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Nature: So difficult to investigate rare side effects of COVID-19 vaccine

Nature: So difficult to investigate rare side effects of COVID-19 vaccine. The combination of active monitoring and targeted clinical trials is not only important to ensure the safety of the current COVID-19 vaccine.

These studies will also provide information for public health policies around strengthening the safety of injections or annual vaccines that may be needed during and after a pandemic.

In mid-March, some European countries suspended the distribution of the COVID-19 vaccine produced by the University of Oxford in the UK and the pharmaceutical company AstraZeneca. Earlier reports stated that some people had blood clotting disorders after being vaccinated.

These decisions are based on the estimated 20 million vaccinated people in the United Kingdom and the European Union, 25 of whom experienced severe blood clots related to low platelet counts, resulting in 9 deaths.

However, the European Medicines Agency (EMA) review of the cases cannot determine whether the reported cases are related to the AstraZeneca vaccine, and concluded that the benefits of the vaccine outweigh any risks.

Since then, these two countries have resumed vaccination, although Germany has stopped vaccination for people under 60, because Germany’s own safety monitoring system reported that 31 of the 2.7 million vaccinated people had serious symptoms. Blood clot.

These events show how challenging it is to prove that the medical problems after immunization (the so-called adverse reactions) are caused by the vaccine itself. Kathryn Edwards, a vaccinologist at Vanderbilt University School of Medicine in Nashville, Tennessee, said public health officials must strike a “delicate balance” when communicating the risk of rare side effects and the risk of severe COVID-19.

Doctors worry that the anti-vaccine movement will exacerbate some communities’ hesitation about vaccines. At the same time, it is important not to ignore the possibility of rare but serious side effects before researchers establish a causal relationship, and this process may take years.

Correlation is not causation

Ideally, adverse events should be directly related to the use of specific laboratory-tested vaccines. For example, the early polio vaccine used a weakened virus to generate immunity. For every 2.4 million doses of vaccine injected, approximately one person will develop polio.

In these cases, the virus strain used in the vaccine can be isolated from the spinal fluid, so it is clear that the vaccine is causing the disease.

However, for most adverse events, this type of test is not possible, either because there is no specific biomarker to test, or because this type of test is impractical. At least in the initial stage, these events are only related to their timing: a person is vaccinated and then experiences side effects at some point later.

This makes it particularly challenging to prove whether the adverse reaction is actually caused by the vaccine, especially when the reaction occurs a few days or weeks after vaccination.

To investigate this connection, researchers conducted studies to determine the incidence of adverse events in the vaccinated population and compared it with the probability of adverse events in the unvaccinated population. They also need to determine the mechanism that may cause the reaction.

Ten years of mystery

During the 2009 H1N1 flu (or swine flu) pandemic, public health agencies in Sweden and Finland warned of narcolepsy (a chronic, debilitating sleep disorder) in children who took a dose of the H1N1 vaccine Pandemrix Incidence rate is rising. According to reports, narcolepsy occurs in about 1 case for every 18,400 doses of vaccine, which is much higher than expected for incidental events.

Public health officials are beginning to worry that an adjuvant, an ingredient in vaccines used to boost the human immune response, may trigger an unexpected immune response and cause disease. If adjuvants do help increase the risk of narcolepsy, this will be an important consideration when designing future vaccines.

Early studies have shown that Pandemrix does increase the risk of narcolepsy in certain age groups, but the results are too variable to draw broad conclusions. More than a decade after that pandemic ended, scientists still did not fully agree on the nature of the link between the pandemic and narcolepsy.

In 2018, Steven Black, a vaccinologist at Children’s Hospital in Cincinnati, Ohio, and a group of international colleagues published a study that concluded that adjuvant alone was not associated with an increased risk of narcolepsy.

The researchers compared the background incidence of narcolepsy in seven countries with the incidence of Pandemrix and two other adjuvant-containing H1N1 vaccination groups. They controlled the spread of the H1N1 virus in every country and believed that reports of narcolepsy had increased throughout Europe after people realized its potential connection with the vaccine.

Except for Sweden, where this signal was first detected, they did not find any evidence of increased risk. However, a consensus report published after the International Association for Biological Standardization (IABS) meeting in Brussels in 2018 concluded that the link between Pandemrix and narcolepsy is consistent in countries where there are reports of increased risk. Although researchers at this meeting believed that the disease was “probably” caused by an unforeseen interaction between Pandemrix and the H1N1 virus, the exact mechanism of this response has not been confirmed.

Rare events

As far as the COVID-19 vaccine is concerned, before the government approves its widespread use, the vaccine that is currently being launched has undergone clinical trials with the participation of thousands of participants. Hilda Bastian said that these clinical trials “are designed to answer questions about efficacy and assess the incidence of fairly common adverse events,” such as pain or headache at the injection site. Many vaccine experts have emphasized that the COVID-19 vaccine is safe and effective for the general population.

But even the largest clinical trials are not designed to detect extremely rare side effects, which may occur in less than 1 in every 10,000 vaccinations. Hilda Bastian said that because hundreds of millions of people are currently vaccinated against COVID-19, even very rare events-such as severe allergic reactions or blood clots-will start to appear in safety reports. The challenge now is to find out which of these events are actually related to the vaccine.

In the United States, the National Institute of Allergy and Infectious Diseases has begun to organize a clinical trial to understand the allergy risk of the mRNA-based COVID-19 vaccine. The mRNA vaccine was developed by Pfizer and BioNTech, and it appears to be mainly affected by women and people with a history of allergies. One study considered these allergic reactions “extremely rare.” If in this carefully controlled trial, the researchers do observe an increase in the rate of severe allergic reactions, this will enable the researchers to “know who is at risk and define the risk” so that doctors can provide better advice.

In Europe, EMA is convening a pharmacovigilance risk assessment committee meeting to further investigate the rare coagulation disorder found in a very small number of people using AstraZeneca vaccine, and will announce the findings in early April. At the same time, some countries have chosen to add warnings to vaccines, while other countries (such as Australia) have postponed vaccination for people with certain diseases.

Better monitoring

Currently, public health agencies track potential side effects through reporting systems, such as the World Health Organization’s platform VigiBase, EMA’s EudraVigilance, and the United States’ vaccine adverse event reporting system. Many countries have systems in which the public and health care workers can submit reports on side effects that occur after injections. This type of monitoring can detect signs of rare adverse events, but most systems are not designed to determine their exact cause. This is because they only contain data on reported events and lack a control group to track adverse events in the unvaccinated population.

An active surveillance system can collect adverse event data (including background rates and post-vaccination data) from electronic health records without relying on people to directly report these data, thereby gaining a more comprehensive understanding of vaccine safety.

In the consensus report of the 2018 IABS meeting, researchers called for the establishment of an international network of active monitoring systems, which will make it easier for public health agencies to share data and is expected to quickly and clearly determine the cause of adverse reactions.

The combination of active monitoring and targeted clinical trials is not only important to ensure the safety of the current COVID-19 vaccine.

These studies will also provide information for public health policies around strengthening the safety of injections or annual vaccines that may be needed during and after a pandemic.

(source:internet, reference only)

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