BA.2.86's Stealthy Rise to Dominance - Also Known as the Pirola Variants - Increased Immune Evasion and Suppression! Analyzing the BA.2.86 Surge Around the World
BA.2.86's Stealthy Rise to Dominance - Also Known as the Pirola Variants - Increased Immune Evasion and Suppression! Analyzing the BA.2.86 Surge Around the World
We are Taking a Deeper Dive Exploring the Pirola Variant's Potential Impact
The Pirola variant family, represented by BA.2.86, is rapidly expanding its presence, approaching an estimated 38% prevalence globally. This swift rise is notably displacing the XBB descendants. Before delving into the details of this trend, it's crucial to grasp that the immunity previously acquired against the XBB variants, commonly present in most individuals, is likely to be surpassed. This sets the stage for a significant increase in reinfections. Several recent studies provide in-depth insights into the mutations and evolutionary path of the BA.2.86 variants, showcasing their ability to outcompete other Omicron variants through heightened immune suppression.
This is especially important because the BA.2.86 sub-variants evade antibodies from XBB.1.5 to which the vaccines are targeted. It is likely that most people have been exposed to at least one of the XBB variants over the past year, but a study assessing the antigenicity and immune evasion capability of BA.2.86 against XBB.1.5-effective neutralizing antibodies revealed a concerning finding. BA.2.86 is antigenically distinct from XBB.1.5 and previous XBB variants, allowing it to escape XBB-induced neutralizing antibodies.
The prevalence of BA.2.86 sub-variants, primarily propelled by JN.1 (BA.2.86.1.1) and more recently by JN.4 (BA.2.86.1.4), may already be approaching a worrisome 40% (30%-50%) worldwide if the trends have continued since the most recent updates on worldwide prevalence. Unless another variant arises to slow down the BA.2.86 sub-variants, they will very likely become dominant, displacing the XBB variants descendents within the next week or two.
All of this and the information we will dig into in this article is very important to understand as we brace for another 4 to 6 weeks of exponential growth. The BA.2.86 sub-variants, particularly JN.1 and the recent JN.4, exhibit even higher immune escape and suppression than the parental BA.2.86 These variants will lead to weakened immune systems and likely become persistent infections in millions of people. People's immune system could remain weakened for many months making them more susceptible to influenza, RSV, norovirus and parainfluenza virus which are all increasing at an exponential rate in the U.S. and likely many other countries. The prevalence of these viruses is escalating exponentially, making each passing day and week riskier for infection or co-infections. Sadly, coinfections of COVID-19 with other viruses are likely to result in more severe outcomes.
We will explore exclusive insights in straightforward language derived from the latest studies. Gain essential information on the rate of transmission, genetic differences, immune evasion and suppression, potential symptom changes, and vaccine implications. Stay ahead with our in-depth analysis and be well-prepared in the quickly-evolving landscape of COVID-19. Subscribe now for a comprehensive understanding of the current situation.
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The latest W.H.O. global prevalence data shows a doubling every one to two weeks. Week 44 was at 8%. If it continued at that pace every week and a half we could be at around 38% with potential variations between 30% and 50%. If this is true then we will likely begin seeing some changes in symptoms and a faster pace of new infections and hospitalizations in the coming weeks.
The W.H.O. data, above, also shows that through week 44, other variants aren't expanding in prevalence anymore, with many declining. In fact, the only category besides BA.2.86 showing growth is unassigned variants. These are likely the newest BA.2.86 sub-lineages, like JN.4.
The sequencing based data, below, is through November 13, 2023. It also confirms this trajectory, showing the exponential curve turning up in multiple countries, reaching between 20% to 30%, two weeks ago. Most countries have little or no sequencing data but we can assume this displacement of the XBB descendants is happening worldwide.
JN.4, possessing heightened immune escape/suppression capabilities, is poised to act as a catalyst, akin to pouring gasoline on a fire, particularly towards mid-December. The graphic below, sourced from the ECDC, illustrates the escalating prevalence of JN.1 and, more recently, JN.4. The data suggests that JN.4 is anticipated to experience substantial gains in prevalence in the forthcoming weeks, potentially exacerbating the already concerning situation.
In the U.S., the CDC updated its Nowcast variant proportions on Monday November 27, 2023 and it shows the prevalence has tripled in the past 2 weeks. They are showing BA.2.86's expansion is largest in the Northeast with prevalence at 13.1% (7.7% - 21.1%) In the U.S. as a whole they are estimating prevalence at 8.8% (4.8% - 15.2%). We are likely at the higher end of that range.
If we accept the prevalence falls within, but on the higher side of that range, and that number doubles in prevalence every week, it would be at over 50% of all cases by mid-December. Historical data has consistently shown that once a new variant surpasses the threshold of 50% to 60% prevalence during an exponential growth period, there is a subsequent surge in hospitalizations and deaths. This trend underscores the importance of closely monitoring and understanding the trajectory of the BA.2.86 sub-variants to prepare for potential challenges in the coming weeks.
CBS news reports that a CDC spokesperson told them in an email that “ JN.1 is the most common version of BA.2.86 in the U.S. CDC projects BA.2.86 and its offshoots like JN.1 will continue to increase as a proportion of SARS-CoV-2 genomic sequences."
Recent Studies on BA.2.86 Variants and the Potential Implications
It is important to note that these studies haven’t had time for peer review yet, but they are from reliable sources and they provide important insights that are relevant now, and will likely be less relevant by the time they are peer reviewed. They are rather technical but we will break it down for you. This is important to understand because it explains why we are seeing these variants displace the XBB descendants as fast as we are and provides clues to how they may impact public health.
A very insightful study that has many implications towards what is about to unfold was published November 21, 2023. Here are some of the key findings, followed by important points quoted from the study.
Genetic Differences:
The BA.2.86 variant has different genetic instructions compared to other versions of the virus, with 36 unique mutations, including 32 substitutions, 3 deletions, and 1 insertion.
Some of these changes make it better at avoiding the body's natural defenses. Mutations like I332V, K356T, V445H, N450D, N481K, A484K, and 483del on BA.2.86's Receptor Binding Domain (RBD) are likely to enhance immune evasion.
The level of evolution in the BA.2.86 variant is comparable to how much the original Omicron evolved from the first COVID in 2019. The number of genetic changes in the BA.2.86 variant, compared to BA.2 and XBB.1.5, is similar to the number of changes observed in the initial Omicron strains when compared to the original Wu-Hu-1 strain.
Immune Evasion Mechanism:
The virus has developed a more efficient way to hide from the body's immune system, making it harder for our defenses to recognize and fight it.
Specific changes in the virus help it hide better and also affect how it attaches to our cells. We will dive into this in more detail in another study below.
Antibody Resistance:
The virus can resist the effects of the antibodies our body produces to fight it and prevent it from infecting our cells.
Even the antibodies that worked against other versions of the virus, like the XBB variants, may not work as well or not at all against this new variant.
BA.2.86 is antigenically distinct from XBB.1.5 and can escape neutralizing antibodies induced by XBB variants.
Vaccine Implications:
The BA.2.86 sub-variants might be different enough that vaccines, which were designed for older versions, may not work as effectively against it.
The body's response to the new variant is not as strong as it is to older variants, making it a bit trickier for our immune system to handle.
Evolutionary Perspective:
The virus is changing over time to become better at avoiding our immune system.
BA.2.86 may have evolved to outcompete other Omicron subvariants by enhancing immune suppression and balancing ACE2 binding through specific mutations like R493Q and F486P.
The mutations in BA.2.86 may be driven by immune pressure, and the evolution involves coordinated changes at different sites through epistatic effects.
Structural Insights:
The researchers looked closely at the virus's structure and found that certain changes in it make it harder for our immune system to fight.
These changes in the virus are why it's causing infections and issues even for people who were protected from earlier versions.
Computational modeling and experimental data indicate that specific mutations (e.g., N460K and F486P) in BA.2.86 are primary determinants of resistance to certain classes of RBD antibodies.
Other mutations (e.g., V445H, N450D, L452W, and A484K) block the binding of different classes of RBD antibodies.
The more technical direct quotes from the study are below for those interested or you can skip to the next section.
"BA.2.86 is also quite different from XBB.1.5 with 36 unique mutations including 32 substitutions, 3 deletions and 1 insertion. Along with the shared mutations with XBB.1.5 (T19I, 24-26del, A27S, G142D, 144del, G339H, G446S, N460K, and F486P), additional mutations I332V, K356T, V445H, N450D, N481K, A484K and 483del on BA.2.86’s RBD are likely to enhance immune evasion. Some of these mutations such as K356T, R403K, V445H, N450D, L452W, delV483 and A484K differentiate BA.2.86 from both BA.2 and XBB.1.5 sublineage and are unique to this specific variant."
"Overall, the number of different mutations in the BA.2.86 variant relative to BA.2 and XBB.1.5 is comparable to number of mutations in the initial Omicron strains relative to the original Wu-Hu-1 strain."
"We performed large scale structure-based mutational profiling of the S protein binding interfaces with distinct classes of antibodies that displayed significantly reduced neutralization against BA.2.86 variant. The results quantified specific function of the BA.2.86 mutations to ensure broad resistance against different classes of RBD antibodies. This study revealed the molecular basis of compensatory functional effects of the binding hotspots, showing that BA.2.86 lineage may have primarily evolved to improve immune escape while modulating binding affinity with ACE2 through cooperative effect of R403K, F486P and R493Q mutations."
“This study provided the first detailed account of the antibody evasion properties of BA.2.86 by evaluating the susceptibility to neutralization by a panel of 25 monoclonal antibodies that retained activity against BA.2, XBB.1.5 and EG.5.1 variants, with 20 of these antibodies targeting the four different RBD epitope classes. In particular, this study established that BA.2.86 variant can be resistant to neutralization by monoclonal antibodies to NTD, SD1, and also RBD classes 1, 2 and class 3 epitopes, and the evasion potential from RBD-targeted antibodies is larger than the corresponding immune escape exhibited by XBB.1.5 and EG.5.1 variants.”
“Antigenicity and immune evasion capability of the BA.2.86 subvariant was tested on a panel of XBB.1.5-effective neutralizing antibodies revealing that BA.2.86 is antigenically distinct from XBB.1.5 and previous Omicron variants and can escape XBB-induced neutralizing antibodies due to N450D, K356T, V445H, L452W, A484K, V483del, and A484K mutations. These findings suggest a complex interplay between the immune evasion capabilities of the BA.2.86 subvariant and the efficacy of certain vaccines. The neutralizing antibody responses against the BA.2.86 variant were considerably lower compared to the responses observed against the BA.2 variant but comparable to those observed against the XBB.1.5, XBB.1.16, EG.5, EG.5.1, and FL.1.5.1 variants.53 This study suggested that the BA.2.86 variant likely evolved directly from the less resistant BA.2 variant, rather than originating from the more highly resistant circulating recombinant variants. Functional studies examined whether BA.2.86 may exhibit growth advantages over other currently circulating Omicron variants, including EG.5.1 and the FLip variant, which contains the L455F and F456L mutation in the background of XBB.1.5 variant.54 Antigenic mapping showed that BA.2.86 may exhibit similar immune evasion as the XBB variants while it is more antigenically similar to early Omicron subvariants BA.1, BA.2, and BA.4/5 and antigenically distinct from the FLip variant."
"These results are consistent with the notion that most of the BA.2.86 mutations may have primarily emerged to improve the evasion of acquired immunity by Omicron variants rather than affecting the ACE2 binding. These findings lend support the evolutionary mechanism according to which emerging RBD mutations in the BA.2.86 variant (particularly N440K, N460K, T478K, N481K, A484K, and F486P) may be primarily driven by the immune pressure-driven changes while the improved ACE2 binding affinity relative to BA.2 is mediated via R403K and R493Q mutations. In general, the results indicated that latest Omicron subvariants including BA.2.86 may evolve to accumulate convergent immune escape mutations while exploiting potential synergistic epistatic effects of selected group of hotspots R403K, R493Q as well as L455F/F456L to enable sufficient ACE2-binding capability. Several lines of evidence indicated that the observed coordination of evolution at different sites is due to epistatic, rather than random selection of mutations."
"BA.2.86 lineage may have evolved to outcompete other Omicron subvariants by boosting immune suppression while balancing binding affinity with ACE2 via through compensatory effect of R493Q and F486P mutations."
"We performed systematic structure-based mutational scanning of the S protein binding interfaces with distinct classes of RBD antibodies that retained activity against BA.2 and XBB.1.5 variants but displayed significantly reduced or completely abolished neutralization against BA.2.86 variant. A comparison of the computationally predicted binding changes with the experimental data in which each of the BA.2.86 mutants was evaluated for antibody binding showed a robust quantitative agreement. We found that N460K and F486P are primary determinants of BA.2.86 resistance to class 1 and 2 RBD antibodies, while other BA.2.86 mutational positions (such as V445H, N450D, L452W and A484K) are recruited to block binding of class 3 RBD antibodies. These findings highlighted the significant role of BA.2.86 mutations that may have emerged to ensure broad resistance against different classes of RBD antibodies."
Reference: “Accurate Characterization of Conformational Ensembles and Binding Mechanisms of the SARS-CoV-2 Omicron BA.2 and BA.2.86 Spike Protein with the Host Receptor and Distinct Classes of Antibodies Using AlphaFold2-Augmented Integrative Computational Modeling” You can access the full study here.
JN.1 (BA.2.86.1.1) Specific Data on Increased Immune Evasion
A study, titled, "Fast evolution of SARS-CoV-2 BA.2.86 to JN.1 under heavy immune pressure", published on November 16, 2023 provides additional evidence that JN.1 (BA.2.86.1.1) and JN.4 (BA.2.86.1.4) will evade the XBB.1.5 immune response as well as the available monoclonal antibodies. It also says that it will outcompete the parental BA.2.86 and the current XBB descendants.
"We found that L455S of JN.1 significantly enhances immune evasion capabilities at the expense of reduced ACE2 binding affinity. This mutation enables JN.1 to effectively evade Class 1 neutralizing antibodies, offsetting BA.2.86's susceptibility and thus allowing it to outcompete both its precursor BA.2.86 and the prevailing variants HV.1 (XBB.1.5+L452R+F456L) and JD.1.1 (XBB.1.5+L455F+F456L+A475V) in terms of humoral immune evasion."
Examining BA.2.86 sub-variants Change of Tactics
A study on BA.2.86 from September highlighted an important point that we should be aware of and could impact how fast the virus is able to replicate and which cells are targeted, increasing the likelihood of the BA.2.86 sub-variants to target the nasal cavity and the lungs.
“Our data shown here suggest that BA.2.86 may have an increased tendency of using the plasma membrane route of entry, as opposed to the endosomal route of entry. Our molecular modeling suggests that mutations present in BA.2.86 and XBB variants can alter the Spike binding to ACE2 receptor, therefore impacting membrane fusion and entry of different target cells. For example, the V445H and R493Q mutations may enhance ACE2 binding by introducing hydrogen bonds between the Spike protein of BA.2.86/XBB.1.5 and the ACE2 receptor. Conversely, the F486P mutation present in XBB.1.5 weakens receptor binding by losing the hydrophobic interaction with F83 of ACE2. Whether or not BA.2.86 will have an increased lung tropism, thus enhanced pathogenesis compared to other Omicron variants, is unknown and needs to be carefully examined.”
Similar to the Delta Variant, the Pirola variant (BA.2.86) has Increased Cell Entry into CaLu-3 cells and Enhanced Cell to Cell Fusion
Delta Variant - “We show increased Calu-3 lung cell entry and enhanced cell-to-cell fusion of B.1.617.2, which may contribute to augmented transmissibility and pathogenicity of this variant. These results identify B.1.617.2 as an immune evasion variant with increased capacity to enter and fuse lung cells." (Published October 2021)
Pirola Variant -"The low cell-cell fusion activity of BA.2.86 between 293T and 293T-ACE2 cells was rescued when 293T and CaLu-3 cells were cocultured, which showed increased fusion for BA.2.86 as compared to XBB.1.5." (Published Sept 12, 2023)
Let’s break down what it means if these variants were to use a different route of cell entry and have an increased infectivity of CaLu-3 cells. To be clear, this is a hypothesized response based on the studies. We need more real world data to know for sure but it’s better to prepare for the worst, while we hope for the best.
Faster Entry and Persistent Infections:
The cell membrane route involves the virus directly fusing with the cell membrane to enter the host cell. This direct fusion might be a quicker process compared to the endosomal route, which involves the virus being taken up by the cell in a vesicle (endosome) before releasing its genetic material.
Increased risk of viral persistence. Combined with the greater immune evasion and suppression, faster entry means faster replication, more time to circulate, and infiltrate into viral reservoirs throughout the body and brain before T-cells can eliminate the infected cells.
Nose and Lungs:
Increased infectivity in the lungs and respiratory tract.
If the virus can enter lung cells more efficiently, it could lead to a higher concentration of the virus in the lungs, potentially resulting in more severe respiratory symptoms.
If these variants have an easier time infecting the epithelial cells in the nasal passages it could result in a greater number of individuals experiencing a runny nose or sneezing as early symptoms, and a greater chance of leading to anosmia (loss of smell).
Brain:
Calu-3 cells, which are often used as a model for respiratory epithelial cells, there might be an increased potential for the virus to affect the blood-brain barrier. A study published in Sept, 2021, says, "these results implicated that SARS-CoV-2 could directly infect endothelial cells, up-regulate MMP9 to degrade basement membrane, and transcytosis through BBB to release virus particles into the parenchyma" The parenchyma refers to the essential brain tissue responsible for carrying out various vital functions.
Impact on Symptoms:
If the virus gains entry into cells faster and replicates swiftly, it could accelerate the appearance of symptoms from the time of exposure. Early signs, beyond body aches, fever, chills, and headaches, may encompass an elevated probability of experiencing a runny nose, sneezing, mild cough, or breathing difficulties. Subsequent symptoms, potentially heightened by these variants, involve the loss of smell or taste, more severe respiratory manifestations, brain fog, and prolonged neurological and cognitive issues.
This is based on the molecular and structural changes observed in the BA.2.86 variant through these studies, but we are lacking the real-world data to know exactly how this will impact people. With that said, it doesn’t mean we can’t be aware of these potential impacts.
As shown in earlier posts, their remain many questions about the efficacy of the XBB.1.5 vaccines against the BA.2.86 variants. You can read more about those questions here.
TACT’s overview and forecast
Unfortunately, everything is unfolding as predicted in earlier updates. The only new variable that could impact us at this point is the JN.4 variant which increases the odds of a larger surge that could potentially rival that of the first Omicron surge at the end of 2021 into 2022. We have less testing and less restrictions than back then, and the original Omicron variant had a later start than the Pirola (BA.2.86) variants. Back in 2021, the most drastic increases in new cases came in mid-December and stopped increasing by the beginning of the second week in January in the U.S., the U.K, Australia and Canada.
This year we don’t have the testing to reflect on cases but we do have limited wastewater testing. The CDC shows that out of 1,727 testing sites, only 1,250 are have current data. The number of sites is to low to begin with, but why are hundreds not reporting data at this critical time of year? A large portion of the wastewater testing sites with current data are showing large, steep increases and the national average is higher than November 26, 2022.
Similarly, why is the CDC updating the variant proportions only every two weeks? This should be increased to every week when we know a new highly evolved variant is rapidly spreading during a period of exponential growth. BA.2.86 wasn’t showing on their variant proportions at the last reporting date and now it has jumped to 3rd nationwide, and 2nd most prevalent in Northeast states. That isn’t nearly enough warning with a variant that has explosive growth potential.
The CDC has refused to acknowledge or update the guidance to reflect that most people are contagious for at least 8 days, with many well beyond that, up to just over 20 days. These failures are costing people their quality of life, shortening lives and killing people. We are seeing variants with higher immune escape than ever before, increasing the risks to public health. The CDC and every public health agency in the U.S. and around the world are failing to warn their citizens of the risks or taking any serious actions to mitigate transmission. If you happen to know of any agency doing so, please share that info.
To show the accuracy and relevance of TACT’s previous forecasts and overviews we will review some of those posts. Keep in mind the ECDC, CDC and W.H.O just raised this to a variant of interest within five days of this writing.
TACT first reported on BA.2.86 August 18th. On September 30th stated, “BA.2.86 prevalence is still quite low but it is here and it is spreading at a faster pace. All of this data points to it having a very real chance of becoming a serious problem going into November and December.” From the October 15, 2023, TACT forecast, “We should prepare for a surge similar to the 2021/2022 Omicron surge that could extend into the first or second week of January. The most likely scenario is that the Pirola family surge will be milder than 2021/2022 but substantially higher than the 2022/2023 surge. Starting in mid-January, we should see exponential decay continuing into February.”
The important message from the November 5th update still holds true, “Cumulative data suggests that the JN.1 sub-variant of BA.2.86 has the potential to become a global dominant variant. While it's early, the current trends indicate its ascent coincides with the exponential spread of COVID, flu, and RSV, presenting a high-risk scenario for millions. Given our limited understanding of this variant's impact on children's developing brains (and immune systems), taking immediate steps to reduce the transmission of airborne viruses in schools and safeguarding healthcare settings is of critical importance.” The rise of BA.2.86, as suggested by this articles catchy title, may seem stealthy to many, but for those following this publication, it was anything but.
COVID is predictable. COVID is preventable.
T.A.C.T. (Together Against COVID Transmission)
Please share any insights, additional information, corrections, ideas, or what’s happening where you are.
I found you just in time for the next big surge. I am 76 and I am very careful and I can protect myself, but I need good information.
Hi TACT...Lots of stuff we could discuss, but I'm going to leave you with this little gem from German Health Minister Lauterbach in case you hadn't seen it. This is a year old and Mr. Lauterbach now claims he was 'misquoted' (sure pal) as someone must have leaned on him HARD.
https://www.archyde.com/studies-give-cause-for-concern-lauterbach-warns-of-incurable-immune-deficiency-caused-by-corona/
Keep your keen eyes alert to the XDD swarm.