"We can’t take vaccine protection for granted. Fortunately, the vaccines we have in the U.S. are working exceptionally well. But it doesn’t mean they always will, as the virus mutates. So that’s a concern...we know there’s going to be further evolution of the virus. Hopefully, it won’t be that we see substantially worse versions of the virus than we’ve already seen. These variants are bad enough."
-Eric Topol MD, director and founder of the Scripps Research Translational Institute
High-resolution version of today's pandemic graphic: https://drive.google.com/file/d/1nhRI4htN57NWrLoIfKfrgeyon3RX5LyW/view?usp=sharing
BACKGROUND
We are seeing evolution in action. We are engaged in a game of dominance with the virus. The human experience in our recorded history is intertwined with the evolution of coronaviruses. That's how life on this planet works- mutations take place and if they confer advantages, they become predominant, whether it's a virus, a fish, your dog or humans. Mutations are a part of life and that's important to understand. COVID evolves new strategies, that's a given. That's expected.
Poor pandemic response, however, created the perfect environment for mutations to take place- unchecked spread, millions of infections worldwide- you could not have given this virus a better environment to evolve. Each new person infected is an opportunity for the virus to mutate. 99.995% of the time, the mutations do not offer any evolutionary advantage to the virus. But when there are thousands and thousands of new infections each day, that virus is literally getting more chances to pull the handle on the genetic slot machine to try and hit the jackpot. We are paying that price in a protracted battle that makes 2021 more difficult than 2020.
Two days ago, the Centers for Disease Control elevated the Delta sub-variant AY.3 to the status of Variant of Concern (VoC).
WHAT IS A VARIANT OF CONCERN?
VoCs demonstrate the following attributes:
-Evidence of impact on diagnostics, treatments, or vaccines
-Widespread interference with diagnostic test targets
-Evidence of substantially decreased susceptibility to one or more class of therapies
-Evidence of significant decreased neutralization by antibodies generated during previous infection or vaccination
-Evidence of reduced vaccine-induced protection from severe disease
-Evidence of increased transmissibility
-Evidence of increased disease severity
There are three known VoCs that are sub-variants of B.1.617.2 (Delta variant)- AY.1 (sometimes called "Delta Plus" in the news), AY.2, and now AY.3.
THE MUTATIONS OF AY.3
The first part of today's graphic comes from data on outbreak.info which is a multi-center effort led by the Scripps Research Institute to track and characterize COVID variants.
The top long horizontal bar is the SARS-CoV-2 genome with each color representing one of the viral genes and the characteristic (or defining) mutations in the colored circles above the genome schematic. Most of the viral genome is taken up by ORF genes- that stands for "Open Reading Frames" and in this virus, the ORF genes encode what are called non-structural proteins or nsp's. An nsp is something that isn't part of the actual structure of the virus but rather are proteins that facilitate viral replication once it has taken over the host cell.
Mutations in the ORF genes and how they impact the nsp's is an exciting area of research that I think will bear significant fruits in the future not just with COVID but with a diverse range of viruses.
The nucleocapsid gene encodes for a protein that forms a complex with the genetic material of the virus- it's a multifunctional protein that in coronaviruses (as well as other viral species) plays a role in the replication of its genetic material.
What has governed much of the discussion in pandemic response are mutations in the spike gene as this is the structure by which the virus does it's work. The second part of the upper part of today's graphic focuses on the spike gene and I've taken outbreak.info's data and compared the key spike mutations amongst the Delta sub-variants AY.1, AY.2, AY.3 (the subject of today's discussion) as well as the B.1.617.2 Delta variant itself.
There are three "mutations of interest" in this variant family:
K417N: The amino acid Lysine (K) is switched to Asparagine (N) at position 417. This is changing from an amino acid that is positively charged to a neutral amino acid. This mutation is an immune escape mutation, meaning it changes an antibody target so that a virus with this mutation can dampen our immune response.
L452R: The amino acid Leucine (L) is switched to Arginine (R) at position 452. This is changing from a smaller amino acid that his hydrophobic to one that is bigger with a positive charge. This mutation was found early on to improve the spike's ability to bind to the host ACE2 receptor which translates into increased transmission (more contagious). However, recent studies have shown this mutation also confers some immune escape capability.
P681R: The amino acid Proline (P) is switched to Arginine (R) at position 681. This mutation is outside of the receptor binding domain and appears to stabilize the spike, which improves its transmission, thereby making the virus more contagious.
Note that the new VoC (AY.3), lacks the K417N mutation. That would ordinarily translate into a possible reduction in transmission (so less contagious) but the epidemiological data suggests otherwise.
EPIDEMIOLOGY OF AY.3 IN THE UNITED STATES
The left side of the lower part of today's graphic shows the prevalence in genomic samples of B.1.1.7 Alpha, B.1.617.2 Delta, and AY.3 in the United States.
It's important to note that genomic surveillance in the United States is slow. The data is typically incomplete for the previous three weeks. It does take time to process, sequence and upload viral genomes to databases like the GISAID database, but two to three weeks looks like a turtle compared to the UK which has a very robust and impressive genomic surveillance effort that has sequences getting uploaded within a few days.
Any trajectory in the prior three weeks is incomplete data- so don't read anything on B.1.617.2 Delta possibly peaking recently. If anything, the data in the prior three weeks is an undercount if the trajectory has been increasing.
You can see from this data plot that there has been an increasing trend for AY.3. This indicates there is something about AY.3 that makes it more transmissible even though it lacks the K417N mutation. But do keep in mind that transmissibility in a community is a complex interaction of a number of factors that are inherent to the virus (mutations), inherent to the community (socio-economic factors and mask mandates), and inherent to the population (behaviors and vaccination uptake).
The US map on the right side shows where AY.3 has been found the most in the last 60 days (percent samples showing AY.3):
Mississippi- 58%
Missouri- 33%
Nebraska- 22%
Oklahoma- 20%
Kansas- 19%
Arkansas- 8%
Note that in the latest vaccination data, Mississippi, Alabama, Oklahoma, Louisiana and Arkansas are in the bottom ten states for vaccination rates. Mississippi is last at 33% and tied with Alabama as of this morning.
KEY POINTS
1/ AY.3 is the latest in a set of sub variants of B.1.617.2 Delta that likely emerged during the massive COVID surge in India earlier in the year. Keep in mind that case surges increase the likelihood of new variants emerging. While 100% prevention of variant emergence is not possible, limiting new infections limits the chances of new variants.
2/ While AY.3 does not have the K417N mutation seen in AY.1 ("Delta Plus") and AY.2, it does possess two mutations in the spike, L452R and P681R, that make it more contagious. In addition, new research has shown that the L452R mutation also confers immune escape capability.
3/ At the genetic level, AY.3 is very similar to B.1.617.2 Delta and it would be reasonable to expect this variant to behave similar to B.1.617.2 Delta. It would be like having a closely related sibling of B.1.617.2 Delta also out causing trouble. It's no coincidence that areas seeing increases in AY.3 are also areas seeing increases in B.1.617.2 Delta.
4/ Given their similarities at the genetic level, AY.3 and B.1.617.2 Delta on the same playing field is like a one-two punch from an epidemiological standpoint.
5/ Variants with increased transmissibility like AY.3 are best countered via public masking in indoor spaces regardless of vaccination status.
6/ The best countermeasures to AY.3 are the same countermeasures we have been pushing for against B.1.617.2 Delta- vaccination, vaccination, vaccination and VACCINATION. But no vaccine is 100% perfect which means we are going to see vaccine breakthroughs.
7/ Vaccination IS NOT A FREE PASS. The design endpoints of the vaccines were the prevention of hospitalization and death. We call this "disease-blocking". They are NOT "infection-blocking"- prevention of mild infection or asymptomatic infection. It is still possible for a vaccinated individual to be contagious, just less so than an unvaccinated individual.
8/ The CDC guidance on those vaccinated not needing masks ONLY works in places were community prevalence of the virus is low AND vaccination rates are HIGH. Unfortunately not many places in the United States meet that criteria.
PARTING THOUGHTS
Holy shit, people. I can't believe we're at this point again in this pandemic. Don't call me a hero if you're just going to ignore or disregard my learned experience and years of scholarship as a physician. I get high fives as a health care hero but then it flips right around and suddenly I'm an asshole for advocating for vaccination.
There is no equivalency of opinion in this pandemic. There is consensus based on scholarship and science and on the other side is just plain ignorant and wrong.
RELEVANT PANDEMIC POSTS
HE SAID WHAT? A WARNING FOR THE UNITED STATES (12 July 2021): https://www.facebook.com/1141591254/posts/10219175207947994
WHERE IS THE DELTA VARIANT SURGING? (11 July 2021): https://www.facebook.com/1141591254/posts/10219170740476310
COVID VARIANTS TABLE UPDATE (30 June 2021): https://www.facebook.com/jp.j.santiago/posts/10219119070944604
MAYO CLINIC GRAND ROUNDS: VACCINES AND VARIANTS (14 June 2021): https://www.facebook.com/jp.j.santiago/posts/10219031846404045
THE MOLECULAR BIOLOGY OF THE E484K MUTATION (10 May 2021): https://www.facebook.com/jp.j.santiago/posts/10218832046529173
IMMUNOLOGY 101: THE IMMUNE SYSTEM- REPOST/UPDATE (05 May 2021): https://www.facebook.com/jp.j.santiago/posts/10218801066954703
COVID VARIANTS OVERVIEW AND UPDATE (22 April 2021): https://www.facebook.com/jp.j.santiago/posts/10218722676514991
NEW COVID VARIANT OF INTEREST: B.1.617 (18 April 2021): https://www.facebook.com/jp.j.santiago/posts/10218699298170547
CASE SURGES CAN RESULT IN COVID VARIANTS (12 April 2021): https://www.facebook.com/jp.j.santiago/posts/10218657527966318
THE OVERVIEW & STATUS OF COVID VARIANTS (9 April 2021): https://www.facebook.com/jp.j.santiago/posts/10218637120816152
QUICK UPDATE: THE COVID FAMILY TREE (01 February 2021): https://www.facebook.com/jp.j.santiago/posts/10218211054244754
COVID MUTANTS: VARIANTS OF CONCERN (31 January 2021): https://www.facebook.com/jp.j.santiago/posts/10218204381877949
COVID MOLECULAR BIOLOGY: THE SPIKE (6 January 2021): https://www.facebook.com/jp.j.santiago/posts/10218019683340601