Award Title: Understanding Mechanisms of Thrombosis and Thrombocytopenia in COVID-19 and with SARS-CoV-2 Vaccines
Funder: Department of Health and Social Care

Abstract: Background to the research_x000D_
The vast majority of people who have a COVID-19 vaccine experience only mild side effects lasting for two or three days. However, in March 2021 reports of a small number of people being admitted to hospital with what could potentially be a very rare side effect of vaccination began to emerge. These people had blood clots in the major veins in the brain or in the abdomen, but at the same time a low level of platelets – which are responsible for clotting – in the blood. The blood clots varied in severity, and sadly, some of the individuals affected by this side effect died. The combination of blood clots with low platelet levels is very uncommon. Although it has been reported previously (even before the pandemic), the clusters of cases were unusual and an association with the vaccines was suggested. It is important to note that the vast majority of individuals given the vaccine do not develop this complex of problems (clots together with low platelets – for which we are using the name thrombotic thrombocytopenia syndrome, or TTS), but about 1 in 100,000 to 1 in a million do. We do not understand why a vaccine that is safe for almost everyone can cause TTS in particular individuals._x000D_
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Aims_x000D_
We aim to: _x000D_
•	Investigate how common TTS was: before COVID-19; in those who have been vaccinated against COVID-19 and in those suffering from COVID-19. _x000D_
•	Understand why a very small number of those vaccinated against COVID-19, and also those with COVID-19 itself, develop blood clotting disorders. _x000D_
•	Investigate the changes in the body that lead to the unique combination of blood clots and low platelet count seen in TTS._x000D_
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Approach_x000D_
We have brought together researchers and doctors from across the UK with expertise in many different areas. These include: using information in electronic health records to understand disease; vaccine safety and effectiveness; understanding how the immune system and the genes controlling the immune system respond to viral infection and vaccination; treating people who have blood clots and understanding how and why blood clots form. Our team will work together to understand the biology behind TTS and develop solutions to prevent and treat TTS._x000D_
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Patient and public involvement_x000D_
We will work with people who have recovered, or are recovering from TTS, and their families to make sure that their voice is heard. We will also engage those with those who have been vaccinated but without side effects. Our PPI group will work closely with each of our groups of researchers to create a shared understanding of the most important research questions, to interpret the experimental results and to create plain language summaries to share the research findings._x000D_
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Impact_x000D_
Our research will discover why COVID-19 vaccines can lead to TTS in rare cases. This will be important for redesigning COVID-19 vaccines to avoid TTS and for development of new vaccines in any future pandemics and against existing diseases for which there is no vaccine. The benefit-risk ratio of the COVID-19 vaccines is highly beneficial. Understanding how TTS develops has the potential to further improve the safety of current and future vaccines.

Lay Abstract: Background_x000D_
Clusters of cases of cerebral venous sinus thrombosis (CVST) or thrombosis in other major veins, together with thrombocytopenia (thrombotic thrombocytopenia syndrome (TTS)) began to emerge following roll-out of SARS-CoV-2 vaccines. Although a mechanistic link is not yet proven, there is strong epidemiological evidence that TTS is a very rare adverse effect of SARS-CoV-2 vaccines, and in particular, adenoviral vectored vaccines. The incidence of vaccine-induced TTS is thought to range between 1 in 100,000 and 1 in 1,000,000 with a fatal outcome in up to 20% of cases._x000D_
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Research question_x000D_
We aim to investigate the mechanisms underlying TTS in response to SARS-CoV-2 vaccination with the ultimate goal of developing novel preventive and interventional strategies. _x000D_
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Aims _x000D_
• Evaluate SARS-CoV-2 vaccine safety using real world epidemiology data._x000D_
• Understand the prevalence of anti-platelet factor 4 (PF4) antibody positivity._x000D_
• Understand the relationship between the immune response initiated by COVID-19, vaccines and haemostatic dysfunction including the underlying genetic factors._x000D_
• Develop in vitro platelet models to understand mechanisms of vaccine associated adverse events, and identify potential therapeutic interventions._x000D_
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Timelines for delivery_x000D_
We expect important findings of relevance to public health to be delivered during the funding period (before August 2022). Our expected outcomes are:_x000D_
• Epidemiological data that provides robust evidence of background rates of thrombocytopenia, thrombosis and TTS, and whether TTS is associated with any of the COVID-19 vaccines, including the magnitude of the effect._x000D_
• Robust laboratory data to show the background rates of anti-PF4 antibodies, and whether they are sensitive and specific indicators of TTS._x000D_
• Novel methods for preventing TTS including potential avenues to modify the vaccines to prevent TTS._x000D_
• Development of a clinical assay for TTS._x000D_
• Identification of improved treatment approaches for TTS to improve its prognosis._x000D_
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Anticipated impact and dissemination_x000D_
Our work will enable regulatory authorities to assess the relative risk of developing TTS in response to SAR-CoV-2 vaccine against that of becoming seriously ill with COVID-19. This understanding is important to ensure that populations worldwide receive maximum benefit from vaccination programmes. Understanding the mechanism for vaccine-induced TTS will inform development of second-generation COVID-19 vaccines and help to identify new therapies to reduce the case fatality rate associated with TTS._x000D_
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Our outputs will be of national and international importance. Initially, we will share new findings with the Vaccine Task Force (VTF), the Joint Committee on Vaccination and Immunisation, and other representatives of the Department of Health and Social Care (DHSC) . The DHSC will determine whether the findings are of ministerial interest. Press releases will be cleared with NIHR, DHSC and the VTF._x000D_
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Investigating the Genetic basis for TTS_x000D_
Genomics England, part of the consortium, is leading and funding complementary work investigating the genomics of thrombosis and thrombocytopenia related to COVID-19 and SARS-CoV-2 vaccines. The whole consortium will work together, and collaborate with other researchers worldwide, to develop a better understanding of TTS and maximise public health impact.

Research Activity Codes: 3.4 VACCINES
Health Categories: CARDIOVASCULAR;INFECTION