27 Oct 2022 Episide 292 New variants omicron reinfections and adapted vaccines

Episode 292: Update on evolution with BA.5 and BA.2 sublineages.  Evolution of immunity after vaccination omicron and breakthrough infections

Dear colleagues,

• These new variants were already  announced in Episode 289, but it is becoming more clear now that mainly BQ.1 and BQ.1.1 may be taking over the epidemic in US and Europe.
• While antibody responses to omicron are weak as a consequences of imprinting, it now seems that memory B cells are gaining affinity over time, but will that save us from new variants?

Par 1 New variants

Ep 292-1: CDC data clearly show that BQ.1, BQ.1.1 and BF.7 are rapidly increasing, while other “new” variants (e.g. BA.2.75 and BA.2.75.2) remain low.

Ep 292-2:  According to ECDC there is a similar evolution in several European countries: in just a few weeks, the proportion of BQ.1 rose in Netherlands to 6 %, Denmark to 8 %, Belgium to 9 %, Italy to 13 %, France to 19 %.   Also in Switzerland 9 % and UK 8 %.

Modeling shows that by the beginning of 2023 BQ.1 would be very dominant in EU (> 80 %)

The key mutations for BQ.1 are K444T and N460K and in addition, there is R346T in BQ.1.1

The variant is originating from central-west Africa and is escaping immunity.  Not so clear whether there is also a transmission advantage. Nu signs of increased disease severity.

Ep 292-3:   WHO update shows all details on BA.5 and BA.2 sublineages.

Ep 292-4: Eric Topol 23 Oct: We're heading into a new BQ.1.1 variant led wave  

The figure shows how a “convergent” set of mutations emerges in the BA.5 derived BQ.1.1, the BA.2 derived BA.2.75.2 and the recombinant XBB, with as major “convergent mutant players” : R346T, K444T, L452R, N460K and F486V.  These variants originate from different parts of the world (India BA.2.75, Singapore XBB, West-Afrika BQ.1). The convergence between them suggests that the immune pressure from infected and/or vaccinated subjects is similar around the world and drives these same escape mutations on a different variant background.

Ep 292-4 B According to the very clear MOH website in Singapore ( https://www.moh.gov.sg/), the number of cases and hospitalizations in Singapore (highly vaccinated: 79 % 3 doses) are coming down again. So the XBB wave is decreasing?

Ep 292-5: Panke Qu bioRxiv 20 Oct: Distinct Neutralizing Antibody Escape of SARS-1 CoV-2 Omicron Subvariants BQ.1, BQ.1.1, BA.4.6, BF.7 and BA.2.75.2

1. In 3 X vaccinated HCW, especially BQ.1.1 and BA.2.75 escape most from neutralization. 

2. Similar pattern of escape after BA.1 or BA.5 infections

Analysis of single mutants shows that N460K is most important for immune escape, followed by K444T and R346T.

Ep 292-6 = Ep 289-14: Yonlung Cao bioRixv 23 Sept: Imprinted SARS-CoV-2 humoral immunity induces converging Omicron RBD evolution.

Also escape from therapeutic monoclonal antibodies:

• • BA.2.75 remains sensitive to Evusheld (COV2-2196 +2130) and bebtelovimab (LY-COV1404) and also to SA55 + SA58.
  • BQ.1.1 however is resistant to Evusheld, Bebtelovimab and even SA58, but remains sensitive to SA55

In B, the affinity for the ACE-2 receptor is show: the lower the IC50 (blocking capacity of soluble ACE-2), the higher the affinity.  Hence, all those variants in blue have a high affinity (incl BA.2.75); while those in red a low affinity. Black (incl BQ.1.1) intermediate affinity

Par 2 Update on effect of mono-valent and bivalent boosters and of reinfection immunity

2.1 Protection against hospitalization by boosting with the monovalent mRNA vaccine in immunocompetent and immunocompromised subjects US

Ep 292-7: Diya Surie MMWR 21 Oct Effectiveness in  immunocompetent subjects

Three-dose VE during BA.1/BA.2 wave 79% during the initial 120 days and         41% after 120 days from vaccination.

                               during BA.5  wave only 60 %                                                                    29 %     

Ep 297-8: Amadea Britton MMWR 21 Oct Effectiveness in immunocompromised subjects

VE was 67% ≥7 days after a third dose during BA.1 predominance but declined during BA.2/ BA.2.12.1 and BA.4/BA.5 predominance to 32% ≥90 days after dose 3 and 43% ≥7 days after dose 4

Conclusion of both authors: Protection against hospitalization by 3 doses of monovalent ancestral vaccine against newer omicron (BA.5) is lower and wanes fast in both immunocompetent and immunocompromised subjects → need for adapted vaccine.

2.2. Immunogenicity of BA.1 and BA.5 adapted vaccines

Ep 292-9: Chalkais NEJM 16 Sept Bivalent omicron BA.1 vaccine (Moderna) as a second booster (4th dose).

The bivalent BA.1 booster (mRNA.1273.214) and the monovalent ancestral (mRNA-1273) induce similar increase in neutralizing Ab against ancestral strain.

Bivalent booster induces 1.6 X higher neut against omicron (BA.1) in subjects without and 2 X higher in subjects with previous infection. 

Titers against omicron remain clearly lower than against ancestral strain.

Titers against BA.4/5 were > 10 times lower: 727.4 (CI, 632.8 to 836.1) and 492.1 (CI, 431.1 to 561.9), respectively, against omicron BA.4 and BA.5.

Moreover, while vaccine effectiveness was not formally assessed,  SARS-CoV-2 infection occurred in 11 participants after the mRNA-1273.214 booster and in 9 participants after the mRNA-1273 booster.  No data on genotyping, but presumably post-BA.1 (hence infection with BA.2 or BA.4/5).

Ep 292-10: Ai’ris Collier bioRxiv 25 Oct Immunogenicity of mono-valent ancestral and bivalent BA.5 vaccine (Pfizer and Moderna) in subjects who had already 3 (2-4) vaccine doses; hence 2nd booster!

Neut titers against ancestral and omicron sublineages

                                               CD8 T responses                                                                            CD4 T responses

In these already repeatedly vaccinates subjects, the bivalent BA.5 boosters did not offer a strong additional immunological advantage: a similarly moderate increase in neutralizing titers and in activated CD4 and CD8 T cells.

The authors conclude:  Our findings suggest that immune imprinting by prior antigenic exposure may pose a greater challenge than currently appreciated for inducing robust immunity to SARS-CoV-2 variants.

2.2. Omicron infection-induced protection against BA.2 and BA.5

Ep 292-11: Christian Hansen Lancet Infect Dis 18 Oct 2022

1. Previous BA1/2 omicron infection in triple-vaccinated individuals provides high amounts of protection against infections with BA.5 (93%) and BA.2 (97 %).   This level of protection is much higher than that provided by previous exposure to alpha or delta.

2.  Vaccine protection against BA.5 infection was similar or slightly weaker than against BA.2 infection, i.e. the slightly higher vaccine coverage in BA.5 cases than BA.2 cases suggests a marginally poorer vaccine effectiveness against BA.5.

3.  BA.5 infections were associated with an increased risk of hospitalisation compared with BA.2 infections.

Implication: The effect of the current BA.5 wave might be small in populations with a high degree of hybrid immunity (ie, via previous infection and vaccines).

Ep 292-12: Qian Wang bioRxiv 24 Oct 2022: Comparing BA.4/5 neutralizing Ab after either 4th dose of monovalent or bivalent vaccine vs BA.4/5 breakthrough infection.

1. BA.4/BA.5 breakthrough infection induced higher ID50 titers against SARS-CoV-2 variants
2. Either a monovalent ancestral or a bivalent BA.5 vaccine as 4th dose had similar neutralizing antibody titers against all SARS-CoV-2 variants tested, including BA.4/BA.5.
3. Nevertheless: ancestral (WT) as 4th dose induced higher neut titers against other “sarbecoviruses”  such as SARS-CoV, Pangolin (GD and GX) as well as the bat virus WIV1. 

Conclusion:  Again arguments in favor of “imprinting” and hybrid immunity.  The 4th dose of WT (ancestral) vaccine provides a small advantage against other human and animal beta CoV (related to SARS-CoV-2), implying a broadening of the immune response in that direction.  

2.3. How is immune memory evolving after omicron breakthrough infection?

Ep 292-13: Zijun Wang J Exp Med vol 219 no. 12: Memory B cell responses to Omicron subvariants after SARS-CoV-2 mRNA breakthrough infection in humans.

Comparing BTI with delta after 2 mRNA vaccines vs. omicron after 3 mRNA vaccinations

• Third antigenic exposure by Delta → strain-specific memory responses and clear increases in the overall potency and breadth of the memory B cells.
• Fourth antigenic exposure with Omicron BA.1 are limited to increased strain-specific memory with little effect on the potency or breadth of memory B cell antibodies.

Delta BTI has a similar effect as 3rd vaccine: increase in neut against WT, Delta and Omicron BA.1, BA.2, BA.4/5

Additional BTI with omicron increases neut titers only against omicron BA.1 and  BA.2, but NOT against WT, Delta or BA.4/5.

Implication: The results suggest that the effect of strain-specific boosting (e.g. by omicron BA.1 vaccine) on memory B cell compartment may be limited and not significantly increase a broad neutralizing effect against subsequent omicron variants (e.g. BA.4/5.

However, observation based on limited time: 1 month after BTI.

Ep 292-14:  Chenzi Kaku bioRxiv 22 Sept Evolution of antibody immunity following Omicron 1 BA.1 breakthrough infection after 6  months

Serum neutralizing Ab titers against all variants decline over 6 months.

But what happens in the germinal centers of lymph nodes where memory B cells reside and potentially evolove?

In the memory B cell compartment between T1 and T2 (= 6 months)

1. Increase of cross-reacting wild type/BA.1 clones

2. Increase of WT/BA.1 cross-neutralizing Ab

3. However: many of the memory clones after 6  months have no potency against mutations, typical of newly emerging variants

Conclusions:

Despite the lower neut titers in the serum 6 months after omicron BTI, memory B cells mature:

• Cross-reactive  (WT/BA.1) antibody responses evolve toward increased BA.1 affinity and neutralization potency against BA.1
• They broadly recognized other SARS-CoV-2 variants, except for BA.4/5, which was associated with a 5-fold loss in affinity for 57% of the WT/BA.1 neutralizing antibodies. → this may provide a certain protection against most omicron re-infections
• RBD positions N460 and F486, which are mutated in emergent variants (B.2.75, BA.2.75.2, BN.1, and BQ.1;); and F486V in BA.4/5, BA.4.6, and BQ.1.1,  were associated with binding escape from “matured” Ab in the memory repertoire →this may explain why new omicron variants with these particular mutations are now emerging.

PERSONAL CONCLUSIONS:

Reinfection with omicron or vaccination with omicron-adapted vaccines results in a more limited protection against new variants, because of “imprinting”: after repeated exposure, our immune system first focuses on epitopes that we have seen before, but part of those have become irrelevant.  Nevertheless, our memory B cells do mature over time and acquire more cross-neutralizing capacity. 

The virus is now confronted with an entire human population that has a certain level of immunity against previous variants and gradually acquires cross-neutralizing antibodies, prevention infection with new, but related variants. Therefore, variants with new sets of mutations arise, that escape even the “matured” B cells.  Those are the “convergent” set that we observe now in the latest variants BA.2.75, XBB, BQ.1 etc, which are creating local epidemics in different places and are competing to create the next “pandemic wave”.

Those new variants are highly transmissible and remain intrinsically pathogenic, but the partial immunity we all have (also at the T cell level) hopefully will prevent new dramatic waves of severe disease and mortality.

Best wishes,

Guido