Delta 4+ variant: Complete vaccine escape & enhanced infectivity with Pfizer vaccine

“Here we suggest an evolutionary pathway by which the Delta variant could achieve complete escape from vaccine-induced immunity”.   Although Pfizer-BioNTech BNT162b2-immune sera neutralized the Delta variant, when four common mutations were introduced into the receptor binding domain (RBD) of the Delta variant (Delta 4+), some BNT162b2-immune sera lost neutralizing activity and enhanced the infectivity.

Unique mutations in the Delta NTD were involved in the enhanced infectivity by the BNT162b2-immune sera. Sera of mice immunized by Delta spike, but not wild-type spike, consistently neutralized the Delta 4+ variant without enhancing infectivity.

The 4 key mutations inserted were K417N, N439K, E484K and N501Y.

 

Preprint: The SARS-CoV-2 Delta variant is poised to acquire complete resistance to wild-type spike vaccines 

 

 

Public Health England releases detailed vaccine breakthrough information

 

So what is Plan B if the vaccines fail?

 

 

280 cases of Delta variant with N501Y, some with E484K too

Delta + Alpha + Beta + Gamma recombinant variant found in Turkey.

 

 

 

 

Image by Elliot Alderson from Pixabay

Preprint: Characterization of the emerging B.1.621 variant of interest of SARS-CoV-2

In this study, we reported the emergence and spread of the novel B.1.621 lineage of SARS-CoV-2, a new VOI with the insertion 146N and several amino acid substitutions in the Spike protein (T95I,Y144T, Y145S, R346K, E484K, N501Y and P681H). Although B.1.621 does not meet all of the VOC classification criteria so far, the set of mutations gathered the Spike protein could confer a synergistic impact on attributes such as reduction of vaccine-induced protection from severe disease, increased transmission and disease severity

Medrxiv preprint: Characterization of the emerging B.1.621 variant of interest of SARS-CoV-2
 

Belgium: 7 fully vaccinated care home residents die after contracting B.1.621 variant first found in Colombia

 

 

Image by gustavo9917 from Pixabay

Preprint: Persistent #coronavirus infection and intra-host evolution in association with advanced HIV infection

“Here we present a case of prolonged infection of greater than 6 months with shedding of high titer SARS-CoV-2 in an individual with advanced HIV and antiretroviral treatment failure. …Through whole genome sequencing at multiple time-points, we demonstrate the early emergence of the E484K substitution associated with escape from neutralizing antibodies, followed by other escape mutations and the N501Y substitution found in most variants of concern.”

Preprint: Persistent SARS-CoV-2 infection and intra-host evolution in association with advanced HIV
infection

 

 

Photo by National Cancer Institute on Unsplash

UK: #coronavirus variant B.1.617.2 within hours of outcompeting B.1.1.7 in Britain

Well that escalated quickly. It took just a little over one month to do it, but B.1.617.2 is now just hours away from outcompeting B.1.1.7 (aka the UK or Kent variant) on a national scale in Great Britain.

Let’s not forget that B.1.1.7 virtually conquered the globe after being discovered in Britain in September 2020.  B117 Infections started to climb rapidly in Britain in December 2020, and it became the dominant sars-cov-2 variant in many countries across the globe shortly thereafter. Now, barely 5 months later, it is being dethroned by a variant that carries neither of the signature sars-cov-2 mutations that were of such concern in the existing VOC’s – E484K and N501Y.

 

This is the same B.1.617.2 / B.1.1.7 chart for India:

 

Charts courtesy of outbreak.info

 

UPDATE 24th May 2021:

UK: PHE data shows B.1.617.2 now outcompetes B.1.1.7

 

OLDER POSTS:

India: The stunning rise of the B.1.617.2 [Delta] #coronavirus variant

 

UK: eleven vaccine breakthrough cases reported for B.1.617.2

UK: Detection of Spike Mutations; D80G, T95I, G142D, △144, N439K, E484K, P681H, I1130V, and D1139H, in B.1.1.482 Lineage (AV.1) Samples from South Yorkshire, UK

“Here we report the discovery of 24 recent B.1.1.482 pango lineage SARS-CoV-2 viruses in South Yorkshire that have acquired approximately 23 additional mutations when compared to the majority of other samples of this lineage. Nine of these additional mutations are found in the spike gene and six represent changes which are found in variants of interest and concern across the world and/or associated with reduced antibody binding (T95I, G142D, △144, N439K, E484K, P681H). Similar mutation profiles were also seen in B.1.1.482 samples from other regions in the UK. We recommended the monitoring of samples of this lineage which is now designated AV.1.”

Virological.org – Detection of Spike Mutations; D80G, T95I, G142D, △144, N439K, E484K, P681H, I1130V, and D1139H, in B.1.1.482 Lineage (AV.1) Samples from South Yorkshire, UK (UK Variant under investigation VUI-21MAY-01)

Virilogical.org report

 

UK: 49 cases of new #coronavirus variant under investigation VUI-21MAY-01 named AV.1

 

Image by Stanislav Hedvik from Pixabay

Europe: B.1.620 #coronavirus variant – definitely one to watch

“Last month, Gytis Dudas was tracking a concerning new coronavirus variant that had triggered an outbreak of COVID-19 in his native Lithuania and appeared sporadically elsewhere in Europe and in the United States. Exploring an international database of coronavirus genomes, Dudas found a crucial clue: One sample of the new variant came from a person who had recently flown to France from Cameroon. A collaborator, Guy Baele of KU Leuven, soon identified six more sequences from people in Europe who had traveled in Cameroon. But then their quest to pinpoint the variant’s origins hit a wall: Cameroon had uploaded a total of only 48 genomes to the global sequence repository, called GISAID. None included the variant”

Sciencemag.org report

 

B.1.620 is also listed as a Variant of Interest by the ECDC:

 

More on the B.1.620 variant traced back Cameroon by Gytis Dudas in the Pango Designation

 

 

Cameroon: travel-driven emergence and spread of SARS-CoV-2 lineage B.1.620 with multiple VOC-like mutations and deletions in Europe

 

Cameroon: travel-driven emergence and spread of SARS-CoV-2 lineage B.1.620 with multiple VOC-like mutations and deletions in Europe

“In this study we have presented evidence that a SARS-CoV-2 lineage designated B.1.620, first detected in Europe in late February, is associated with Central Africa, where it appears to circulate at very high prevalence, and has been introduced into Europe and the US on multiple occasions. A fair number of known B.1.620 genomes that were sequenced in Europe stem from travel-related cases returning from Cameroon, suggesting that it is likely to be the immediate source of this lineage.”

VOC amino acid changes lineage B.1.620 shares most in common with:

B.1.1.7 (ORF1a: SGF3675/3677Δ, S:Y144Δ, S: HV69/70Δ, S: P681H, and S: D1118H)

P.1 (ORF1a: SGF3675/3677Δ, S:P26S, S:E484K, S: T1027I) and

B.1.351 (ORF1a: SGF3675/3677Δ, S: E484K, S: LLA241/243Δ)

MedrXiv preprint Travel-driven emergence and spread of SARS-CoV-2 lineage B.1.620 with multiple VOC-like mutations and deletions in Europe

 

 

Image by rem734 from Pixabay

WHO: Newly designated VOC within lineage B.1.617 – update on Delta coronavirus variant

In consultation with the WHO SARS-CoV-2 Virus Evolution Working Group, WHO has determined that viruses within the lineage B.1.617 have been characterized as a VOC. B.1.617 contains three sub-lineages, which differ by few but potentially relevant mutations in the spike protein as well as prevalence of detection globally.

As of 11 May, over 4500 sequences have been uploaded to GISAID and assigned to B.1.617 from 44 countries in all six WHO regions, and WHO has received reports of detections from five additional countries. Though there may be important differences among the three sublineages, currently available evidence is too limited for VOI/VOC characterization by sublineage.

Future delineation of sublineages as VOIs/VOCs may be possible as our understanding by sublineage and relative importance of their epidemiology increases. At the present time, WHO has designated B.1.617 as a VOC based on early evidence of phenotypic impacts compared to other circulating virus variants, namely:

  • B.1.617 sublineages appear to have higher rates of transmission, including observed rapid increases in prevalence in multiple countries (moderate evidence available for B.1.617.1 and B.1.617.2), and
  • Preliminary evidence suggests potential reduced effectiveness of Bamlanivimab, a monoclonal antibody used for COVID-19 treatment, and potentially slightly reduced susceptibility to neutralisation antibodies (limited evidence available for B.1.617.1).

Viruses in the B.1.617 lineage were first reported in India in October 2020. The resurgence in COVID-19 cases and deaths in India has raised questions on the potential role of B.1.617 and other variants (e.g., B.1.1.7) in circulation. A recent risk assessment of the situation in India conducted by WHO found that resurgence and acceleration of COVID-19 transmission in India had several potential contributing factors, including increase in the proportion of cases of SARS-CoV-2 variants with potentially increased transmissibility; several religious and political mass gathering events which increased social mixing; and, under use of and reduced adherence to public health and social measures (PHSM). The exact contributions of these each of these factors on increased transmission in India are not well understood.

Approximately 0.1% of positive samples in India have been sequenced and uploaded to GISAID to identify SARS-CoV-2 variants. The prevalence of several VOCs including B.1.1.7 and B.1.612 sublineages increased concurrent to the surge in COVID-19 cases reported in India. While B.1.1.7 and B.1.612.1 variants have begun to wane in recent weeks, a marked increase in the proportion of viruses sequenced as B.1.612.2 has been observed over the same period. Since the identification of these variants through late April 2021, B.1.617.1 and B.1.617.2 accounted for 21% and 7% of sequenced samples from India, respectively.

A preliminary analyses conducted by WHO using sequences submitted to GISAID suggests that B.1.617.1 and B.1.617.2 have a substantially higher growth rate than other circulating variants in India, suggesting potential increased transmissibility compared. Too few sequences of B.1.617.3 have been detected to date to assess its relative transmissibility. Other studies suggest that the case numbers increased more rapidly during the most recent surge when variants B.1.1.7 and B.1.617 were circulating, compared to the first surge (June to October 2020).

A structural analysis of B.1.617 receptor binding domain (RBD) mutations (L452R and E484Q, along with P681R in the furin cleavage site) suggest that mutations in these variants may result in increased ACE2 binding and rate of S1-S2 cleavage resulting in better transmissibility, and possibly capacity to escape binding and neutralization by some monoclonal antibodies.

In a preliminary study on hamsters, infection with B.1.617.1 resulted in increased body weight loss, higher viral load in lungs and pronounced lung lesions as compared to B.1 variants (D614G).

Potential impacts of B.1.617 lineage on effectiveness of vaccines or therapeutics, or reinfection risks, remain uncertain. Preliminary laboratory studies awaiting peer review suggest a limited reduction in neutralisation by antibodies; however, real-world impacts may be limited. e One study found a seven-fold reduction in neutralization effectiveness against B.1.617.1 of antibodies generated by vaccination with Moderna – mRNA-1273 and Pfizer BioNTech-Comirnaty vaccines.

A second study also found a reduction in neutralization against virus carrying the E484Q mutation (contained in B.1.617.1 and B.1.617.3) for Pfizer BioNTech – Comirnaty vaccine, similar to that found with the E484K mutation.

A third study reviewing a limited sample of convalescent sera of COVID-19 cases (n=17) and sera from recipients of the Bharat – Covaxin vaccine (n=23) concluded that most neutralizing activity against B.1.617 was retained.

A fourth study reported an approximately three-fold decrease in neutralization activity by plasma from recipients of Pfizer BioNTech – Comirnaty vaccine (n=15) against B.1.617, and a limited two-fold decrease by convalescent sera from cases with severe COVID-19 (n=15). The same study showed that B.1.617.1 (with additional spike mutations R21T, and Q218H) mediates increased entry into certain human and intestinal cell lines, and was resistant to the monoclonal antibody Bamlanivimab; however, it was efficiently inhibited by Imdevimab and by a cocktail of Casirivimab and Imdevimab.

Outside of India, the United Kingdom has reported the largest number of cases sequenced as B.1.617 sub-lineages, and recently designated B.1.617.2 as a national variant of concern. This follows a recent steep increase in the number of cases sequenced as B.1.617 sublineages, and a national assessment that characterized B.1.617.2 as at least equivalent in terms of transmissibility as VOC B.1.1.7; however, they noted insufficient data to assess the potential for immune escape.

As of 5 May, the United Kingdom has reported 520 genomically confirmed B.1.617.2 cases (of which approximately two-thirds were domestically acquired), 261 confirmed B.1.617 cases (without further delineation), and nine confirmed B.1.617.3 cases.

Further robust studies into the phenotypic impacts of these variants, including impacts on epidemiological characteristics (transmissibility, severity, re-infection risk, etc.) and impact on countermeasures, are urgently needed.

WHO COVID-19 Weekly Epidemiological Update –  Data as received by WHO from national authorities, as of 9 May 2021, 10 am CET

 

WHO: B.1.617 Indian #coronavirus strain is now a Variant of Concern or VOC

 

Photo by Charlie Costello on Unsplash

NEJM “a recombination event between B.1.1.7 and B.1.526” #coronavirus variants

Examination of the SARS-CoV-2 sequences revealed that both patients were infected with variant viruses. Rapid identification of sequence variants by targeted PCR amplification showed that neither sequence precisely fit any known clade. Some of the substitutions in Patient 1 (T95I, del144, E484K, A570D, D614G, P681H, and D796H) were shared with B.1.526 (T95I, E484K, and D614G6), and three substitutions were shared with Patient 2 (in whom the variants T95I, G142V and del144, F220I, R190T, R237K, R246T, and D614G were detected). Whole viral genome sequencing revealed several additional substitutions, including D796H, present in a guanine–cytosine–rich region not identified by targeted PCR. These substitutions may decrease sensitivity to convalescent serum11 and may have some unique noncoding changes as compared with the clades first identified in Wuhan, the United Kingdom, and New York City.

Although more detailed analysis of whole-genome sequencing from Patient 1 was undertaken, we could not conclude that the variant in this patient was a Pango lineage because it was only present in a single person.

Its closest links on the phylogenetic tree were the variant first identified in the United Kingdom (B.1.1.7) and the variant first identified in New York City (B.1.526), but with considerable differences. It will be of interest to determine whether this may have resulted from a recombination event between B.1.1.7 and B.1.526, as has been recently reported for recombination between the B.1.1.7 lineage and the “wild-type” lineage first identified in Wuhan. Alternatively, shared substitutions may be the result of convergent evolution.

NEJM: Vaccine Breakthrough Infections with SARS-CoV-2 Variants

 

See also:

NEJM: In two #coronavirus vaccine breakthrough cases “examination of the SARS-CoV-2 sequences revealed that both patients were infected with variant viruses” .. “neither sequence precisely fit any known clade”

Nepal: new coronavirus daily case rate still closely tied to India’s outbreak

Nepal’s daily coronavirus case is still closely tracking that of its neighbour India, Nepal may also be in need of assistance with medical supplies and equipment to alleviate suffering within the next 7 days.

“Nepal Health Ministry says situation unmanageable as hospitals run out of beds The country’s health system cracks as coronavirus cases surge, crossing the 5,000 mark.” Kathmandu Post Report

See aso:

Nepal: rise in #coronavirus cases has similar trajectory to India driven by B117 and B1617

 

Household transmission of R.1 #coronavirus lineage with spike E484K mutation in Japan

In this study, we conducted genetic surveillance and identified R.1 lineage harboring E484K mutation in RBD by whole genome sequencing. The R.1 lineage was observed in three patients and transmitted among relatives in Japan. To investigate the global distribution of R.1  lineage, we next collected registration data from the EpiCoV of GISAID database [28]. As of March 5, 2021, a total of 305 samples of R.1 lineage had been registered from all over the world, with the majority spread in the USA (44%, 135/305) and Japan (28%, 84/305) (Figure 1A and Table 1). R.1 lineage was first reported in Texas, USA at the end of October 2020, and was found in Japan at the end of November 2020. The number of detected lineages has changed in a similar trend between the USA, Japan and other countries (Figure 1A), implying that SARS-CoV-2 R.1 lineage may have emerged in several regions at approximately the same time.

MedrXIV preprint: Household transmission of SARS-CoV-2 R.1 lineage with spike E484K mutation in Japan

R.1 details above from COV-lineages.org

 

See also:

USA: large covid-19 outbreak in Kentucky with R.1 #coronavirus lineage variant after vaccine breakthrough with Pfizer

 

 

Image by Masashi Wakui from Pixabay

NEJM: In two #coronavirus vaccine breakthrough cases “examination of the SARS-CoV-2 sequences revealed that both patients were infected with variant viruses” .. “neither sequence precisely fit any known clade”

Examination of the SARS-CoV-2 sequences revealed that both patients were infected with variant viruses. Rapid identification of sequence variants by targeted PCR amplification showed that neither sequence precisely fit any known clade. Some of the substitutions in Patient 1 (T95I, del144, E484K, A570D, D614G, P681H, and D796H) were shared with B.1.526 (T95I, E484K, and D614G6), and three substitutions were shared with Patient 2 (in whom the variants T95I, G142V and del144, F220I, R190T, R237K, R246T, and D614G were detected).

NEJM article  “Vaccine Breakthrough Infections with SARS-CoV-2 Variants”

 

Image by Daniel Roberts from Pixabay

Brazil: First confirmed death from #coronavirus REINFECTION reported

A 39-year-old Brazilian man who died of COVID-19 last month was suffering from a second bout of the illness, researchers said on Tuesday, making it the country’s first confirmed death from coronavirus reinfection. Both episodes involved variants with the E484K mutation.

The man, from Campo Bom in the southern state of Rio Grande do Sul, had a history of chronic cardiovascular disease and diabetes. He first tested positive on November 30 but details about his symptoms – if any – are unclear. Genomic sequencing revealed the P.1 variant.

The patient fell ill a second time about 3 months later and tested positive on March 11, according to researchers at Feevale University. His initial symptoms were fatigue and respiratory distress, but his condition worsened and he was transferred to the ICU, where he was intubated and died on March 19.

Genomic sequencing of the sample from the second episode revealed the P.2 variant, which is classified as a Variant of Interest.

 

 

Image by laridra from Pixabay