Episode 264: Omicron subvariants
Still catching up on Omicron. Herewith some recent papers with many thanks to Patrick again. In the first paragraph will discuss the “biological” characteristics of those variants (epidemio- viral- cellular tropism – pathogenicity – immune escape). In the second paragraph, some data on susceptibility to therapeutic monoclonal antibodies are considered and in the last paragraph, the public health burden is elaborated.
PAR 1 BA.2 SUBVARIANTS
Ep 264-1: Evolution of BA.2 subvariants in various countries
Ep 264-2: Amy Maxmen Bature Briefing 27 May 2022: A guide to the tangled Omicron family
How the new viruses are named
PANGO: The initial letters in the name reflect when Pango gave the lineage a label, following in a sequence from A to Z, then from AA to AZ, BA to BZ, and so on. Separated by a full stop, the next numbers indicate the order of branches from that lineage. For example, BA.1,BA.2, BA.3, BA.4 and BA.5 are the first five branches descending from an original Omicron ancestor. And BA.2.12.1 is the 12th lineage to branch off from BA.2, and then the first named branch on that 12th bush
WHO: If a variant evades the immune system much more effectively than others in circulation, causes more severe disease or is much more transmissible, the WHO might determine it to be a ‘variant of concern’ and change its name to a Greek letter
Whereas Pango’s technical names are meant to help researchers track SARS-CoV-2 evolution, the WHO’s system places a priority on the ease of communication to the public.
Ep 264-3: Wang bioRxiv 26 May: SARS-CoV-2 Omicron BA.2.12.1, BA.4, and BA.5 subvariants evolved to extend antibody evasion
Sensitivity to sera from vaccinated and boosted individuals:
- BA.2.12.1 is only modestly (1.8-fold) more resistant than BA.2.
- BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections
Role of mutations:
- L452 mutations to M/Q or R in all BA.2 subvariants enhance escape
- F486V in BA.4/5 enhances escape, but reduces fitness → compensated by R493Q
Sensitivity to therapeutic mAbs: only bebtelovimab (LY-COV1404) retains full potency against both BA.2.12.1 and BA.4/5.
Ep 264-4: Kimura bioRxiv 26 May: Various characteristics of BA-2 subvariants
- Spike L452R/Q/M mutations in BA.4/5, BA.2.12.2 and BA.2.9.1/BA.2.13 resp. increase the effective reproduction number of BA.2
- BA.4/5 is resistant to the immunity induced by BA.1 and BA.2 infections:
- BA.1 and BA.2 (primo) Infection induce weak neutralization (A and C)
- BA.1 and BA.2 breakthrough infection induce strong neut against BA.1,; but lower neut against BA.2 and its subvariants (B and D)
- BA.2.12.1 and BA.4/5 more efficiently spread in human lung cells than BA.2 (but similar to BA.1)
- BA.4/5 is more pathogenic than BA.2 in hamsters
Ep 264-5: Alejo medRxiv 30 May pre-omicron infections protect 67 % against omicron in unvaccinated subjects.
- BA.2 subvariants are clearly more infectious.
- Especially BA.4/5 and to a lesser extent the other BA.2 subvariants escape from immunity by vaccination and infection and may be more pathogenic (infection of alveolar cells and clear pathology in hamsters).
- Nevertheless, there is still a level of protection by previous infection and/or vaccination, which may prevent serious illness.
PAR 2: ACTIVITY OF THERAPEUTIC MONOCLONAL ANTIBODIES
See Episode 253 for early in vitro data
Ep 253-3: Takashita NEJM Feb 2022 focus on BA.2
Etesevimab and Bamlanivimab essentially inactive against BA.2
REGN combination and Sotrovimab lose a lot (50- 60 X)
Evusheld still active, but based on Cilgavimab only
Remdesivir (GS-441524), Molunipiravir (EIDD-1931) and Nirmatrelvir (PF-07321332) fully active
Ep 253-4: Bruel medRxiv 12 March comparison BA.1 vs BA.2 v
- The Eli Lilly cocktail (Bam-Ete) and the REGN cocktail (Casi-Imde) no longer useful for omicron
- Sotrovimab loses most activity against BA.2, but keeps activity against BA.1
- Evusheld keeps some activity against BA.2, less against BA.1 but fully dependent on Cilgavimab
Ep 264-6: Young-Xu medRxiv Retrospective clinical data:
Using US real-world data from predominantly vaccinated, immunocompromised Veterans (> 65 yrs), administration of tixagevimab/cilgavimab (Evusheld) was associated with lower rates of SARS-CoV-2 infection, COVID-19 hospitalization, and all-cause mortality during the Omicron surge (until April 2022.
However: Current data indicate that tixagevimab/cilgavimab maintains neutralization
against Omicron BA.2 and BA.2.12.1, but this effect may be attenuated with BA.4 and BA.5?
Anti-Spike monoclonal antibodies
REGN10987 + REGN10933
Cilgavimab + Tixagevimab
COV2-2130 + COV2-2196
Etesevimab + Bamlanivimab
(Eli Lilly co.)
LY-CoV016 + LY-CoV555
Clearly, according to these data, (from Ep 264-3), the Regeneron and Eli Lilly combinations are not really active against any omicron variant, while Evusheld is poorly active against omicron BA.1 but more active against BA.2, BA.2.12.1 and BA.4/5
CONCLUSION: While Regeneron and Eli Lilly cocktails are essentially inactive against omicron, Evusheld loses activity against BA.1, while maintaining more activity against BA.2 subvariants. The real world data of 264-4, most gathered during the BA.1 epidemic, are therefore rather encouraging and suggest that it’s effect will at least be maintained or even improved during the present epidemic with BA.2 and it’s subvariants .
PAR 3 LONG COVID AND MORTAILITY before and during omicron era
Ep 264-7: Al-Aly Nat Med Long COVID after breakthrough SARS-CoV-2 infection (BTI) in very large US Veterans cohort = before omicron (Jan-Dec 2021)
- Excess of death and post-acute sequelae in vaccinated subjects 6 month after BTI, as compared with vaccinated controls without SARS-CoV-2
- Clear evidence that severity of acute phase (hospitalization or ICU) predisposes to this increases risk.
- Lower risk of death and post-acute sequelae of vaccinated BTI subjects compared with non-vaccinated SARS-CoV-2 infected
- Vaccination before infection confers only partial protection in the post-acute phase of the disease
- Emphasize the need for continued optimization of strategies for primary prevention of BTI
Ep 264-8: Summary of the study in Nature Briefing, emphasizing that it contains
- no omicron data
- no date on booster vaccination
Ep 264-9: Faust JAMA 20 May 2022 Excess mortality in Massachusetts during delta and omicron waves
More all-cause excess mortality during the first 8 weeks of Omicron period than during entire 23-week Delta period.
Although numerically there were more excess deaths in older age groups, there was excess mortality in all adult age groups, as recorded in earlier waves, including in younger age groups.
Ep 264-10: Sarah Tartof Lancet Resp Dis 6 May 2022: Waning effectiveness against hospital and emergency department admission after receiving a third dose of BNT162b2 vaccine is occurs mainly in high-risk (immune compromised) individuals.
Ep 264-11: Benjamin Mueller NYT 31 May 2022: In 2021 people 65 and older died from Covid at lower rates than in previous waves. But with Omicron and waning immunity, death rates rose again.
Ep 264-12: Holly Else Nature T1ç May 2022 Tallying the health toll of COVID-19.
The paper discusses the challenges to measure the health toll, but it is presumably considerable:
Omicron is not a mild virus. Especially older people, those with a weakened immune system, but also younger people without a full vaccination course, remain susceptible to severe disease.
Full (2X) vaccination provided some degree of protection against death and long COVID upon BTI in the pre-omicron era. Effect of booster vaccination and of omicron BTI on long COVID unclear.
Question: do we need to roll out the 4th vaccine dose and/or do we take other (non-pharmacological) measures?
21 June 2022 Episode 268 Pathogenicity of BA.2 sublineages and RNA vaccines for toddlers
> More info
15 June Episode 266: New antiviral, omicron-specific vaccine and weak cross-neutralization and cross-protection within the omicron family.
> More info
8 May 2022 Episode 260 Omicron-specific vaccines and immunity to new omicron BA.2 subvariants
> More info