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As the country and the world eagerly await vaccines to curb the Covid-19 pandemic and allow us to return to normal social and economic activities, preparing to monitor these vaccine for safety is critical task.

Safety is a key consideration for any medical product that will be administered to millions of healthy people. To ensure that vaccines against SARS-CoV-2, the virus that causes Covid-19, are very safe and that the public trusts the vaccine program, the U.S. needs a safety monitoring system that is rigorous, rapid, objective, and transparent.

The H1N1 vaccine program in 2009 and 2010, with which we were both involved, provides a model for doing this.

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The novel influenza A virus known as H1N1 emerged in the U.S. in the spring of 2009 and spread quickly across the country and around the world. Relying on the same licensed process used each year for the seasonal flu vaccine, manufacturers developed a vaccine for the H1N1 virus. Between October 2009 and April 2010, about 80 million Americans received the vaccine, preventing between 700,000 and 1.5 million cases of H1N1 flu, thousands of hospitalizations, and between 200 and 500 deaths.

Why is safety monitoring needed after vaccines are found to be very safe and effective in the rigorous process of testing them in randomized controlled trials? Those trials establish which vaccines are effective and identify their most common adverse effects. But adverse reactions that are uncommon, appear only after a delay, or occur in subpopulations excluded from or inadequately included in clinical trials may not emerge until the vaccine is being widely used.

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Another reason is that when vaccinating a large number of people, some will have heart attacks or strokes, develop diabetes or dementia, experience new-onset epilepsy, or have other health issues. Rapid and rigorous science is needed to determine if these events were caused by the vaccine or would have happened regardless of vaccination.

The process for separating real adverse reactions from coincidental events must be rapid and credible.

In 2009, the assistant secretary for health, who was also the director of the National Vaccine Program, formed a federal Immunization Safety Task Force to coordinate all federal vaccine safety efforts. The National Vaccine Program Office, under the direction of the assistant secretary for health and the assistant secretary for preparedness and response, with the support of the Food and Drug Administration and other government agencies and departments, first turned to large health databases that had already been used for vaccine safety monitoring. One is the Vaccine Safety Datalink, overseen by the Centers for Disease Control and Prevention, which has health information for about 10 million individuals through eight managed care organizations. This effort also looked to other large health databases that had some experience with epidemiological studies, such as the Centers for Medicare and Medicaid Services (those over 65 and insured through Medicare), the Department of Defense (military), the Department of Veterans Affairs (veterans and federal employees), and the Indian Health Service (Native Americans).

The National Vaccine Program Office, Harvard Medical School, and Harvard Pilgrim Health Care also built a new system called the Post-Licensure Rapid Immunization Safety Monitoring (PRISM) network that linked four large health plans in different parts of the country with eight state immunization registries that included 38 million individuals.

All the data received by the government were completely anonymous and de-identified: The data holder (managed care organizations, health insurance companies, and the like) kept all of the data while the safety system simply received counts of events with basic information, like days after vaccination the adverse event occurred and the age of the individual who experienced it.

The National Vaccine Program Office convened an independent group of experts — and by that we mean independent from vaccination program purchasing, distribution, and promotion, as well as independent from conflicts of interest — to conduct rapid reviews of the available safety data. They were solely responsible for looking at the safety of the vaccine, not its benefits. The safety data were presented to this group every two weeks, and it publicly discussed its reports once a month.

All of these plans were made available in advance to the public and stakeholders. The program worked with the media, state, and local health departments, and medical associations to make them aware of the safety program.

These systems were set up to be sensitive — we didn’t want to miss anything — knowing there would likely be false positives that turned out upon investigation not to be true vaccine adverse reactions.

There were initial weak signals for three adverse events: immune thrombocytopenia, a shortage of blood cells called platelets that are needed for normal blood clotting; Bell’s palsy, a sudden paralysis of one side of the face; and Guillain-Barré syndrome, a disorder in which the immune system attacks nerves throughout the body. These data were reviewed by the independent group of experts and publicly reported.

Careful examination of the data indicated that the weak signals for thrombocytopenia and Bell’s palsy were not due to the vaccine, but Guillain-Barré syndrome was. The group concluded that the vaccine caused one to three cases of Guillain-Barré syndrome per million people vaccinated — a risk that paled in comparison to the benefits of the vaccine, which included the prevention of death.

By the time the pandemic had faded, the H1N1 vaccine helped millions of people stay healthy without a safety problem — real or coincidental — derailing the program. This system to identify safety issues was developed using the principles of good governance and public health practice to ensure trust: rigor, objectivity, and transparency.

The need for monitoring the safety of SARS-CoV-2 vaccines after they are licensed and are being widely used is far greater today than it was for H1N1. Public health officials had decades of experience with influenza and influenza vaccines, and much was already known about the safety of these vaccines. In contrast, no coronavirus vaccine has ever existed. And some of the new vaccines are based on novel technologies, such as mRNA or DNA, and new vectors, such as the adenovirus.

Add in vaccine hesitancy, which has only grown as a problem over the last decade. In 2019, the World Health Organization declared vaccine hesitancy to be one of the top 10 global health threats. Politicization of the U.S.’s Covid-19 response, coupled with increasing distrust of the government, increases the risk of a Covid-19 vaccine safety scare undermining the vaccine program and public confidence.

Efforts are underway to develop systems for monitoring Covid-19 vaccine safety, but it is not yet clear who is in charge. The Trump administration combined the National Vaccine Program Office with another office and it no longer has vaccine safety expertise. PRISM, which now has the capacity to anonymously assess the safety of the vaccine in 60 million people, is currently not being used for this monitoring.

The plan is for safety data to be overseen by the CDC’s Advisory Committee on Immunization Practices. This is an incredibly important and valuable committee, but it will be involved in recommending who gets which Covid-19 vaccine. The H1N1 experience demonstrated that under these extraordinary circumstances, an independent group responsible only for safety assessment can add to the credibility of the effort.

Leadership is necessary to ensure that all hands are on deck and these efforts are coordinated — across the nation and the world. Large health system databases are available in many countries, and global cooperation can boost understanding of safety questions as they arise.

We must prepare now for the launch of Covid-19 vaccines by setting up in advance these systems for vaccine safety monitoring to make sure the vaccines are very safe and to inspire the confidence necessary for a successful vaccination program.

Daniel Salmon is the director of the Institute for Vaccine Safety at the Johns Hopkins Bloomberg School of Public Health and the former director of vaccine safety for the National Vaccine Program Office. Joshua Sharfstein is professor of the practice in health policy and management at the Bloomberg School of Public Health and former principal deputy commissioner of the U.S. Food and Drug Administration. This article represents their views, not necessarily the views of Johns Hopkins University.

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