22 March 2022 Episode 251 : Cross-reactivity revised; Qatar cohort and omicron sublineages; therapeutic monoclonals and omicron; comparing vaccines for immune responses

Tue, 03/22/2022 - 11:32

Dear colleagues,

No strict overall theme for this episodes, but interesting emerging data on omicron sublineages…. Enjoy reading.



Cross-reactivity rather pathogenic?

As you know from my previous episodes, I have always been skeptical about claims that cross-reactivity between  “common cold” beta CoV (OC23 and HKU1) could be a significant protective mechanism against COVID.  Here is a paper that suggests a rather negative role of this type of cross-reactivity.

Ep 251-1: Jiong Wang JID Jan 2022

  1. Kinetics of HCoV-OC43 and HKU1 anti-spike (S) IgG levels correlate with anti-SARS-CoV-2 IgG during acute infection. (DFSO = days from symptom onset)


  1. Association between elevated anti-S Ab of SARS-CoV-2, HKU1 and OC23 (but not alpha CoV 229E and NL63 with disease severity.


  1. Changes in SARS-CoV-2 (P = .0112) and OC43 (P = .0047) anti-S IgG were highly associated with the mean change in maximum SOFA (sequential organ failure assessment) scores on the day of serum sampling.  


Conclusion: direct evidence that

  •  preexisting β-HCoV S-reactive antibodies are associated with the SARS-CoV-2–specific antibody response,
  • OC43 anti-S and SARS-CoV-2 anti-S2 antibodies highly correlate with the COVID-19 severity.

Potential mechanisms (if more than association): pre-existing beta-HCoV anti-S2 memory B cells preferentially drive cross-reactivity to non-neutralizing SARS-CoV-2 S2 Ab, which:

  • Rather enhance cellular infection
  • Activate complement and the coagulation cascade.


Hospitalizations during Delta on Omicron wave in US

Ep 251-2: Taylor MMWR 18 March


During omicron (January 2022), almost 3 times more hospitalization than during delta wave in  unvaccinated adults and those vaccinated with a primary series.  Those with a booster were better protected against hospitalization.  

Rates among non-Hispanic Black adults increased more than rates in other racial/ethnic groups.



Several interesting cohort studies from Qatar

Qatar organized a nation-wide cohort since 28 Feb 2020 and followed up infections, vaccinations and (sublineages), which provided a wealth of data…

Ep 251-3: Chemaitelly medRxiv 18 March Comparison protective effect by natural infection versus mRNA vaccination over entire pandemic period (Feb 2020 – March 2022). 


Natural infection was associated with:

  • 50% lower incidence of SARS-CoV-2 infection than mRNA primary-series vaccination.
  • lower incidence of COVID-19 hospitalizations in previously infected than vaccinated, but COVID-19 hospitalizations were rare for both the natural-infection and vaccinated cohorts.


  • vaccine protection against infection waned with time after the second dose,
  • natural immunity demonstrated hardly any waning in protection for eight months

Omicron wave led to

  • a massive increase in incidence of reinfections in both the natural-infection and  vaccinated cohorts.
  • Yet, natural infection was still associated with 50% lower incidence than BNT162b2 vaccination, and 40% lower incidence than mRNA-1273 vaccination.


Ep 251-4: Qassim medRxiv Comparison BA.1 versus BA.2

Both Omicron:

  • Lower viral load if previous infection or vaccination, but VL increases with time since vaccine
  • Higher VL in men and increasing with age
  • Higher VL is symptomatic
  • Higher VL during peak of infections

BA.2 higher viral load, signifying higher infectiousness


Ep 251-5: Chemaitelly medRxiv 25 Feb  Protection of Omicron sub-lineage infection against reinfection with another Omicron sub-lineage 




Remember UK Health Security Agency 10 March 2022: Vaccine effectiveness similar against BA.1 and BA.2






Delta versus omicron breakthrough infections


  1. Induction of natural neutralizing antibodies after vaccine breakthrough infections


Ep 251-6: Seaman medRxiv 3 March Distinct profile of neutralization during convalescence


  • Viral load at the time of infection was inversely correlated with antibody binding and neutralizing antibody responses
  • Across all variants tested, convalescent neutralization titers in unvaccinated individuals were markedly lower than in vaccinated individuals.  (in the former case: immunity after infection only; in the latter case it is  hybrid immunity: first vaccine then breakthrough infection)
  • For individuals infected with the Delta variant, neutralizing antibody responses were weakest against BA.2, but stronger against D614G and delta
  • Infection with Omicron BA.1 variant generated a broader response against all tested variants, including BA.2.




  1. Effectiveness of therapeutic monoclonal combinations in immunocompromised subjects against delta and omicron breakthrough


Ep 251-7:  Bruel medRxiv 12 March 2022: Seroneutralization of Omicron BA.1 and BA.2 in patients receiving anti-SARS-CoV-2 monoclonal antibodies


Comparing Roche Ronapreve (Casirivimab + Imdevimab) and Astra-Zeneca Evusheld (Cilgavimab + Tixagevimab):

  • Ronapreve recipients all neutralized delta but did not neutralize BA.1 and weakly impaired BA.2.
  • With Evusheld, all delta neutralized;  BA.1 in 19/29 and BA.2 all (but weakly)
  • 4 breakthrough infections with omicron (1 identified as BA.1, others unclear sublineage).


Anti-Omicron activity of Ronapreve, and to a lesser extent that of Evusheld, is reduced in patients’ sera, a phenomenon associated with decreased clinical efficacy.


Explanation: Fig 1: Sensitivity of variants to various purified mAbs,  including Eli Lilly’s Bamlanivimab-Etsesivimab, Ronapreve



Delta sensitive to most monoclonals tested (except Bamlanivimab)

BA.1 and BA.2 not sensitive to Bamlanivimab, Etesivimab, Regdanvimab, Casivirimab and Tixagevimab

BA.1 fully sensitive to Sotrovimab, not sensitive to Imdevimab, but still partly sensitive to Cilgavimab

BA.2 not sensitive to Sotrovimab,  partly sensitive to Imdevimab and fully sensitive to Cilgavimab


Fig 2: Sensitivity to sera from patients, either (1) untreated (naïve) or treated with (2) Ronapreve or with (3) Evushield or (5) Ronapreve + Evushield mixted



Delta well neutralized, but

  • BA.1 insensitive to Ronapreve-sera and weakly sensitive to Evushield sera
  • BA.2 weakly sensitive to Ronapreve and more sensitive to Evushield, , but less than delta.



Ep 251-8: Benotmane medRxiv 19 March 21, 2022: Apparent failure of Evushield to protect kidney transplant patients against omicron


Of the 416 KTRs who received intramuscular prophylactic injections of EvusheldTM (150 mg

tixagevimab and 150 mg cilgavimab),

  • 39 (9.4%) developed COVID-19: all symptomatic (except 1)
  • Hospitalization for 14 (35.9%) and ICU in 3 patients
  • Two KTRs died of COVID-19 ARDS


SARS-CoV-2 sequencing in 15 cases (BA.1, n = 5; BA.1.1, n = 9; BA.2, n=1).

Viral neutralizing activity of the serum against BA.1 variant was negative in the 12 tested patients


Suggesting that this prophylaxis strategy provides insufficient protection against this variant of concern




Side-by-side humoral and cellular memory to 4 COVID vaccines  


= first comparison by the same lab, using standardized methods


Ep 251-9: Zeli Zhang medRxiv 21 March 2022 compares Ab, CD4 and CD8 T responses to Pfizer, Moderna, Janssen (Ad26 COV2.S) and Novavax over 6 months


  1. Neut Ab: peaking at T3 for mRNA (= 2-3 weeks after 2nd dose); then declining; while lower but increasing for Janssen.  Novavax at later timepoints comparable with mRNA  







F = at T4 (6 months)




  1. CD4 T 100% of individuals made memory CD4+ T cells, with cTfh (follicular T cells for B cell maturation) and CD4-CTL (cytolytic cells) highly represented after mRNA or NVX30 CoV2373 vaccination.



Spike specific T follicular helper cells: similar levels for various conditions after 6 months (in E)   



Spike-specific cytolytic CD4 T cells: more represented after mRNA (and Novavax) than after Janssen



  1. CD8 T : about 2/3 after 6 months with comparable levels after mRNA and Janssen





    • mRNA vaccinees had substantial declines in neutralizing antibodies, while memory T cells and B cells were rather stable over 6 months.
    • Janssen elicit not strongest responses but both Ab and T cells stable over 6 months







  1. The role of cross-reactivity with common cold beta CoV in COVID pathogenesis remains controversial:partly protective versus contributing to pathogenesis ?


  1. Despite omicron being intrinsically less severe, it caused a huge wave of hospitalizations in US, especially in non- or incompletely (no booster) vaccinated individuals and non-hispanic blacks.


  1. The Qatar cohort offers exciting insights:
    • Prior infection provides a better and more durable protection against (re)infection than vaccination, even against omicron.
    • BA.2 higher viral load (more infectious) than BA.1.
    • BA.1 and BA.2 provide cross-protection against each other.
    • (UK data: mRNA vaccination + booster provides similar protection against BA.1 and BA.2).


  1. Complex pattern of sensitivity to commercially available therapeutic monoclonal Ab:
    • Delta sensitive to most monoclonals tested (except Bamlanivimab from Eli Lilly cocktail)
    • Both omicron sublineages resistant to Eli Lilly and  
    • BA.1 completely resistant to Ronapreve, but fully sensitive to Sotrovimab
    • BA.2 completely resistant to Sotrovimab, but some remaining sensitivity to Ronapreve(?)
    • BA.1 and BA.2 less sensitive to Evusheld, with more residual sensitivity for BA.2


Usefulness of mAb to prevent/treat omicron in immune suppressed individuals clearly lower


  1. mRNA vaccines elicit the strongest Ab responses on the short term, but waning, while Adeno-Janssen lower initial T and B responses, but rather stable. Protein Novavax limited data, but rather similar to mRNA.



Best wishes,