AstraZeneca ChAdOx1-S COVID-19 vaccine

The TGA has previously published about the AstraZeneca COVID-19 vaccine and blood clots and included information in this week's COVID-19 vaccine safety report.

To date, one case of thrombosis with thrombocytopenia reported in Australia has been assessed by the Vaccine Safety Investigation Group (VSIG). The VSIG is an independent expert advisory group comprising experts in vaccine safety, public health, vaccine confidence and relevant medical specialists in blood disorders, immunology, gastroenterology, infectious diseases, convened by the TGA to assess such cases. The VSIG concluded that, based on available data, there was insufficient evidence to firmly confirm that the clot was caused by the vaccine, but emerging evidence suggests a likely association. However, this conclusion will be reviewed as further information becomes available.

The TGA is carefully reviewing all Australian reports of blood clots following the AstraZeneca vaccine, and are requesting further information from reporters where needed. Any further suspected case will be referred to the VSIG for assessment.

The TGA has also been in regular contact with overseas regulators on the subject. Over the last two evenings we attended the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) meeting which discussed the risk of rare and unusual blood clotting issues in adults who have received the AstraZeneca COVID-19 vaccine. The issue was also discussed several times over the last few days by TGA with the UK Medicines and Health products Regulatory Agency (MHRA) and Joint Committee on Vaccines and Immunisation (JCVI), which advises UK health departments on immunisation.

The EMA has found that there is a possible link between the AstraZeneca COVID-19 vaccine and very rare cases of unusual types of blood clots with low platelets, with most case reports in women under 60 years of age, within 2 weeks of vaccination. Blood clots occurred in veins in the brain (cerebral venous sinus thrombosis, CVST) and abdomen and in arteries.

However, TGA notes that an association with gender has not been firmly established. An alternative explanation for the greater number of case reports in women is that in several cohorts vaccinated with the AstraZeneca COVID-19 vaccine (e.g. health care workers) there are significantly more women than men.

The TGA also notes that the benefit/risk ratio of vaccinating with the AstraZeneca COVID-19 vaccine increases rapidly with increasing age over 50. This is because mortality and life-threatening illness from COVID-19 infection increases dramatically with age. For example of the 909 COVID deaths reported in Australia as of 8 April 2021, only 5 deaths were in persons aged 49 and below (www.health.gov.au/resources/covid-19-deaths-by-age-group-and-sex - external site). In other words, 99.5 % of Australian COVID-19 deaths were in those 50 and older.

The EMA PRAC reviewed 86 cases reported as of 22 March 2021 (62 CVST and 24 of other thromboses with thrombocytopenia), 18 of which were fatal. PRAC noted that in Europe and the UK about 25 million people had received the AstraZeneca vaccine. They stated that "the reported combination of blood clots and low blood platelets is very rare and the overall benefits of the vaccine in preventing COVID-19 outweigh the risks of side effects".

The UK regulator (MHRA) issued new advice on the afternoon of 7 April (UK time) concluding "a possible link between COVID-19 vaccine AstraZeneca and extremely rare, unlikely to occur blood clots". The MHRA reviewed 79 UK cases of thromboses accompanied by thrombocytopenia reported as of 31 March 2021 (44 CVST and 35 of other thromboses), with 51 of these case reports in women. There were 19 deaths.

MHRA reported that by 31 March 2021, 20.2 million doses of the COVID-19 Vaccine AstraZeneca had been given in the UK, meaning that the overall risk of the rare blood clots was approximately 4 people in a million who receive the vaccine.

The TGA and Australian Technical Advisory Group on Immunisation (ATAGI) continue to urgently review this information and other data as part of our enhanced safety monitoring of COVID-19 vaccines.

ATAGI met yesterday to discuss the Europe and UK advice in the Australian context. ATAGI has recently published information about the potential risk of blood clots following immunisation with COVID-19 vaccines for consumers - external site and health professionals - external site. The advice includes information about symptoms that might prompt further action and how they can be managed and treated (such as seeking medical attention). This evening, ATAGI released updated advice.

The TGA encourages health professionals and consumers to report suspected side effects following immunisation with COVID-19 vaccines. Every report is valuable and contributes to our safety monitoring.

The TGA has worked with AstraZeneca to update the Product Information for the vaccine to include the latest information about the risk of very rare cases of thrombosis (blood clots) with thrombocytopenia (low blood platelet count). An updated Product Information, effective 8 April 2021 is available on the TGA website. Further updates are under consideration in light of international developments and the most recent ATAGI advice.

Further information about how to report suspected side effects to a COVID-19 vaccine is available on our website.

The Australian Technical Advisory Group on Immunisation (ATAGI) advice on the AstraZeneca COVID-19 vaccine in response to new vaccine safety concerns

8 April 2021

Summary

• ATAGI notes further evidence of a rare but serious side effect involving thrombosis (clotting) with thrombocytopenia (low blood platelet count) following receipt of COVID-19 Vaccine AstraZeneca.
• ATAGI recommends that the COVID-19 vaccine by Pfizer (Comirnaty) is preferred over COVID-19 Vaccine AstraZeneca in adults aged under 50 years. This recommendation is based on the increasing risk of severe outcomes from COVID-19 in older adults (and hence a higher benefit from vaccination) and a potentially increased risk of thrombosis with thrombocytopenia following AstraZeneca vaccine in those under 50 years.
• COVID-19 Vaccine AstraZeneca can be used in adults aged under 50 years where the benefits clearly outweigh the risk for that individual and the person has made an informed decision based on an understanding of the risks and benefits.
• People who have had the first dose of COVID-19 Vaccine AstraZeneca without any serious adverse effects can be given the second dose, including adults under 50 years.

Background – Thrombosis with thrombocytopenia syndrome and COVID-19 Vaccine AstraZeneca

ATAGI recommends that all adults are vaccinated against COVID-19. The COVID-19 pandemic is continuing to cause severe disease around the world, with many lives being lost. The Australian population remains vulnerable to COVID-19 and most Australians have not yet been vaccinated and are not immune.

ATAGI advised on 25th March 2021 - external site that there was a potential safety concern being investigated overseas, involving cases of thrombosis (blood clots) and thrombocytopenia (low blood platelet count) occurring after COVID-19 Vaccine AstraZeneca. On 2nd April 2021 - external site ATAGI reported that a probable case had been reported in an Australian vaccine recipient, and issued an updated advice for healthcare providers - external site.

This 'thrombosis with thrombocytopenia syndrome' (TTS) is a newly described serious condition, with unusual blood clots in the brain (cerebral venous sinus thrombosis) or in other parts of the body, associated with low platelet levels. Some researchers have provisionally called this condition 'vaccine induced prothrombotic immune thrombocytopenia' (VIPIT). However, the causal relationship and exact mechanism leading to this condition is not yet understood. Some people have antibodies which activate platelets (anti-PF4 antibodies). These antibodies have been detected in another disorder triggered by the drug heparin, which has a similar presentation.

ATAGI and other Australian officials continue to consult with the WHO, UK, European and other regulatory agencies in countries where use of the AstraZeneca COVID-19 vaccine has been widespread. Further information from the UK and Europe is still emerging. The European Medicines Agency (EMA) stated - external site on 7 April 2021 that a causal relationship between the AstraZeneca vaccination and thrombosis in combination with thrombocytopenia is plausible.

In the UK, where approximately 20.2 million doses of AstraZeneca COVID-19 vaccine have been administered, their regulatory agency, the MHRA have advised - external site that the evidence of a link is stronger but more work is still needed.

ATAGI is aware of more cases of TTS being reported from other countries, and has reviewed all available data and research provided by AstraZeneca, as well as independent expert groups. Some countries that are using the AstraZeneca COVID-19 vaccine have made precautionary decisions about pausing or limiting its use based on the potential risk of this serious adverse event. These decisions are also informed by the local risk for COVID-19, how much of the population is already immune from vaccination and in what age groups, and whether they have an alternative supply of vaccines.

The risk-versus-benefit assessment for the use of AstraZeneca COVID-19 vaccine will be different for Australia compared to other countries, such as those with widespread transmission. This includes countries in our region such as those currently experiencing very serious outbreaks of COVID-19, such as Timor Leste, Papua New Guinea and others.

Key Considerations

The following information has been considered by ATAGI in relation to its new recommendations:

Local epidemiology

Vaccine availability and uptake

Evidence regarding TTS

Benefit-to-risk assessment

• While Australia currently has very low or no community transmission of COVID-19, this could change, particularly in the context of high global transmission rates, including of new variants of the virus. The risk of serious disease and death in Australia remains, even as borders controls and other measures continue.
• Although Australia has had few deaths from COVID-19 in young adults until now, large outbreaks in other countries have caused many thousands of deaths in young adults, indicating that the risk for serious outcomes exists across the age spectrum.
• The AstraZeneca vaccine is highly effective at reducing the risk of death or severe disease from COVID-19 across all adult age groups. At the present time, the AstraZeneca vaccine is the only vaccine option for reducing this risk for many Australians, since the global availability of alternative vaccines is highly constrained.
• ATAGI recognises this safety concern will likely impact on confidence in being vaccinated with AstraZeneca vaccine in all age groups.
• Until the Government can increase supply of COVID-19 vaccines other than AstraZeneca, overall coverage under Australia's COVID-19 vaccine program will likely be reduced. This will likely impact the time frame to which the Australian population is protected against COVID-19.
• In the short term, delays in vaccine uptake increase the vulnerability of the Australian population to outbreaks of COVID-19 and the attendant risk of death and serious morbidity, especially among older Australians.
• The AstraZeneca vaccine appears likely to be causally-linked with a risk of this newly recognised thrombosis with thrombocytopenia syndrome.
• There is currently uncertainty in, and different reported rates of risk, for this adverse event.
• Studies have suggested it may occur in approximately 4 – 6 people in every one million people in the 4-20 days after the first dose of vaccine. However, higher rates have been reported in Germany and some Scandinavian countries.
• Some evidence suggests the risk of this condition occurring may be somewhat higher in people of a younger age, however a small number of cases have been reported in people of different ages (including older adults).
• While there have been more reports of TTS in women in some settings, this may be because more vaccine doses have been given to women. In one country the reported rate of TTS (number of cases adjusted for the number of men and women vaccinated) was similar in men and women.
• TTS can cause serious long term disability or death (with death occurring in approximately 25% of reported cases).
• So far no specific biological risk factors or pre-existing medical conditions have been found to modify (i.e. increase or decrease) the risk of TTS occurring after AstraZeneca vaccine.
• We do not yet know to what extent earlier recognition of this syndrome and improved treatments will improve patient outcomes. More cases can be expected to occur, albeit rarely.
• Comirnaty (the Pfizer COVID-19 vaccine) does not appear to carry a risk of TTS.
• ATAGI consider that the individual benefit-to-risk balance of vaccination with COVID-19 vaccine AstraZeneca in Australia varies with age. The risk of ongoing health issues and death from COVID-19 is highest in older age groups, particularly rising from 50 years of age. By comparison, the rate, and thus possibility of disability and death from TTS may be higher in younger people. This age-specific benefit-to-risk balance is demonstrated in an analysis from the UK.
• Younger people with certain underlying medical conditions are also at increased risk of severe outcomes from COVID-19, which affects their individual benefit-to-risk balance.
• ATAGI respects a person's choice to make an informed decision on whether to accept the risk of COVID-19 vaccination with the AstraZeneca vaccine. ATAGI recognise that it is difficult for people to assess their personal risk where there is uncertainty about the short and long term risk of severe COVID-19 in different age groups, and the evidence around benefit and risk of the AstraZeneca vaccine is changing quickly.
• In the context of the ongoing risk of COVID-19 in Australia, ATAGI considers that the benefit-to-risk balance is favourable for use of AstraZeneca vaccine in all older adult age groups.
• ATAGI also consider that population coverage under Australia's COVID-19 vaccine program will likely be impacted until such time that an increased supply of alternative safe and effective vaccines can be secured.

Recommendations

ATAGI recommends that:

1. At the current time, use of Comirnaty COVID-19 vaccine (Pfizer) is preferred over AstraZeneca COVID-19 vaccine in adults aged < 50 years who have not already received a first dose of AstraZeneca vaccine. This is based both on the increased risk of complications from COVID-19 with increasing age (and thus increased benefit of vaccination), and the potentially lower, but not zero, risk of TTS with increasing age.
2. Immunisation providers should only give a first dose of AstraZeneca COVID-19 vaccine to adults aged < 50 years of age where benefit clearly outweighs risk for that individual's circumstances.
3. People who have had their first dose of COVID-19 Vaccine AstraZeneca without any serious adverse effects can be given their second dose. This includes adults under 50 years of age. People who have had blood clots associated with low platelet levels after their first dose of COVID-19 Vaccine AstraZeneca should not be given their second dose.
4. That the Department of Health further develop and refine resources for informed consent that clearly convey the benefits and risks of AstraZeneca vaccine for both immunisation providers and consumers of all ages.

This advice may be revised as more information becomes available or if the epidemiological situation changes, particularly if there is, or is likely to be significant community transmission.

ATAGI supports the Australian Government's ongoing efforts to procure more or bring forward the delivery of alternate COVID-19 vaccine brands to replace the use of AstraZeneca COVID-19 vaccine that would have been administered to persons under 50 years of age. Where possible, onshore manufacturing of alternative safe and effective vaccines should be considered.

ATAGI intends to review other current COVID-19 vaccine recommendations as soon as practicable. This includes recommendations on vaccination for those who have a past history of heparin induced thrombocytopenia (HIT), central venous sinus thrombosis (CVST), and/or have other thrombosis risk factors, and those who are pregnant.

Further data and outcomes of investigations from the UK, Europe and other countries will continue to be reviewed over the coming days to weeks. ATAGI recommendations may change as a result of this ongoing assessment of new and emerging evidence over coming days and weeks.

Definitions

• Thrombosis with thrombocytopenia syndrome (TTS) is a rare and new syndrome which has been reported after being given the AstraZeneca COVID-19 vaccine. It may be caused by this vaccine. The condition involves blood clots (occurring in body sites like the brain or abdomen) together with low platelet levels.
• Thrombosis is the formation of a blood clot, which prevents blood flowing normally through the body.
• Thrombocytopenia is a condition in which you have a low blood platelet count. Platelets (thrombocytes) are blood cells that help blood clot. Platelets stop bleeding by clumping and forming plugs in blood vessel injuries.