.1% of infections 32/

covid.cdc.gov/covid-data-tra…

Recent #ICMR study shows that people who had received #Covaxin developed 23% lower levels of Abs against #delta infections (compared to infections of the B.1 strain); 33% lower against AY.1 & nearly 47% lower against AY.3 33/
thehindu.com/news/national/…

However, the prevalence of AY.1 & AY.3 is extremely low in India, with only 60-odd cases & few deaths have been reported so far 34/

livemint.com/news/india/mah…

Overall, the delta variant’s sub-lineages don’t ring too many alarm bells. To date, there is no clear evidence that it conveys enough of a benefit to the virus to allow it to dominate the original Delta 35/

The Delta-D?
New reports show that the delta phylogeny could be separated into 5 distinct clades – from A to E, each characterised by a specific set of substitutions. These clades are in addition to the three recently noted VOIs, AY.1, AY.2 & AY.3. 36/

medrxiv.org/content/10.110…

Delta D clade is becoming more dominant. Although the delta-D is characterized by an excess of non-synonymous (NS) mutations, scientists noted no notable differences between delta-D and delta-A/B/C/E vis-à-vis viral load, age distribution and immune evasion 37/

The global increase in Delta’s prevalence has happened concurrently w/ increasing prevalence of DeltaD, suggesting what we now call ‘delta’ is specifically the Delta D.
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science.thewire.in/the-sciences/a…

38/end

New study shows that #Delta spike #P681R mutation enhances SARS-CoV-2 fitness over Alpha variant through improving spike protein processing

biorxiv.org/content/10.110…