Episode 348: Update on COVID variants, vaccination and Sotrovimab.

Sat, 09/02/2023 - 21:28

Episode 348: Update on COVID variants, vaccination and Sotrovimab.

Dear colleagues,

While we are enjoying an Indian summer, it is time to re-evaluate the situation: what is the evolution of variants and what are the implications for vaccination and therapy in the coming Autumn.  

As you might remember, the XBB.1.5 became dominant in the Spring (Ep 304) and it was decided to develop an new booster mRNA based on this variant. However, several other variants (XBB.1.16, BQ.1, BN.1 etc) emerged, but they were more or less related.  Of special interest are the new variants “Eris” EG.1.5 (XBB.1.5 carrying the immune escape F456L and the compensatory L455F see Ep 342) as well as the ”Pirola” (BA.286, which represents a major shift, since it  carries over 30 mutations see Ep 345). The question is whether these variants could jeopardize the effect of a booster with XB.1.5


Par 1 RECENT EVOLUTION OF VARIANTS Ep 348-1 ECDC report of 2 Sept and Ep 348-2 CDC


  • Increase in cases, especially in 80+  but no clear trend of hospitalization.
  • 56 % XBB.1.5 + F456L (some of those will be EG.1.5) > 36 % XBB.1.5 >>> 3 % BA.2.75 > 2 % XBB
  • Eleven cases of BA.2.86 have been reported worldwide by 1 Sept:
    • In EU/EAA Denmark (10), France (1), Portugal (2) and Sweden (5).
    • Outside of the EU/EEA, these were Canada (1), Israel (1), South Africa (3), the UK (1), and the US (4).
    • Detection in waste water samples from several more countries, both within and outside of the EU
  • No evidence of increased severity for XBB.1.5 + F456L or BA.2.86 so far

CDC: rather similar picture with EG.1.5 (XBB.1.5 + F45L and L455F) > FL.1.5.1 (= XBB.1.5 + F456L)


Update on BA.2.86 by Eric Topol (Ep 348-3) and Yunlong Cao



BA.2.86 shows lower infectivity than XBB.1.5. 

EG.5.1 has similar infectivity (because of compensatory  M455F “flip” mutation)

Immune escape:

  1. Sotrovimab is the only mAb still active against BA.2.86
  2. EG.5 and even more BA.2.86 largely escape from XBB-infection/vaccination induced antibodies.

Note: BTI = breakthrough infection with XBB or BA.5/BF.7 after vaccination is presumably with Chinese inactivated virus.

Remark by Eric Topol: Of course, …, BA.2.86 can pick up more mutations to be more transmissible, so only over many weeks ahead will we be able to know if this is the next path for the virus’s evolution.


Par 2 XBB.1.5 VACCINE: encouraging immunogenicity (Ep 348-5 Chalkias medRxiv 24 Aug)


XBB.1.5-containing monovalent and bivalent vaccines elicited potent neutralizing responses against variants of the omicron XBB-lineage (XBB.1.5, XBB.1.6, XBB.2.3.2) as well as more recent (EG.5.1, FL.1.5.1) variants.


Set-up: 50 subjects: Monovalent = mRNA-1273.815 ( 50 µg XBB.1.5 spike mRNA)

51 subjects:  Bivalent = mRNA-1273.231 (25-μg XBB.1.5 and 25-μg BA.4/BA.5 spike mRNAs)


This booster was 5th dose after 3 doses original (D614G Spike RNA ) and 4th dose bivalent D614G + BA4/5 Spike RNA.




  1. Similar neutralizing Ab induced by monovalent or bivalent vaccine: neut titers to XBB.1.5, XBB.1.16 and BQ.1.1 lower than to  BA.4/5 or D614G, but still rather hogh




  1. Neutralization of newer circulating variants EG.1.5 and FL.1.5.1 (both containing F456L) are similar as to XBB.1.5 and XBB.1.16. Prior infection increases all neut titers (= hybrid immunity)  




Par 3 Fc mediated EFFECTOR FUNCTIONS (ADCC and ADCP)  in sensitivity to Sotrovimab and immune memory


Ep 348-6: Amin Addetia Nature 30 Aug Neutralization, effector function and immune imprinting of Omicron variants.


This paper has two main lines of evidence:


  1. The prophylactic/therapeutic mAb Sotrovimab (S309)  binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5
  2. Vaccine-elicited human plasma antibodies cross-react with and trigger Fc mediated effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309.


The message of this paper is that ”Fc dependent effector functions”, such as an antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADP), could at least partly compensate for decreased neutralization (due to accumulating escape mutations in Omicron variants): while, because of decreased neut, these Ab are less ablez to prevent infection, they could still prevent severe disease.


Evidence on Sotrovimab (S309)




Panel a and b show that neutralization capacity of Sotrovimab is lower for some Omicron variants: to 50 % neutralize  BQ.1.1, BF.7, BN.1 much higher concentrations of Sotrovimab are needed


Panel d shows that ADCC and ADCP (Ab-dependent cytotoxicity and phagocytosis) of Sotrovimab is nevertheless rather similar across variants.  However, these functions are lost when the S309 GRLR (G236R/L328R) mutant is used (which has no Fc binding capacity).


In panel f Sotrovimab (WT) or S309GRGL are used prophylactically before infection of ACE2-Mice with BQ.1.1: in all conditions both mAb protect against body weight less, but the Fc-deficient S309GRGL is clearly less able to suppress viral load than  WT Sotrovimab.


Evidence from vaccination and breakthrough infection

                            1                                        2                                        3                                        4





Panels a show that

  • 1: vaccination with Wuhan induces good neutralization against Wuhan, but less and less against successive Omicron variants
  • 2: booster with bivalent vaccine increases all titers, but naut against omicron remains weak
  • 3: pre-Omicron breakthrough (BTI) + Bivalent vaccine enhances the responses
  • 4: Omicron BTI increases all titers, but titers against XBB.1.5 remain relatively low


Panel d: ADCC against all tested variants remains rather similar!


This favorable result is being explained by the dominance of cross-reacting memory B cells….




  1. The newer XBB.1.5 based variants, carrying the F456L, are becoming dominant in Europe and US, while the BA.2.86 variant with many more mutations is still rare, but could increase fitness by additional mutations.
  2. The XBB.1.5  mRNA vaccine (either monovalent or bivalent) induces reasonable neutralizing Ab titers, including against F456L mutants such as EG.5 and FL.1.5.1.  Nevertheless the titers are much lower than against BA.4/5 (4 X) and D614G (10-20 X).  BA.2.86 was not tested.
  3. Weak neutralization could be compensated by Fc mediated effector functions such as Ab-dependent cytotoxicity and phagocytosis.  Along with T cell immunity, ADCC and ADCP, may be important to prevent severe diseases, even if vaccinees get infected.
  4. Sotrovimab remains a very potent mAb: despite rather weak neutralization, it may also act vie ADCC and ADCP.  It should be considered for both prophylaxis and therapy in immune compromised patients.     


Best wishes,