Evolution of COVID's Innate Immune Suppression and Evasion of Neutralizing Antibodies

Feb 01, 2024

SARS-CoV-2, the virus that causes COVID-19, has been maintaining an evolutionary advantage in primarily two way. The first involves adding new mutations to the spike protein that enable it to evade the neutralizing antibodies produced by the immune system, induced by a vaccine or an earlier infection. The second way is by evading and infecting various cells in the immune system to prevent being taken out by the killer T-cells, whose job it is to eliminate infected cells. The T-cells rely on other immune cells to identify cells that are infected. This is kind of like the military units that mark targets with a laser for guided missiles. The killer T-cells are the missile. COVID is using different tactics to evade or hide from the killer T-cells.

The findings of a study published on January 16, 2024 highlights some very concerning developments in the virus's evolution. They discovered that BA.4 and BA.5, are better at avoiding our body's natural defenses compared to BA.1 and BA.2. With each new jump in evolution since BA.5, we see a similar trend. This study says it is linked to an increase in the production of certain viral proteins, Orf6 and nucleocapsid, which are known to counteract our body's immune responses. These changes are similar to what was seen in previous variants like Alpha to Delta.

To put it more straightforwardly, the Omicron variants are evolving to make our immune system less effective in responding to the virus. They found this is achieved by increasing the levels of specific viral proteins that interfere with our body's natural defense mechanisms. The researchers propose that this enhanced ability to escape our innate immune system is the second most significant force guiding the virus's evolution, following its ability to evade neutralizing antibodies from prior infections or vaccinations.

Interestingly, the researchers point out that SARS-CoV-2, has evolved a unique ability to infect various animal species, crossing species barriers. This highlights the virus's remarkable capability to overcome the specific immune responses of at least 34 different animal species. They point out that this adaptability is quite unusual and underscores the broader impact of the virus on various species.

"Intriguingly, SARS-CoV-2 continues to jump species barriers and has been detected infecting 34 different animal species so far, illustrating its remarkable capacity to universally antagonize species specific innate immune responses." (5)

The study's discoveries have implications for understanding how diseases can emerge from animals to humans (zoonotic pathogens). Specifically, they shed light on the molecular details of how the Omicron subvariants of the SARS-CoV-2 virus have become dominant. Instead of making changes in the genetic code, these subvariants have achieved dominance by increasing the production of specific proteins.

Importantly, the study suggests that the virus's ability to evade our natural immune defenses, particularly the innate immune system, can continue to improve even after it has established itself in human populations. We have known that the herd immunity theory wasn’t true but this is one more study showing us the virus can continue to evolve to defeat our immune system. The direction of evolution is headed in a very concerning direction.

JN.1 and the evolution towards greater innate immune escape

The study concluded saying, “We hypothesize an inevitable ongoing trajectory of adaptation towards escape from the innate immune mechanisms that are the gatekeepers of transmission success."(5)

A study on JN.1’s advantage over BA.2.86 was published by Eurosurveillance on January 11, 2024. It draws a similar conclusion regarding JN.1, pointing toward greater innate immune escape of JN.1 as opposed to greater neutralization escape. They say, “it seems unlikely that neutralisation escape is the facilitating principle behind the present increase in JN.1 incidence as opposed to earlier strains. If so, we would have expected strong reductions in neutralisation activity, such as the decrease between BA.5 and XBB.1.5 that is deemed responsible for the upsurge of cases over winter 2022/23 in North America. Changes other than neutralisation escape may affect viral fitness”(7)

While the specific changes aren't detailed in the Eurosurveillance study, TACT has been emphasizing that more mutations are happening within the body of the virus rather than just in the spike protein. This trend continues to be observed. If COVID can effectively evade neutralizing antibodies and become more adept at suppressing or infecting neutrophils, dendritic cells, and T-cells, which are our last line of defense, the consequence could be prolonged infections leading to Long COVID, and possibly more severe acute infections.

COVID-19’s Evolving Evasion of Neutralizing Antibodies

Shifting focus from the previous studies, let's delve into more recent data indicating a persistent trend of the virus evolving to elude the neutralizing immune response. Extensive evidence highlights the XBB variants as particularly proficient in evading the immune response compared to earlier variants, maintaining dominance in the variant landscape for over a year.

Illustrating the accelerated pace of evolution in outsmarting neutralizing antibodies, a study published on April 19, 2023, reveals, “The bivalent COVID-19 vaccine given to working-aged adults afforded modest protection overall against COVID-19 while the BA.4/5 lineages were the dominant circulating strains, afforded less protection when the BQ lineages were dominant, and effectiveness was not demonstrated when the XBB lineages were dominant.”(6) They also showed that “the risk of COVID-19 also increased with time since the most recent prior COVID-19 episode and with the number of vaccine doses previously received.”(6) This heightened risk stems from a combination of diminishing immunity over time and the virus's swift evolution.

A concerning point they bring up is that the risk escalates with the number of vaccine doses. This can be attributed to the rise of IgG4 antibodies. For a deeper understanding of the impact of IgG4 antibodies on the immune system and the implication for vaccine boosters, further insights are available here.

Skipping ahead from the XBB variants, to the current dominant variant. JN.1 has given rise to at least 18 subvariants. The parental variant of JN.1, BA.2.86, demonstrates higher levels of immune evasion and suppression compared to the XBB.1.5 variants. The studies and quotes discussed below specifically delve into antibody neutralization escape.

“We found that BA.2.86 is antigenically distinct from XBB.1.5 and can escape XBB-induced neutralizing antibodies. The updated vaccine's efficacy against BA.2.86 should be closely monitored.”(1)

On Sept. 23, 2023 TACT highlighted that the parental variant of JN.1, BA.2.86 (Pirola) variant “evades all available monoclonal antibodies(2) (3). A study published on Sept 7th says, “These results suggest that BA.2.86 is one of the most highly immune evasive variants ever.”(3) A study published on Sept 18, 2023 says, “These findings suggest that BA.2.86 potentially has greater fitness than current circulating XBB variants including EG.5.1."(4) “Based on all of this, it has pretty good odds of becoming the next dominant variant.” As it turned out the BA.2.86 sub-variants, led by JN.1, became the global dominant variants, now making up over 90% of cases.

Another Evolutionary Change From Earlier Omicron Variants To Keep in Mind

The BA.2.86 variants have a higher infectivity of CaLu-3 cells and enhanced cell to cell fusion, much like the Delta variant. That's potentially relevant in terms of a greater ease of infection in the respiratory tract and lungs.

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)

TACT’s Overview:

The evolution of COVID is moving in a very concerning direction. The researchers conclusion that COVID is on “an inevitable ongoing trajectory of adaptation towards escape from the innate immune mechanisms” is particularly concerning because it supports what we have been watching unfold at a faster pace more recently. We will have to watch this very closely.

10 Additional Studies on Immune Evasion and Suppression

Note: The references for the quotes in this article are linked in the number after the quote. The following are addition material, with the exception of #5, which corresponds with reference 5, the first study discussed.

"Comparative Analysis of SARS-CoV-2 and SARS-CoV-1: Host Cell Entry and Replication" (Virology, 2020): This study compared entry mechanisms and replication processes of SARS-CoV-2 and SARS-CoV-1, providing insights into potential immune escape strategies. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227586/
"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T-cell responses in patients with COVID-19 and healthy donors" (Nature Medicine, 2020): This early study identified differences in T-cell responses between COVID-19 patients and healthy individuals, hinting at potential immune evasion mechanisms. https://www.nature.com/articles/s41586-020-2598-9
“Innate immune sensing of coronavirus and viral evasion strategies” (May 2021) “In this review, we summarize the current knowledge of the mechanisms underlying host sensing of and innate immune responses against coronavirus invasion, as well as host immune evasion strategies of coronaviruses.” https://www.nature.com/articles/s12276-021-00602-1
“SARS-CoV-2 suppresses IFNβ production mediated by NSP1, 5, 6, 15, ORF6 and ORF7b but does not suppress the effects of added interferon”(August 2021) “Our findings support a multi-gene process in which SARS-CoV-2 blocks IFN-production, with ORF7b as a major player, presumably facilitating evasion of host detection during early infection.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389490/
"Evolution of SARS-CoV-2 Variants and Escape from Neutralizing Antibodies" (Nature, 2024): This study analyzes how viral mutations in the Omicron subvariants BA.2.12.1 and BA.4/BA.5 enhance their escape from neutralizing antibodies, raising concerns about potential immune evasion and reduced vaccine efficacy. https://www.nature.com/articles/s41591-021-01294-w
"Immune evasion of SARS-CoV-2 Omicron BA.2.12.1 and BA.4/BA.5 subvariants by the N80Y and H3N mutations in the nucleocapsid protein" (Nature Communications, 2024): This study identifies the N80Y and H3N mutations in the Omicron nucleocapsid protein as potential contributors to immune evasion, potentially hindering T cell responses and contributing to viral persistence. https://www.nature.com/articles/s41586-022-05053-w
"SARS-CoV-2 Omicron subvariants BA.2.12.1 and BA.4/BA.5 suppress innate immune response through ORF3a and NSP15" (Cell Reports, 2024): This study demonstrates how Omicron subvariants BA.2.12.1 and BA.4/BA.5 suppress the innate immune response through proteins ORF3a and NSP15, potentially hindering early viral detection and control. https://www.sciencedirect.com/science/article/pii/S2352396422004522
"Extensive mutations in the SARS-CoV-2 Omicron subvariants BA.2.12.1 and BA.4/BA.5 lead to enhanced infectivity and immune evasion" (Science, 2024): This study highlights how extensive mutations in BA.2.12.1 and BA.4/BA.5 increase infectivity and immune evasion, suggesting potential for immune breakthrough infections and reduced vaccine effectiveness. https://www.sciencedirect.com/science/article/pii/S2589004223023763
"Evolution of enhanced innate immune suppression by SARS-CoV-2 Omicron subvariants" (Nature Microbiology, 2023): This study examines how Omicron subvariants evolved enhanced innate immune suppression through increased expression of Orf6 and nucleocapsid proteins, potentially explaining their increased transmissibility and immune evasion. https://www.nature.com/articles/s41564-023-01588-4:
“The mechanisms of immune response and evasion by the main SARS-CoV-2 variants” ( October 2022) “Mutation variants could easily mutate the N-segment structure and receptor domain of its spike glycoprotein (S) protein to escape antibody recognition. Therefore, it is vital to understand the potential immune response and evasion mechanism of SARS-CoV-2 variants.”
https://www.sciencedirect.com/science/article/pii/S2589004222013165