opinion: what's the risk of the astrazeneca shot?
the muddled messaging around vaccine safety and blood clot risk threatens our ability to understand risk.
7 minute read
a health worker prepares a dose of the astrazeneca vaccine in madrid on march 24, 2021.
gabriel bouys
/
afp via getty images
the astrazeneca vaccine is both highly effective and safe in preventing death from the ravages of covid-19. its use will also be critical for world health, since it is the least expensive, most widely available and easiest to administer vaccine. so why is it now seen as inferior and its use clouded by safety and efficacy concerns?
marshall mcluhan said that “one of the effects of living with electric information is that we live habitually in a state of information overload. there is always more than you can cope with.” it is often difficult to process the constant stream of information and misinformation that we are exposed to and to put it in the proper perspective.
is the az vaccine effective? the simple answer is — again — yes. the challenge is that when compared to mrna vaccines, it is not as effective in preventing mild to moderate disease but is highly effective in preventing death which is a critical benefit. the integrity of this message has been harmed by the company itself. it mismanaged the dosing in the phase 3 approval trial and didn’t include enough older patients to convince the fda that it was adequately effective in this high risk population. the company then slightly misrepresented benefit in the follow up trial mandated by the fda, where they did show efficacy in older people. unfortunately, astrazeneca halted the data submission two weeks early, to show a 79 per cent — rather than a still good 76 per cent — efficacy in preventing symptomatic infection. this again undermined confidence in the company’s veracity.
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it again hyped the vaccine by saying the vaccine was 100 per cent effective in preventing the critical end point of death in trials. relatively few people developed covid-19 in the vaccinated arm, but just because no one died in a very small sample doesn’t mean that death is impossible in those to be vaccinated. real world data from millions of people who have been given the astrazeneca vaccine continue to show very low mortality risk, yet a small number will still have a bad outcome. this risk remains minimal when compared to the very real and much greater risk of delayed vaccination. the fear caused by hype and some disinformation leads to increased vaccine hesitancy, a much larger population risk.
but is it safe?
again, the answer is yes, but with a caveat. rare complications may only be discovered after tens of millions of people have been vaccinated. to date, other than rare, non-fatal allergic reactions, the mrna vaccines made by pfizer and moderna have been exceptionally safe, and have performed beyond expectations. it would not be surprising to find that a vaccine has a risk of serious complication in one in a million people. identifying who is at risk, the mechanism of harm and mitigation strategies are what is required when surveillance detects a possible hazard.
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what is the blood clotting hazard?
the initial concern raised was that there was an increased risk of a rare blood clotting complication associated with a 40 per cent mortality rate in affected individuals. initial reassurance by the company and data scientists was that there was no overall higher risk of clotting in those vaccinated. what has emerged based on german and other european data is that a rare and highly specific type of clotting can occur that’s similar to another immune mediated drug reaction to the blood thinner heparin. the condition is called heparin induced thrombocytopenia or hit. this similar mechanism of occurrence provides a greater cause and effect link that it is due to vaccination by az.
our blood is made up of red blood cells that carry vital oxygen to our organs, white blood cells that help fight infection and blood platelets that appropriately clot our blood to prevent bleeding.
in people who develop hit, there is a rare immune reaction such that the drug triggers an immune complex that can form between the drug and a specific platelet factor 4 (pf4). the body treats this complex as an invader fighting it with an antibody that destroys the platelets, leading to low platelet counts as the clue. paradoxically, while low platelets may lead to excessive bleeding in a normal situation, with hit the disruption of platelets and release of pro-clotting particles can cause excessive clotting in different organs, with a high risk of serious complications or death. the diagnosis is made by low platelet counts, high pd4 antibody levels in the blood and clotting complications.
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it was noted that about 25 europeans developed blood clots — nine of whom died — out of about 20 million people who received the az vaccine. many had unusual brain blood clots. this initially led to the likely incorrect conclusion that it was a one in a million complication and, perhaps even unrelated to vaccination.
german scientists, however showed that this clotting greatly resembled hit with low platelets, rare blood clotting patterns and elevated pf4 antibody blood levels by immunoassay. they therefore said it was more likely a complication directly associated with az vaccination and labelled the syndrome vipit, vaccine-induced prothrombotic immune thrombocytopenia.
this led many european countries to halt az vaccination. since as with hit, vipit is more commonly seen in women and was seen mainly in women under 55, canada’s naci suggested holding back az vaccination of those under 55 until further review was undertaken. to date, no vipit cases have been reported after over 300,000 az vaccinations in canada, but this vaccine has not yet been used in very many people under age 55.
what’s the risk?
millions of patients are treated with full dose heparin annually and the risk of hit is about one in 500 and suspected by an initial fall in platelets. this risk is accepted as the small cost of often life-saving anticoagulant therapy.
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by comparison the risk of vipit is either one in a million for all those vaccinated or perhaps one in 125,000 for women under age 55. since vaccines are mainly given to unmonitored healthy people, there is no early warning system for this very rare complication. it appears to occur between four to 20 days after vaccination and no relationship to risk factors has yet been established, other than being female and under 55. it currently has about a 40 per cent mortality, hopefully lower with greater recognition, thus the reasonable concern. if detected early it is treatable with drugs.
did naci do the right thing?
the role of regulatory and advisory bodies is to sift through the science carefully and to advise based on relative risk and best options. there already is a great deal of vaccine hesitancy based on politics as well as dangerous and misleading information posted on social media. with variants now dominating, especially the b.1.1.7 strain first seen in the u.k., there is a large increase in infections and more people under the age of 55 are requiring hospitalization admission and intensive care. a significant number will develop blood clots as a complication of covid-19 and die, likely at least 100 times more frequently than with this rare complication of vaccination. as dr. scott gottlieb, the former fda commissioner has predicted, we likely need to get at least 25 per cent of the population vaccinated to reduce bad outcomes in a major way. the u.s. and the u.k. are already almost there. israel has been there for a long time and normal life has resumed. canada lags far behind, thus large scale, rapid vaccination remains essential. vaccine hesitancy will cost many lives.
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it appears quite safe to continue to use the az vaccine for those over 55 who constitute the highest at risk population for bad covid-19 outcomes. we are not yet at the stage of having enough supply to vaccinate people under 55, so the current guidance will not yet have a great direct impact. we have a few weeks to study the risk benefit profile a little longer and make the right decision as more evidence comes in. it likely is also safe for younger men and i suspect guidance will be amended as more safety data also confirms this. we don’t have enough mrna vaccine to immunize everyone below the age of 55 and the az vaccine will need to continue to play an important role in canada’s vaccine delivery plans and even more so for the rest of the world. even now, the current risk of the az vaccine for young women is far lower than the excess risk of complications arising from covid-19 infection. many more women will die if the wait too long for a different vaccine and more older seniors will die as a result of second doses being delayed inappropriately to vaccinate healthy young people.
everything in life has a risk. we have to understand what that risk is, but also understand the much greater risk of delay. the risk to most people given the az vaccine is extremely small. companies and advisory bodies need to help guide that risk/benefit calculus with honest, transparent and timely research and updates. we all will get to make informed decisions that should be guided not by unreasonable fear but by facts and clarity of understanding.
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as churchill said “fear is a reaction, courage is a decision.” we need the strength to accept small risk without unreasonable fear and the courage to proactively protect ourselves and our loved ones. we have to trust that despite muddled messaging, that science and wisdom will yet prevail.
dr. harry rakowski is an academic toronto cardiologist.
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