18 January 2022 Episode 226: Epidemiology, clinical, testing and hybrid immunity

Dear colleagues,

After short updates on epidemiological forecasts of the omicron wave and  two clinical papers, I will come back on rapid testing, on which much of the “relaxation” of isolation and quarantine is based. In my opinion, there is really a big problem of reliability and sensitivity for many of the tests…

Afterwards, I will discuss some interesting new immunological data, related to vaccination in immune compromised patients, prevention of post-COVID and hybrid immunity (by vaccination + breakthrough infection).   

All information is based on medRxiv preprints of the last few weeks.  

See

EPIDEMIOLOGY

Three studies try to predict the evolution of omicron

Ep 226-1: Schlickeiser deduces mainly from Denmark and extrapolates mainly to Germany. The peak will be reached between Feb 1 and 15 with a 7 days incidence of new cases between 7,000 and 29,000 per 100,000 inhabitants !  Despite the much lower pathogenicity and the large ICU capacity, they predict that the German health system will have problems to cope.

Ep 226-2:  Roberts predicts that the US will reach a peak of almost 900,000 cases per day around this time (half Jan) and that omicron will die out by 30 January….  In the meantime, we know that the recorded maximum case number was 894,879 on Jan 7, with a clear decline since then.

Ep 226-3: Huang makes a prediction of cases in the first half of 2022 and foresees small resurgences around April in north hemisphere countries and around and June in  south hemisphere countries.

Wait and see….

CLINICAL

Ep 226-4: Prediction of hospitalization risk

Simple risk scores applicable to outpatient and telehealth settings

• based on age, co-morbidities and dyspnea plus respiratory rate or oxygen saturation
• can identify patients with very low (1.6% to 1.7%), low (5.2% to 5.9%), moderate (14.7% to 15.6%), and high risk (32.0% to 34.2%) of hospitalization.

The Lehigh Outpatient COVID Hospitalization (LOCH) risk score is available online as a free app: https://ebell-projects.shinyapps.io/LehighRiskScore/

Ep 226-5: Lindsey Wang comparison of risks for severe clinical outcomes in US children under 5 with first SARS-CoV-2 infection during the Omicron wave is significantly lower than during Delta waves.

• Emergency department visits: 18.83% vs. 26.67% (risk ratio or RR: 0.71 [0.66-0.75]);
• Hospitalizations: 1.04% vs. 3.14% (RR: 0.33 [0.26-0.43]);
• ICU  admissions: 0.14% vs. 0.43% (RR: 0.32 [0.16-0.66]);
• Mechanical ventilation: 0.33% vs. 1.15% (RR: 0.29 [0.18-0.46]).

See also article in Financial Times https://www.ft.com/content/28be9d3f-0b12-4c33-bda9-fbff375c0b7e.  For those (like me) who have no full access

Countries with high exposure to the Omicron variant are recording record numbers of child coronavirus hospitalisations, adding to the pressures on healthcare systems, although health experts have stressed that the vast majority of cases were mild.

Data from Europe and the US show more child admissions in recent days than at any time during the pandemic, but severe cases are rare in the youngest age groups and Omicron infections generally looked similar to other common respiratory illnesses.

Paediatric admissions in France are nearly six times greater than the previous high of August 2021, while case rates among English under-5s are more than three times higher than last winter’s peak. About 80 under-5s are being admitted daily to hospital in England, up from the previous record of 24 last summer. The US under-5s hospitalisation rate has jumped to more than four in 100,000, from 2.5 per 100,000 in December, and is by far the highest rate during the pandemic.

TESTING

Rather poor results with Binax-NOW (Abbott)

Ep 226-6: Adamson 5 Jan 2022 Discordant SARS-CoV-2 PCR and Rapid Antigen Test Results

Based on viral load and transmissions confirmed through epidemiological investigation, most Omicron cases were infectious for several days before being detectable by rapid antigen tests.

Figure 1. Discordance in PCR and Rapid Antigen Test Results

1. Shown are Cycle Threshold (Ct) counts and rapid antigen test results from paired samples of infected patients
2. Kaplan Meier analysis of time from positive PCR to positive rapid antigen test

Ep 226-7: Regan 27 Dec 2021: Detection of the omicron variant virus with the Abbott BinaxNow

All omicron and delta specimens with concentrations of 100,000 copies/swab or greater were positive by the BinaxNow Assay, a concentration similar to previously reported limits of detection for this assay.

Assay sensitivity diminished below that

Ep 226-8: Schrom 12 Jan 2022 medRxiv Direct Comparison of SARS CoV-2 Nasal RT- PCR and Rapid Antigen Test (BinaxNOW) at a Community Testing Site During an Omicron Surge.

• Sensitivity of single nasal test was 95.2% (Ct < 30) 82.1% (Ct < 35) and 65.2% (all PCR+)
• A single oral rapid antigen test failed to detect 91% (20 of 22) of specimens that

were BinaxNOWTM positive from the standard nasal sampling

Conclusion: As currently recommended, repeat testing should be done for high- risk persons with an initial negative antigen test result.

Ep 226-9: Kanjilal 11 Jan 2022 Analytic sensitivity of the Abbott BinaxNOW™

Similar (rather poor) sensitivity for delta and omicron

Comparison of multiple rapid antigen test with PCR for omicron vs delta

Ep 226-10: Beklitz 17 Jan 2022 Sensitivity of SARS-CoV-2 antigen- rapid tests for Omicron variant

Very similar delta and omicron naso-pharyngeal swabs, based on PCR Ct and infectious virus nevertheless have very different results in antigen tests:

• In 4/7 tests sensitivity for omicron is significantly lower
• Flowflex, Wondfo and Tigsun similar sensitivity for delta and omicron, with Flowflex performing best  (90 %) and Tigsun very poorly (50%).   

IMMUNOLOGY

VACCINATION

Ep 226-11: Corradini Humoral and T-cell immune response after three doses of mRNA SARS-CoV-2 vaccines in fragile patients, with hematological malignancies (HM), solid tumors (ST),  immune-rheumatological diseases (ID) or neurological diseases (ND) with various types of immunomodulatory therapies.

1. Classified according to disease type

1. Antibody responses:

• After two doses (T1): seroconversion lower rate was observed in HM (52.4%) and ID (51.9%) patients compared to ST (95.6%) and ND (70.7%);
• After three doses (T3): increase in all categories, but relative differences persist

2. T cell responses to S peptides: T cell responses rather similar in various diseases after 2 doses with clear positive effect of booster.

2.   Classified according expected immune-suppressive risk of therapy

3. Effect on humoral responses: especially the anti-B cell therapy, anti-CD20 (Rituximab), anti-CD19 T cell therapy and allogeneic hematopoietic stem cell  therapy suppress antibody responses.

4. T cell responses: rather preserved even with highly immune suppressive therapy

Conclusions:

• Immunosuppressive treatment more than disease type per se is a risk factor for low humoral response after vaccination.
• The booster dose can improve both humoral and T-cell response.

Ep 226-12: Favorable effect of Pfizer vaccine on long-COVID

Vaccination with at least two doses of COVID-19 vaccine was associated with a substantial decrease in reporting the most common post-acute COVID-19 symptoms, bringing it back to baseline.

HYBRID IMMUNITY and Omicron:

Ep 226-13: Limited cross-variant immunity after infection with the SARS-CoV-2 Omicron variant without vaccination.

Mouse data:

• Sera from Omicron-infected mice only neutralize Omicron, sera from Delta-infected mice are broadly effective against Delta and other VOCs, including Omicron.

Human data:

• Sera from Omicron and Delta breakthrough cases reveals effective crossvariant neutralization induced by both viruses in vaccinated individuals

Ep 226-14: Immunity in Omicron SARS-1 CoV-2 breakthrough COVID-19 in vaccinated adults.

Very elegant and thorough study of omicron and delta breakthrough infections (BTI) in vaccinated subjects, compared to healthy donor vaccinated subjects:

1. In BTI increased activated CD8 T cells

• Delta BTI more spike oriented
• Omicron BTI: more non-spike (ORF1ab, ORF3 and Nucleoprotein)

2. Activated Follicular Helper T cells (TFH): B cell helper

3. Boosted humoral responses

The rapid release of Spike and RBD-specific IgG+ B cell plasmablasts and memory B cells into circulation after omicron BTI suggested affinity maturation of antibodies and that concerted T and B cell immunity may provide durable broad immunity

Ep 226-15: Imprinted SARS-CoV-2-specific memory lymphocytes define hybrid immunity

As compared to previously naïve subjects, those that were first infected and next vaccinated showed:

• More SARS-CoV-2 RBD-specific memory B cells and variant-neutralizing antibodies
• Distinct population of IFN-𝛾/IL-10-positive memory SARS-CoV-2 spike-specific CD4+ T cells

These CD4 T characteristics are “imprinted” by infection, as they could NOT be elicited by additional vaccination and therefore are part of “hybrid immunity”.

SOME CONCLUSIONS

Epidemio + clinic

1. Epidemiological modeling suggests that the major Omicron wave will be very substantial in case number, but of rather short duration, with potentially a resurgence in April.
2. Children’s hospital admissions are peaking in Europe and US, but severity is only 1/3 of delta.

Testing

3. The sensitivity of the BinaxNOW antigen test is low in the first days of an omicron infection and for Ct values > 30, but it may be similar to Delta.
4. Out of 7 other antigen test 4 have a very low sensitivity for Omicron and  only Flowflex has a sensitivity of around 90 % for both Delta and Omicron.

Vaccination

5. Immunosuppressive treatment more than disease type per se is a risk factor for low humoral response after vaccination, while T cell responses are less affected. The booster dose can improve both humoral and T-cell response, but in heavily treated hematological malignancies and immune rheumatoid diseases 50 % of the patients fail to seroconvert, while most solid tumor and neurological patients do respond.
6. Vaccination with at least two doses of Pfizer vaccine prevented post-COVID symptoms.

Nature of “hybrid immunity”

7. For a broad neutralization response both vaccination and omicron breakthrough infection may be needed = hybrid immunity.
8. Omicron breakthrough infection after vaccination indeed stimulates both follicular helper T cells and memory B cells, with ensuing antibodies against Spike, but it also includes cytotoxic CD8 T cell response towards more conserved non-Spike viral proteins, potentially providing broad protective immunity.
9. Imprinting by infection involves IFN-gamma and Interleukin-10 producing CD4 T cells.

Best wishes,

Guido