Wed, 10/05/2022 - 12:58
Dear colleagues,
The BA.2-derived BA.2.75 (nick-name “black horse” or centaurus” has been considered as a potential new pandemic virus, but it’s prevalence outside of India fails to dramatically increase. I will summarize the main literature on epidemiological, virological, immunological, clinical and therapeutic aspects of BA.2.75 in chapter 1.
The latest “new kid in town” is BQ.1.1, which is derived from BA.5 and has important immune evasive capacity. It will be framed amongst other new variants in Chapter 2.
CHAPTER 1 THE BA.2.75 STORY
BA.2.75 emerged in India in the Spring and has taken over the local epidemic (now 75 %). In view of its wide range of mutations, with clear evidence of both immune escape and higher affinity for the ACE-2 receptor, the expectation was that it would rapidly spread around the world. As of the end of Sept, it is still increasing in various countries and has reached a worldwide prevalence of 3 %, but it hasn’t really taken over the pandemic.
Experiments in animals (hamsters and ferrets) confirmed the high replication capacity, superior to BA.5. (Par 1)
BA.2.75 has a low sensitivity to neutralization by plasma vaccinated with either inactivated or mRNA vaccine. Breakthrough infection with either BA.1 or BA.2 increases the neutralization of the plasma towards BA.2.75. The pattern is, however, very similar to BA.5. So there is no clear-cut “immunological” benefit of BA.2.75 vs BA.5. (Par 2)
The clinical picture of BA.2.75 in India is rather “normal”, certainly not as dramatic as Delta, but the only clinical paper has a weak methodology (telephone interview of patients) (Par 3)
Finally, BA.2.75 remains sensitive to the main antivirals and to the mAb Bebtemovimab. BA.2.75 is partially resistant to Evusheld (but slightly more sensitive than BA.5).
Ep 289-1 William Haseltine 11 July: BA.2.75: A Dark Horse In The Covid Pandemic 11 July
BA.2.75 was independently derived from BA.2, significantly differing from BA.4 and BA.5.
Venn-diagram showing common mutations of BA.2.75 and BA.5 in the middle
and BA.2.75 specific mutations at the right in
- non-structural proteins: NSP-3 (S403L, P822S); NSP-6 ((F108L); NSP-8 (N118S) and NSP-12 (G671S)
- Spike: K147E, W152R, F157L, I210V, G275S, G339H, G446SD and N460K.
- E (=Env) protein: T11A19E
BA.2.75 Spike protein mutations. Those in red are found in BA.2.75. Those in blue are unique to BA.2.75, meaning they are not in BA.2. The sole mutation highlighted in green indicates that the position was reverted from Q493R back to Q493 in BA.2.75. Those in black are not found in BA.2.75 or BA.2 but are found in other Omicron strains
Haseltine ends with a warning:
To have such unique mutations at this stage of the pandemic when the virus has mutated into hundreds, even thousands of competing strains is astounding. These mutations likely have health officials on high alert, as a wealth of new mutations could indicate increased transmissibility or immune evasion if the variant catches fire like its predecessor.
Par 1 Virological aspects
Ep 289-2: Ryuta Uraki bioRxiv 26 Aug: BA.2.75 is clearly “fitter” than BA.5 in infection experiments in Syrian hamsters.
- BA.2.75 gives higher viral load in the lung than BA.2 or BA.5, but still less than B.1.617.2 (= delta)
- In competition assays, BA.2.75 replicated better than BA.5 in both nasal turbinate and lungs: even if only 20 % of the inoculum is BA.2.75 and 80 % BA.5 (as in c), the resultant concentration of BA.2.75 in the lungs and nasal turbinate increases to 50 % on average. When equal proportions of both are in the inoculum (b), BA.2.75 almost “wipes out” the BA.5
Ep 289-3: Se-Mi Kim: bioRxiv 28 Sept: Importance of P323L and G671S mutations in NSP-12 protein (= RNA dependent polymerase) in ferret infection experiments.
- The P323L mutation present in Alpha, Beta, Delta and Omicron results in enhanced transmissibility due to the increased viral growth properties and extended infectious virus shedding duration in the upper respiratory tract.
- All Omicron variants, from BA.1 to BA.5, commonly harbor the NSP12 P323L mutation and BA.2.75 Omicron variants also carry the NSP12 P323L/G671S mutation, similar to the Delta variant. This combined mutation has the highest replication capacity at 33°C (T° of nasal turbinates)
Replication and transmission of SARS-CoV-2 variants in ferrets
Mutations in NSP12,especially those in Delta and BA.2.75, increases viral replication in the upper respiratory tracts, which promotes the high transmissibility of SARS-CoV-2 VOC strains.
Ep 289-4: Aki Sugano bioRxiv 1 Sept: BA.2.75 much more infective than previous variants?
BA.2.75 has both the highest docking affinity and the longest evolutionary distance from the Wuhan S gene.
These results suggest that BA.2.75 infection can spread farther than can infections of preexisting variants.
Par 2 Immunological aspects: effect of vaccination and breakthrough infection on BA.2.75
Ep 289-5: Xun Wang medRxiv 8 Aug 2022: Neutralization of various Omicron (incl BA.4/BA.5 and BA.2.75) by Sera from Booster Vaccination or BA.2 Breakthrough Infection
Healthy donors with 3 X inactivated BBP vaccine or 2 X inactivated + 1 X protein ZF001
Donors with hybrid immunity : 2 X inactivated + BA.2 breakthrough
- Although BA.2.75 accumulated the largest number of mutations in its spike, BA.4 and BA.5 showed the strongest serum escape.
- BA.2 breakthrough infection increases neutralization titers against all different variants, especially titers against BA.2 and its derivative sub-lineages, including BA.2.75, but also BA.4/5.
Ep 289-6: Chengzi Kaku medRxiv 22 Sept: Immune escape by various Omicron sublineages after BA.1 breakthrough infection
In this setting, escape by BA.2.75 seems moderate: in between BA.2 and BA.4/5: spike mutations N460K in BA.2.75 and F486V most probably have a role in immune escape.
Neutralization remains rather stable after 6 months
In depth analysis of memory B cells, showed evolution (somatic hypermutation) over 6 months that could broaden the antibody response upon re-encounter with SARS-CoV-2
Ep 289-7 Xuping Xia bioRxiv 8 Aug: Effect of 3 and 4 RNA vaccines as well as BA.1 breakthrough infection
- BA.2.75 is “equally” evasive as BA.5 to 3 or 4 mRNA vaccines (measured as neutralizing antibodies)
- Neut against BA.2.75 as compared with BA.5 by BA.1 breakthrough: less enhanced after 2 mRNA doses, but more enhanced after 3 mRNA doses
Par 3 Epidemiology and Clinic
Ep 289-8 Cobas WHO report 111 26 September
Clearly: India remains the hotspot for BA.2.75: up to 75 % at the end of Sept.
It remains a minority in other countries, but is growing to 3 % worldwide
Ep 289-9: Rajesh Karyakarte medRxiv 9 Sept: Early and Preliminary Assessment of the Clinical Severity of the Emerging SARS-CoV-2 Omicron Variants in Maharashtra, India
As can be seen, the BA.2.75 (yellow) is increasing between June and August
A total of 228 cases with either BA.2.74, BA.2.75 or BA.2.76 were contacted by phone:
1) Clinical status
5.7 % no symptoms
94.3 % symptoms: fever > cough > cold > fatigue > myalgia
14.5 % hospitalized of whom 93 % conservative treatment, 5 % oxygen
1.3 % death (3 persons in total)
2) Vaccination status:
96 % vaccinated with 72.6 % 2 doses and 26 % 3 doses.
Conclusion: The three BA.2 sublineages are causing mild disease in India. However, BA.2.75 has key mutations that are notable for accelerated growth and transmission and require close and effective monitoring
Par 4 Treatment
Ep 289-10 Shuetsu Fukushi NEJM Efficacy of antiviral agents against BA.2.75
These data suggest that
- Remdesivir, Molnupiravir, and Nirmatrelvir remain effective against BA.2.75
- Bebtelovimab and Tixagevimab–Cilgavimab (= Evusheld) have neutralizing activity
BA.2.75 is less susceptible to Casirivimab–Imdevimab (Regenron cocktail) and Sotrovimab in the clinical setting
Ep 289-11: Sheward Lancet Infect Dis 1 Sept: Rather similar data:
- As compared to BA.2 and BA.5, BA.2.75 is slightly less sensitive to Bebtelovimab and more sensitive to Evusheld
- Interesting observation of a “boost” of neutralization in the Swedish population against BA.2, BA.5 and BA.2.75 by an infection wave with BA.1/BA.2 during the winter of 2021-22.
Ep 289-12: Yamasoba bioRxiv 15 July: also rather similar data
Ep 289-13 Young-Jun Park bioRxiv 22 Aug: S2X324 is a new “ultrapotent pan-variant” SARS-CoV-2 neutralizing antibody, which neutralizes BA.2.75 well (just a little bit less)
CHAPTER 2: Some data on other new variants, including BQ.1.1
BQ.1.1 is derived from BA.5, but has greater comparative growth advantage BA.5 about 5.3 times (531%) and has a relative growth advantage BA.2.75.2 About 3.2 times (327%),
Mutations in Spike as compared to BA.5: a lot in common, but 3 additional R3467, K444T and N460K
Differences with BA.2.75: amino-acids 69-70 are missing, L452R, K444T, G339D, and F486V are present
- Rapid increase in the number of infections of BQ.1.1, especially in the UK: the first sample was found on August 26, 2022, now 28 cases (September 22, 2022). 78 cases have been found worldwide, including England, the United States, France, Australia, Italy, Denmark, Belgium , Japan, Austria, Netherlands, Germany.
Ep 289-14: Yonlung Cao bioRixv 23 Sept: Imprinted SARS-CoV-2 humoral immunity induces converging Omicron RBD evolution
This is a very important paper with some focus on BA.2.75 and BQ.1.1. Various sublineages from either BA.2 or BA4/5 are being compared for their mutations, growth advantage, affinity for ACE-2 and sensitivity to monoclonal antibodies and plasma from vaccinated individuals (without or with subsequent breakthrough infections with BA.1, BA.2 or BA.5).
- In recent BA.2 and BA.5 sublineages, we see a number of similar “convergent” mutations (in b) many of which show high relative growth advantage over BA.5 (which has already an extensive growth advantage)
- Many of these newer variants escape from monoclonal antibodies.
- As we have seen 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 all except 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
- Neutralization by plasma from vaccinated (inactivated vaccine) + breakthrough infect. with Omicron variants.
BA.2.75 is moderately resistant to neutralization with plasma from vaccinated, with some increased sensitivity to plasma from breakthrough infected subjects
BQ.1.1 is very resistant to plasma from vaccinated and the increase after breakthrough infection is very limited.
- Accumulation of additional “key mutations” in BA.2.75 or BA.5 Spike leads to complete neutralization-resistance
While BA.2.75 and BA.5 still show sensitivity to particular monoclonals and after vaccination (+/- breakthrough), they become very resistant with additional mutations. Panel C shows that these mutations also lower the affinity for the ACE-2 receptor (higher IC50), but it remains in the “black” (intermediate) range, hance higher than D614G (= European variant of Wuhan -see point 2 B).
Conclusion:
- BA.2.75.2 and BQ.1.1 are the most antibody-evasive circulating strains, far exceeding BA.5.
- As few as five additional convergent mutations based on BA.5 or BA.2.75 could completely evade most plasma samples, including those from BA.5 breakthrough infection, while retaining sufficient hACE2-binding affinity.
→ Current herd immunity and BA.5 vaccine boosters may not provide sufficiently broad protection against infection with new variants. Therefore, broad-spectrum SARS-CoV-2 vaccines
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