6 Jan 2022 Episode 217 Pre-omicron children and BTI; Omicron: rapid tests, T and B responses, therapeutic antibodies

Episode 217:      Pre-omicron children, breakthrough.   Omicron: rapid tests, T and B responses to vaccines and therapeutic antibodies

Dear colleagues,

SARS-CoV-2 (and especially Omicron) not only triggers a tsunami of infections, but also  of preprints…

I’ll try to summarize them as concisely as possible. Fasten your seatbelts: it is a long and windy road….

First we look again at data on children and breakthrough infections pre-omicron.  

Children in US and UK (pre-omicron)

Ep 217-1: Retrospective US study April 2020-Sept 2021 in 0-11 years old:

4,573 hospital admissions, 2/3 in 0-4 years and ¼ with immune compromise; 23 % in ICU and 7 % mechanical ventilation

… children aged 0-11 years can experience severe COVID-19 illness requiring hospitalization and substantial hospital resource use, further supporting recommendations for COVID-19 vaccination.

Ep 217-2: Birth cohort since 1997 of 1.226 million CYP in Scotland Feb-Dec 2020

• 179/1000 positive PCR and 29/1000 hospital admissions.
• As expected chronic conditions, particularly multiple types of conditions, was strongly associated with COVID-19-related admissions across all ages. (HR = 12)
• Nevertheless: 89 % of admitted children had no chronic condition recorded.

These results provide evidence to support risk/benefit analyses for pediatric COVID-19 vaccination programs.

Breakthrough infections (pre-omicron)

Ep 217-3:  Fisman in Canada Dec 2020-Oct 2021.

As we know: risk of reinfection remains low 4-6 months after 2 doses and increases thereafter.

Other factors:

• Increased in  2 X AZ only vaccinated, but lower when AZ + mRNA as compared to 2 X RNA.
• Higher reinfection with advancing age (from teens to 80+), priority health condition (1.2 X); HCW (2 X); congregate living (3.8 X).  

Ep 217-4: Prunas in Israel June – Dec 2021 adolescents 12-16 yrs protection to infection and COVID:

• From 2 weeks till 3 months after 2nd dose: 85 resp 90 %
• Between 3 and 5 months: 75 resp 78 %
• After 5 months: 58 resp 65 %

CONCLUSIONS:

1. The rare, but severe, complications, even in children without underlying conditions, are the basis for vaccination recommendation in young children.  
2. Confirmation of waning immunity to pre-omicron VOC, especially from 4-6 months after vaccination, also in adolescent, underpin the booster recommendation

OMICRON:         We will look again at rapid antigen test performance for omicron,

Then at effects of vaccines on antibodies and T cells.

Finally, we will evaluate the potential of existing and new therapeutic antibodies against omicron.

1. Evaluation of rapid antigen tests for omicron

Ep 217-5: Preprint of Bekliz and Eckerle

At first view, only the Wondfo test, seems reliable as it is always positive when cultivable virus is present and negative when it is absent.

Ep 217-6:  Adamson investigated a high-risk occupational case cohort of 30 individuals with daily testing during an Omicron outbreak in December 2021 with salivary PCR  and nasal rapid tests

Clearly, both Quidel and Abbott remained falsely negative during several days.  Obviously, in retrospect, it would have been better to take a saliva (or throat) sample in stead of nasal for the rapid test too.

CONCLUSION: Urgent need for thorough evaluation of rapid tests for omicron, including sensitivity and site of  sample collection (nose, saliva, throat?) before advising their use as alternative for PCR.

2. Effectiveness of vaccines against omicron: ANTIBODIES and B CELLS

Ep 217-7: Buchan in Canada comparing Vaccine Effectiveness against infection in 3400 omicron, 9200 delta and 471,000 test negative controls after full vaccination + booster.

• VE against delta: declined after 2 doses, but recovered to 93 % > 7 days after booster.
• VE against omicron: absent after 2 doses, and recovered to 37 % > 7 days after booster.

Ep 217-8:   Memet In vitro neutralization in HCW after 2 or 3 doses: beta and delta behave very similarly

Ep 217-9: Sho Miyamoto Hybrid immunity and breakthrough infection

In vitro neutralization of omicron weak after mRNA vaccination, but stronger, if breakthrough infection with alpha or delta had occurred.

• time interval between vaccination and infection, rather than the variant types of infection, was significantly correlated with magnitude and potency of Omicron-neutralizing antibodies.

Ep 217-10: Marit Van Gils, comparing 4 vaccines 2 weeks after 2nd dose for neutralization of VOC:

Clearly, Moderna is superior for omicron > Pfizer, while AZ and Janssen induce almost no neut.

Ep 217-11: Vaccine in vitro neutralization responses:

• Heterogenous responses to 2 doses, very weak for beta and omicron in pregnancy
• Very good effect of booster also for omicron in health care workers. Ep 217-12: Very interesting paper on the effect of booster vaccine on memory B cells:

Upon vaccine boosting: resting preexisting memory and naive follicular B cells that:

• recognize epitopes outside the receptor-binding domain (non- RBD epitopes) in the wild type spike protein
• and that also cross-react with the Omicron variant spike protein

preferentially differentiate into effector B cells.

Preferential boosting of B cells that recognize cross-reactive B cell epitopes, possibly B cells generated by sequential exposure to seasonal coronaviruses and the wild type SARS-CoV-2

vaccine derived spike protein,

• reflect the importance of pre-existing cross-reactive memory in rapid responses to novel pathogens;  
• may prove key to the attenuation of Omicron COVID-19 disease severity in populations with already existing cross-reactive immunity.

CONCLUSION: Elements for better vaccine-antibody protection against omicron:

• Type of vaccine: Moderna = superior; adenoviruses inferior, but heterologous boost with mRNA = very favorable.
• Hybrid immunity (infection + vaccination) is best
• Booster broadens the B cell memory to cross-reactive epitopes outside the receptor binding domain, which may contribute to attenuation of Omicron disease and protect against novel pathogens as well.

3. Effectiveness of vaccines against omicron: T CELL RESPONSES

Ep 217-13: Jinyan Liu: After either mRNA or Janssen vaccine there are preserved cross-reactive T cell responses to omicron Spike peptides, while neut Ab are very weak.

Ep 217-14: Lorenzo de Marco:  Preserved T cell reactivity to the SARS-CoV-2 Omicron variant indicates continued protection in vaccinated individuals.

Despite this very positive message, these authors actually observed some reduction in T cell responses towards omicron spike:

• T cell responses to peptides covering the mutated regions in the Omicron variant were decreased by over 47% compared to the same regions of the ancestral vaccine strain.
• However, overall reactivity to the peptide library of the full-length protein was largely maintained (estimated 83%).

No significant differences in loss of immune recognition were identified between groups of

donors with different vaccination and/or infection histories.

Ep 217-15: Naranbhai: T cell reactivity to the SARS-CoV-2 Omicron variant is preserved in most but not all prior infected and vaccinated individuals.  In this case both Spike and non-Spike (nucleoprotein, membrane, envelope and 3A) are used.  Conclusion similar to Ep 219-14:

• T cell responses in persons with prior infection, vaccination, both infection and vaccination, and boosted vaccination are largely preserved to Omicron spike and non-spike proteins.
• A subset of individuals (~21%) with a >50% reduction in T cell reactivity to the Omicron spike.
• Booster vaccination substantially enhanced T cell responses to Omicron spike.

Ep 217-16: Fanglei Zuo Heterologous mRNA boost after 2 doses of inactivated vaccines very strongly enhances T and B responses against omicron spike.

CONCLUSION: Cross-reactivity against VOC including omicron is better preserved at the T cell level and may contribute to protection against disease.

4. Resistance of omicron to plasma and therapeutic antibodies + NOVEL POTENTIAL THERAPEUTIC MAbs

Ep 217-17: Very comparable neutralization resistance of profile of plasma from convalescent or vaccinated subjects against omicron and against PMS20 (a SARS-CoV-2 virus that was made resistant in vitro by culturing in the presence of suboptimal concentrations of neutralizing plasma

Booster effect and hybrid immunity

Ep 217-18: Max Kozlov in Nature reports on the deficiency of most therapeutic antibodies against omicron, except Sotrovimab (Vir-GSK and DXP-604 (BeiGene and Singlomics in Bejing)

Ep 217-19: Aggarwal on Sotrovimab mexRxiv 15 Dec

Ep 217-20: Tada bioRxiv 30 Dec finds also a rather high EC50 value for Sotrovimab against omicron  (suggestive of in vivo resistance)   further analyzes why omicron is resistant to the commercially available nAb,  by investigating the effect of individual omicron-associated mutations.

Clearly the most crucial resistance-associated mutation in omicron are:

• for Casivirimab K417N and Q493K
• for Imdevimab: N440K, but certainly G446S
• for REGN-CoV2: the crucial mutations was not identified
• for Bamlanivimab: E484A and Q493K
• for Etesevimab: K417N
• for Sotrovimab: S371L and S373P  

Ep 217-21: Delphine Planas in bioRxiv 15 Dec shows also remaining neutralizing activity for

Sotrovimab > Adintrevimab > Cilgavimab > Evusheld.

Ep 217-22: Yinlong Cao on SARS-CoV-2 and pan-sarbeco monoclonals (Nab as potential drugs)

Fig. 4: Omicron escapes most NAb drugs.

a, Neutralization of SARS-CoV-2 variants of concern by 9 Nab drugs. The pseudovirus neutralization assays for every VOC were performed in biological triplicates. IC50 labeled is the average of three replicates shown

b, The sarbecovirus neutralization and binding capability of selected potent Omicron-neutralizing antibodies. Monoclonal antibody HG1K (IgG1 antibody against  Influenza A virus) was used as the negative control.

Ep 217-23: Cameroni bioRxiv 20 Dec present a very large panel of Nab,

• Most (26 out of 29) receptor-binding motif (RBM)-directed monoclonal antibodies (mAbs) lost in vitro neutralizing activity against Omicron, with only three mAbs, including the ACE2-mimicking S2K146 mAb1, retaining unaltered potency.
• A fraction of broadly neutralizing sarbecovirus mAbs recognizing antigenic sites outside the RBM, including sotrovimab2, S2X2593 and S2H974, neutralized Omicron.

Broadly neutralizing sarbecovirus mAbs recognizing epitopes conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.

CONCLUSION:

• Omicron has rendered most clinically used neutralizing human monoclonals useless, with the possible exception of Sotrovimab (contradictory in vitro data).
• The “silver lining” is that several groups have already panels of in vitro broad cross-neutralizing antibodies, but, obviously, more time will be needed to evaluate them in vivo.

I hope you enjoyed this longest-ever episode!

Best wishes,

Guido