When is the fact that Event B follows Event A proof that A causes B? The temporal sequence is a prerequisite for causation, but, in and of itself, the time sequence proves very little. Vaccines are a case in point. If many people receive a vaccine, some percentage of them will experience the slings and arrows of outrageous fortune. Some of them will suffer trauma from, say, automobile accidents. But non-vaccinated people also are caught up in auto accidents—perhaps even more often than their more cautious counterparts who chose to be vaccinated. Thus, the mere number of reports of the sequence of events A and B is not proof of any association between A and B, let alone a causal connection.
Furthermore, even if the incidence of accidents turned out to be greater among the vaccinated part of the population, the question of what might explain this association would need to be answered. Suppose, for instance, that the vaccine confers protection against Lyme disease, which is caused by a bacterium transmitted by certain tick bites. The vaccinated group might include disproportionately many hunters. Possibly, many of them may drive late at night, when they are tired, on dark, narrow, and winding roads, through woods teeming with deer and elk—factors that expose the hunters to a greater risk of an accident. The driving conditions are, in this hypothetical situation, a confounding variable.
The Loss of LYMErix
The link between Lyme-disease vaccine and automobile accidents is totally fictitious, but the history of the LYMErix vaccine provides an oft-told cautionary tale risk perception and evaluation. In the early 1990s, SmithKlineBeecham developed LYMErix to stop infections by the spirochetal bacterium Borrelia burgdorferi that causes Lyme disease. The vaccine targeted a protein (called outer-surface protein A, or OspA) of the bacterium. In a clinical trial, individuals given three doses of LYMErix showed a 76% reduction in Lyme disease in the following year, with no significant side-effects. The U.S. Food and Drug Administration approved LYMErix on December 21, 1998.
But within a year, there were reports of adverse reactions after vaccination. The media carried stories of "vaccine victims," and the Philadelphia law firm of Sheller, Ludwig & Bailey filed a class action against SmithKlineBeecham. Other lawyers did the same.
By 2001, with over 1.4 million doses distributed in the United States, there were 59 reports of arthritis possibly associated with vaccination. The incidence was essentially the same as that in unvaccinated individuals. In addition, the data did not show a temporal spike in arthritis diagnoses after the second and third vaccine dose (an outcome that would be expected for the immune-mediated phenomenon that plaintiffs and others maintained was a side effect of the vaccine). The FDA found no suggestion of harm from the Lyme vaccine. Nevertheless, it soon reconvened its advisory panel for a raucous meeting with the LYMErix manufacturer, independent experts, practicing physicians, the "vaccine victims," and their lawyers.
Although the panel made no changes to the product's labelling or indications, vaccine sales plummeted. On February 26, 2002, GlaxoSmithKline (the successor to SKB) withdrew LYMErix from the market. On July 9, 2003, GSK settled the class actions by agreeing to pay over one million dollars to plaintiffs' lawyers' for their fees and expenses—and nothing to the "vaccine victims."
Flash forward to 2021.
The British-Swedish pharmaceutical company AstraZeneca produced a vaccine developed by researchers at Oxford University that uses a harmless virus, modified to contain the DNA code for a protein on the surface of the virus (SARS-CoV-2) that causes COVID-19. When this altered (recombinant) virus (called ChAdOx1) infects human cells, they cell read the inserted sequence and make copies of the SARS-CoV-2 protein. 1/ The copies induce an immune response to SARS-CoV-2. Clinical trials in various countries suggested an overall efficacy of about 70%, 90%, and 62% (with substantial margins of error) depending on the doses.
As countries rushed to vaccinate their populations, reports of blood clots following vaccinations received intense publicity. Although the company and international regulators say there is no evidence that the shot is to blame, much of Europe (Denmark, Germany, France, Italy, Spain, Ireland, the Netherlands, Norway, Sweden, Latvia, and Iceland) as well as Congo and Bulgaria suspended use of the vaccine.
The World Health Organization and the European Medical Agency (EMA), however, continued to recommend the vaccine's use. In a statement issued today, the EMA emphasized that "the vaccine is not associated with an increase in the overall risk of blood clots (thromboembolic events) in those who receive it." A blogger for Science Translational Medicine remarked that
AstraZeneca has said that they’re aware of 15 events of deep vein thrombosis and 22 events pulmonary embolisms, but that’s in 17 million people who have had at least one shot—and they say that is indeed “much lower than would be expected to occur naturally in a general population of this size“. It also appears to be similar to what’s been seen with the other coronavirus vaccines, which rather than meaning “they’re all bad” looks like they’re all showing the same baseline signal of such events across a broad population, without adding to it.
Is a lower rate of clots for vaccinated individual real? An explanation (other than statistical error in comparing low probability events) comes from the chair of the EMA safety committee. Dr. Sabine Straus told the Wall Street Journal that "since blood clots are associated with Covid-19, by inoculating people against the disease, the vaccine 'likely reduces the risk of thrombotic incidents overall.'”
In an interview for Stat, University of Pennsylvania biostatistician Susan Ellenberg explained that
Vaccines protect against one thing: the infection or the infection plus disease. They don’t protect you against everything else that might possibly happen to you. There’s no reason to think that somehow there’s a magical period of time like, you know, four days or a week or two weeks after you get vaccinated, when none of those other horrible things are going to happen to you.
In response to the EMA's reassurances, France, Italy, Spain and Portugal reinstated vaccinations. Officials in other countries frame their actions to halt vaccinations as "precautionary". 2/ But the vaccine itself is a precaution, prompting University of Cambridge statistician David Spiegelhalter to counter that “the cautionary approach would be to carry on vaccinating. Casting doubt—lasting doubt—on the safety of the vaccines is not a precautionary position.”
The Next Day
Researchers studying the vaccine recipients diagnosed with cerebral venous sinus thrombosis (CVST) are convinced that it results from an autoimmune response. "Pål André Holme, a professor of hematology ... who headed an investigation into the Norwegian cases, said his team had identified an antibody created by the vaccine that was triggering the adverse reaction." His conclusion that "nothing but the vaccine can explain why these individuals had this immune response" is shared by German researchers independently looking at "13 cases of CVST detected among around 1.6 million people who received the AstraZeneca vaccine." British regulators continued to characterize the allegedly causal link to the vaccine as unproven. So did the EMA, which noted that "a causal link ... is possible and deserves further analysis.”
Two Weeks Later
From Gretchen Vogel & Kai Kupferschmidt, Side Effect Worry Grows for AstraZeneca Vaccine, Science, 372:14-15, Apr. 2, 2021, https://science.sciencemag.org/content/372/6537/14, DOI: 10.1126/science.372.6537.14:
... This week, Canada and Germany joined Iceland, Sweden, Finland, and France in recommending against the vaccine's use in younger people, who seem to be at higher risk for the clotting problem and are less likely to develop severe COVID-19. .... The highly unusual combination of symptoms—widespread blood clots and a low platelet count, sometimes associated with bleeding—has so far been reported from at least seven countries. ... Estimates of the incidence range from one in 25,000 people given the AstraZeneca vaccine in Norway to at least one in 87,000 in Germany. .... The United Kingdom remains a puzzle. Despite administering more than 11 million AstraZeneca doses, it has so far reported only a handful of suspicious clotting cases. But the U.K. did not limit the vaccine to younger groups, so the average age of recipients there may be older. ...
Researchers in Germany have proposed that some component of the vaccine triggers a rare immune reaction like one occasionally seen with the blood thinner heparin, in which antibodies trigger platelets to form dangerous clots throughout the body. This week the team posted case descriptions of what they call vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) on the preprint server Research Square. ...
Even if VIPIT isn't the whole story, multiple other researchers told Science they are now convinced the vaccine somehow causes the rare set of symptoms. If true, that could be a serious blow to a vaccine that is central to the World Health Organization's push to immunize the world. ...
NOTES
- LYMErix also was a recombinant vaccine.
- Germany's healthcare ministry argued that for Germany, at least, the expected number of cases of cerebral vein thrombosis was only 1.4, making the 7 cases that occurred valid grounds to pause mass vaccinations. However, if there were many subcategories of clotting-related events considered and if this is the only one to display an apparently elevated level, the pattern would not be surprising. Moreover, the EMA looked at adverse events in more than a single country when making comparisons.
REFERENCES
- European Medicines Agency, COVID-19 Vaccine AstraZeneca: Benefits Still Outweigh the Risks Despite Possible Link to Rare Blood Clots with Low Blood Platelets, Mar. 18, 2021, https://www.ema.europa.eu/en/news/covid-19-vaccine-astrazeneca-benefits-still-outweigh-risks-despite-possible-link-rare-blood-clots
- Matthew Herpe, The Curious Case of AstraZeneca’s Covid-19 Vaccine, Stat, Mar. 15, 2021, https://www.statnews.com/2021/03/15/the-curious-case-of-astrazenecas-covid-19-vaccine/
- Ivan F. N. Hung & Gregory A. Poland, Single-dose Oxford–AstraZeneca COVID-19 Vvaccine Followed by a 12-week Booster, Lancet, Mar. 6, 2021, 397(10277): P854-855, https://doi.org/10.1016/S0140-6736(21)00528-6
- Derek Lowe, What is Going on with the AstraZeneca/Oxford Vaccine?, Science Translational Medicine, Mar. 16, 2021, https://blogs.sciencemag.org/pipeline/archives/2021/03/16/what-is-going-on-with-the-astrazeneca-oxford-vaccin
- Smriti Mallapaty & Ewen Callaway. What Scientists Do and Don’t Know about the Oxford–AstraZeneca COVID Vaccine. Nature News Explainer, Mar. 24, 2021, https://www.nature.com/articles/d41586-021-00785-7
- Daniel Michaels, AstraZeneca’s Covid-19 Vaccine Cleared by EU After Blood-Clot Concerns, Wall St. J., Mar. 18. 2021, https://www.wsj.com/articles/astrazenecas-covid-19-vaccine-is-cleared-by-europe-after-blood-clot-concerns-11616083845?mod=hp_lead_pos1
- L. E. Nigrovic & K. M. Thompson, The Lyme Vaccine: A Cautionary Tale, Epidemiology & Infection, 135(1):1–8 (2007), doi: 10.1017/S0950268806007096, PMCID: PMC2870557
- Bojan Pancevski, Scientists Say They Found Cause of Rare Blood Clotting Linked to AstraZeneca Vaccine, Wall St. J., Mar. 19, 2021 4:02 pm ET, https://www.wsj.com/articles/scientists-say-they-found-cause-of-blood-clotting-linked-to-astrazeneca-vaccine-11616169108
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