2 January 2022 Episode 214 Omicron testing and viral dynamics

Sun, 01/02/2022 - 21:13

Dear colleagues,

Omicron is spreading very rapidly, but seems to be (relatively) less severe.  Therefore, the balance between the public health benefit of a fixed period of 7-10 days of self-isolation (which was evident for previous VOC) is now being questioned and weighed against the economic and psycho-social drawbacks of this strict strategy.   A “flexible” approach, based on antigen test negativation as a “release permit” is being proposed.  

In order to make a rational decision, it is important to investigate a few questions:

  • How sensitive are antigen-based tests for omicron?
  • How well do antigen tests predict infectiousness?
  • What do we know about viral load and viral dynamics of omicron?     

As you will see, data are accumulating rapidly, but they are not yet completely conclusive: based on preprints, which are not always consistent and/or extrapolate from pre-omicron VOC ….

For the referred papers see:

TEST SENSITIVITY

Ep 214-1: Nicholas Barasch medRxiv 27 Dec shows that an RT-PCR, designed to detect the typical alpha characteristics N501Y, E484K and del69-70 from beta and gamma, is also able to recognize omicron, but not delta, hence making the differential diagnostics.  

Ep 214-2: Gert Marais medRxiv 24 Dec convincingly shows that saliva samples are more sensitive than mid turbinate samples for omicron detection by RT-PCR (100% resp 86 % positive percent agreement); whereas the opposite is true for delta (76 resp 100 % PPA).

Interestingly, the median time from symptom onset to positive test for Delta and Omicron assigned cases was 3 days (range: 1-10) and 2 days (range: 0-7).

 

Implications:

  • The current standard of care for diagnosis using swabs of the nasal or nasopharyngeal mucosa may be suboptimal for the Omicron variant.
  • This finding supports the ex-vivo finding of improved viral replication in upper respiratory tract tissue and possibly altered tissue tropism.
  • There is a shorter interval between symptom onset and positive PCR for Omicron.

 

Ep 214-3: Bekliz medRxiv 22 Dec based on cultured virus sensitive of antigen tests was clearly lower for omicron as compared to other variants.  The Ag test analyzed:

 

I) Panbio COVID-19 Ag Rapid test device (Abbott); II) Standard Q COVID-19 Ag (SD Biosensor/Roche); III) Sure Status (Premier Medical Corporation),

The three latter being WHO-EUL approved and thus of high global public health relevance,

 

IV) 2019-nCoV Antigen test (Wondfo);   V) Beijng Tigsun Diagnostics Co. Ltd (Tigsun);                           VI) Onsite COVID-19 Ag Rapid Test (CTK Biotech);        VII) ACON biotech (Flowflex),

Several of them being on the waiting list for WHO-EUL approval.

 

Ep 214-4: James Regan 27 Dec evaluate the sensitivity of the antigen BinaxNow test by Abbott on two omicron and two delta samples, obtained by nasal swab and used in a dilution series.  They claim that both omicron and delta samples remain positive at 100,000 copies/swab.  (I find the band of the second omicron sample very faint, but the three independent readers even agreed on the positivity of 25,000 copies.  See Fig 1 p. 5).

 

Ep 214-5: Statement of FDA on 28 Dec 2021

On antigen tests

  • RADx conducted initial laboratory tests using heat-inactivated samples for some of the currently available antigen tests, which were able to detect the omicron variant, with similar performance when detecting other variants.
  • It is important to note that these laboratory data are not a replacement for clinical study evaluations using patient samples with live virus, which are ongoing

On molecular tests: FDA provides lists of tests that, based on the omicron mutations, will show drop-out of either Nucleocapsid or Spike target.

See: https://www.fda.gov/medical-devices/coronavirus-covid-19-and-medical-devices/sars-cov-2-viral-mutations-impact-covid-19-tests

Ep 214-6: An example of analytical evaluation of 22 kits for delta detection and correlation with infectivity

  1. Detection limit: logistic regression analysis demonstrated that:
  • 11 kits had a 50% detection probability for viral loads >106 RNA copies/mL, and
  • 7 kits had 50% detection probabilities >105 RNA copies/mL, equivalent to approximately 3.7 x 103 TCID50/mL

When compared to the manufacturer’s stated sensitivity in the accompanying IFU documentation, 12 kits were less sensitive

 

  1. Correlation with infectivity: comparison PanBio (Abbott):

Compared to RT-PCR the Abbott PanBio COVID-19 Ag test was 52.6%  concordant, with a 50% detection probability for infectious cell culture at 5.9 log10 RNA copies/mL.

Antigen test concordance was 97.6% (95% CI, 86.3% to 100.0%) compared to cell culture positivity.

Conclusions:

  • Antigen test positivity correlated with positive viral culture, suggesting antigen test results may determine SARS-CoV-2 transmission risk = OK
  • However, analytical sensitivity varied considerably between kits highlighting the need for ongoing systematic post-market evaluation = less OK.

 

Ep 214-7: Kirby medRxiv 23 Dec 2021 compares PCR, antigen test and viral culture (the latter a proxy of infectivity) in over 200 samples March-June 2021 (hence several variants in US).  There is a   

  • A viral load threshold of 100,000 copies/mL was 95% sensitive and  72% for predicting viral culture positivity.
  • Prediction of viral culture positivity: the microfluidics assay LumiraDx 90 % sensitivity while the lateral flow tests BD Veritor, CareStart and Oscar Corona were less sensitive ( each about 74%).

Clearly, antigen testing is a reasonable, but not perfect proxy of viral culture positivity, hence infectiousness?

 

LFAs = threshold positivity lateral flow antigen assays

LumiraDx: threshold positivity microfluidics antigen test

PCR = threshold PCR positivity

VIRAL DYNAMICS:

 

Ep 214-8: Sofonea Omicron in France, with forecast medRxiv 1 Jan 2022

 

Remarkably: the Ct values for Omicron are higher than for other variants, thus lower viral load, despite higher transmissibility

Forecast  (Fig 2)

  • ‘Optimistic’ scenario, we assume a 3-fold reduction of Omicron virulence compared to Delta, a 75% vaccine efficacy against infection, and 95% against critical forms.

→ less than 4,000 ICU occupancy = still feasible

  • Pessimistic’ scenario, virulence is only divided by 2 compared to Delta, and vaccine effectiveness is only 40% against infection and 80% against critical forms.

more than 5,000 ICU occupancy = over the capacity!

 

Ep 214-9: Technical Briefing UK 31 Dec 2021

 

Study 1: Risk for hospital admission omicron = 50 % delta; ICU = 33 % delta. 

 This risk is reduced by 81% after 2 or 3 vaccine doses

Study 2:  Combined with the protection against becoming a symptomatic case, this gives a vaccine  effectiveness against hospitalization of 88% (78 to 93%) for Omicron after 3 doses of vaccine.

 

However, these lower risks do not necessarily imply reduced hospital burden over the current epidemic wave, given the higher growth rate and immune evasion observed with Omicron.

 

A total of 57 people have died of Omicron up to 29 December 2021.

 

Ep 214-10: In a Danish household study, Frederik Lyngse doesn’t see a systematic difference between viral loads in primary cases with either the Delta or Omicron VOC

 

 

Ep 214-11: In South-African people living with HIV, enrolled in a Moderna vaccination study in Nov-Dec 2021, 31 % were positive for Omicron, but asymptomatic and half of those had high viral load (Ct < 25).

 

Ep 214-12: Abdullah Syed medRxiv 1 January offers an explanation for higher infectivity despite lower viral load: Omicron shows 3-fold higher capsid assembly and cell entry relative to Delta, a property conferred by S and N protein mutations.

 

Ep 214-13: Kissler NEJM Dec 2021 described viral dynamics and clearance in great detail in alpha ans delta.  The most important conclusion:

Faster clearance among vaccinated breakthrough infections in 5.5 days interval 4.6-6.5) versus unvaccinated participants: with a mean of 7.5 days (6.8 to 8.2), respectively.

The shorter clearance time led to a shorter overall duration of infection among vaccine recipients.

 

Ep 214-14: Based on these observations, Bill Quilty proposes “test-to-release from isolation” strategy

 

His conclusion: Our analysis, albeit with pre-Omicron parameters (Ep 214-13), indicates very low risk associated with reducing the fixed isolation period to 7 days which may be even further reduced when combined with test-to-release schemes such as a 3 or 5 day wait followed by daily testing until receiving 2 consecutive days of negative results.

Comparison of policy outcomes for vaccinated populations.

A) Number of days saved vs. a 10-day isolation policy per individual and

B) days infectious in the community per 10,000 infected individuals following release from isolation for 3, 5, and 7 days wait after an initial positive test to initiate testing and number of consecutive days of negative tests required for release.

C) Use of tests with the different strategies

 

Points indicate mean and error bars represent the 95% uncertainty interval.

For days saved, the first day testing positive is considered the minimum mandatory isolation, so for example, a “3 day wait” is equal to 1 day + 3 days wait to then test again on day 4.

 

Preliminary conclusions

 

  • It is possible, but not yet formally established, that lateral flow antigen tests for nucleocapsid are less sensitive for omicron.
  • Whether omicron has a similar kinetics and viral load (as compared to delta) still needs to be established, but the infectious interval seems shorter and there are more asymptomatic cases.   
  • Antigen positivity (if sufficiently sensitive) is clearly associated with “cultivability”, which may be a proxy of infectiousness.
  • A policy to stop the isolation after 2 consecutive negative antigen tests may be a compromise between public health and other priorities.

 

Best wishes,

 

Guido

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