Thu, 01/20/2022 - 20:39
Dear colleagues,
In this episode some new data on the effects and importance of children’s vaccination and disease manifestation. Next, I will open a chapter on the possibility of better antibody therapeutics and vaccines, based on targeting more conserved epitopes, shared by all sarbeco viruses
CHILDREN
- Vaccination
Ep 227-1: RNA vaccination clearly protects against multi-systemic inflammatory syndrome (MIS) in adolescents (12-17 yeas) in France. Nevertheless, there are rare cases at a rate of 1 % in comparison with unvaccinated adolescents.
The low reporting rate of this syndrome after mRNA vaccination, compared to the rate of MIS-C among same age children infected by SARS-CoV-2, supports the benefit of SARS-CoV-2 vaccination
Ep 227-2: Waning anti-SARS-CoV-2 antibodies in adolescents (12-16 yrs) after 2 doses of Pfizer mRNA vaccine support urgent authorization for a COVID-19 mRNA booster.
Ep 227-3: Moderna vaccination elicits robust humoral immunity to SARS-40 CoV-2 in children 6-11
- Moderna vaccine elicits specific IgG and neut response, surpassing adults at a matched 100μg dose, but more variable immunity at a 50μg dose
- Irrespective of titer, children generated antibodies with enhanced Fc-receptor binding capacity: suggesting enhanced effector function.
- Children generated cross-VOC humoral immunity with robustly preserved omicron Spike-receptor binding
Conclusion: Moderna at adult dose of 100 µg might offer better protection to children 6-11 years than the now standard dose of 50 µg.
2) Clinical aspects of pediatric COVID
Ep 227-4 A and B: Retrospective study in 25 hospitals of 6 subsaharan countries on 469 hospitalized children 0-19 yrs with COVID
- 115 (24.5%) co-morbidities: hypertension; chronic lung disease and hematological disorders associated with severe outcome, BUT many children hospitalized with COVID without previous health problem.
- 69 intensive care
- 39 (8.3 %) died:
- 18 MISC of whom 4 died
Clearly: morbidity and mortality rates amongst these African children higher than in high income countries: 8.3 % in this series vs 1 % or less in UK and US.
In this study the influence of some potentially important variables such as other infections (malaria…) or malnutrition were not really investigated.
The previous study was on pre-omicron cases in various African countries: the next study focuses on omicron in South-Africa
Ep 227-5: Rapid rise in paediatric COVID-19 hospitalisations during Omicron wave, Tshwane District, South Africa
Description:
- Out of 6287 pediatric COVID diagnoses: 465 (7 %) hospitalisations; all unvaccinated
- Age: young children (0-4 yrs) most affected
- Common symptoms: fever (47%), cough (40%), vomiting (24%), difficulty breathing (23%), diarrhoea (20%) and convulsions (20%).
- Therapy: 25 % oxygen, 6 % ventilated
- Mortality: 4 (out of 139), all related to complex underlying pathologies (not COVID).
Comparison with previous waves:
- Apparently less severe: shorter hospital stay and lower mortality
- Less pneumonia, lower need for ventilation
- No MISC yet (?) is a late complication
- Convulsions is relatively new: underlying encephalitis?
Ep 227-6: Pediatric symptoms in Europe/US? Unfortunately, I could not find a formal study yet. The paper I quote here is an “advice to parents”. It states that all COVID symptoms can be present, similar to Delta, but that the most common ones are rather “common-cold-like”:
Runny nose, Sneezing, Sore throat, Headache, Fatigue (either mild or severe)
In addition, sometimes, there are “croup-like” symptoms:
- Barking cough that sounds like a seal and usually worsens at night
- Hoarse, raspy voice; difficulty swallowing
- Shortness of breath
- Stuffy or runny nose
- Irritability and Fever
CONCLUSIONS
- mRNA protect adolescents for 99 % against MISC (pre-omicron)
- A booster might be needed in adolescents
- An adult dose of Moderna might protect children of 6-11 yrs better against omicron
- Pre-omicron morbidity and mortality in hospitalized sub-Saharan children was higher than in Europe or US
- In South-Africa, Omicron resulted in higher hospitalization of children, but the clinical picture was different (less pneumonia, more convulsions…) and less severe.
- Omicron in children in US also associated with more upper respiratory, including “croup-like”, symptoms.
- MISC after omicron still unclear, maybe too early?
NEXT GENERATION BROAD NEUTRALIZING ANTIBODIES
Broad neutralizing human monoclonal Ab have been derived from either SARS-CoV-1 (Sotrovimab S309) or SARS-CoV-2 (all others) convalescent patients. They have been shown to neutralize all SARS-CoV-2 variants, (including omicron in some cases) and have an even broader spectrum, including SARS-CoV-1 and other related Sarbecoviruses.
Sarbecoviruses belong to lineage B of the Coronaviruses and include the human SARS-CoV(1) and SARS-CoV-2, as well as the related bat and civet viruses in clade 1 a and b resp, which use ACE-2 as the cellular receptor. Besides, there is a number of other animal viruses, which do not use ACE-2. See below.
Obviously, these mAbs are candidates to be developed as prophylactic or therapeutic agents.
Ep227-7: Cameroni distinguished 5 different binding sites in the receptor-binding domain (RBD) and identifies 6 human mAb that retain neutralizing activity against omicron (< 10 fold loss as compared to Wuhan strain), specific for RBD sites
- Site I: S2K146, S2X324, S2N28
- Site II: S2X259
- Site III: none
- Site IV: Sotrovimab (S309)
- Site V: S2H97
As can be seen in the figure, S2K146 has a binding site that is very close to the ACE-2 footprint, hence it is an “ACE-2 mimic”, S2X259 partly overlaps with ACE-2, whereas Sotrovimab binds completely outside ACE-2 footpri
Ep 227-7 A: Park et al in Science show that the “ACE-2 mimicking S2K146 has a “pan-sarbeco” neutralizing ability, as it also neutralizes SARS-CoV-1 and all clade1a and clade1b Sarbecoviruses that use ACE-2, including bat and Pangolin viruses related to SARS-CoV-2 as well as civet and bat viruses related to SARS-CoV-1.
Interestingly S2K146 protects against SARS-CoV-2 Beta challenge in hamsters and viral passaging experiments reveal a high barrier for emergence of escape mutants, making it a good candidate for clinical development
Ep 227-7 B: Tortoricci in Nature shows that S2X259 mAb has also a very broad spectrum of ACE-2 using human and potentially zoonotic sarbecoviruses.
Moreover, prophylactic and therapeutic administration of S2X259 protects Syrian hamsters against challenge with the prototypic SARS-CoV-2 and the B.1.351 VoC.
Ep 227-7 C: Starr in Nature July 2021 focuses on S2H97, which has a very broad binding activity towards all Sarbecoviruses, not only the ones that use ACE-2 (class 1a and 1b), but also class 2 and 3, which do not use ACE-2. However, while it has a low ng/ml neutralizing activity against SARS-CoV-2, it is rather weak against SARS-CoV-1 (high ng to low µg/ml range).
Prophylactic administration to Syrian hamsters protected them against SARS-CoV-2 challenge.
Ep 227-7 D: Nature paper already from July 2020 showing that S309 (parental antibody of Sotrovimab) also neutralizes various Sarbecoviruses, including SARS-CoV-1 and SARS-CoV-2, but also the bat WIV1 virus.
Ep 227-8: Martinez in Sc Transl Med about DH1047 mAb, with also broad neutralizing activity against SARS-CoV, bat coronaviruses WIV-1, RsSHC014, and SARS-CoV-2 variants and prophylactic as well as therapeutic activity in mice. Omicron was not yet formally tested, but most likely it will be sensitive.
Ep 227-9: Penfei Wang Em Micr Infect: Similar in vitro results with mAb 2.36
Ep 227-10: Tingting Li Nat Comm Dec 2021: Three mAbs 7D6, 6D6 and 16D8 with low µg/ml neutralizing activity in vitro against SARS-CoV-1 and SARS-CoV-2.
Ep 227-11: VanShylla in Cell Host and Microbe shows that SARS-CoV-2 elite neutralizers
generate a highly diverse and potent Ab response that can yield sarbeco CoV cross-reactive and SARS-CoV-2 broad Neut Abs with up to 100% coverage against RBD escape variants and variants of concern (omicron not yet included)
Plot evaluating the IC50 values of the broadest (100%) and most potent NAbs against SARS-CoV-2 pseudovirus variants with spike sequence of B.1, B.1.1.7, B.1.351, B.1.429, B.1.617, and B.1.617.2 are compared to published monoclonal antibodies. REGN antibodies tested up to 5 mg/mL. Gray area in (C) highlights values below 0.02 mg/mL, and black bars denote geometric means.
DEVELOPMENT OF SARBECO VACCINES
All these papers show that natural human monoclonal antibodies, elicited by either SARS-CoV-1 or SARS-CoV-2 can cross-neutralize these two viruses, but also related bat, pangolin and/or civet beta-CoV. Therefore, it should be possible to design vaccination strategies that result in such cross-neutralizing, which hopefully would not only protect us against different variants of SARS-CoV-2, but could also prevent new zoonotic infections….
Ep 227-12: Burnett in Immunity: Immunizations with diverse sarbecovirus receptor-binding
domains (RBD) elicit SARS-CoV-2 neutralizing antibodies against a conserved site of vulnerability
These are studies in mice transgenic for human immunoglobulins. It was shown that immunization with either SARS-CoV-1, -2 or the related bat RATG13 elicited some cross-reactive antibodies
Cross-reactive antibodies use recurrent IGHV/IGKVs that mainly bind the class 4 epitope “supersite”
Some of these Ab could effectively cross-neutralize and were characterized by an elongated CDRH3 that obstructed ACE2-RBD interactions.
Ep 227-13: Walls in Cell provides more direct evidence of broadly protective sarbecovirus
Immunity, elicited by receptor-binding domain nanoparticle vaccines.
They construct nanoparticles (NP) with trimeric Spike receptor binding domain (RBD) from either the bat virus WIV1, RATG13 and the human SARS-CoV-1 and SARS-CoV-2.
They immunized mice with single RBD-NP from single viruses, a cocktail of the 4 or “mosaic RBD-NP, which carry all 4 RBD on each particle.
Vaccination with this tetravalent mosaic RBD (mRBD-NP) or with a trivalent RBD without SARS-CoV-1 (mRBD-NP D0) provided high neutralizing titers against both SARS-CoV-1 and SARS-CoV-2 and protected against a challenge with SARS-CoV-1 (See Fig 5 and 6).
CONCLUSIONS
- There is a good number of broad cross-neutralizing antibodies derived from convalescent (and elite-neutralizing) COVID patients. Many of those have shown activity against all SARS-CoV-2 variants (some including Omicron, but also against SARS-CoV-1 and even against potentially zoonotic viruses in bats, pangolins and/or civets. Some have shown prophylactic or therapeutic activity against experimental infection in mice or hamsters
- Strategies to induce pansarbeco immunity by vaccination are being developed. The mosaic RBD-nanoparticles look promising at first view…
Best wishes,
Guido
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