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The Oxford/AstraZeneca (AZ) COVID-19 vaccine is “safe and effective” and the benefits outweigh the risks observed with blood clotting, announced the European Medicines Agency (EMA) today.
The agency was responding to concerns, raised by European governments, about a possible connection between the vaccine and blood clotting events, including deaths.
But after a preliminary review of this safety signal in vaccinated individuals with the Oxford/AZ vaccine, an extraordinary meeting of the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) was held.
Emer Cooke, EMA executive director, called the vaccine “safe and effective, and its benefits in protecting people from COVID-19…outweigh the possible risks,” adding that, “the vaccine is not associated with an increase in the overall risk of thromboembolic events of blood clots.”
At the time of review, the UK had vaccinated 11 million people, compared to 7 million in the European Economic Area (EEA), but a small number of cases of rare and unusual but very serious clotting disorders triggered a more focused review.
By March 16, there were seven reports of disseminated intravascular coagulation (DIC) and 18 cases of cerebral venous sinus thrombosis (CVST). Most of these occurred in the under 55 age group, and the majority were women. Nine cases were fatal.
Sabine Strauss, MD, Chair of PRAC, pointed out that, “these cases of thrombosis and thrombocytopenia have shown a predominance in certain groups, predominantly women, and mainly younger women.”
However, she added that: “it is too premature to conclude a specific group, because the background rate might be different in this group [younger women, under 50 years], and more women might have been vaccinated in this group.”
Different EU Member States have vaccinated different populations. In the UK, vaccinations have been given to more older people than in Europe.
Cooke added that based on the evidence available, including laboratory results, clinical and autopsy reports, “we still cannot rule out, definitively, a link between these cases and the vaccine.”
She added that the EMA was launching additional investigations to understand more about the rare cases, including targeted observational studies, and stressed that all side effects needed to be reported to ensure up-to-date information on risks was made available.
In total, the number of thromboembolic events including those reported after vaccination, both in pre-licensing studies and during vaccination roll-out, is 469, 191 of them from the EEA.
Strauss noted that “this is lower than that expected in the general population and allows the PRAC to conclude that there is no increase in overall risk of blood clots with this vaccine.”
However, upon detailed analysis, an increase in cases of DIC and CVST were identified 7 to 14 days post-vaccination, although absolute numbers are small. “These conditions are linked to low levels of blood platelets also known as thrombocytopenia,” explained Strauss.
Based on pre-COVID figures, it was calculated that less than one reported case of DIC might have been expected by March 16 among people under 50 within 14 days of receiving the vaccine, whereas five cases were reported. Similarly, on average 1.35 cases of CVST might have been expected among this age group whereas by the same cut-off date there had been 12. This rise was not observed in the over-50 years age group.
“At the moment, evidence is not sufficient to conclude with certainty whether these adverse events are caused by the vaccine or not,” Strauss said, adding that such cases were not seen in the large clinical trials but that PRAC will continue to gather more information on these conditions, and will conduct additional studies.
Other hypotheses that might explain these cases include the possibility that COVID-19 is a risk factor for thromboses, as is post-COVID syndrome, said Strauss.
Her EMA colleague, Peter Arlett, Head of Data Analytics and Methods Task Force, added that further expert advice from laboratory analyses to understand more about potential mechanisms, and epidemiological data would be sought.
Other Related Concerns
Some reports have suggested concerns with particular batches of vaccine. Strauss added that the committee had found, “no evidence of a quality or a batch issue, not even for the special cases.”
In the US, the New York Times recently reported that 36 cases of immune thrombocytopenia (ITP) had been documented in people who had received the Pfizer and Moderna vaccines. “PRAC has highlighted ITP as a signal of concern with all available vaccines, and this is ongoing,” said Strauss.
Asked whether the EMA was monitoring for other thromboembolic events with the other three vaccines approved in Europe, that now include Pfizer, Moderna and Johnson & Johnson, Cooke said that they were, and that they were also in close contact with other regulators worldwide so alerts would be made known in a timely way. “Now, with increasing awareness, we may also see an increase in reports from all vaccines.”
Given the finding that there are more reports of the rare clotting events in younger women, Strauss was asked whether there was any possibility of a link with oral contraceptives or smoking. “It is always a distinct possibility,” she said. “In general, we know that CVST occurs at a certain background level, and one risk factor is the oral contraceptive. This is one thing we will investigate in the near future.”
“Smoking is of course a well-known cause of thrombosis but I don’t know if it is a risk factor for these very rare cases, but we are looking into it,” she added.
Commenting on the EMA conclusion of its preliminary review, Doug Brown, PhD, Chief Executive of the British Society for Immunology said: “We must remember that COVID-19 is a disease that can have serious consequences in its own right, including the development of coagulation problems.”
In the case of the AstraZeneca/Oxford vaccine, the EMA have concluded the vaccine is safe and effective and recommend the continuation of the vaccine rollout, a viewpoint backed up by the UK regulator, the MHRA, he noted.
“Whilst safety is always the foremost concern, this episode shows that the monitoring systems are working as they should. Vaccination is the safest and most effective way to protect yourself from falling ill with COVID-19,” Brown said.
“Vaccine safety is paramount and we welcome the regulators’ decisions which affirm the overwhelming benefit of our vaccine in stopping the pandemic,” said Ann Taylor, Chief Medical Officer at AstraZeneca. “We trust that, after the regulators’ careful decisions, vaccinations can once again resume across Europe.”
The summary of Product Characteristics (SmPC) and the patient leaflet for the Oxford/AZ vaccine is being updated to ensure the risks identified are documented, and the EMA advises that patients be made aware and be vigilant of the small possibility of blood clotting syndromes.