A quantitative risk-benefit analysis of ChAdOx1 nCoV-19 vaccine among people under 60 in Italy

ChAdOx1 nCoV-19 is a vaccine against the COVID-19 infection that was granted a conditional marketing authorization by the European Commission in January 2021. However, following a report from the Pharmacovigilance Risk Assessment Committee (PRAC) of European Medicines Agency, which reported an association with thrombo-embolic events (TEE), in particular Disseminated intravascular coagulation (DIC) and Cerebral venous sinus thrombosis (CVST), many European countries either limited to individuals older than 55-60 years or suspended its use. We used publicly available data to carry out a quantitative risk-benefit analysis of the vaccine among people under 60 in Italy. Specifically, we used data from PRAC, Eudravigilance and ECDC to estimate the excess number of deaths for TEE, DIC and CVST expected in vaccine users, stratified by age groups. We then used data from the National Institute of Health to calculate age-specific COVID-19 mortality rates in Italy. Preventable deaths were calculated assuming a 72% vaccine efficacy over an 8-month period. Finally, benefit-risk ratio of ChAdOx1 nCoV-19 vaccination was calculated as the ratio between preventable COVID-19 deaths and vaccine-related deaths, using Monte-Carlo simulations. We found that among subjects aged 20-29 years the benefit-risk [B-R] ratio was not clearly favorable (0.70; 95% Uncertainty Interval [UI]: 0.27-2.11). However, in the other age groups the benefits of vaccination largely exceeded the risks (for age 30-49, B-R ratio: 22.9: 95%UI: 10.1-186.4). For age 50-59, B-R ratio: 1577.1: 95%UI: 1176.9-2121.5). Although many countries have limited the use of the ChAdOx1 nCoV-19 vaccine, the benefits of using this vaccine clearly outweigh the risks in people older than 30 years. The use of this vaccine should be a strategic and fundamental part of the immunization campaign considering its safety and efficacy in preventing COVID-19 and its complications.

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A Quantitative Benefit–Risk Analysis of ChAdOx1 nCoV-19 Vaccine among People under 60 in Italy

Vaccines ◽

10.3390/vaccines9060618 ◽

2021 ◽

Vol 9 (6) ◽

pp. 618

Author(s):

Raffaele Palladino ◽

Daniele Ceriotti ◽

Damiano De Ambrosi ◽

Marta De Vito ◽

Marco Farsoni ◽

...

Keyword(s):

Risk Analysis ◽

Sinus Thrombosis ◽

Age Groups ◽

Cerebral Venous Sinus Thrombosis ◽

European Medicines Agency ◽

Uncertainty Interval ◽

R Ratio ◽

Pharmacovigilance Risk Assessment Committee ◽

Assessment Committee ◽

Excess Number

The Oxford-AstraZeneca ChAdOx1 nCoV-19 is a vaccine against the COVID-19 infection that was granted a conditional marketing authorization by the European Commission in January 2021. However, following a report from the Pharmacovigilance Risk Assessment Committee (PRAC) of European Medicines Agency, which reported an association with thrombo-embolic events (TEE), in particular disseminated intravascular coagulation (DIC) and cerebral venous sinus thrombosis (CVST), many European countries either limited it to individuals older than 55–60 years or suspended its use. We used publicly available data to carry out a quantitative benefit–risk analysis of the vaccine among people under 60 in Italy. Specifically, we used data from PRAC, Eudravigilance and ECDC to estimate the excess number of deaths for TEE, DIC and CVST expected in vaccine users, stratified by age groups. We then used data from the National Institute of Health to calculate age-specific COVID-19 mortality rates in Italy. Preventable deaths were calculated assuming a 72% vaccine efficacy over an eight-month period. Finally, the benefit–risk ratio of ChAdOx1 nCoV-19 vaccination was calculated as the ratio of preventable COVID-19 deaths to vaccine-related deaths, using Monte-Carlo simulations. We found that among subjects aged 20–29 years the benefit–risk (B-R) ratio was not clearly favorable (0.70; 95% Uncertainty Interval (UI): 0.27–2.11). However, in the other age groups the benefits of vaccination largely exceeded the risks (for age 30–49, B-R ratio: 22.9: 95%UI: 10.1–186.4). For age 50–59, B-R ratio: 1577.1: 95%UI: 1176.9–2121.5). Although many countries have limited the use of the ChAdOx1 nCoV-19 vaccine, the benefits of using this vaccine clearly outweigh the risks in people older than 30 years. Study limitations included risk of underreporting and that we did not provide age-specific estimates. The use of this vaccine should be a strategic and fundamental part of the immunization campaign considering its safety and efficacy in preventing COVID-19 and its complications.

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Risk-benefit analysis of the AstraZeneca COVID-19 vaccine in Australia using a Bayesian network modelling framework

10.1101/2021.09.30.21264337 ◽

2021 ◽

Author(s):

Colleen L Lau ◽

Helen J Mayfield ◽

Jane E Sinclair ◽

Sam J Brown ◽

Michael Waller ◽

...

Keyword(s):

Bayesian Network ◽

Sinus Thrombosis ◽

Severe Disease ◽

Age Groups ◽

Case Fatality ◽

Benefit Analysis ◽

Network Modelling ◽

High Transmission ◽

Blood Clots ◽

Risk Benefit Analysis

Thrombosis and Thromobocytopenia Syndrome (TTS) has been associated with the AstraZencea (AZ) COVID-19 vaccine. Australia has reported low TTS incidence of <3/100,000 after the first dose, with case fatality rate (CFR) of 5-6%. Risk-benefit analysis of vaccination has been challenging because of rapidly evolving data, changing levels of transmission, and age-specific variation in rates of TTS, COVID-19, and CFR. We aim to optimise risk-benefit analysis by developing a model that enables inputs to be updated rapidly as evidence evolves. A Bayesian network was used to integrate local and international data, government reports, published literature and expert opinion. The model estimates probabilities of outcomes under different scenarios of age, sex, low/medium/high transmission (0.05%/0.45%/5.76% of population infected over 6 months), SARS-CoV-2 variant, vaccine doses, and vaccine effectiveness. We used the model to compare estimated deaths from vaccine-associated TTS with i) COVID-19 deaths prevented under different scenarios, and ii) deaths from COVID-19 related atypical severe blood clots (cerebral venous sinus thrombosis & portal vein thrombosis). For a million people aged >70 years where 70% received first dose and 35% received two doses, our model estimated <1 death from TTS, 25 deaths prevented under low transmission, and >3000 deaths prevented under high transmission. Risks versus benefits varied significantly between age groups and transmission levels. Under high transmission, deaths prevented by AZ vaccine far exceed deaths from TTS (by 8 to >4500 times depending on age). Probability of dying from COVID-related atypical severe blood clots was 58-126 times higher (depending on age and sex) than dying from TTS. To our knowledge, this is the first example of the use of Bayesian networks for risk-benefit analysis for a COVID-19 vaccine. The model can be rapidly updated to incorporate new data, adapted for other countries, extended to other outcomes (e.g., severe disease), or used for other vaccines.

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Case Study of Pediatric Cerebral Sinus Venous Thrombosis Center of a Low Middle-Income Country

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/10760296211022847 ◽

2021 ◽

Vol 27 ◽

pp. 107602962110228

Author(s):

Bushra Moiz ◽

Ronika Devi Ukrani ◽

Aiman Arif ◽

Inaara Akbar ◽

Muhammed Wahhaab Sadiq ◽

...

Keyword(s):

Sinus Thrombosis ◽

Care Center ◽

Tertiary Care ◽

Age Groups ◽

Activated Protein C ◽

Positive Association ◽

Cerebral Venous Sinus Thrombosis ◽

P Value ◽

Middle Income ◽

Duration Of Symptoms

Pediatric cerebral venous sinus thrombosis (CVST) is rare but a potentially fatal disease requiring its understanding in local setting. In this study, we observed the clinical course, management, and outcome of pediatric patients with sinus thrombosis in a tertiary care center at Pakistan. Patients between age 0 to 18 years of both genders diagnosed with sinus thrombosis during 2011 to 2020 were included. Data was collected through in-house computerized system and SPSS version 19 was used for analysis. Of 143492 pediatric admissions, 32 (21 males and 11 females) patients with a median (IQR) age of 4.5 years (0-16) had CVST. This is equivalent to 18.5 CVST events per million pediatric admissions. Adolescents were mostly affected, and the overall mortality was 7%. Primary underlying disorders were infections (59%), hematological neoplasms (12.5%), thrombotic thrombocytopenic purpura (3%) and antiphospholipid syndrome (3%). Activated protein C resistance (44%) was the most common inherited thrombophilia. Twenty-one (66%) patients were anemic with a mean (±SD) hemoglobin of 9.0 g/dL (±2.3). Regression analysis showed a positive association of anemia with multiple sinus involvement ( P-value 0.009) but not with duration of symptoms ( P-value 0.344), hospital stay ( P-value 0.466), age ( P-value 0.863) or gender ( P-value 0.542) of the patients. SARS-COV2 was negative in patients during 2020. Adolescents were primarily affected by sinus thrombosis and infections was the predominant risk factor for all age groups, with a low all-cause mortality. A high index of clinical suspicion is required for prompt diagnosis and intervention.

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Post‐SARS‐CoV‐2‐vaccination Cerebral Venous Sinus Thrombosis: an analysis of cases notified to the European Medicines Agency

European Journal of Neurology ◽

10.1111/ene.15029 ◽

2021 ◽

Author(s):

Katarzyna Krzywicka ◽

Mirjam R Heldner ◽

Mayte Sánchez van Kammen ◽

Thijs van Haaps ◽

Sini Hiltunen ◽

...

Keyword(s):

Sinus Thrombosis ◽

Cerebral Venous Sinus Thrombosis ◽

Venous Sinus ◽

European Medicines Agency ◽

Venous Sinus Thrombosis ◽

Analysis Of Cases

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Age-Stratified Risk of Cerebral Venous Sinus Thrombosis After SARS-CoV-2 Vaccination

Neurology ◽

10.1212/wnl.0000000000013148 ◽

2021 ◽

pp. 10.1212/WNL.0000000000013148

Author(s):

Katarzyna Krzywicka ◽

Anita van de Munckhof ◽

Mayte Sánchez van Kammen ◽

Mirjam R Heldner ◽

Katarina Jood ◽

...

Keyword(s):

Sinus Thrombosis ◽

Absolute Risk ◽

Age Groups ◽

Cerebral Venous Sinus Thrombosis ◽

Venous Sinus ◽

Age Group ◽

Background Rate ◽

Venous Sinus Thrombosis ◽

The Absolute ◽

Using Data

Background and ObjectivesCerebral Venous Sinus Thrombosis (CVST) as a part of the thrombosis and thrombocytopenia syndrome is a rare adverse drug reaction of SARS-CoV-2 vaccination. Estimated background rate of CVST with thrombocytopenia is 0.1 per million per month. We assessed the age-stratified risk of CVST with and without thrombocytopenia after SARS-CoV-2 vaccination.MethodsWe estimated the absolute risk of CVST with and without thrombocytopenia within 28 days of first dose of four SARS-CoV-2 vaccinations, using data from the European Medicines Agency’s EudraVigilance database (until 13 June 2021). As a denominator, we used data on vaccine delivery from 31 European countries. For 22.8 million adults from 25 countries, we estimated the absolute risk of CVST after the first dose of ChAdOx1 nCov-19 per age category.ResultsThe absolute risk of CVST within 28 days of first dose vaccination was 7.5 (95%CI 6.9-8.3), 0.7 (95%CI 0.2-2.4), 0.6 (95%CI 0.5-0.7) and 0.6 (95%CI 0.3-1.1) per million of first doses of ChAdOx1 nCov-19, Ad26.COV2.S, BNT162b2 and mRNA-1273, respectively. The absolute risk of CVST with thrombocytopenia within 28 days of first dose vaccination was 4.4 (95%CI 3.9-4.9), 0.7 (95%CI 0.2-2.4), 0.0 (95%CI 0.0-0.1) and 0.0 (95%CI 0.0-0.2) per million of first doses of ChAdOx1 nCov-19, Ad26.COV2.S, BNT162b2 and mRNA-1273, respectively. In recipients of ChAdOx1 nCov-19, the absolute risk of CVST, both with and without thrombocytopenia, was the highest in the 18-24 years age group (7.3 per million, 95%CI 2.8-18.8 and 3.7 per million, 95%CI 1.0-13.3, respectively). The risk of CVST with thrombocytopenia in ChAdOx1 nCov-19 recipients was the lowest in the age group≥70 years (0.2, 95%CI 0.0-1.3). Age <60 compared to ≥60 was a predictor for CVST with thrombocytopenia (incidence rate ratio 5.79; 95%CI 2.98-11.24, p<0.001).DiscussionThe risk of CVST with thrombocytopenia within 28 days of first dose vaccination with ChAdOx1 nCov-19 was higher in younger age groups. The risk of CVST with thrombocytopenia was slightly increased in patients receiving Ad26.COV2.S, compared with the estimated background risk. The risk of CVST with thrombocytopenia was not increased in recipients of SARS-CoV-2 mRNA vaccines.

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Thrombosis with Thrombocytopenia Syndrome After Administration of AZD1222 or Ad26.COV2.S Vaccine for COVID-19: A Systematic Review

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/10760296211068487 ◽

2021 ◽

Vol 27 ◽

pp. 107602962110684

Author(s):

Usama Waqar ◽

Shaheer Ahmed ◽

Syed M.H.Ali Gardezi ◽

Muhammad Sarmad Tahir ◽

Zain ul Abidin ◽

...

Keyword(s):

Systematic Review ◽

Venous Thrombosis ◽

Sinus Thrombosis ◽

Case Reports ◽

Age Groups ◽

Cerebral Venous Sinus Thrombosis ◽

Funding Agency ◽

For Profit ◽

Level Data ◽

Management Approaches

Background Cases of thrombosis with thrombocytopenia syndrome (TTS) have been reported following vaccination with AZD1222 or Ad26.COV2.S. This review aimed to explore the pathophysiology, epidemiology, diagnosis, management, and prognosis of TTS. Methods A systematic review was conducted to identify evidence on TTS till 4th September 2021. Case reports and series reporting patient-level data were included. Descriptive statistics were reported and compared across patients with different sexes, age groups, vaccines, types of thrombosis, and outcomes. Findings Sixty-two studies reporting 160 cases were included from 16 countries. Patients were predominantly females with a median age of 42.50 (22) years. AZD1222 was administered to 140 patients (87·5%). TTS onset occurred in a median of 9 (4) days after vaccination. Venous thrombosis was most common (61.0%). Most patients developed cerebral venous sinus thrombosis (CVST; 66.3%). CVST was significantly more common in female vs male patients (p = 0·001) and in patients aged <45 years vs ≥45 years (p = 0·004). The mortality rate was 36.2%, and patients with suspected TTS, venous thrombosis, CVST, pulmonary embolism, or intraneural complications, patients not managed with non-heparin anticoagulants or IVIG, patients receiving platelet transfusions, and patients requiring intensive care unit admission, mechanical ventilation, or inpatient neurosurgery were more likely to expire than recover. Interpretation These findings help to understand the pathophysiology of TTS while also recommending diagnostic and management approaches to improve prognosis in patients. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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RTS,S/AS01, a vaccine targeting pre-erythrocytic stages of Plasmodium falciparum

Emerging Topics in Life Sciences ◽

10.1042/etls20170101 ◽

2017 ◽

Vol 1 (6) ◽

pp. 533-537

Author(s):

Lorenz von Seidlein ◽

Borimas Hanboonkunupakarn ◽

Podjanee Jittmala ◽

Sasithon Pukrittayakamee

Keyword(s):

Protective Efficacy ◽

Age Groups ◽

Sub Saharan Africa ◽

Phase Iii ◽

European Medicines Agency ◽

Older Children ◽

Pivotal Phase ◽

Malaria Epidemiology ◽

Maximum Benefit ◽

Sub Saharan

RTS,S/AS01 is the most advanced vaccine to prevent malaria. It is safe and moderately effective. A large pivotal phase III trial in over 15 000 young children in sub-Saharan Africa completed in 2014 showed that the vaccine could protect around one-third of children (aged 5–17 months) and one-fourth of infants (aged 6–12 weeks) from uncomplicated falciparum malaria. The European Medicines Agency approved licensing and programmatic roll-out of the RTSS vaccine in malaria endemic countries in sub-Saharan Africa. WHO is planning further studies in a large Malaria Vaccine Implementation Programme, in more than 400 000 young African children. With the changing malaria epidemiology in Africa resulting in older children at risk, alternative modes of employment are under evaluation, for example the use of RTS,S/AS01 in older children as part of seasonal malaria prophylaxis. Another strategy is combining mass drug administrations with mass vaccine campaigns for all age groups in regional malaria elimination campaigns. A phase II trial is ongoing to evaluate the safety and immunogenicity of the RTSS in combination with antimalarial drugs in Thailand. Such novel approaches aim to extract the maximum benefit from the well-documented, short-lasting protective efficacy of RTS,S/AS01.

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