8 May 2022 Episode 260 Omicron-specific vaccines and immunity to new omicron BA.2 subvariants

Sun, 05/08/2022 - 20:00

Episode 260: Omicron-specific vaccines and immunity to new omicron BA.2 subvariants

Dear colleagues,

While preparing a lecture, I came across some puzzling data on omicron-specific vaccines. Patrick Smits also send me several preprints that shed some new light on the immunity against omicron-subvariants.

Par 1 How useful could Omicron-specific vaccines be? 

Ep 260-1: I-Jung Lee bioRxiv 31 Jan 2022: Omicron-specific mRNA vaccine in lipo-nanoparticles can induce potent neutralizing antibody response against Omicron itself in mice, but the inclusion of epitopes from other variants (in casu Delta) seems required for eliciting cross-neutralizing antibodies.


Fig. 1 RBD mRNA constructs and RBD-LNP vaccine


Fig. 2 Neutralization capacity of various RBD-LNP vaccine immunized mouse sera against D614G, Beta, Delta, and Omicron SARS-CoV-2 pseudovirus variants



  • Bivalent vaccine composed of both Omicron and Delta RBD-LNP in half dose, elicited slightly higher and broader responses than delta alone. 
  • The omicron-delta hybrid elicited a broader response than omicron vaccine, higher titers against omicron, but  lower titers against WT, beta, delta than either delta or WT vaccine


Ep 260-2: Gagne bioRxiv 4 Feb 2022: mRNA-1273 = wild type)  or mRNA-Omicron boost in vaccinated macaques elicits comparable B cell expansion, neutralizing antibodies and protection against Omicron




Ep 260-3: Yi Wu bioRxiv 1 March 2022 Omicron-specific mRNA vaccine elicits potent immune

responses in mice, hamsters, and nonhuman primates


Figure 3. SOmicron-6P Provides Robust Protection against Omicron in Syrian Hamsters.




Figure 4. SOmicron-6P Induces Omicron-Specific Immunity in Macaques.




Ep 260-4: Pai Peng bioRxiv 17 March 2022 Extensive neutralization against SARS-CoV-2 variants elicited by Omicron-specific RBD protein subunit vaccine booster in mice


  • Three doses of Omicron-RBD immunization elicit comparable neutralizing antibody (NAb) titers with three doses of WT-RBD immunization to the homologous (pseudo)virus, but the neutralizing activity was not cross-active.
  • By contrast, two doses of WT-RBD with an Omicron-RBD booster increased the NAb geometric mean titers against Omicron by 9 folds and showed cross-neut against both WT and current VOCs





Ep 260-5: Qidong Hu bioRxiv 18 March 2022 Chimeric mRNA based COVID-19 vaccine induces protective immunity against Omicron and Delta


The figures are of poor quality, therefore I try to summarize in text

  • Concept of  mutated furin cleavage site, providing a stable S protein remains fully immunogenic
  • Prime-boost with the various variant (VOC) of this mRNA construct provided variant-specific neut in mice.
  • Beta-Furin and Washington (WA)-Furin mRNAs showed potent cross-reactivity and also cross-protection  with other VOCs (WA = very similar to wild-type)
  • Nevertheless Omicron challenge escaped from these immune responses, but was sensitive to omicron mRNA vaccination
  • The novel concept is an hybrid mRNA, based on omicron-furin, with inserted delta RBD →

inducing potent and broadly acting nAb against Omicron (both BA.1 and BA.2) and Delta, (however protection against challenge was not shown).


General conclusion par 1


Note: “Omicron” in all these experiments is presumably the BA.1 subvariant.


To overcome escape by omicron, most of these studies suggest that WT vaccination should be completed by omicron specific vaccine, either in a “bivalent” or “hybrid” approach in a two-dose scheme. 


With regard to a three-dose scheme, the papers by Gagne (260-2) and Peng (260-4) seem contradictory:

  • Gagne shows  in macaque equal protection by 3 X WT versus 2 X WT + 1 X Omicron
  • Peng finds that 2 X WT + 1 X Omicron elicits a higher and broader neut response than either 3 X WT or 3 X Omicron.


There are several differences between both studies:

  • Gagne uses mRNA of full Spike in macaques
  • Peng uses protein of RBD in mice  


A suivre


Par 2:  News on Omicron sub variants


Ep 260-6: Catherine Mary in Le Monde 4 May 2022 discusses in semi-lay language the various hypotheses on how the evolution of SARS-CoV-2. Original French version in A; good translation (by Wim Vandamme) in B.  Nothing new for the “episode readers”, but more narrative and didactic.


Ep 260-7: Smriti Mallapathy Nature Briefing 5 May 2022: Most US kids have caught the coronavirus, antibody survey finds with doubling in young children during omicron wave.




Ep 260-8:  Kadjai Kahn Nature 4 May 2022: Omicron infection enhances Delta antibody

immunity in vaccinated persons  (but in fact also against beta and D614G)


Comparison of neutralization capacity in the Omicron/BA.1 infected + vaccinated (n=15) versus Omicron/BA.1 infected unvaccinated (n=24) participants against Omicron/BA.1, Omicron/BA.2, Beta, Delta and ancestral/D614G viruses.  (vaccine = Pfizer-BNT162b2 or J&J-Ad26.CoV2.S)





  • Vaccination combined with Omicron/BA.1 infection hybrid immunity should be protective against Delta and other variants.
  • In contrast, infection with Omicron/BA.1 alone offers limited cross-protection despite moderate enhancement.


Ep 260-9: Naranbhai 19 March 2022: T cell reactivity to the SARS-CoV-2 Omicron variant

is preserved in most but not all individuals



Ep 260-10: Xiaoliang Xie May 2022 Res Square:  BA.2.12.1, BA.4 and BA.5 escape antibodies elicited

by Omicron BA.1 infection. (and various therapeutic mAbs as well)


  1. BA.2, BA.2.12.1 and BA.4/BA.5 viruses exhibit stronger neutralization evasion against the plasma of 3-dose CoronaVac vaccinees and, most strikingly, of vaccinated BA.1 convalescents.

= escape from both inactivated vaccinees and hybrid immunity !!




Explanation = mutations in R346 and L452: R346K (BA.1.1), L452M (BA.2.13), L452Q (BA.2.12.1) and L452R (BA.4/BA.5)


  1. Further escape from therapeutic mAbs: activity against SARS-CoV-2 variants and sarbecoviruses by therapeutic neutralizing antibodies. green, IC50 < 30ng/mL; red, IC50 > 1,000ng/mL; *, IC50 > 10,000ng/mL



According to these authors LYCoV1404 (Bebtelovimab) and COV2-2130 (Cilgavimab) can still effectively neutralize BA.2.12.1 and BA.4/BA.5, but the SA55 and SA58 mAb, invented by two of the authors (Xiaoliang Sunney Xie and Yunlong Cao) show the most potent and broad Pan-sarbeco profile.


Ep 260-11: Yamashoba bioRxiv 3 May 2022: Sensitivity of novel SARS-1 CoV-2 Omicron subvariants, BA.2.11, BA.2.12.1, BA.4 and BA.5 to therapeutic monoclonal antibodies



In this experiment, Bebtelovimab is still active against all subvariants, while Cilgavimab retains its activity against BA.2.12.1, but not against BA.4/5!!!  



Conclusions par 2:


  1. Omicron BA.1 infection alone fails to induce much cross-neut in non-vaccinated subjects (also not against BA.2), but hybrid immunity induces strong cross-neut after BA.1 infection in Pfizer and Janssen vaccinated subjects.
  2. There is accumulating evidence that induction of T cell immunity against structural proteins other than Spike (nucleocapsid, membrane, envelope) could broaden protection against variants.  
  3. BA.2, BA.2.12.1 and BA.4/BA.5 viruses escape from both 3 X CoronaVac and hybrid immunity.  Also the sensitivity to therapeutic mAbs is further decreased (with some discrepancy with regard to Cilgavimab between the two studies). Nevertheless there are still mAbs (such as SA55 and SA58) which can potently neutralize all subvariants


Best wishes,