27 January 2022 Episode 231: Omicron sublineages future; children and vaccination; hybrid immunity

Thu, 01/27/2022 - 19:56

Dear colleagues,

Thanks to several amongst you (including Patrick, Benson, Dieter…) I could bring together a nice series of papers on various topics…


  1. Omicron, its subvariants and the future

There is a heated ongoing debate in the media about the significance of BA.1 versus BA.2

Ep 231-1: Press report, based on declaration of Statens Serum Institute claiming that BA.2 is more contagious, but with similar disease presentation as BA.1

Ep 231-2: Genome surveillance data in Belgium of 25 January


  • Still 3.3 % Delta and 96.5 Omicron, with only 2.1 % BA.2 and 1 family cluster with BA.3
  • Out of 194 confirmed BA.1 hospitalizations, only 3 were fully vaccinated (confirming the protective effect of vaccines against hospitalization).
  • Pfizer will compare its Omicron based mRNA vaccine in 3 cohorts: (1) after 2 doses of Wuhan based mRNA; (2) After 3 doses; (3)  unvaccinated.  See also Ep 231-5)  

Unfortunately:  Not large enough that it would give data on how strategies compare in terms of how many people are infected or develop COVID symptoms (see Press release Ep 231-2 B).

Ep 231-3: William Haseltine discusses the “Omicron family” and concludes that “Each of these variants (BA.1, BA.2, BA.3) is as different from one another as Alpha, Beta, Gamma, and Delta are from one another

My question: what is the immunological consequence: could someone be infected first with BA.1 and next with BA.2?


Ep 231-4: Martin in bioRxiv 18 January Selection analysis identifies unusual clustered mutational

changes in Omicron lineage BA.1 that likely impact Spike function

In this complex paper, Martin points to the fact that of the 30 Spike mutations of Omicron BA.1 there are two different types (see Table 1 and Fig 1):

  1. Those that under positive selection (beneficial for fitness of the virus) and are often seen in other variants (alpha, beta, gamma, delta)
  2. Those that are neutral or under negative selection (rather negative for fitness) and therefore only rarely or temporarily found previously.  

These “negative”, at first view maladaptive, mutations are present in 3 clusters,

  • Cluster 2 in the receptor binding motif RBM (hence directly in contact with ACE-2)
  • Cluster 1 in a more distant part of the receptor binding domain (RBD) potentially involved in the “up” or “down” orientation of the Spike and
  • Cluster 3 in the S1-S2 cleavage and fusion domain.   


Obviously, this is no coincidence: the combination of these individually “maladaptive” mutations must have a clear advantage for Omicron with regard to immune escape, preferential use of the endosomal entry mechanism, tropism for upper respiratory cells etc. 

The authors conclude that the complex combination of mutations of  BA.1 is involved balancing multiple fitness trade-offs between:

(1) immune escape vs. affinity for human and/or animal ACE2 proteins;

(2) efficient proteolytic priming with TMPRSS2 which expedites cellular entry via the cell surface vs increased resistance to endosomal restriction factors (such as IFITM proteins) which enable more efficient cellular entry via the endocytic route;

(3) preferred tropism for cells in the upper respiratory tract vs preferred tropism for cells in the lower respiratory tract, and

(4) increased propensity for Spike monomers to switch from the down to up configurations and overall Spike trimer stability.


Fortunately, the collection of mutations in BA.1 appear at present to have tilted the balance of these and other trade-offs towards the virus having decreased clinical severity in humans.


Complex evolutionary remodelling of important functional elements of SARS-CoV-2 are not just possible, but are potentially already occurring unnoticed in other poorly sampled lineages.

 BUT …. We should not complacently assume that the balance of fitness trade-offs achieved by the

extensively evolved VOCs that succeed BA.1 will be similarly tilted towards lower severity


Ep 231-5: Very interesting and didactic webinar of today on omicron


Ep 231-6 A: Kai Kuperschmidt in Science Insider on the present and future

  • Rather mild in South-Africa: Omicron is unlikely to account for more than 5% of COVID-19 deaths in the country. Madhi optimistic about the future. A serosurvey he led in Gauteng province, home to one quarter of South Africa’s population, showed close to 70% of unvaccinated people carried SARS-CoV-2 antibodies at the start of the Omicron wave. In the next survey, he expects that number to have gone up to at least 85%, a level that should prepare South Africa for a post-Omicron future.


  • Not so mild in the US: in part because its vaccination rate is relatively low. It is seeing more than 2000 deaths daily, as many as during the peak of the Delta wave. Although cases are now declining in New York, Florida, and California, the wave is still building elsewhere.


  • Future uncertain: Omicron has shown that even a relatively mild wave can put a tremendous burden on health systems and societies as a whole, and it’s unclear
    • how long will Omicron immunity last,
    • how will the virus evolve
    • how often will breakthrough infections lead to long-term health problems
    • the proliferation of animal reservoirs is also worrying: e.g. hamsters infected in a Singapore animal shop
    • the emergence of a variant able to evade not just human antibodies, but also evade the T cell response, which protects from severe disease and death.


Ep 231-6 B: Aris Katzourakis in Nature 27 Jan 2022 on the danger of the “endemicity” concept.


The same virus can cause endemic, epidemic or pandemic infections: it depends on the interplay of

  • a population’s behaviour, demographic structure, susceptibility and immunity,
  • plus whether viral variants emerge


There is a widespread, rosy misconception that viruses evolve over time to become more benign. This is not the case: there is no predestined evolutionary outcome for a virus to become more benign, especially ones, such as SARS-CoV-2, in which most transmission happens before the virus causes severe disease.


The best way to prevent more, more-dangerous or more-transmissible variants from emerging is to stop unconstrained spread, and that requires many integrated public-health interventions, including, crucially, vaccine equity.


  1. Children


Ep 231-7: University of Mississippi:  Unvaccinated kids bear brunt of COVID-19,studies show

Journalist summary of Ep 231-8, 9, 10.


Ep 231-8: Charlotte Hobbs on COVID-19 in children in 2020 (before maternal or children vaccination):

  • Of all 630 hospitalized children with severe COVID 20 % were infants (> 7 days and < 1year) and 75 v % of those were < 6 months
  • 66 % previously healthy
  • Respiratory complaints most pronounced with 13 % mechanica               l ventilation

To protect infants + children under 5 years maternal (also postpartum) and household vaccination is important.


Ep 231-9: Two doses of Pfizer vaccine in adolescents July -Oct 2021 effectiveness against

  • Hospitalization =95 %; ICU = 98 %
  • All 7 deaths in non-vaccinated group


Ep 231-10 = Ep 219-2:  MMWR paper on effectiveness against MISC


  1. Booster Vaccine


Ep 231-11: Abbu-Raddad in medRxiv 24 Jan 2022: confirmation that Pfizer booster is 50 % effective against symptomatic omicron as compared to 2 doses only.  Very few severe cases.


Ep 231-12: Atmar NEJM 26 Jan 2022 Heterologous booster


Better  neut against D614G than homologous, if primary vaccination was Janssen Ad26.COV-2S


CD4 (Th1 and Th2) as well as CD8 T cell responses boosted, except homologous Janssen Ad26


Remarkably:  Spike-specific CD8+ T-cell levels were more durable in the Ad26.COV2.S-primed recipients (confirmation of previous observations), and heterologous boosting with the Ad26.COV2.S vaccine substantially increased spike-specific CD8+ T cells in the mRNA vaccine recipients.


  1. Hybrid immunity


Ep 231-13: Walls Cell Jan 2022: SARS-CoV-2 breakthrough infections elicit potent, broad and durable neutralizing antibody responses

  1. Breakthrough infections after vaccination,
  2. Subjects who were vaccinated after infection = hybrid immunity
  3. Individuals vaccinated three times

have serum neutralizing activity of comparable magnitude and breadth,


While SARS-infection or 2 vaccinations only induce moderate levels of neutralizing antibodies


→ increased exposures to SARS-CoV-2 antigen(s) enhance the quality of antibody responses.




Serum samples were obtained from individuals who had a breakthrough infection (n=15, magenta triangle), who were previously infected in 2020nthen vaccinated (n=15, teal diamond, infected/vaccinated,

who have been vaccinated only (n=15, orange circle),

or who were infected only in 2020 in Washington State (n=15, gray square, HCP).


All neutralization assays were performed using VeroE6-TMPRSS2 as target cells at least in duplicate.

(A) SARS-CoV-2 G614 S VSV pseudotype. (B) SARS-CoV-2 Delta S VSV pseudotype. (C) SARS-CoV-2 Beta S VSV. (D) SARS-CoV-2 Omicron S VSV pseudotype. (E) SARS-CoV S VSV pseudotype

neutralization. # of doses: number of vaccine doses received.

(F) Fold change of 614G:Delta/Beta/Omicron/SARS-CoV colored green (small fold change) to red (large fold

change). Shown are representative GMTs from at least 2 independent experiments


Ep 321-14: Timothy Bates Science 25 Jan 2022 Vaccination before or after SARS-CoV-2 infection leads to

robust humoral response and antibodies that effectively neutralize variants


Very similar findings, but no Omicron included.


  1. Varia


Ep 321-15: Rhia Kundu Nature Communications Memory T cells, cross-reactive with common CoV,  associate with protection against SARS-CoV-2 infection in COVID-19 contacts


As you can see, there is a signal for IL-2 production, but it is really “at the verge of significance”.  Hence, I would not count too much on cross-reactivity, but rather on specific vaccination…. 


Ep 321-16: Caroline Quach medRxiv 24 Jan 2022: Should healthcare workers with SARS-CoV-2 household exposures work?


Study on 475 HCW with high risk household contact Dec 20 ’21 till Jan 17 ’22:

  • 50 % remained negative
  • Of those who became positive
    • 82 % already positive at first testing and they were quarantined
  • Of those negative who were allowed to work: only 15 % became positive
  • Remaining negative was associated with:
    • No symptoms at initial evaluation (OR = 3.8)
    • Having received a booster > 7 days before (OR = 1.88)


Conclusion: Allowing triple vaccinated asymptomatic HCWs who are known household contacts of confirmed COVID-19 cases to work is likely a safe alternative, when staff shortage is anticipated.


Ep 321-17: Abbu-Raddad NEJM Nov 2021: Reinfections in Qatar early 2021 are usually mild




Of 1304 identified reinfections,

  • 413 (31.7%) were caused by the beta variant,
  •  57 (4.4%) by the alpha variant,
  • 213 (16.3%) by “wild-type” virus,
  • 621 (47.6%) were of unknown status





  1. Omicron
    • BA.2 is not more pathogenic, but it is not excluded that it (partly) escapes from antibodies, elicited by BA.1  
    • Very remarkable clusters of “negative/neutral” mutations, which most probably contribute to Omicron’s “special features” (immune escape, Spike flexibity and stability preferential entry via endosomal pathway and tropism for upper airway, lower disease severity…)
    • Future difficult to predict but evolution towards “endemicity’ does not necessarily mean that SARS-CoV-2 will become more benign


  1. Children
    • Disproportionate disease burden in infants and small children must be countered by vaccination of pregnant women and household members
    • Clear protections from mRNA vaccination in adolescent against severe disease, including MISC
  2. Booster:
  • Confirmation of protective effect against symptomatic omicron
  • Heterologous regimens slightly better than homologousn including T cell immunity


  1. Hybrid immunity: breadth and amplitude of neutralization superior to dual vaccination, irrespective of order vaccination-infection. Triple vaccination similarly potent as hybrid immunity.


  1. Varia:
  • Cross reactive T cells to common CoV may contribute to protection against SARS-CoV-2
  • Highly exposed but triple vaccinated and asymptomatic HCW can safely work.
  • Reinfections rarely severe.   


  1. Epidemiological Note


Ep 321-18 from Our World in data COVID-19


Weekly confirmed cases per million:

Denmark: 50,000; Belgium: 30,000; Netherlands: 25,000; US, UK and Germany: each 10,000


Weekly hospital admission per million

US: 400; DK: 300; BE and UK: 200; NL and GE: 50


Excess deaths (percent): all down to 0  



That’s it for today.


Best wishes,