This episode will be focusing on clinical aspects, but first some feedback/extension on drug chapters
- Remarks from a colleague at ITM:
Both molnupiravir and paxlovid have been evaluated so far in (largely) unvaccinated patients (most of them being rather young obese) infected with “previous” COVID strains/variants. It can be assumed that the impact on fully vaccinated (high risk) “omicron patients” will be less substantial (lower baseline risk of hospital admission), meaning that the number needed to treat to prevent one hospitalization will be much higher than in the publications. Both drugs are now available in Belgium (very limited amount) for research purpose and possibly (nosocomial) outbreak control…
Maybe good to inform that (once again) our UK colleagues are progressing in the evidence generation with an RCT evaluation of molnupiravir through a platform trial in GP practice (PANORAMIC), and later on paxlovid I guess. There are discussions for Belgian GP academic centers to join…
ITM participates to the DNDI-led ANTICOV trial that aims at evaluating several of these drugs (fluoxetine, ivermectin, budenoside, nitazoxanide,…) in African COVID outpatients….
- A reaction from Philip Hyndman about interferon:
Concerning inhaled interferon beta 1a, there is potentially some good news on the near horizon. The FDA designed Global Phase 3 Hospital readout is anticipated imminently. We are likely talking a matter of days as opposed to weeks. The founder of Synairgen, Sir Stephen Holgate was recently interviewed on Medscape and also the CEO a couple of days later. Both videos provide a good approximation on where the company is at and where they expect to be in case of positive readout.
Additionally, in the outpatient setting, they progressed from Phase 2 to Phase 3 in the NIH ACTIV-2 study.
- Ep 223-1: In vitro evidence that all forerunner antivirals (Remdesivir, Molnupiravir and Nirmatrelvir are equally active across VOC, including omicron.
Ep 223-2: A new intranasal broad-spectrum blocker of SARS-COV-1 and -2 including omicron! TriSb92 is a trimeric human antibody mimetic targeted against a conserved region in the receptor-binding domain of the Spike.
- Sub- or low nanomolar activity in vitro.
- Intranasal administration of 5-50 microgram of TriSb92 (5 or 50 micrograms) up to 8 hours before challenge with SARS-CoV-2 B.1.351 (beta) efficiently protected mice from infection.
I will first summarize some big studies about the general population in South-Africa and US, next a focus on pediatric cases in UK and US, then on pregnancy and finally viral dynamics.
Ep 223-3: Nicole Wolters: Early evidence of lower omicron pathogenicity (21 Dec 2021)
- During co-circulation of Delta and Omicron (Okt-Dec):
- Omicron lower odds of hospitalization aOR 0.2 (0.1-0.3).
- After hospitalization, however: odds of severe disease did not differ (after controlling for the predisposing factors).
- Comparing Omicron in Oct-Dec with Delta April-Nov: omicron overall lower odds of severe disease (aOR 0.3, 95% CI 0.2-0.5), again after controlling for predisposing factors.
Interpretation: Two factors at play:
- Omicron intrinsically less prone to hospitalization, but can make susceptible people very ill.
- Lowering of disease severity over time (within non-omicron): effect of increasing immunity?
Ep 223-4: Marie-Ann Davis: Further evidence of lower omicron pathogenicity and influence of immunity by prior infection or vaccination in Western Cape.
The most interesting Table 2 shows which factors determine severity (hospitalization and/or death) over the various waves in South-Africa (alpha, beta, delta and omicron). Extreme left is NOT adjusted for “immunity” (by prior infection or vaccination) and extreme right after adjustment:
- Overall the known factors for severity remain after adjustment: male sex, advancing age, and co-morbidities (current TB > diabetes > chronic kidney disease > HIV > chronic pulmonary disease > hypertension.
- Overall, also prior infection has OR of 0.28 (72 % protection) and full vaccination OR of 0.42 (58 % protection).
- Chances on hospitalization or death in different waves: with delta (3rd) wave as reference = 1
- Unadjusted for prior infection or vaccination: beta wave = 0.71 and omicron = 0.43
- After adjustment: beta = 0.88 and omicron = 0.72
Hence, according this analysis, the delta virus was the worst, but the lower severity of both beta and omicron are partly intrinsic and partly due to (prior) acquired immunity.
In fact for omicron: the overall almost 60 % lower severity is 50-50 due to intrinsic lower pathogenicity and higher immunity by prior infection or vaccination.
Ep 223-5: Palleker in a very short paper on few data, suggests that death during the fourth (omicron) wave is less due to pneumonia than in the third (delta) wave. Anecdotal. To be confirmed.
Ep 223-6: Lewnard on Southern California
During a period with mixed Delta and Omicron variant circulation, SARS-CoV-2 infections with presumed Omicron (based on SGTF) variant infection were associated with substantially reduced risk of severe clinical endpoints and shorter durations of hospital stay.
235 = 0.5 %
222 = 1.3 %
Hospital stay (median)
Ep 223-7: Christensen reports on similar data from Houston Texas
Compared to Alpha or Delta variants, Omicron patients were
- significantly younger,
- had significantly increased vaccine breakthrough rates,
- and were significantly less likely to be hospitalized.
- less intense respiratory support
- and had a shorter length of hospital stay,
All consistent with decreased disease severity.
CONCLUSIONS: Omicron has similar risk factors but appears less severe, in terms of hospital admission, duration, intensive care and death. Also less pneumonia. This may be partly intrinsic and partly due to acquired immunity by prior infection or vaccination.
Focus on children
Ep 223-8: Technical briefing UK Health Security Agency nr 34 (14 Jan)
- Different symptoms between delta and omicron: especially more “sore throat” and less “loss of taste and smell” in omicron versus delta
- Rapid and sustained increase in pediatric hospital admissions, especially in age 0-5 yrs. However: statement of Royal College of Pediatricians states:
We are also reassured to hear that very few children and young people admitted to hospital with Omicron are needing pediatric intensive care.
- Vaccine efficacy (general n population, not focused on children)
- against symptomatic disease is moderate (even after booster),
- efficacy against hospitalization needs booster: only 44 % 25 + weeks after 2 doses, but rises strongly after booster and remains > 80 % even 10+ weeks after booster.
Ep 223-9: Report from New York on omicron: many similar findings, but also some interesting ones:
Analysis of hospital admissions:
- Strongest increase in hospital admissions in youngest (0-11) and oldest (+ 65) age groups
- The new admissions per 100 cases for unvaccinated persons
- 18+ decreased by 62.2%, suggesting decreased severity of the Omicron variant in adults.
- children 12-17 years, this decline was 45%, with fewer than 1 admission per 100 cases in both time periods.
- For unvaccinated children 5-11 years, there was a 71.5% increase in new admissions.
- Similarly, for children 0-4 years, all unvaccinated, there was a 48.2% increase
Taken together, these results suggest that greater inherent severity of the Omicron variant (as compared to delta) may also play a role in increasing rates of hospitalizations for children ≤11 years, relative to adults and children 12-17 years
- Amongst admitted children: 50 % had no comorbidities
- Hospital stay is limited to 1 week, suggesting not very severe disease
Analysis of vaccine effectiveness in children
For laboratory confirmed infections:
- For children 5-11 years, in the week of December 20-26, rates were 3.2-fold higher for those unvaccinated relative to vaccinated.
- Children 12-17 yrs: 2.6-fold higher rates for unvaccinated children
→ estimated vaccine-effectiveness of 62% against COVID infection
For hospital admissions:
- Higher in unvaccinated (1.56/100,000 persons) versus vaccinated children (0.31/100,000 persons): 5 fold increase in unvaccinated, thus vaccine efficacy against hospitalization of 81 %
- Nevertheless: Similar to cases, the rate of hospitalizations among fully-vaccinated children has been increasing more rapidly than the rate among unvaccinated children, which is reflected in a decrease of VE against hospitalization from 95 % to the just mentioned 81 % in 12-17 yrs (see Table 11)
- More hospital admissions in younger children with omicron, 50 % without co-morbidities: so omicron at first view more severe than Delta for children (more hospitalizations), BUT less severe course during hospitalization. Remark: no precise data with regard to MISC
- Vaccine effect similar as in adults: moderate protection against infection and COVID, strong, but slightly waning effect against hospitalization.
Ep 223-10: Shannon Hall in Nature News 12 Jan 2022: Overview of COVID risks during pregnancy:
- 5-15 times more likely to die and 14 times more likely to be intubated
- up to 22 times more likely to give birth prematurely
- 2.7 times more stillbirth
mRNA vaccination during pregnancy is safe and protective levels of antibodies are induced.
The evidence of clinical protection by vaccination is less clear:
- Theiler (Ep 223-11) finds evidence of lower prevalence of SARS-CoV-2 infection (1.4 versus 11.3 %), but no difference in pregnancy outcome.
- Morgan (Ep 223-12) finds clear evidence of lower severe COVID and more pregnancy complications in the unvaccinated women, but the numbers are still low (see Table 2)
Ep 223-13: Interesting study, comparing viral dynamics of delta and omicron.
- Peak viral concentration tends to be higher in delta,
- but clearance somewhat faster in omicron infections
→ Unclear whether these differences are attributable
to more immunity in this largely vaccinated population
or intrinsic characteristics of the Omicron variant?
→ Omicron’s infectiousness may not be explained by higher viral load measured in the nose
and mouth by RT-PCR
9 August Episode 279: BA.2.75, novel monoclonal Ab, polymerase and anti-inflammatory treatment options
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2 August 2022 Episode 278: Follow up on novel vaccine concepts: mucosal application and broadening towards “pansarbeco”
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19 July 2022 Episode 275 SARS-CoV-2 infection or vaccination, risk of reverse transcription
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3 July 2022 Episode 271: Fourth dose; variant specific booster, Bebtelovimab and BA.2.75
> More info