15 June Episode 266: New antiviral, omicron-specific vaccine and weak cross-neutralization and cross-protection within the omicron family.

Episode 266: New antiviral, omicron-specific vaccine and weak cross-neutralization and cross-protection within the omicron family.

Dear colleagues,

As you have noticed, It is already more than one week since my last episode, because of a number of other duties…. But I’ll try to catch up (with some help from my friends e.g. Patrick).

Ensitrelvir = S-217622

Remember Ep 244-4 and Ep 244-5:

Ep 244-4:  Unoh bioRxiv 26 Jan 2022: Preclinical development of S-217622

• S-217622 exhibited antiviral activity in vitro against all SARS-CoV-2 variants and showed favorable pharmacokinetic profiles in vivo for once-daily oral dosing.
• Furthermore, S-217622 inhibited intrapulmonary replication of SARS-CoV-2 in mice.

Ep 244-5: Sasaki bioRxiv 15 Feb 2022: extensive studies in hamsters showing clear-cut antiviral effect of S-217622, but also mitigation of body weight loss and lung pathology of infected animals, treated from the day of infection or from the next day. (MPV = Molnupiravir 200 mg/kg)

Reducing transmission: only the contact hamsters were prophylactically treated with S-217622 or MPV (b.i.d.) n, o, Viral RNA levels (n) and virus titers (o) in lungs from the contact hamsters after 6 days of co-housing with the infected hamster

Now there are results from a human phase 2a study

Ep 266-1: Mukae et al medRxiv 17 May 2022

Set-Up: Three small groups of patients with mild-moderate COVID, treated for 5 days: either 125, 250 or 0 mg of Ensitrelvir per day. 

Results: Ensitrelvir faster and more pronounced decrease in viral titer (TCID50) and viral load (RNA)

But no significant difference in symptom score

Interpretation: favorable profile according to authors for 2 reasons:

• Principal: orally available non-peptidic, non-covalent cysteine protease inhibitor, unlike the peptide-like nirmatrelvir : challenges remain for improving the target selectivity and PK profiles of peptide-like covalent inhibitors owing to the intrinsic nature of the reactivity, low membrane permeability and low metabolic stability.
• Activity: Viral RNA reduction superior with Ensitrelvir =: -1.4 log10  on day 5, while Nirmatrelvir/Ritonavir = only – 0.868 log10 on day 5 (and Molnupiravir only  -0.547 log10)

OMICRON-specific Moderna mRNA vaccine

Remember non-conclusive preclinical results in Ep 260

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.

Now there is a favorable press-release  (unfortunately not yet a manuscript  preprint!)

Ep 266-2: PBS News Hour 8 June 2022 Moderna says new COVID-19 vaccine protects against omicron

Comparing either the original (Wuhan) mRNA or a “combo” (Wuhan + Omicron) in 300-400 triple vaccinated subjects:

The bivalent vaccine sparked a nearly eight-fold rise in neutralizing antibodies capable,  which was 1.75 times better than the antibody jump from simply giving a fourth dose of the original vaccine, Moderna said.

Ep 266-3: New York Times specifies that these results relate to omicron BA.1.  Neutralization against the presently circulating BA.2 subvariants was reported to be 3-4 times lower.

Interpretation:  These first results in humans suggest a rather small advantage of a bivalent Wuhan-Omicron 4th vaccine dose in terms of neutralizing antibodies, but the question is how big this advantage really is with regard to protection against infection and disease by the presently circulating and future variants.

FOURTH DOSE

Ep 266-4: Grewal medRxiv 1 June: effectiveness of a fourth mRNA > 84 days after 3rd dose in long-term resident elderly using a sensitive test-negative control study 30 Dec 21 – 27 April 22

Ep 266-5: Nielsen medRxiv 1 June 2022 (2 doses of) Vaccine effectiveness in previously infected subjects during alpha, delta and omicron period versus previously infected but non-vaccinated . 

As expected VE was highest against alpha 85 % and delta 88 %, but lower against omicron (BA.1).

These data once again show the importance vaccination in previously infected subjects.

HOW MUCH CROSS-NEUTRALIZATION AND PROTECTION within OMICRON FAMILY?

Remember the omicron family (from Ep 266-10)

Ep 266-6: Reynolds Science 14 June describes a very complex effect of previous infectiin with various variants of concern (VOC) and triple vaccination on the T and B cell responses of HCW

• As expected triple vaccination enhanced B and T cell immunity against previous  VOC, but responses against B.1.1.529 (omicron BA.1) spike was reduced
• Previously infection-naïve HCW who became infected during the B.1.1.529 wave showed enhanced immunity against earlier VOC, but reduced nAb potency and T cell responses against B.1.1.529 itself.
• Previous Wuhan Hu-1 infection abrogated T cell recognition and abrogated any enhanced cross-reactive neutralizing immunity on infection with B.1.1.529.
• Similarly, infection with the earlier B.1.1.7 (Alpha) variant resulted in less durable binding antibody against B.1.1.529.

Illustration: Interaction of infection-naïve status or previous infection in combination with triple vaccination on neutralization of several VOC

Doughnuts showing the relative proportion of HCW with nAb IC50 of <50 (white), 50-199 (25% gray), 200-1,999 (50% gray), 2,000-19,999 (75% gray) and ≥ 20,000 (black)

• Against Wuhan Hu-1, Alpha to Omicron live virus
• In infection-naive HCW (n= 11) or HCW with laboratory confirmed infection during the Omicron (n = 11), Wuhan Hu-1 (n = 4) or Wuhan Hu-1 followed by Omicron, (n = 6) waves

at 14w (median 14w, IQR 3w) after the third vaccine dose.

Neut Ab against omicron BA.1 induced by omicron infection but always weaker than against other VOC, even after omicron infection itself.

Wuhen followed by omicron reduces the Neut Ab respons to Omicron.

Ep 266-7: Lapointe medRxiv 21 May 2022: Serial infection with BA.1 and BA.2 in triple vaccinated young individual, despite very good levels of neutralizing Ab.

Clearly, the strong "hybrid" immunity (by triple vaccination + BA.1 infection) failed to protect against

BA.2. Moreover, reinfection increased BA.1 and BA.2-specific responses only modestly

Implication: Remaining risk of Omicron infection in fully vaccinated individuals highlights the

importance of personal and public health measures as vaccine-induced immune responses wane

Ep 266-8:  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)

Conclusions

• 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

Ep 266-9: Kadjai Kahn medRxiv 1 May 2022 Follow-up of same set-up with BA.5  and BA.5

• The low absolute neutralization levels for BA.4 and BA.5, particularly in the unvaccinated group, are unlikely to protect well against symptomatic infection.
• Remark that cross-protection after BA.1 infectiin + vaccination is also lower against BA.4 and BA.5 than against beta, delta and D614G (see Ep 266-7)

→ BA.4 and BA.5 have potential to result in a new infection wave in previously BA.1 infected subjects and maybe also in vaccinated + BA.1 infected subjects.

Ep 266-10:  Quant Science Immunology 2 June 2022 Omicron BA.1 breakthrough infection drives cross-variant neutralization and memory B cell formation against conserved epitopes

Omicron BA.1 breakthrough infection in Pfizer BNT162b2-vaccinated individuals resulted in strong neutralizing

activity against Omicron BA.1, BA.2 and previous SARS-CoV-2 VOCs, but not against Omicron BA.4 and BA.5.

Observed weak cross-neutralization is clearly in line with Ep 266-8 and 9

Ep 266-11: Hachmann medRxiv 19 May 2022 Neutralization Escape by the SARS-CoV-2 Omicron Variants BA.2.12.1 and BA.4/BA.5

B. Neutralizing antibody (NAb) titers by a luciferase-based pseudovirus assay in individuals 6 months following initial BNT162b2 vaccination (Prime) and 2 weeks following BNT162b2 boost (Boost).

C. NAb titers in “hybrid immune” individuals following infection with BA.1 or BA.2. All were vaccinated (except for the one individual with negative NAb titers).

Ep 266-12: Tuekprakhon Cell June 2022: Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from post vaccine and post- BA.1 infection serum.

Similar data, though less pronounced decrease in titer

BA.4 also escapes from most monoclonal Ab, but Evusheld as well as Sotovimab retain a reasonable activity.

Neutralizing

Anti-Spike monoclonal antibodies

Sotrovimab

Xevudy

S-309

VIR-7831

GSK4182136

Imdevimab +

Casirivimab 

Ronapreve (EU)

REGEN-COV (US)

REGN10987 + REGN10933

Cilgavimab + Tixagevimab

Evusheld

AZD7442

AZD1061 + AZD 8895

COV2-2130 + COV2-2196 

Etesevimab + Bamlanivimab

(Eli Lilly co.)

LY-CoV016 + LY-CoV555

Ep 266-13 : Advice EDCTP 13 June 2022:

Countries should remain vigilant for signals of BA.4 and BA.5 emergence and spread; maintain sensitive and representative testing and genomic surveillance with timely sequence reporting, and strengthen sentinel surveillance systems(primary care ILI/ARI and SARI). Countries should continue to monitor COVID-19case rates - especially in people aged 65 and older - and severity indicators such as hospitalizations, ICU admissions, ICU occupancy and death.

Ep 266-14: UK Health Security Agency Report of 12 May

Apparently, this is the most recent update.  I could not find any real-world data  vaccine effectiveness against BA.2 subllineages yet.

CONCLUDING REMARKS

1. Ensitrelvir = S-217622 is a promising SARS-CoV-2 protease inhibitor.  Pending phase 3 and resistance profile, there is a chance that it could be an alternative to Paxlovid. 
2. The omicron-specific mRNA vaccine is still based on BA.1 and induces only marginally increased neutralization.  Remains to be seen if it will really able to prevent breakthrough with BA.2 sublineage variants (such as BA.2.12.1, BA.4 and BA.5).
3. Ample evidence that omicron BA.1 infection, even in combination with mRNA wild-type triple vaccination, cannot fully prevent infection with BA.2 sublineages. BA.1 seems to “manipulate” the B and T immune system.    Nevertheless, the UK Health Security Agency shows that even 15 weeks after a triple dose, mRNA vaccination still protects > 40 % against both BA.2 and BA.1, but no real world data on BA.4/5 yet.

Best wishes,

Guido