21 February 2022 Episode 242 : Omicron sublineages, super-infection and reinfections

Mon, 02/21/2022 - 18:53

Dear colleagues,

Before addressing these topics, please find an “epilogue” on the long COVID in attachment: a list of interesting recent papers collected by Patrick Smits.

In this episode, I will address 4 related topics:

-          Significance of omicron sublineages in vitro, in hamsters and in humans

-          Delta versus omicron: differences in clinical profile and superinfection

-          Reinfections by omicron

What is the significance of omicron sublineages?

Ep 242-1: Yamasoba bioRxiv 15 Feb 2022: Virological characteristics of 1 SARS-CoV-2 BA.2 variant

1)      Although BA.1 and BA.2 are monophyletic, their sequences differ by 50 amino acids, approximately twice the differences between four VOCs (Alpha, Beta, Gamma and Delta) and Wuhan-Hu-1 (see a)

2)      The reproductive number  of BA.2 is 1.4 X higher than BA.1 (see d)

3)      Similar replication in Vero cells (the lab standard), but more replicative in human epithelial nasal cells, more fusogenic (less dependent on TMPRSS2)


BA.2 less sensitive to antibodies, induced by vaccination or previous infection

5)      BA.2 is more pathogenic in hamster model: more weight loss and more positive cells in lung, alveolar damage and lower oxygen saturation: all similar to B.1.1 (: D614G strain)


Ep 242-2: Iketani bioRxiv 15 feb 2022 Antibody Evasion Properties of SARS-CoV-2 Omicron Sublineages


In this paper, 3 sublineages are distinguished: BA.1; BA.1 + R346K mutation (= BA.1.1) and BA.2. 

The epidemiological and genetic characteristics are shown


Remarkably according to these authors, the escape from vaccine-induced antibodies is similar in these 3 sublineages and also the escape from most therapeutic monoclonals, except that Sotrovimab (S309) keeps a reasonable activity against BA.1 and BA.1+R356K,  while it loses activity against BA.2


Ep 242-3: Yu medRxiv 7 Feb 2022 concludes on “comparable neutralization after (Pfizer) vaccination”, although, in fact BA.2 is just a bit less sensitive, even after 3 vaccinations or after BA.1 infection


Ep 242-4: Eliot medRxiv 6 Feb 2022 confirms that BA.2 in UK showed a growth advantage over the BA.1 sublineages in January.


Ep 242-5: Peter Lyngse medRxiv 30 Jan in Denmark also shows higher susceptibility to BA.2 than BA.1, but transmissibility of BA.2 as compared to BA.1 was only increased in unvaccinated subjects, while vaccinated subjects showed LOWER transmissibility of BA.2 as compared to BA.1


Despite these indications of enhanced infectiousness of the BA.2 lineage and despite  relaxation of COVID measures in both countries, COVID cases are decreasing!


Ep 242-6: Wolter medRxiv 19 feb 2022 on BA.1 and BA.2 in South-Africa. 


As can be seen, while the total number of cases dropped during December and January, the proportion of presumed BA.2 increased from 3 to 80 %.  (In this case, the “S drop-out” or S-gene negative was considered BA.1, while S-gene positive is BA.2, see Episode 238).  

Importantly, no difference was observed between presumed BA.1 and BA.2 with regard to risk on hospitalization or severe disease.


And what about BA.3?

Ep 242-7: Desingu and Nagarjan in J Med Virol: the minority sublineage BA.3 contains a mixture of mutations Spike mutation from BA.1 and BA.2, without specific mutations of its own.  Is that the reason why this sublineage apparently remains very low (< 1 %) in frequency?


Intermezzo on delta versus omicron


Ep 246-8:  Menni SSRN Feb 2022: Clinical differences between delta and omicron in carefully matched populations (age, sex and vaccination)

1)      Symptomatology: omicron much more sora throat (OR = 1.43) and much less loss of taste and smell (OR = 0.17), but also less lower respiratory tract involvement, less sneezing, ear ringing, brain fog, hair loss, blisters….

2)      Duration of symptoms is 2 days less (7 versus 9) and risk on hospitalization is lower (OR = 0.75).


Ep 242-9: Rockett medRxiv  15 Feb ’22 Co-infection with delta and omicron in two unrelated hemodialysis kidney patients. No evidence of recombination.



Ep 242-10: Mallapaty on reinfections in Nature Briefing 16 Feb.  Very clear statistics from England, showing that omicron is the major culprit.


Two sets of data on prevention of reinfection

Ep 242-11: Effectiveness of previous infection (Qatar):

-          Against symptomatic reinfection: 90.2% against alpha; 86 % against beta; 92 % against delta and only 56 % against omicron.

-          Against severe, critical or fatal infection: 69 % against alpha; 88 % against beta; 100 % against delta and 87 % against omicron.  (this is based on low numbers).

Despite the limitation, it is clear that protection against symptomatic infection by omicron is lowest, but that protection against severe disease is similar for omicron as for other variants.


Ep 242-12: Effectiveness of RNA vaccines (US) was as expected:  3 doses of mRNA vaccine, relative to being unvaccinated and to receipt of 2 doses, was associated with protection against both the Omicron and Delta variants, although the higher odds ratios for Omicron suggest less protection for Omicron than for Delta.



1)      Omicron BA.1, BA-2 and BA-3 show large genetic differences, but BA-3 Spike has no specific mutations  (is a mixture).

2)      BA.3 has remained a very minor species everywhere, while BA.2 has taken over the BA.1 epidemic in South-Africa, Denmark and England. BA.2 has indeed a higher replicative capacity than BA.1 (and delta).

3)      In vitro, BA.2 seems to grow better in nasal epithelial cells than BA.1, but in the hamster model it is also more pathogenic than BA.1. In fact, it produces similar weight loss, infection in the lung, alveolar damage and decrease of oxygen saturation as the B.1.1 (or D614G) strain, which was responsible for the first worldwide pandemic wave.  

4)      BA.1 and BA.2 are much less susceptible than wild-type, B.1.1 and delta to antibodies, induced by previous infection or vaccination.  Some manuscripts but not all, suggest that BA.2 is even more resistant than BA.1 to in vitro neutralization.  The detailed “real world” household transmission studies provide a mixed picture: whereas susceptibility to infection by BA.2 is 2-3 times increased as compared to BA.1, regardless of vaccination status, transmissibility is only increased from unvaccinated, but actually relatively decreased from vaccinated subjects.  In any case, in Denmark, BA.2 has taken over BA.1.

5)      Interestingly, however, according to Ep 242-3, BA.1 infection induces antibodies, capable to neutralize BA.2, probably explaining why the (relative) take-over by BA.2 in South-Africa, Denmark and England did NOT result in a new (absolute) rise in cases, but, on the contrary occurred during a decline, while anti-COVID measures were relaxed.        

6)      In one paper, BA.2 is much more resistant to S309 (or Sotrovimab) than BA.1, leaving no options for antibody therapy.

7)      While symptomatology and disease severity are similar between BA.1 and BA.2, there are clear differences in symptoms between omicron and delta: more sore throat for omicron, more sneezing, conjunctivitis, neurological and respiratory symptoms for delta.

8)      As compared to delta, previous infection or 3 X vaccination protected less against omicron infection, but equally well against severe disease.  


Note: At first view, the hamster data, showing that BA.2 has a higher pathogenicity than BA.1 and is, in fact, rather similar to the original B.1.1 (D614G) strain may seem in contradiction with the clinical observation that BA.1 and BA.2 are similarly “mild” as compared to previous variants. Obviously, this discrepancy may be due to the limitations of the hamster model (not fully representative of human situation).  However, it could also be due to a different context: the hamsters were “immunologically naïve” to SARS-CoV-2, while most humans, infected with omicron BA.2 have been either vaccinated or previously infected with a SARS-CoV-2 variant.  Therefore, it is not sure what the disease profile of omicron (BA.1 or BA.2) will be in a “immunologically naïve” human population….  


Best wishes,