Omicron

entire page in work and subject to changes.

not only explorative but partly speculative

only summary and some refs are available

Summary
Hypotheses for the high Transmission Rates
References

Summary

Omicron is a SARS-CoV-2 lineage. However it has features different from all previous lineages (usually referred as variants) of SARS-CoV-2:

Symptoms: Rather than a typical respiratory disease, there are reports for more systemic symptoms such as night sweets and tiredness. Cough is still observed though.
Transmission and Immune Status:
- Previous infections provide a lower protection compared to the protection they provided against previous variants.
- The transmission rate observed is much higher than the rates observed for the previous variants. This is the case in many different settings: household transmission, social events and populations level increase in cases. Noteworthy, many locations where very high transmission rates are observed have high vaccination rates.
- For vaccines, early data indicate, that initially there is a protection, but after a few months there seems to be an increased risk of infection.
- Acquired immunity (infection and vaccines) still protects against severe disease once infected.
Mutation Distribution: Omicron has a lot of mutations in the spike of which a surprisingly large number in RBD. In the NTD part of the spike there is also an insertion which hasn’t been seen before. NSP6 mutated also at an increased mutation rate. The mutation rate in the other genes seems to be at a comparative level as observed for other lineages.
Biology of Omicron
- Observations for the Cell Tropism and Entry: Omicron enters cells mainly through the endosomal pathways where the priming occurs by endosomal proteases such as cathepsins. Omicron is not well primed at the cells surface by TMPRSS2. Accordingly Omicron infects cells through by the endosomal pathway where the spike is primed by cathepsins. Since lungs cells support mainly the cell surface pathway with TMPRSS2 priming, other lineages such as Delta infects lungs cells much better than Omicron. Also cell cell fusion requires cell surface priming of the spike e.g. by TMPRSS2 and accordingly Omicron hardly induces cell fusion.
- Observed Tissue Tropism: In agreement with the cell tropism, Omicron infects less the lungs than the previous variants as animal experiments and the observed disease patterns indicate.

A central part of this chapter, is the hypothesis that Omicron can replicate in immune cells such as macrophages. Such an immune cell tropism would explain many observations such as the high attack rates (immune cells actively take up virions), the changed symptoms (immune cell produce different cytokines) and increased infection rates a few months after systemic immunization. The negative vaccines efficacies a few months after vaccination can be attributed to increased phagocytosis induced by spike binding antibodies.

The explanation that Omicron escapes of spike targeting antibodies, just explains competition advantages over other variants such as Delta in populations with high prevalence of antibody based immunity. However it does not explain the high attack rates, the changed symptoms and negative vaccine efficacies.

As noted antibodies inducing phagocytosis seem to enhance the probability of infection and possibly also enhance the disease. However other parts of acquired immunity such as antibodies inducing cellular cytotoxicity or T cells can also protect and ameliorate the disease. Observations that upon infection, acquired immunity still has protective effect against severe disease can be due to these mechanisms. The immune mechanisms induced differ from natural infection and the different vaccines, for example natural infection induces both local and systemic T cells and intramuscular vaccination mostly induces systemic T cells. The antibody effector functions also differ.

Initially this chapter was posted to argue a changed tropism of Omicron towards immune cell infection. This hypothesis is still part of the chapter, though major reworkings are in progress.

Hypotheses for the high Transmission Rates

Hypothesis Immune Cell Infection

How an altered Tropism explains the Observations

One possible explanation for the above observations, is a shift of tropism away from differentiated respiratory tract epithelial cells towards immune cells such as macrophages:

Symptoms: Symptoms such as night sweets and tiredness are frequently observed for microorganisms infecting macrophages such as HIV, some flaviviruses and tuberculosis.
Transmission: The higher infection rates can be explained by S targeting antibody mediated infection enhancement (AIE): Virions opsonized with S targeting antibodies are taken up by phagocytes such as macrophages (F_c induced phagocytosis). Since the phagocytes actively move around to take up virions, the chances for phagocytosis are much higher than a match with ACE2 on an airway epithelial cell through undirected movement.
Acquired Immunity:
- Natural Infections: The protection is lowered compared to other variants but still available. A possibly explanation is, that while ABs inducing phagocytosis increase the infection rates, T cells and ABs inducing cellular cytotoxicity (antibodies targeting e.g. the S2 part of S, the N protein or some NSPs) still provide protection both systemic and throughout the respiratory tract.
- Vaccines: First some protection against infection is observed, however after a few months an increased risk of infection is observed compared to unvaccinated. This suggests AIE by F_c induced phagocytosis since the antibody types inducing phagocytosis decrease slower than the neutralizing activity and antibodies inducing cytotoxicity. That despite AIE the diseases mostly are neither severe nor systemic is possibly due to systemic T cells protecting the alveoli, the lymph system and the blood.
Mutation Distribution: The spike of coronaviruses is a key determinant which cells they enter and a changed tropism would explain the high number of mutations. The mutation distribution with many mutation in the RBD indicates a relaxed evolutionary pressure on the RBD, alternate entry pathways could have enable this high mutation rate. The insertion in NTD of domain of the spike is possibly acquired from the human coronavirus E229, a human coronavirus which frequently enters macrophages. NSP6 infers with autophagy pathways, so mutations in this protein possibly enable escape from intracellular vehicles (possibly endosomes in phagocytes, to check).

Antibody dependent disease enhancement (ADE) denotes when antibodies increase the disease. ADE is mainly observed for RNA+ viruses such as flaviviruses (e.g. dengue virus) and some coronaviruses (e.g. feline coronavirus). ADE can be due to antibody induced infection enhancement (AIE) i.e. higher viral loads, an increase immune pathology without increased viral loads or both combined. Here AIE used, since the observations indicate that the infection probability is increased by spike targeting antibodies.

A change of tropism towards macrophages is possible in theory since other human coronaviruses such as MERS and E229 can infect and replicate inside macrophages. Additionally a tropism for macrophages is observed for animal coronaviruses. Arteriviruses which also belong to the order of Nidovirales and share key molecular features even mainly have a tropism for myeloid immune cells [to confirm and cite].

Hypothesis Immune Escape Only

How Escape of Spike binding Antibodies could explain the Observations

The spike mutations enable Omicron to escape spike binding antibodies: Antibodies induced by previous variants or by vaccines based on previous variants bind much less to the Omicron spike than all other lineages so fare. This reduces the protection by spike targeting antibodies.

For muscular administrated vaccines, for which spike targeting antibodies are likely central to the immunity in the conducting respiratory tract, the protection against infection in the conducting airways likely significantly decreases or even vanishes (a protection in the lungs,i.e. against pneumonia, through circulating T cells recognizing conserved epitopes in the S2 part of the spike is still excepted).
For naturally acquired immunity a reduction of protection occurs since one part of natural immunity are spike targeting antibodies. The magnitude of this effect depends how important spike targeting antibodies are for naturally acquired immunity.

Likelihood of the Explanations

Likelihood by Immune Protection Mechanism

The likelihood of the possible explanations depends by which mechanism(s) the acquired immunity works both for vaccines and natural infections. Acquired immunity can protect through:

Antibody mediated immunity. Antibodies can provide protection through neutralizing activity (spike binding only and mostly RBD) and by opsonizing to virions for phagocytosis (spike binding only), antibody-dependent cellular cytotoxicity (Chapter Antibodies) or induce an other immune mechanisms such as the complement or cytokines production.
T cells mediated immunity. One form of protection by T cell immunity are cytotoxic CD8 cells which detect and eliminate infected cells. In the conducting airways (bronchi, trachea, to some extent URT) these are mostly tissue resident T cells [to confirm and cite]. The alveoli are additionally supervised by T cells circulating in the blood [to cite].

For coronavirus immunity all the above mechanism are observed. The relative importance of the different mechanisms is not quite clear (yet) however. Natural infection induce both antibodies and tissue resident T cells. There is good evidence that tissue resident T cells play an important role. Explanation 2 though, is only likely when the protection is predominately provided by spike binding antibodies, else there is not reason that Omicron escapes natural immunity significantly better than other variants: 1) Omicron just mutated much in the outer part of the spike but not in other antigenic sites targeted by naturally acquired immunity such as the N and the E protein. 2) for the previous variants such as alpha, beta and delta hardly any protection reduction of natural immunity has been observed despite these variants also have some escape mutations.

=> Hypothesis immune escape only is unlikely.

Likelihood by the observed Transmission Rates

The extremely high attack rates observed e.g. at single dinner over 70% of the participants got infected. Such high attack rates are more likely and enabled for viruses infecting immune cells: The infections do not depend anymore on the virus randomly match with an epithelial cell but rather the immune cells actively take up the virions.

Virions getting moved in the respiratory tract and infection upon matched with a suitable cells is like throwing balls at random and see how many hit go into the goal. When virions can infect collecting immune cells, the virions are still are subject to movements they can’t control, however the immune cells actively move around and collect them. => Each collected virion is a potentially a goal from a virus perspective.

=> Hypothesis Immune Cell Infection is likely.

Significance of a changed Tropism

A change of tropism towards immune cells and upper respiratory tract cells changes the disease cause profoundly:

Acquired immunity is not necessarily helpful anymore. Since if Omicron can replicate well in immune cells, antibody mediated uptake can yield to an increased replication which is a form of antibody-dependent enhancement (ADE).
The disease course can change:
- Epithelial cell infections can go unnoticed until a high viral is reached. A very high number of viruses in the lungs, in the late stage of the disease, then can cause ARDS mainly through inflammation. This is the main disease pattern observed for SARS-CoV-2 variants until Omicron.
- Viruses infecting immune cells usually cause symptoms earlier since immune cells have quite sensitive pathogen recognition receptors, however the viruses can travel with immune cells, cause systemic disease and infect various locations throughout the body.
  
  (speculative comment) For immunized people, cross reactive T cells likely prevent a systemic spread and keep the infections localized to the respiratory tract. Cross reactive T cells are induced by natural infection and most (all?) approved Covid vaccines (‘mRNA’ vaccines, adeno virus vaccines and inactivated virus vaccines all induce solid T cell immunity [to cite]). For people without antibodies, Omicron may not be able to infect immune cells well and thus an infection is possibly less likely. Additionally 1) the epithelial cell layer may prevent a systemic spread since coronavirus virions are quite large, 2) Omicron has acquired this tropism fairly recently and possibly cannot (yet) evade the strong innate detection mechanism of immune cells well.

The SARS-like disease patterns could disappear and omicron induced disease could become prevalent.

References

Refs Biology of Omicron

Zhang

Zhang X, Wu S, Wu B, Yang Q, Chen A, Li Y, Zhang Y, Pan T, Zhang H, He X. SARS-CoV-2 Omicron strain exhibits potent capabilities for immune evasion and viral entrance. Signal Transduction and Targeted Therapy. 2021 Dec 17;6(1):1-3.

Summary Jawaid

Jawaid, M. Z., Baidya, A., Mahboubi-Ardakani, R., Davis, R. L., & Cox, D. L. (2021). Simulation of the omicron variant of SARS-CoV-2 shows broad antibody escape, weakened ACE2 binding, and modest increase in furin binding. bioRxiv.

Summary He

He X, Hong W, Pan X, Lu G, Wei X. SARS‐CoV‐2 Omicron variant: characteristics and prevention. MedComm.

Hu

Hu, J., Peng, P., Wu, K., Long, Q. X., Chen, J., Wang, K., … & Huang, A. L. (2021). Reduced infectivity but increased immune escape of the new SARS-CoV-2 variant of concern Omicron. bioRxiv.

AB evasion but less efficient replication in

Refs Omicron Treatment

Chong

Chong Z, Karl CE, Halfmann PJ, Kawaoka Y, Winkler ES, Yu J, Diamond MS. Nasally-delivered interferon-λ protects mice against upper and lower respiratory tract infection of SARS-CoV-2 variants including Omicron 2.

Summary Bojkova

Bojkova, D., Widera, M., Ciesek, S. et al. Reduced interferon antagonism but similar drug sensitivity in Omicron variant compared to Delta variant of SARS-CoV-2 isolates. Cell Res (2022). https://doi.org/10.1038/s41422-022-00619-9

Refs Omicron Spike Binding by Simulations

Glocker

Glocker, M. O., Opuni, K. F., & Thiesen, H. J. (2021). Compared with SARS-CoV2 wild type’s spike protein, the SARS-CoV2 omicron’s receptor binding motif has adopted a more SARS-CoV1 and/or bat/civet-like structure. bioRxiv.

less binding

Fratev

Fratev, F. (2021). The High Transmission of SARS-CoV-2 Omicron (B. 1.1. 529) Variant is Not Only Due to Its hACE2 binding: A Free Energy of Perturbation Study. bioRxiv.

less binding

Kumar

Kumar S, Thambiraja TS, Karuppanan K, Subramaniam G. Omicron and Delta Variant of SARS‐CoV‐2: A Comparative Computational Study of Spike Protein. Journal of Medical Virology. 2021 Jan 1.

Analysis of molecular properties by several computational tools. Docking energies using HEX tool predict -540 for Omicron, -530 for delta and -500 for wild type => Omicron better binding. More alpha helices for delta (23.5%) compared to 22% for delta.

Sadek

Sadek, A., Zaha, D., & Ahmed, M. S. (2021). Structural Insights of SARS-CoV-2 Spike Protein from Delta and Omicron Variants. bioRxiv.

Carter

Carter C, Airas J, Parish CA. Wild Type and Omicron SARS-CoV-2 Spike Receptor Binding Domains Bind Similarly to the Human ACE2 Receptor: An MM-GBSA Study.

similar binding

Refs Tropism of Omicron

Summary HKUMed

HKUMed finds Omicron SARS-CoV-2 can infect faster and better than Delta in human bronchus but with less severe infection in lung, December 2021 https://www.med.hku.hk/en/news/press/20211215-omicron-sars-cov-2-infection

A tropism for the bronchi and less for the lungs is good since a severe disease is much when the lungs are infected. In view of the hypothesis of immune cell infection, this study does not tell a tropism for macrophages, it just indicates a changed tropism. A tropism for the bronchi could explain some vaccine escape since they are farther away from systemic immunity. Tough escaping natural immunity is unlikely by a tropism for the bronchi alone.

Chan

Chan MC, Hui KP, Ho J, Cheung MC, Ng KC, Ching R, Lai KL, Kam T, Gu H, Sit KY, Hsin M. SARS-CoV-2 Omicron variant replication in human respiratory tract ex vivo.

Marais

Marais, G. J. K., Hsiao, N. Y., Iranzadeh, A., Doolabh, D., Enoch, A., Chu, C. Y., … & Hardie, D. R. (2021). Saliva swabs are the preferred sample for Omicron detection. medRxiv.

Zhao

Zhao H, Lu L, Peng Z, Chen LL, Meng X, Zhang C, Ip JD, Chan WM, Chu AW, Chan KH, Jin DY. SARS-CoV-2 Omicron variant shows less efficient replication and fusion activity when compared with delta variant in TMPRSS2-expressed cells: Omicron variant replication kinetics. Emerging Microbes & Infections. 2021 Dec 27(just-accepted):1-8.

Summary Willett

The hyper-transmissible SARS-CoV-2 Omicron variant exhibits significant antigenic change,vaccine escape and a switch in cell entry mechanism https://www.gla.ac.uk/media/Media_829360_smxx.pdf

The study does bundles different laboratory and epidemiological investigations, there the findings are grouped by investigations type (and not by methods/results as normally)

Antibody Binding: Omicron escapes antibodies well

Acquired Immunity Effects: The vaccines effects are determined by test-negative case control design.s

Cell Entry Route: Omicron enters mostly through the endosomal activated by cathepsins and not through the cell surface route activated by TMPRSS2.

Sato

Sato K, Suzuki R, Yamasoba D, Kimura I, Wang L, Kishimoto M, Ito J, Morioka Y, Nao N, Nasser H, Uriu K. Attenuated fusogenicity and pathogenicity of SARS-CoV-2 Omicron variant.

Refs Animal Models

Summary Diamond

Diamond, Michael & Halfmann, Peter & Maemura, Tadashi & Iwatsuki-Horimoto, Kiyoko & Iida, Shun & Kiso, Maki & Scheaffer, Suzanne & Darling, Tamarand & Joshi, Astha & Loeber, Samantha & Foster, Stephanie & Ying, Baoling & Whitener, Bradley & Floyd, Katharine & Ujie, Michiko & Nakajima, Noriko & Ito, Mutsumi & Wright, Ryan & Uraki, Ryuta & Simon, Viviana. (2021). The SARS-CoV-2 B.1.1.529 Omicron virus causes attenuated infection and disease in mice and hamsters. 10.21203/rs.3.rs-1211792/v1.

Background

Collaboration of different research groups of the SARS-CoV-2 Assessment of Viral Evolution (SAVE) program of the National Institute of Allergy and Infectious Diseases (NIAID) in the US.

Methods

Replication of B.1.1.529 (Omicron) and other SARS-2 strains such as B.1.351 (Beta, HP01542), B.1.617.2 (Delta, strain hCoV-19/USA/WI-UW-5250/2021) in

in different mice: 129 mice at different ages, C57BL/6 mice, K18-hACE2 mice (human ACE2)
in different hamsters: syrian hamsters with native ACE2 and hACE2 hamsters

Results in Short

In mice, Omicron causes attenuated disease compared to other variants, the Omicron viral loads are similar in the lungs and the nose.
In hamsters, the the viral loads in the nose are similar to WT-like SARS-2 strains but the viral loads are much lower in the lungs compared to WT-like strains and compared to the viral loads in the nose. Thus in hamster, similar to observations in humans, the tropism shifts away from the lungs.

Results

Figure 1 shows the results for mice:

Wild-type vs native ACE2: Beta replicates better in ACE2-wild-type mice than Omicron, which indicates that Omicron may not bind that well to ACE2-wild-type (absolute values and relative percentages to other strains which are all similar). The viral loads are more similar between Omicron and Beta in K18-hACE2 mice (Figure 1g)
Viral Load in the nose vs lungs: In mice (but not in hamsters Figure 2), the viral load of Omicron is higher in the lungs than in the nose (absolute values and as relative to WT-like S2 strains) both for ACE2-wild-type mice and hACE2 mice.
Disease observed: Omicron caused milder diseases even in hACE2 mice where similar viral loads have been observed.

Figure 2 shows the results for syrian and hACE2 hamsters:

Wild-type vs native ACE2: hACE2 has not much effects on the viral loads of WT-like SARS-2 strains and Omicron.
Viral Load in the nose vs lungs: Omicron replicates to similar titres as WT-like SARS-2 strains, however Omicron replicates less well in the lungs both compared to WT-like strains and in absolute values (except in one experiment, where the viral load in the lungs are higher than in the nose, Figure 2f).
Disease observed: Omicron causes attenuated diseases:
- nearly no weight loss (a-e and l)
- lower CT scores (k)
- higher survival (m)
- Pathology by microscopy (Figure 3)

Summary Shuai

Shuai H, Chan JF, Hu B, Chai Y, Yuen TT, Yin F, Huang X, Yoon C, Hu JC, Liu H, Shi J. Attenuated replication and pathogenicity of SARS-CoV-2 B. 1.1. 529 Omicron. Nature. 2022 Jan 21:1-.

Summary partly based on an earlier version, only partly checked for updates

Methods

How Omicron behaves (accessed by RdRp gene copies, sgRNA of the E gene, virus titres) in compared to WT, Alpha, Beta, Delta with

In vitro experiment with different cells: Calu3, Caco2, VeroE6 with and without TMPRSS2 and 293T-ACE2 with and without TMPRSS2.
In vivo experiment with K18-hACE2 transgenic mice and wildtype C57B6 mice.

Results in Short

Omicron enters cells not via TMPRSS2 priming and in agreement replicates less in cells lines where TMPRSS2 priming is common such as Calu3 (lung cells) and Caco-2.
In mice, Omicron causes an attenuated disease and replicates less than other variants both in the nose and the lungs.

Results

Figure 1:

Omicron replicates less well in the cell lines Calu3 and Caco2 and similarly in VeroE6 compared to WT, Alpha, Beta, Delta.
The cell viability (VeroE6-TMPRSS2) is highest in Delta and Omicron.

Figure 2: TMPRSS2 expression on 293T-ACE2 or VeroE6 increases the entry of pseudoviruses with spikes from WT, Alpha, Beta and Delta, however TMPRSS2 expression hardly affects entry with Omicron spikes. In agreement camostat has limited effects on entry.

Figure 3 and 4: Omicron in K18-hACE2 mice:

Omicron replicates less in both in nasal turbinate and the lungs compared to WT and Delta which replicate similar. Accessed by RdRp gene copies, subgenomic E and infectious titres which all produce similar results. Similarly, lower replication of Omicron compared to Alpha is observed in C57B6 wildtype mice as shown in Extended Data Fig. 2..
Also IP-10 and IFN gamma are lower in Omicron than Delta which in turn are lower than WT.
Weight loss and death rate from high to low: Alpha, WT, Beta, Delta, Omicron (Figure 3 e and f).
Omicron induces less lung pathology (Figure 4).

=> In mice, Omicron replicates less and causes a less severe disease.

Summary Yuan

Yuan, S., Ye, Z. W., Liang, R., Tang, K., Zhang, A. J., Lu, G., … & Chan, J. F. (2022). The SARS-CoV-2 Omicron (B. 1.1. 529) variant exhibits altered pathogenicity, transmissibility, and fitness in the golden Syrian hamster model. bioRxiv.

“One Sentence Summary: The novel SARS-CoV-2 Omicron variant, though less pathogenic, is highly transmissible and outcompetes the Delta variant under immune selection pressure in the golden Syrian hamster COVID-19 model.”

Experiment 1: Pathogenicity of Omicron versus Delta in Syrian Hamsters

(key findings shown in Figure 1 in the paper)

Methods Experiment 1:

At 0 dpi,intranasal inoculation with 100μL of DMEM containing 10^5 PFU of SARS-CoV-2.
At 2 dpi, 4 dpi, and 7 dpi (n=5 per variant per time-point) determine
- the viral load by qRT-PCR, virus titer by plaque assay
- histopathology by immunofluorescent staining.
- body weight and clinical score
- cytokines produced

Experiment 2: Contact and non-contact transmissions of the Omicron and Delta variants in Syrian Hamsters

(key findings shown in Figure 2 in the paper)

Both variants readily transmit via contact reaching 100% in the experiment setting for both variants
High aerosol transmission and a tendency to be 10% higher for Omicron.

Experiment 3: Competition assays between Omicron and Delta

(key findings shown in Figure 3 in the paper)

IN VITRO: In lung derived Calu-3 cells, Delta outcompetes Omicron without antibodies (Fig 3 A and B). Omicron outcompetes Delta in the presence of antibodies against WT-like strains (Fig. 3 D)
IN VIVO: Methods: Naive and vaccinated hamsters (by inactivated virus vaccine) were six index hamsters were infected intranasally with 10^5 PFU of a mixture of both viruses (1:1 ratio). Replication by viral load at 2 dpi and transmission by co-housing for 4 hours at 2 dpi. Results: In naive Syrian hamsters, Delta outcompetes Omicron by higher viral replication and onwards transmission to naive hamsters. In vaccinated index hamsters Omicron outcompetes Delta with higher replication and slightly higher onwards transmission to naive hamsters. // The viral loads of Delta were much higher in naive index hamsters at 2 dpi (Figure 3 I), which can explain the higher Delta transmission when co-housed in naive animals.

Refs AB Binding and Neutralization

Wilhelm

Wilhelm, A., Widera, M., Grikscheit, K., Toptan, T., Schenk, B., Pallas, C., … & Ciesek, S. (2021). Reduced Neutralization of SARS-CoV-2 Omicron Variant by Vaccine Sera and monoclonal antibodies. medRxiv.

Roessler

Roessler, A., Riepler, L., Bante, D., von Laer, D. and Kimpel, J., 2021. SARS-CoV-2 B. 1.1. 529 variant (Omicron) evades neutralization by sera from vaccinated and convalescent individuals. medRxiv.

Wang

Wang, X., Zhao, X., Song, J., Wu, J., Zhu, Y., Li, M., … & Wang, P. (2021). Homologous or Heterologous Booster of Inactivated Vaccine Reduces SARS-CoV-2 Omicron Variant Escape from Neutralizing Antibodies. bioRxiv.

Refs T Cell Immunity

Keeton

Keeton, R., Tincho, M. B., Ngomti, A., Baguma, R., Benede, N., Suzuki, A., … & Riou, C. (2021). SARS-CoV-2 spike T cell responses induced upon vaccination or infection remain robust against Omicron. medRxiv.

Naranbhai

Naranbhai V, Nathan A, Kaseke C, Berrios C, Khatri A, Choi S, Getz MA, Tano-Menka RK, Ofoman O, Gayton AC, Senjobe F. T cell reactivity to the SARS-CoV-2 Omicron variant is preserved in most but not all prior infected and vaccinated individuals. medRxiv. 2022 Jan 1.

Jergovic

Resilient T cell responses to B.1.1.529 (Omicron) SARS-CoV-2 variant Mladen Jergovic, Christopher P. Coplen, Jennifer L. Uhrlaub, Shawn C. Beitel, Jefferey L. Burgess, Karen Lutrick, Katherine D. Ellingson, Makiko Watanabe, Janko Nikolich-Žugich medRxiv 2022.01.16.22269361; doi: https://doi.org/10.1101/2022.01.16.22269361

Choi

Choi, S.J., Kim, DU., Noh, J.Y. et al. T cell epitopes in SARS-CoV-2 proteins are substantially conserved in the Omicron variant. Cell Mol Immunol (2022). https://doi.org/10.1038/s41423-022-00838-5

Refs Genetics of Omicron

Durmaz

Structural-bioinformatics analysis of SARS-CoV-2 variants reveals higher hACE2 receptor binding affinity for Omicron B.1.1.529 spike RBD compared to wild-type reference.

Venkatakrishnan

Venkatakrishnan AJ, Anand P, Lenehan PJ, Suratekar R, Raghunathan B, Niesen MJ, Soundararajan V. Omicron variant of SARS-CoV-2 harbors a unique insertion mutation of putative viral or human genomic origin.

The proposed insertion mechanism is visualized in a (5-Minutes) video on the youtube channel Hussain Biology: Omicron Variant Common Cold Ins214EPE Mutation (https://www.youtube.com/watch?v=fRJMmUmduI4)

Kannan

Kannan SR, Spratt AN, Sharma K, Chand HS, Byrareddy SN, Singh K. Omicron SARS-CoV-2 variant: Unique features and their impact on pre-existing antibodies. Journal of Autoimmunity. 2022 Jan 1;126:102779.

Lippi, Henry

Lippi G, Mattiuzzi C, Henry BM. Updated picture of SARS-CoV-2 variants and mutations. Diagnosis. 2021 Dec 23.

Refs Omicron Epidemiology

Karim

Karim, S., & Karim, Q. A. (2021). Omicron SARS-CoV-2 variant: a new chapter in the COVID-19 pandemic. Lancet (London, England), 398(10317), 2126–2128. https://doi.org/10.1016/S0140-6736(21)02758-6

Cedro-Tanda

Cedro-Tanda, A., Gomez-Romero, L., de Anda-Jauregui, G., Garnica-Lopez, D., Alfaro-Mora, Y., Sanchez-Xochipa, S., … & Herrera, L. A. (2022). Early genomic, epidemiological, and clinical description of the SARS-CoV-2 Omicron variant in Mexico City. medRxiv.

Refs Epidemiology in South Africa

Pulliam

Pulliam, J.R., van Schalkwyk, C., Govender, N., von Gottberg, A., Cohen, C., Groome, M.J., Dushoff, J., Mlisana, K. and Moultrie, H., 2021. Increased risk of SARS-CoV-2 reinfection associated with emergence of the Omicron variant in South Africa. medRxiv.

Refs Epidemiology in Norway

Brandal

Brandal LT, MacDonald E, Veneti L, Ravlo T, Lange H, Naseer U, Feruglio S, Bragstad K, Hungnes O, Ødeskaug LE, Hagen F. Outbreak caused by the SARS-CoV-2 Omicron variant in Norway, November to December 2021. Eurosurveillance. 2021 Dec 16;26(50):2101147.

Jalali

Jalali, N., Brustad, H. K., Frigessi, A., MacDonald, E. A., Meijerink, H., Feruglio, S. L., … & De Blasio, B. F. (2022). Increased household transmission and immune escape of the SARS-CoV-2 Omicron variant compared to the Delta variant: evidence from Norwegian contact tracing and vaccination data. medRxiv.

Refs Epidemiology in the UK

Summary UK Technical Briefing 31

SARS-CoV-2 variants of concern and variants under investigation in England https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1040076/Technical_Briefing_31.pdf

The results from a cohort analysis on household transmission between 15 and 28 November 2021 with 72761 Delta index cases and 121 Omicron index cases yields a 2.6 unadjusted odds ratio increase and an increase of 3.2 if adjusted (Table 2.).
Data from the NHS test and trace system from November (Delta) and early December (Omicron) show: From Table 3 it is visible that the household attack rate of Omicron is with 21.6% about double as high than the attack rate for Delta which is 10.7%. The adjusted OR is 2.09 (1.54 - 2.79).
The risk for reinfection for Omicron seems to be much higher than for delta: a preliminary adjusted estimate is 5.2 (95% CI: 3.4 to 7.6) // 25 of 361 were reinfections whereas 336 of 85460 non Omicron cases between 20.11. and 5.12; adjustment seems to be important due systematic biases as noted in the text on page 22.
In Figure 9 the variation of spike mutation in the sub-lineages BA.1 and BA.2 are displayed.
In Figure 10 a maximum likelihood phylogeny for Omicron VOC-21Nov-01 (B.1.1.529) genomes as of 7 December 2021 is shown. South african but also US and UK samples are well distributed across the tree.

Refs Epidemiology in the US

CDC Response Team

COVID C, Team R. SARS-CoV-2 B. 1.1. 529 (Omicron) Variant—United States, December 1–8, 2021. MMWR. Morbidity and mortality weekly report. 2021 Dec 17;70(50):1731-4.

CDC Tracker

https://covid.cdc.gov/covid-data-tracker/#variant-proportions https://covid.cdc.gov/covid-data-tracker/#trends_dailycases_7daytestingpositive

cases increase roughly linearly since 10.11.21 (~76K) to 19.12. (~130K)
Omicron share
- 20.11.: 0.0%
- 27.11.: 0.1% (0%-0.1%)
- 4.12.: 0.7% (.4% - 1.1%)
- 11.12.: 12.6% (5% - 26%)
- 18.12.: 73% (34% - 95%)

Refs Epidemiology in Canada

Ontario Case Numbers

Covid cases in Ontario Canada by vaccination status: https://covid-19.ontario.ca/data/case-numbers-and-spread

BC Case Numbers

Covid cases in British Columbia Canada by vaccination status: https://public.tableau.com/app/profile/bccdc/viz/BCCDCCOVID-19SurveillanceDashboard/Introduction

Refs Disease Caused by Omicron

Public Health Ontario

Ontario Agency for Health Protection and Promotion (Public Health Ontario). Early estimates of Omicron severity in Ontario based on a matched cohort study, November 22 to December 17, 2021. Toronto, ON: Queen’s Printer for Ontario; 2021. https://www.publichealthontario.ca/-/media/documents/ncov/epi/covid-19-epi-enhanced-estimates-omicron-severity-study.pdf?sc_lang=en

Lippi, Mattiuizzi

Lippi, Giuseppe, Camilla Mattiuzzi, and Brandon M. Henry. “Is SARS-CoV-2 Omicron (B. 1.1. 529) variant causing different symptoms?.” (2022).

Christensen

Christensen PA, Olsen RJ, Long SW, Snehal R, Davis JJ, Saavedra MO, Reppond K, Shyer MN, Cambric J, Gadd R, Thakur RM. Early signals of significantly increased vaccine breakthrough, decreased hospitalization rates, and less severe disease in patients with COVID-19 caused by the Omicron variant of SARS-CoV-2 in Houston, Texas. medRxiv. 2022 Jan 1:2021-12.

Davies

Davies, M. A., Kassanjee, R., Rousseau, P., Morden, E., Johnson, L., Solomon, W., … & Boulle, A. (2022). Outcomes of laboratory-confirmed SARS-CoV-2 infection in the Omicron-driven fourth wave compared with previous waves in the Western Cape Province, South Africa. medRxiv.

Lewnard

Lewnard, J. A., Hong, V. X., Patel, M. M., Kahn, R., Lipsitch, M., & Tartof, S. Y. (2022). Clinical outcomes among patients infected with Omicron (B. 1.1. 529) SARS-CoV-2 variant in southern California. medRxiv.

Abdullah

Abdullah F, Myers J, Basu D, Tintinger G, Ueckermann V, Mathebula M, Ramlall R, Spoor S, de Villiers T, Van der Walt Z, Cloete J. Decreased severity of disease during the first global omicron variant covid-19 outbreak in a large hospital in tshwane, south africa. International Journal of Infectious Diseases. 2021 Dec 28.

Veneti

Veneti, L., Bøås, H., Kristoffersen, A. B., Stålcrantz, J., Bragstad, K., Hungnes, O., … & Whittaker, R. (2022). Reduced risk of hospitalisation among reported COVID-19 cases infected with the SARS-CoV-2 Omicron BA. 1 variant compared with the Delta variant, Norway, December 2021 to January 2022. Eurosurveillance, 27(4), 2200077. https://doi.org/10.2807/1560-7917.ES.2022.27.4.2200077 Received: 21 Jan 2022; Accepted: 25 Jan 2022

Auvigne

Auvigne, V., Vaux, S., Le Strat, Y., Schaeffer, J., Fournier, L., Montagnat, C., … & du Chatelet, I. P. (2022). Serious hospital events following symptomatic infection with Sars-CoV-2 Omicron and Delta variants: an exposed-unexposed cohort study in December 2021 from the COVID-19 surveillance databases in France. medRxiv.

Nyberg

Nyberg T, Ferguson NM, Nash SG, Webster HH, Flaxman S, Andrews N, Hinsley W, Bernal JL, Kall M, Bhatt S, Blomquist PB. Comparative Analysis of the Risks of Hospitalisation and Death Associated with SARS-CoV-2 Omicron (B. 1.1. 529) and Delta (B. 1.617. 2) Variants in England.

Refs Omicron Viral Load

Puhach

Puhach O, Adea K, Hulo N, Sattonnet-Roche P, Genecand C, Iten A, Bausch FJ, Kaiser L, Vetter P, Eckerle I, Meyer B. Infectious viral load in unvaccinated and vaccinated patients infected with SARS-CoV-2 WT, Delta and Omicron. medRxiv. 2022 Jan 1.

Tham

Tham, K. W., Tan, K. S., Ong, S. W., Koh, M. H., Tay, D. J. W., Aw, D. Z. H., … & Tambyah, P. (2022). Differential aerosol shedding of SARS-CoV-2 Delta and Omicron variants during respiratory activities.

Refs Epidemiological Vaccines Effectiveness

Buchan

Buchan et al Effectiveness of COVID-19 vaccines against Omicron or Delta infection medRxiv preprint doi: https://doi.org/10.1101/2021.12.30.21268565; this version posted January 1, 2022

Eggink

Eggink, D., Andeweg, S. P., Vennema, H., van Maarseveen, N., Vermaas, K., Vlaemynck, B., … & Knol, M. J. (2021). Increased risk of infection with SARS-CoV-2 Omicron compared to Delta in vaccinated and previously infected individuals, the Netherlands, 22 November to 19 December 2021. medRxiv.

Hansen

Hansen, C. H., Schelde, A. B., Moustsen-Helms, I. R., Emborg, H. D., Krause, T. G., Mølbak, K., & Valentiner-Branth, P. (2021). Vaccine effectiveness against SARS-CoV-2 infection with the Omicron or Delta variants following a two-dose or booster BNT162b2 or mRNA-1273 vaccination series: A Danish cohort study. medRxiv.

Refs Antibody Types and their Kinetics

Separate chapters with the immune responses and kinetics from vaccination and natural infection are planned. The references below contain finding on antibody F_c induced functions both induced by vaccination and natural infection and how these effects change by time.

Summaries below are in work and unfinished.

Farkash

Farkash et al., Anti-SARS-CoV-2 antibodies elicited by COVID-19 mRNA vaccine exhibit a unique glycosylation pattern, Cell Reports (2021), https://doi.org/10.1016/j.celrep.2021.110114

Methods

Anti-RBD total IgG and subclass responses at
- 2 weeks -> vaccinated: n = 127 of which 60 less than 60 years; Covid: 5 with mild and 4 with severe disease
- 5 weeks -> vaccinated: n = 127 (same cohort as after 2 weeks); Covid: 16 with mild and 12 with severe disease
IgG levels were determined by ELISA.

Results

Figure 1: BNT162b2 induces mainly IgG1 and IgG3 (Figure 1 D) and the ratio IgG1 + IgG3/(IgG2 + IgG4) is even increased after the 2nd dose (Figure 1 E)
Figure 2:
- Overall IgG level tend to be inversely correlated to age (Figure 2. A and B)
- IgG subclasses are similar for over and under 60 years (Figure 2. C)
- FcR2a and FcR3a binding tend to be slightly higher for those over 60 years.
  
  in work

Lee

Lee WS, Selva KJ, Davis SK, Wines BD, Reynaldi A, Esterbauer R, Kelly HG, Haycroft ER, Tan HX, Juno JA, Wheatley AK. Decay of Fc-dependent antibody functions after mild to moderate COVID-19. Cell Reports Medicine. 2021 May 9:100296. https://doi.org/10.1016/j.xcrm.2021.100296

Kaplonek

Kaplonek et al. Subtle immunological differences in mRNA-1273 and BNT162b2 COVID-19 vaccine induced Fc-functional profiles bioRxiv preprint doi: https://doi.org/10.1101/2021.08.31.458247; this version posted August 31, 2021

Background

mRNA-1273 offers a higher protection than BNT-162b2 in real world scenarios. One goal of the investigation whether such differences could be due to differences in antibody types.

Methods

Determine the AB profiles (F_c profiles and effector functions induced (phagocytosis, cellular toxicity, complement activation) against different variants and from different forms of immunization (mRNA-1272, BNT162b2 and natural infection).

Methods Details

Participants:

The measure the ABs responses against wild type infections (Figure 1) and Alpha/Beta/Gamma (Figure 2): 28 participants with mRNA-1273 and 45 with BNT162b2.
Comparison of antibody profiles were compared across mRNA-1273 (n = 16) and BNT162b (n = 15) vaccines and 10 convalescents (Figure.3) against WT, Alpha=B.1.1.7, Beta=B.1.351, Gamma=P1, Delta1=B.1.617.1 and Delta2=B.1.617.2

Atyeo

Atyeo C, DeRiso EA, Davis C, Bordt EA, De Guzman RM, Shook LL, Yonker LM, Fasano A, Akinwunmi B, Lauffenburger DA, Elovitz MA. COVID-19 mRNA vaccines drive differential antibody Fc-functional profiles in pregnant, lactating, and nonpregnant women. Science Translational Medicine. 2021 Oct 27;13(617):eabi8631.

Adhikari

Adhikari, A., Abayasingam, A., Rodrigo, C., Agapiou, D., Pandzic, E., Brasher, N. A., … & Tedla, N. (2021). Longitudinal characterisation of phagocytic and neutralisation functions of anti-Spike antibodies in plasma of patients after SARS-CoV-2 infection. bioRxiv.

Bartsch

Bartsch, Y., Tong, X., Kang, J., Avendaño, M. J., Serrano, E. F., García-Salum, T., … & Alter, G. (2021). Preserved Omicron Spike specific antibody binding and Fc-recognition across COVID-19 vaccine platforms. medRxiv.

Refs ADE

Wan

Wan Y, Shang J, Sun S, Tai W, Chen J, Geng Q, He L, Chen Y, Wu J, Shi Z, Zhou Y, Du L, Li F. 2020. Molecular mechanism for antibodydependent enhancement of coronavirus entry. J Virol 94:e02015

Arvin

Arvin AM, Fink K, Schmid MA, Cathcart A, Spreafico R, Havenar-Daughton C, Lanzavecchia A, Corti D, Virgin HW. A perspective on potential antibody-dependent enhancement of SARS-CoV-2. Nature. 2020 Aug;584(7821):353-63.

Shen

Shen XR, Li Q, Li HL, Wang X, Wang Q, Zheng XS, Geng R, Zhang YL, Li B, Jiang RD, Liu MQ. Antibody-Dependent Enhancement of SARS-CoV-2 Infection of Human Immune Cells: In Vitro Assessment Provides Insight in COVID-19 Pathogenesis. Viruses. 2021 Dec;13(12):2483.

Maemura

Maemura T, Kuroda M, Armbrust T, Yamayoshi S, Halfmann PJ, Kawaoka Y. Antibody-Dependent Enhancement of SARS-CoV-2 Infection Is Mediated by the IgG Receptors FcγRIIA and FcγRIIIA but Does Not Contribute to Aberrant Cytokine Production by Macrophages. Mbio. 2021 Sep 28;12(5):e01987-21.