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Safety Assessment
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Sarah Gould and Lauren Black

Safe Vaccines Take Several Steps

How safety testing contributes to vaccine development

Vaccine development typically takes years, even decades. How then could companies deliver COVID-19 vaccines in a matter of months? Can we trust the process? These two questions have been dominating the airwaves ever since the first three candidates in the pipeline were authorized by regulators, a mere 11 months after SARS-CoV-2 emerged in China. We hope Eureka’s five-part series, The Vaccine Journey, on how vaccines are developed—from discovery through manufacturing—helps answer some of these questions and reassures readers that vaccines are generally very safe. Charles River scientists Sarah Gould< PhD, and Lauren Black, PhD, explain how they look at safety in the early stages of vaccine development.

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Vaccine safety is on everyone’s minds. Our hope for getting COVID-19 under control hangs on three tenets: vaccines, treatments, and social precautions to contain the pandemic. As a new disease, there was no off the shelf vaccine at first. Whilst one was developed, social precautions were instituted at local and regional levels across the globe – but without an agreed upon standard, the disease spread through local interactions and international trade and travel. Vaccines are the medical success story that have provided a way to control infectious diseases.

Vaccine types fall can be simplistically divided into three categories: whole-pathogen vaccines that use killed or weak versions of the pathogen to create an immune response, subunit vaccines that use a part of the pathogen or its toxins, and nucleic acid vaccines (mRNA); all of which stimulate  the immune system to fight the pathogen. Each of these vaccine types has its own safety concerns that need to be tested. Some of those tests are handled by companies like Charles River in safety assessment teams.

Toxicology

The key focus of any toxicology assessment for a vaccine is to assess the local and systemic toxicity, relating to the immune response provoked by the vaccine.

Other safety endpoints may be considered depending on the other ingredients of the vaccine, including excipients, adjuvants and process residues, but generally these ingredients have been previously assessed or are at such low doses that they are below the toxicology level of concern.

Special populations, such as pregnant women, need to be assured that the vaccine won’t harm the growing baby. As such a reproductive and developmental toxicology studies will also be conducted.

Toxicology studies will use vaccine formulations similar to what you may eventually receive at the clinic, although usually an extra dose is given to the model species. Next there will be an assessment of the local reactions at the site of injection and the systemic toxicity, investigating effects on a list of organs – including the immune system, skin, lungs, heart, kidney, brain, liver, and kidneys, to name but a few.

Local Reactions

All aspects of the chemical makeup of the final product are assessed for safety. The most The Vaccine Journey, Part 4, toxicology testing, COVID-19common safety consideration at this stage is local reactivity, or pain at the injection site.

Getting a vaccine may cause some pain at the site of injection or even mild flu like symptoms. However, it doesn’t usually last long, may be a day or two at the worst and is a sign the vaccine is working. A vaccine works by stimulating the immune system, and just under the skin are immune cells that set to work immediately once the vaccine is injected.

The vaccine is, by design, recognized by the body as an invader, just like a virus or bacteria. The cells set to work to develop the antibodies needed to fight the invader.  This means that when you next encounter the real virus you will already have some antibodies ready to fight. The reason that more than one shot may be needed relates to the number of antibodies that can be stimulated at one time. This can be different for different vaccines.

Safety risks and benefits

Vaccines have an extremely good safety record. That doesn’t mean that they can’t come with some effects, but those tend to be mild and short lived. In rare cases the effects are more severe, but the risks are weighed against the severity and chances of contracting whatever illness the vaccine is meant to fight. The benefits of a vaccine are far outweighed by the risks of an unvaccinated population, as history has proven.

If there are any concerns, particularly if there is a family history concerns, then discussion with a health care worker is imperative.

Emergency use

For situations like the COVID-19 pandemic, emergency use authorization comes into play. These measures help researchers develop their vaccines or treatments more quickly without cutting safety corners. These policies allow regulatory agencies to offer more flexible schedules and priority review of data to speed up development.

For example, under emergency use, different tests can be done simultaneously instead of consecutively. This is a risk for the vaccine developer – if a vaccine fails one test while others are being run, it will need to go back a step and address the issue before rerunning all subsequent tests. However, if all tests go smoothly, then you have significantly sped up the process.

Government regulators across the globe worked together to speed up the development of a COVID-19 vaccine – without compromising on safety. If you are able to get the vaccine for yourself, you are the recipient of the work of thousands or researchers, regulators, and technicians around the world, working together to bring this pandemic under control.

Lauren Black, PhD, is a Distinguished Scientist with Charles River’s Scientific Advisory Services. She has helped clients shepherd many drugs through the FDA approval process; before CRL, she worked at FDA CBER and CDER in transplant drugs, vaccines, and other immune agents.

Sarah Gould, PhD, is a Senior Principle Scientific Advisor with a proven track record of delivering toxicology programs supporting numerous world wide regulatory submissions for drug products, including 15 years in vaccine submissions, work on adjuvant safety and a contributor to the WHO, 2013 vaccine guideline