Last week, many countries had suspended AstraZeneca's COVID-19 vaccine over reports of clotting and bleeding events among recipients. The suspension has been lifted (albeit with some lingering concerns), so here is the rundown of reports and expert statements to endorse the safety and benefits of the vaccine.

For our comprehensive coverage and latest updates on COVID-19 click here.

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The year 2020 saw a series of unprecedented events associated with the spread of a new viral disease that challenged the whole world. WHO declared COVID-19 as a pandemic, over a year ago on March 11, 2020. An important step to vanquish the virus was to develop effective vaccines.

Oxford University's AstraZeneca vaccine (AZ Vaccine, known as Covishield in India), is one of the vaccines among the seven developed across three platforms by multidisciplinary teams of specialists in many countries. According to Adam Finn, Professor of Paediatrics, University of Bristol, the vaccine is highly effective at preventing severe COVID symptoms even after just one dose, which is also observed in elderly vulnerable people. Supplies are ramping up, somewhat slower than originally hoped – but rapidly nonetheless – in many countries across the world. “Other vaccines are, so far, less widely available and tend to be more expensive and more difficult to handle and distribute”, he clarified.

Recent developments appear to throw a spanner in the fireworks. Eighteen countries have placed some restrictions over the use of the AstraZeneca vaccine after there have been reports of blood clotting disorders in some countries. This may cause a serious setback to immunization programmes in many countries. However, the preliminary reviews by specialists and regulatory agencies indicate that the benefits of vaccination far outweigh the risk, if there are observed to be any side effects.

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Countries that have restricted the use of AZ

Presently, Denmark, Norway, Bulgaria, Iceland, France, Germany, Italy, Spain, Portugal, Slovenia, and Cyprus have suspended all use of the vaccine. Five other countries (Austria, Estonia, Latvia, Lithuania, and Luxembourg) have paused the use of a single batch of a million doses of the vaccine.

The Norwegian Medicines Agency stated that it was looking into several cases of blood clots or reduced platelet counts, including at least one death from a brain haemorrhage. The number of countries pausing or delaying the use of AZ vaccine against COVID-19 rose to 16. Very recently, Sweden and Venezuela also joined the group. India continues to use Covishield.

“Our programme with Covishield implementation in the country will go on with full vigour," NITI Aayog member for health, Vinod K Paul asserted during a press conference on March 17 (Businessinsider.in, March 17, 2021). The consensus among specialists and specialists’ organizations on the issue is against stopping the use of AZ vaccine in immunisation programmes. In this context, India’s decision is pragmatic, sensible and appropriate.

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"No indication AZ vaccine caused blood disorders": WHO, EMA

The nationalgeographic.com quoted the World Health Organization and the European Medicines Agency (EMA) saying that there is currently no indication that the AZ vaccine causes blood clots and have recommended its continued use. AstraZeneca has said that there have only been 37 adverse incidents related to blood clots among the 17 million people who have been vaccinated in the EU and United Kingdom through March 8. The company’s chief medical officer Ann Taylor stated that the figure “is lower than the hundreds of cases that would be expected among the general population."

Public must rely on authentic agencies

Media coverage of the topic may leave the public confused. On the flip side, vast sections of society tend to believe social media as a dependable source of information. They must rely on only statements from authentic sources such as the WHO, the Indian Council of Medical Research, the Centers for Disease Control and Prevention, Public Health England, Health Canada, European Medicines Agency among others. It is important to trust regulatory agencies. Those who are scientifically inclined may also rely on the statements of independent specialists on any special issue.

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Views of specialists

Taking note of the restrictions enforced by many countries on the AZ vaccine, over a dozen specialists in the UK published their views on the website of the Science Media Centre on March 16, 2021, and on March 15, 2021. While appreciating the concern shown, some of them criticised the decision to stop the immunisation programme though temporarily. Following are a few comments that were noted: 'Blood clot effects same or possibly lower in vaccinated groups; vaccination delay unjustified'.

According to Dr Michael Head, Senior Research Fellow in Global Health, University of Southampton, "The decisions by France, Germany and other countries look baffling. The data we have suggest that numbers of adverse events related to blood clots are the same (and possibly, in fact, lower) in vaccinated groups compared to unvaccinated populations. The UK MHRA, WHO and also the International Society on Thrombosis and Haemostasis have recommended continuing the Oxford AstraZeneca vaccine rollout."

“Halting a vaccine roll out during a pandemic has consequences. This results in delays in protecting people, and the potential for increased vaccine hesitancy, as a result of people who have seen the headlines and understandably become concerned. There are no signs yet of any data that really justify these decisions," he cautioned.

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Immunisation programs

Dr Pauline Paterson, Assistant Professor and Co-Director of The Vaccine Confidence Project team, London School of Hygiene & Tropical Medicine stated that "Rarely has an immunisation program been more important to the wellbeing of a population. With so much at risk, confidence in the available vaccines and the willingness to receive them is paramount".

“Past research has shown that vaccine scares, legitimate or not, have derailed immunisation programmes. A country-level decision to suspend a vaccine program due to safety concerns does affect confidence globally, but it is only through acknowledgement of safety fears, together with prompt and scientifically based responses that confidence can be sustained. Critically, communication must be timely, transparent and internationally consistent, to maintain and build the public trust without which any rollout however logistically effective will fail”, she cautioned.

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Benefits far outweigh the possible risks

Dr Phil Bryan, Medicines and Healthcare products Regulatory Agency (MHRA) Vaccines Safety Lead, asserted that the benefits of the vaccine in preventing COVID-19, with its associated risk of hospitalisation and death, far outweigh the risks of side effects. People should go and get their COVID-19 vaccine when asked to do so.

“It is still the case that it has not been confirmed the reported blood clots were caused by the COVID-19 Vaccine AstraZeneca. Blood clots can occur naturally and are not uncommon. Our role is to continually monitor safety during widespread use of a vaccine”, he said. He assured the public that they have in place a proactive strategy to do this. “We also work closely with our public health and international partners in reviewing the effectiveness and impact of the vaccines to ensure the benefits continue to outweigh any possible side effects," Dr Bryan added.

The MHRA encourages anyone to report any suspicion or concern they have beyond the known, mild side effects on the Coronavirus Yellow Card site. Reporters do not need to be sure of a link between a vaccine and a suspected side effect but are still encouraged to report.

Prof Adam Finn, Professor of Paediatrics, University of Bristol, conceded that they now find themselves in a predicament with regard to programmes to prevent COVID by vaccination across Europe and globally. He clarified, “In the UK, where more doses of the vaccine have been given than in any other European country – and where a well-established safety monitoring and adverse event reporting system is in place – no increase in the number of cases of blood clotting illnesses above what would normally be expected has been reported."

Dr Finn disclosed that the details of cases are now being studied by the medicines regulatory authorities. So far their opinions have been reassuring. We expect to hear more from the European Medicines Agency earlier and more from the UK regulator too in the coming days.

"We know the risks of COVID are real – both of severe illness in the short term, and of long term problems among some who recover from the acute infection. We know the AZ vaccine prevents these problems and risks and that, when used widely, it can help us overcome the pandemic and all its consequences. We know that rolling out the vaccine fast and at scale is important for that protection. We know that the vaccine causes no severe permanent side-effects or that, at the very worst, any such side-effects are so rare that they are proving almost impossible to detect despite millions of doses of vaccine having been administered. We should understand the need to investigate any concerns that arise and feel reassured that this is being done thoroughly. While that goes on, we should allow our policy decisions and our personal decisions to be driven by what we do know and not what we don’t," he pleaded.

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AstraZeneca: Risks vs benefits

Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, made the most interesting observations.

“The first concerns that were expressed related to blood clotting in general particularly four strokes and clots on the lungs. These are very well known effects of the virus that causes COVID-19. More recent concerns have related to another type of blood coagulations disorder called thrombocytopenia. This also is well known to occur in patients who get COVID-19. Further detailed concerns from Germany relate to a much rarer form of thrombosis in the brain". He suggested, “It still remains the case that a very likely explanation of at least some of the clotting disorders seen is a result of COVID-19 rather than the vaccine”.

“There are published papers that make clear that these problems definitely occur in COVID-19 and there is no doubt that all the vaccines in use prevent that disease. Hence the risk and benefit balance for the AstraZeneca vaccine remains clearly in favour of its benefits," he argued.

He listed six papers in mainstream journals to show that COVID-19 itself causes serious adverse health effects such as thrombocytopenia, blood coagulation disorders, cerebral Venous Sinus Thrombosis etc (Please use the link given elsewhere at Science Media Centre website to get details)

Professor Evans quoted a paper in the New England Journal of Medicine to buttress the point. This paper stated that “On admission, lymphocytopenia was present in 83.2% of the patients, thrombocytopenia in 36.2%, and leukopenia in 33.7%”.

He concluded,

"The situation is that we know that COVID causes major problems to the body’s coagulation systems, and many of these are very common in Covid, some with serious outcomes. Hence, even if there were a problem, acknowledged to be very rare with the AZ vaccine, the overall benefit would be so much greater than any speculative harm.  Investigate possible association, and also consider the real harm from delays in the immunisation campaign."

Prof Paul Hunter, Professor in Medicine, The Norwich School of Medicine, University of East Anglia, said: “The report from the Paul Ehrlich Institute gives a diagnosis for recent reports of adverse events following administration of the Oxford AstraZeneca vaccine, Cerebral Venous Sinus Thrombosis (CVT)." In the briefing, it was stated that seven cases have been identified in 1.6 million vaccinated (about 4.5/million post-vaccination).

While it has been reported that background incidence of CVT is only 2 to 5 cases per million per year and was considered to be very rare, more recent papers have suggested it is more common than previously thought. A study from Australia found 15.7 cases per million per year (Stroke. 2016) and one from the Netherlands 13.2 cases per million per year (Stroke. 2012).

The reported incidence was actually higher in people under 50 than in people over 50 years old. So the estimated background incidence of it is only 2 to 5 cases per million per year would appear to be underestimated by about 4 to 8 fold. “So we would normally expect to see about 1 or 2 cases per month per million people, in people under 50. So it does appear that CVT has been reported more commonly than expected at least in Europe. However, one of the key problems with identifying an association between rare/uncommon events is that it is not just one type of possible event that is being looked for. When you consider that there are quite a few possible diseases then the probability of such a statistical clustering for one outcome is actually quite high even when no cause and effect exists.

A paper published in Nature, 2020 stated, “Against this, the infection mortality rate in men in their mid-40s from COVID is of the order 0.1% or about 1000 deaths per million infections substantially greater than the risk of CVT. Clearly, this possible association needs to be thoroughly investigated, but we do need to consider the real harm from delays in immunisation campaigns at a time when the incidence of COVID is still increasing in several European counties when deciding whether or not to pause vaccination campaigns."

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Concerns valid, but halting mass vaccination disproportionate

Dr Stephen Griffin, Associate Professor in the School of Medicine, University of Leeds said, "The news that Germany and other countries have suspended roll out of the AZ vaccine is disappointing. Whilst it is right that any possible links between serious adverse reactions to vaccines are investigated, it is important to establish the likelihood of causation, as opposed to the association, when doing so."

He clarified, “The numbers of clotting events associated with the vaccine are very small, and according to the figures from AZ are well below the average that you might expect in any given population – we must remember that many millions of people have been safely vaccinated. Moreover, it is likely that the early stages of the European rollout have primarily comprised elderly and more clinically vulnerable patients, which might be expected to have a much higher incidence of random clotting-related events."

“Thus, the concerns raised in my view, whilst valid and worthy of investigation, are probably not proportionate to the response in terms of halting mass vaccination in multiple countries. Since many European countries are currently experiencing another resurgence of SARS-CoV2 infections, and yet are lagging behind in terms of the roll-out, the importance of continuing the vaccination programmes cannot be underestimated, and the harm caused by depriving people of access to a vaccine will likely vastly outweigh even the worst-case scenario if any link to the clotting disorders is eventually found. It should also be noted that nationwide gestures such as this are bound to fuel hesitancy, or more extreme anti-vaccine sentiment, further undermining the vaccination effort," he cautioned.

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Present status of COVID-19

As of the early hours of March 17, 2021, the number of COVID-19 cases globally rose to 121,218,061, deaths stood at 2,681,667 and recoveries at 97,766,428 as noted by worldometers.info. Presently, the virus raises its head in many countries forcing them to enforce more restrictions.

Five States of Maharashtra, Punjab, Karnataka, Gujarat and Tamil Nadu continue to report a surge in the COVID daily new cases. They cumulatively account for 78.41% of the new cases reported in the past 24 hours. 26,291 new cases were registered during that period. We must strictly enforce covid norms, trust regulatory agencies and encourage mass vaccination campaigns.

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Safety of AstraZeneca vaccine: An update

Here are a few statements released by global agencies.

1. WHO Global Advisory Committee on Vaccine Safety (GACVS) COVID-19 subcommittee: Based on a careful scientific review of the available information, the subcommittee concluded that the AstraZeneca COVID-19 vaccine (including Covishield) continues to have a positive benefit-risk profile, with tremendous potential to prevent infections and reduce deaths across the world. (Full statement in the link below) [1]
2. European Medicines Agency: EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) concluded its preliminary review of a signal of blood clots in people vaccinated with COVID-19 vaccine AstraZeneca at its extraordinary meeting of 18 March 2021. The Committee confirmed that the benefits of the vaccine in combating the still widespread threat of COVID-19 (which itself results in clotting problems and may be fatal) continue to outweigh the risk of side effects. The vaccine is not associated with an increase in the overall risk of blood clots (thromboembolic events) in those who receive it. [2]

There is no evidence of a problem related to specific batches of the vaccine or to particular manufacturing sites. However, the vaccine may be associated with very rare cases of blood clots associated with thrombocytopenia, i.e. low levels of blood platelets (elements in the blood that help it to clot) with or without bleeding, including rare cases of clots in the vessels draining blood from the brain (CVST). [2]

3. Medicines and Health care products Regulatory Agency (MHRA): Following suspensions by some countries of the COVID-19 Vaccine AstraZeneca over suspected blood clots, the MHRA confirms that the benefits of the vaccine in preventing COVID-19 far outweigh the risks. People should still go and get their COVID-19 vaccine when asked to do so. [3]

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Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr K S Parthasarathy is a former Secretary of the Atomic Energy Regulatory Board and a former Raja Ramanna Fellow, Department of Atomic Energy. A Ph. D. from the University of Leeds, UK, he is a medical physicist with a specialisation in radiation safety and regulatory matters. He was a Research Associate at the University of Virginia Medical Centre, Charlottesville, USA. He served the International Atomic Energy Agency as an expert and member in its Technical and Advisory Committees.