COVID-19 Delta Variant A.Y.12 Is Fast Spreading In India and A.Y.3 Is Able To Infect The Vaccinated

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INSACOG or the India SARS-CoV-2 Genome consortium reports prevalence of the Delta variant sub-lineage A.Y.12 in India that has been linked to a COVID-19 surge in Israel.

Interestingly the Delta variant (B.1.617.2) has ‘birthed’ several sub-lineages or second generation variants or sub-species that bear most of its characteristic mutations but are different in other ways.  

To date, a total of 27 such second generation Delta variants have been identified with 22 assigned the names A.Y.1 to 22 and another as A.Y.3.1 and the other 4 are being studied still.
 
One of these sub-lineages, called Delta AY.12, has all the characteristic Delta mutations except one.
 
It was reported that the spike in cases in Israel is of concern because it’s a country with nearly 60% of its adults fully vaccinated and reports that the Pfizer vaccine’s effectiveness in that country is significantly less than what emerged over clinical trials.
 
The Delta variant, the most widely prevalent variant of concern in India, is being “reclassified” to another sub-lineage that has been associated with a large number of cases in Israel, the India SARS-CoV-2 Genome (INSACOG) consortium, which tracks emerging variants, said in a report on Monday.
 
The INSACOG report noted, “The reclassification is primarily to assist micro-epidemiology and is not based on acquisition of significant mutations. Thus, it is not currently known whether AY.12 is clinically different from Delta. No new mutations of concern are noted in the spike protein (S). However, its rapid growth in Israel means that it should be examined further.”
 
Dr Anurag Agrawal, Director, CSIR-Institute of Genomics and Integrative Biology told Thailand Medical News, “The Delta variant, because of its preponderance in coronavirus cases globally, has several sub-lineages, making it necessary to reclassify them as not doing so would make naming them unwieldy.

A large number of cases in Israel have been linked to AY.12. In India, there are several micro-lineages and some of them are AY.12. We need to wait and watch to see how significant this micro-lineage is in driving infections in India. But as of now, it has exactly the same risk classification, no more and no less, than Delta.”
 
A detailed and complete reclassification and estimating the prevalence of AY.12 in India is expected to take some time, according to the INSACOG. “Since the AY.12 definition is inconsistent, final numbers will take some time. AY.12 analysis will be added to the portal (a public website), along with other new lineages, once there is greater consensus,” their report noted.
 
To date, according to INSACOG, about 70,000 coronavirus samples have been sequenced for their genomic structure, of which 50,000 have been allotted to various lineages. About 60% of them consist of international variants of concern or interest (VoC or VoI) that are globally tracked and linked to outbreaks as well as instances of vaccine breakthrough and reinfections.
 
Within these VoC, the Delta variant comprises 70% of samples. The Delta plus cases, in which AY.12 is include d, only number 67, though this is expected to swell after the reclassification.
 
Although the overall trajectory of daily cases in India is downwards, Kerala has reported nearly 31,000 cases on Wednesday, which accounts for nearly all of India’s caseload.
 
Some Indian researchers are claiming that the AY.12 sub-lineage has gain the right configuration to become more transmissible but this claim however warrants further studies.
 
A.Y.3 More Potent In Terms Of Causing Breakthrough Infections?
 
In another development, a research team from VA Boston Healthcare System, Boston University School of Medicine and Harvard Medical School has expressed concerns about the Delta variant’s A.Y.3 sub-lineage after it was found that transmission of the Delta Variant AY.3 could occur among fully vaccinated people even in a controlled environment of an inpatient medical-surgical ward.
 

The study team said, “It remains to be determined whether the Delta variant AY.3 lineage is more transmissible than the Delta Variant B.1.617.2. Our findings do raise concern that without stricter risk mitigation, nosocomial (originating in a hospital) transmission of the Delta variant and Delta sub-lineages will occur more frequently than with prior, less transmissible variants, even in vaccinated persons.” 
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2021.08.05.21261562v1
 
While so called ‘experts’ are claiming that the Delta sub-lineages were purely created for epidemiological purposes only and to monitor cluster spreads and there is no cause for alarm, the fact is that each of these sub-lineages possess unique mutations, deletions etc that are showing different characteristics in terms of viral fitness, transmissibility, virulence to even pathogenesis. Further detailed studies are currently underway and in a few weeks times we should have more concrete published data on the uniqueness of each of these sub-lineages.


Transmissibility – How does it spread from one host to another? How easily is it spread?
What do we know?

SARS-CoV-2 is passed easily between humans, primarily through close contact and aerosol transmission.34, 88, 323, 541

  • As of 8/12/2021, COVID-19 has caused at least 205,368,850 infections and 4,334,088 deaths globally.390 In the US, 36,305,005 cases and 619,098 deaths390 have been confirmed. Cases32, 569 and fatalities are underestimated.379, 582, 730, 834
  • SARS-CoV-2 can spread via aerosol or “airborne” transmission315 beyond 6 ft in certain situations823 such as enclosed spaces with inadequate ventilation.126 The risk of infection from fomites (e.g., currency)758 is believed to be low.346 Vertical transmission is rare.751 Nosocomial (hospital) transmission is underestimated and driven by superspreading events.501

At least six variants (Delta, Gamma, Alpha, Beta, Kappa, Eta) have higher transmission rates than the original, non-variant SARS-CoV-2 lineage.105

  • The Delta (B.1.617.2) variant is highly transmissible, with an estimated R0 of 5-9.105, 525 This is far higher than wild-type SARS-CoV-2 (R0 = 2.2 to 3.1).513, 593, 660, 839, 868 As of 7/31/2021, the Delta variant (and subvariants AY.1, AY.2, and AY.3) account for more than 93% of newly sequenced cases in the US.121 Low vaccination rates facilitate COVID-19 transmission.407
  • Household secondary attack rates of the Delta variant can be as high as 53%,216 and may be higher in individuals younger than 10.27 Early evidence suggests that the Delta variant spreads rapidly in schools.759
  • The Delta variant may lead to higher viral load (RNA copies) in infected individuals compared to those with wild-type SARS-CoV-2 or other variants.392 The viral load (RNA copies) of vaccinated individuals with breakthrough Delta variant infection was found to be similar to infected, unvaccinated individuals in several studies,90, 659 suggesting that breakthrough cases may be equally capable of transmitting to others (though infectious virus was not measured directly in these studies).
  • ·  Outbreaks of the Delta variant can occur even in areas with appropriate PPE use and high vaccination levels.354

COVID-19 vaccines reduce transmission rates by approximately 54% (range of 38-66%).694

  • Vaccination provides protection to uninfected individuals by reducing viral load753 and transmission.340, 530

The amount of infectious virus emitted from an infectious individual is unclear, but appears highly variable.

  • Exhaled breath may emit 105-107 genome copies per hour.506 Individual emission rates vary substantially.723, 854 Loud vocalization (e.g., singing, shouting) has been associated with greater indoor transmission risk.724
  • Higher viral loads in COVID-19 patients result in higher secondary attack rates, with a rate of 12% with viral loads below 106 genome copies/mL (nasopharyngeal swab), and 24% with viral loads more than 1010 viral genome copies/mL.519 Higher viral loads have also been associated with larger SARS-CoV-2 clusters433 and increased indoor transmission risk.69

Asymptomatic or pre-symptomatic individuals can transmit SARS-CoV-2649 and play a large role in new case growth.466

  • Individuals are infectious for 1-3 days prior to symptom onset.41, 809 Pre-symptomatic74, 423, 719, 736, 847, 871 or asymptomatic50, 372, 504 patients can transmit SARS-CoV-2.491 Most transmission occurs before symptoms begin463 and within 5 days of symptom onset,319 as demonstrated by case studies146 and models.756
  • Asymptomatic individuals transmit SARS-CoV-2 less often than symptomatic individuals,64, 96, 744 causing 66%463 to 83%552 fewer secondary cases, potentially due to lower viral loads.170

Infection risk is particularly high indoors,56 while outdoor transmission is rare.97

  • SARS-CoV-2 may be spread by conversation and exhalation11, 462, 682, 725 in indoor areas such as restaurants271, 471 or offices.267 Clusters are often associated with large indoor gatherings,448, 594 including bars,681 restaurants,860 and gyms.141, 454
  • In an experiment at a concert held when community prevalence was low, COVID-19 transmission was inhibited through the use of natural ventilation, rapid COVID-19 tests (Panbio Ag, Abbott), universal N95 masking, and temperature checks.653

Household transmission is rapid,18 and household contacts spread infection more than casual community contacts.562

  • The secondary attack rate of SARS-CoV-2 is 24% on average,176 but higher for symptomatic index cases, spouses of index cases, and adults.509 High viral load may increase transmission risk.406
  • In an outbreak of the Delta variant, transmission occurred in 46% of households, with 80-100% of those household members becoming ill, resulting in a secondary attack rate of 53%.216

Superspreading events (SSEs) appear common in SARS-CoV-2 transmission and may be crucial for controlling spread.

  • Most new infections come from a few infectious individuals (overdispersion parameter k = 0.2-0.5).17, 239, 443, 447, 796, 870

Rates of transmission on public transit are unclear but appear low,301 particularly on airplanes.591

  • Several studies have identified plausible transmission on airplanes49, 154, 357, 412, 548 despite pre-departure screening.739 Fluorescent tracer research on commercial airplanes suggests a low risk of aerosol or surface transmission during flights,707 though leaving middle seats open may reduce aerosol exposure.209 Outbreaks have also been linked to trains368 and buses.503

Infection in children is underestimated,224, 762 and children of any age can acquire and transmit infection.721 There is some evidence that younger children (<10-15) are less susceptible384, 452 and less infectious463 than older children and adults.302

  • Children seem to transmit SARS-CoV-2 less often than adults, though few studies have addressed this directly.292 Children appear to have lower concentrations of viral RNA170 and infectious virus than adults.98

Transmission in schools is generally low,284, 362, 398, 846, 877 follows community incidence130, 312, 722 and can be mitigated.300

What do we need to know?

We need to know the relative contribution of different routes of transmission and the effect of new variants.

  • What is the emission rate of infectious particles while breathing, talking, coughing, singing, or exercising (for all variants)?
  • Are certain variants more transmissible in different subpopulations or age classes (e.g., children)?193

How important are meteorological conditions to SARS-CoV-2 transmission?507

Genomics – How does the disease agent compare to previous strains?
What do we know?

Current evidence suggests that SARS-CoV-2 accumulates mutations at a similar rate as other coronaviruses.

  • Preliminary genomic analyses that the first human cases of SARS-CoV-2 emerged between 10/19/2019 – 12/17/2019.35, 57, 638
  • The estimated mutation rate for SARS-CoV-2 is 6×10-4 nucleotides per genome per year.782
  • Reducing infections is crucial for reducing the emergence of new variants.754
  • There are US trackers for SARS-CoV-2 variants116 and the mutations that underlie them.441
  • Immunosuppressed patients are a possible source of viral variants due to prolonged virus replication within a single host.12
  • The WHO has applied different names to major SARS-CoV-2 variants using Greek letters.822
  • B.1.1.7 (20I/501Y.V1) (VOC202012/01) (Alpha) – The B.1.1.7 variant (Alpha) is associated with a 50-75% higher transmission rate than wild-type virus,185, 789 potentially due to higher patient viral loads,102, 280, 413 higher rates of symptomatic illness,6 and a longer infectious period.231 Contains several Spike protein mutations (HV 69-70 deletion, N501Y, N493K).639
  • There are currently no concerns relating to the efficacy of the Pfizer/BioNTech545, 844 or Moderna vaccines,840 and the AstraZeneca/Oxford vaccine appears to show efficacy against B.1.1.7 (though lower than efficacy against non-variant SARS-CoV-2).237 Serum from patients with non-B.1.1.7 variant SARS-CoV-2 can neutralize B.1.1.7 virus.618
  • The E484K mutation has appeared independently in several individuals with the B.1.1.7 variant in the UK320 and US.516
  • B.1.617.2 (Delta)– Variant of concern824 initially identified in India in January 2021, containing several mutations of concern (E484Q and L452R).704 The variant has been documented in California and the UK.348 Initial research suggests that this variant is more transmissible825 and more virulent849 than non-variant SARS-CoV-2.
  • Resists neutralization by certain monoclonal antibodies360 and is more resistant to vaccine-derived antibodies than non-variant SARS- CoV-2; serum from patients given mRNA vaccines was able to neutralize the B.1.617.1 (Kappa) lineage.228
  • B.1.617.2 contains 13 sub-lineages with four being monitored in the US: AY.1, AY.2, AY.3, AY.3.1.576 AY.1 and AY.2 possess a mutation of concern at K417N that is also present in B.1.351 (Beta) and P.1 (Gamma) variants.441 This mutation has shown to affect class I antibody binding314, 521 and reduce binding affinity to ACE2 but provides stability to ACE2 binding in the presence of the E484K mutation.521, 728
  • B.1.351 (20H/501Y.V2) (Beta) – First identified in South Africa in December 2020747 with notable mutations N501Y, E484K, and K417N.575 This variant is resistant to neutralization from convalescent plasma and vaccine recipient sera.797 Preliminary studies from Moderna,841 Johnson and Johnson,230 AstraZeneca,544 and Novavax572 suggest a lower vaccine response to this variant, though the Pfizer/BioNTech vaccine appears to generate neutralizing ability in laboratory487 and human trials.616
  • Convalescent serum from patients with B.1.351 infection shows high neutralization ability against non-variant virus.132
  • The B.1.351 variant is partially resistant to the monoclonal antibody casirivimab and is fully resistant to bamlanivimab.359
  • Comparison of the severity and fatality of the Beta variant vs the Alpha variant found that Beta had a higher prevalence of severe disease, higher advancement to critical disease and a higher fatality rate.14 Comparison of cases in South Africa from the first to second wave, when the Beta variant became prevalent, found increased hospitalization and mortality rates, though some of the increased mortality could be due to the increased pressure on the health care system.387
  • P.1 (20J/501Y.V3) (Gamma) – First identified in Brazil,249 contains various mutations including K417N, E484K, and N501Y.249
  • The variant is estimated to be 1.7-2.4 times more transmissible than non-variant SARS-CoV-2.250
  • Prior infection with non-variant SARS-CoV-2 is estimated to provide only 54-79% protection against infection with the P.1 variant,250 potentially explaining the resurgence of COVID-19 in Manaus, Brazil after a large initial epidemic.100, 674
  • Partially resistant to the monoclonal antibody casirivimab and is fully resistant to bamlanivimab.359
  • Appears less resistant to neutralization than the B.1.351 variant despite three critical shared mutations (E484K, K417N/T, and N501Y), suggesting RBD mutations are not the only factor influencing variant immune escape.202
  • Preliminary analysis suggests this variant leads to increased mortality in younger individuals, specifically those age 20-29.196
  • The H655Y mutation, which was seen in early human isolates, is associated with resistance to human antibodies,55 and has arisen in experimental animal models of SARS-CoV-2 infection.82, 244 Experimental studies in mink found increased viral cell entry, transmission, and host susceptibility with this mutation.244
  • C.37 (Lambda variant) – In vitro studies suggest two single mutations (T76I, L452Q) make the Lambda variant more infectious than wild- type virus, while a deletion mutation (RSYLTPGD246-253N) increases antibody resistance.417

B.1.429 (Epsilon) ([CAL.20C (20C/S:452R)] [GH/452R.V1 (B.1.429+B.1.427)]) – L452R563 mutation located on the Spike protein was first reported in Denmark384 and has increased in prevalence in California.163 The B.1.429 lineage is more transmissible and leads to more severe disease than non-variant SARS-CoV-2,509 and is partially resistant to antibodies.192, 775

What do we need to know?

We need to identify differences in transmissibility or severity caused by different SARS-CoV-2 mutations and variants.

  • What are the mechanisms driving the resistance of variants to neutralization by the immune system?
  • How do variants affect the likelihood of reinfection or coinfection?
  • How will vaccination affect prevalence and competitive advantage of current and future SARS-CoV-2 variants?

How prevalent are coinfections with multiple strains, and what is their clinical progression?233

. . . . . .

reference link : DHS SCIENCE AND TECHNOLOGY – Master Question List forCOVID-19 (caused by SARS-CoV-2) Monthly Report 13 August 2021


This observational study included all persons diagnosed with breakthrough SARS-CoV-2 infections at the VA Boston Healthcare System (VABHS) from March 11, 2021 to July 31, 2021, including those tested for surveillance, admission, symptoms, and as part of an outbreak investigation in July 2021.

SARS-CoV-2 infection was diagnosed by reverse-transcription polymerase chain reaction (PCR) (Cepheid). Variants were identified by MassARRAY SARS-CoV-2 Variant Panel (36-plex PCR, Agena BioScience) for most breakthrough cases after June 2021 Viral genomic sequencing was performed by the Jackson Laboratory.

Discussion
Cryptic transmission of the Delta variant occurred among asymptomatic, vaccinated inpatients on a single inpatient ward. The source may have been a patient whose infection arose after preadmission testing from a pretesting exposure or from a subsequent hospital exposure that was not identified despite extensive contact tracing. Infection spread among vaccinated patients and extended to a vaccinated HCW and a vaccinated visiting family member.

This cluster might not have been discovered save for a routine discharge test that triggered follow-up contact tracing, because most patients were asymptomatic when diagnosed, and some patients were discharged prior to the discovery of the outbreak. These observations contrast with a report that unvaccinated persons were the sole source for breakthrough infections in HCW with the Alpha variant.8

High viral load increases the risk for transmission of SARS-CoV-2;14 therefore, the high viral load of the Delta variant in asymptomatic vaccinated persons likely increases the risk for nosocomial transmission. Because the incubation period for SARS-CoV-2 infection is 2-14 days, screening for SARS-COV-2 infection, even on the day of admission, will not detect any infections arising from exposure on the day prior to admission or many infections arising from earlier exposures.

Hence, the use of sensitive tests15 for postadmission surveillance of inpatients, regardless of vaccination status, may be necessary to prevent nosocomial infection during surges of highly transmissible variants.

Though reports have identified transmission from HCW to patients as an important route for nosocomial SARS-CoV-2 infection,16,17 here, transmission likely occurred between patients and from patients to the sole infected HCW and to a visitor. Of note, infection spared all but one of 168 HCW that were exposed to infected patients.

That transmission was primarily among patients and not between patients and HCW perhaps reflected the fact that HCW wore surgical masks and patients did not. Hence, despite the high viral load of their patients, masking combined with vaccination may have protected HCW during this outbreak. Encouragement of patient masking might further decrease nosocomial Delta variant infection.

Our findings support a growing literature that vaccination does not prevent the development of high viral load in the nasopharynx of persons infected with the Delta variant or the propensity for asymptomatic transmission,10,11 in contrast to findings with earlier variants.6-9 Brown et. al. 11 recently described community transmission of the Delta variant B.1.617.2 in a cohort of predominantly vaccinated persons who congregated unmasked in indoor spaces.

High viral load did not differ between vaccinated and unvaccinated persons. In that study, sequencing identified the Delta variant (B.1.617.2) in 89% of cases and the Delta AY.3 sublineage in just 1%. In the current study, sequencing identified the Delta AY.3 sublineage 4 of 4 cases. Our observations indicate that transmission of the Delta variant sub-lineage AY.3 may occur among vaccinated persons even in the more controlled environment of an inpatient medical-surgical ward.

It remains to be determined whether the Delta variant AY.3 lineage is more transmissible than the Delta Variant B.1.617.2. Our findings do raise concern that without stricter risk mitigation, nosocomial transmission of the Delta variant and Delta sublineages will occur more frequently than with prior, less transmissible variants, even in vaccinated persons.

This observational study has several limitations. The outbreak included a small number of individuals. The absence of full viral genome sequencing on all 8 cases prevented clear identification of the source and trajectory of viral transmission.

One case was not typed to positively identify the Delta variant. Finally, though the data demonstrate that asymptomatic infection and transmission of the Delta variant may occur in vaccinated persons, this study does not address the relative risk for Delta variant infection in vaccinated versus unvaccinated persons.

reference link : https://www.medrxiv.org/content/10.1101/2021.08.05.21261562v1.full-text

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