28 Dec 2021 Omicron and Molnupiravir

Ep 210 : Omicron

Dear colleagues,

After a short break, some very recent papers on omicron, with many thanks to Patrick and Ruud (who remained very active).  It is not yet complete, but my laptop is still not working properly.  Hopefully more tomorrow.

Ep 210-1 : Staten Serum Institute Report of 27 Dec

Remarks by R Westendorp:

• The % omicron of the total number of infections has risen to 72% on 21/12; so Delta has been completely supplanted by omicron in a short time (in all age groups) and we need not doubt the higher infectivity

• This is most likely the reason that the number of infections remains high; the number of infected had risen to 16,000 on Boxing Day; a record – an increase despite the gradually increasing hygiene measures

• The number of infected persons entering the hospital within 48 remains approximately half of the other variants (0.5 vs. 1.0%) and indicates a lesser severity, but this number has not yet been corrected for the (younger) age.

Ep 210-2:  Omicron outbreak at a private gathering in the Faroe Islands, infecting 21 of 33 triple-vaccinated healthcare workers.

• Al infected participants were fully vaccinated with the mRNA vaccine BNT162b2 (Comirnaty; BioNTech,Mainz, Germany) and had received a third booster dose within the last two and a half months, and none had a history of previous SARS-CoV-2 infection.
• All infected participants had a negative test taken within 36 hours before the gathering. Most had performed a PCR test, while five had taken a lateral flow test.
• All the reported cases were symptomatic. None were admitted to the hospital.
• This report demonstrates that the Omicron variant can lead to super-spreading events even in triple vaccinated people.

Ep 210-3: Aurelien Sokal medRxiv 22 Dec 2021:  Immune escape of SARS-CoV-2 Omicron variant from mRNA vaccination-elicited RBD-specific memory B cells.

As could be expected, omicron evades recognition of a large (> 70%) fraction of over 300 monoclonal antibodies, naturally expressed  by memory B cells of mRNA vaccinated subjects.   Hence, the “maturation” of B cells that spontaneously occurs after mRNA vaccination, which implies a “broadening” even to new variants (such as Delta) observed in the past, only poorly works against omicron.  These observations contribute to the explanation why fully vaccinated people are vulnerable to omicron more than to Delta.   

Ep 210-4: Khan medRxiv 27 Dec 2021: Omicron infection enhances neutralizing immunity against the Delta variant

In this preprint, 13 patients (between 20-40 yrs) with detectable Omicron were studied at diagnosis and 2 weeks later.   Of these, 7 were previously vaccinated with either Pfizer or Janssen.  11 were hospitalized.  Very small numbers, but yet, it is evident from Fig 1 that:

• Neutralizing titers against both omicron and delta were boosted
• Vaccinated subjects had higher neutralization titers than non-vaccinated

This pattern of cross-neutralization was not seen before in South-Africa, where immunity elicited by Delta infection does not cross-neutralize Beta virus and Beta elicited immunity does not cross-neutralize Delta well

Hence the (very preliminary) conclusion of the authors:

• Results are consistent with Omicron displacing the Delta variant, since it can elicit immunity

which neutralizes Delta making re-infection with Delta less likely. In contrast, Omicron escapes Delta neutralizing immunity and therefore may re-infect Delta infected individuals.

• The implications of such displacement would depend on whether Omicron is indeed less pathogenic than Delta. If so, then the incidence of Covid-19 severe disease would be reduced and the infection may shift to become less disruptive to individuals and society.

Ep 210-5 A: Thorne Nature 23 Dec: Evolution of enhanced innate immune evasion by SARS-CoV-2

The authors attract attention to mutations in the Alpha variant outside the Spike protein (in Nucleoprotein, ORF6 and ORF9), which act as enhancers of antagonists to the interferon pathway  in airway epithelial cells.  ORF9 is overexpressed and interacts with a human protein TOM9 that is important for sensing viral RNA, but the cell can partly counteract this effect by phosphorylation.

Ep 210-5 B: Waldman in Science News specifies that similar mutations are present in Delta and Omicron, indicating that all these variants have evolved to escape the innate immunity by interferon.   Clearly:

- The increased infectivity or in vivo replication of these variants may partly be explained by this evasion of first line of defense

- It can also be suggested  that interference with the interaction between the viral ORF9 and the human TOM-9 could be the basis for new therapeutics.

Ep 210-6: Very conditional FDA approval for Molnupiravir, the anti-SARS-CoV-2 Merck, which acts by inducing mutations in the virus.  There are concerns about limited efficacy, especially against Delta (and omicron?) and the risk on mutagenicity….. Lots of restrictions: not more than 5 days and not in children or pregnancy….

Best wishes,

Guido