Why testing & mitigating Injection Site Reactions is critical during drugs/vaccines development?

When a foreign substance, such as a vaccine or medication, is injected into the body, the immune system recognizes it as an invader and begins to mount a defense. This defense can include the release of inflammatory molecules, such as cytokines and chemokines, and the recruitment of immune cells to the site of the injection.

These immune responses can result in ISRs, which can include redness, swelling, pain, and warmth at the site of the injection^{1, 2, 3}. These reactions are generally mild and short-lived, and most people recover without any complications.

It is well recognized that ISRs are a common side effect associated with many drugs, particularly those that are administered subcutaneously or intramuscularly, like anakinra⁴, cetrorelix⁵, and adalimumab⁶. In addition to these drugs mentioned, some examples of other drugs that have been associated with ISRs include insulin⁷, growth hormone⁸, and etanercept⁹.

In some cases, however, ISRs can be more severe, and may require medical attention. These can include large swelling, redness, tissue necrosis, abscess formation, ulceration, severe pain, or allergic reactions. It’s particularly the case with administration of medication such as Influenza, Rabies, Yellow fever and Pertussis vaccine¹⁰, as well as Interferon¹¹.

In addition, ISRs may also lead to anxiety or fear about receiving subsequent injections, which contribute to non-compliance. For example, a patient may become reluctant to take medication or avoid future injections altogether out of fear of experiencing a reaction again.

Insulin was the first biologic ever developed, and was reported to be used by 7.9 millions of American with diabetes¹² in 2021.
Injection site reactions are a common side effect of insulin injections, and can include redness, swelling, and pain at the injection site. Severe reactions, such as abscess formation, can occur in rare cases.
A study called “Correlates of insulin injection omission”, published in 2010 in Diabetes Care, assessed factors associated with patient frequency of intentionally skipping insulin injections. Results shown that 20% of the 502 adults included in the study would intentionally omit to take their insulin, one of the reason being injection pain¹³.

Not complying with insulin therapy, usually leads to poor blood sugar control and potential permanent complications such as retinopathy, neuropathy, and cardiovascular disease.

Pain and discomfort at the time of injection or soon after is a common thought when talking about HPV vaccine.
In 2021, the study “How much will it hurt? HPV vaccine side effects and influence on completion of the three-dose regimen¹⁵ reported that 64% of parents of a daughter receiving a dose of HPV vaccine were complaining about pain. Although the study concluded that pain from HPV vaccine was equivalent to that from other adolescent vaccines, such reactions lead to vaccine hesitancy and decreased compliance with the vaccine schedule.

In 2015, the study “Safety of human papillomavirus vaccines: a review” , published in Expert Opinion on Drug Safety reported that: “public concern and rumors about adverse events (AE) represent an important barrier to overcome in order to increase vaccine coverage. Passive surveillance of AEs is an important tool for detecting safety signals, but it should be complemented by activities aimed at assessing the real cause of all suspect AEs.”

Methotrexate is a small molecule used in various autoimmune conditions. A paper published in May 2022 reviewed a case of injection site reaction following subcutaneous injection of methotrexate. While rare in that case, those adverse events can, here again, lead to discontinuation of treatment.

Cetrorelix, authorized as Cetrotide^® by the European Medicines Agency in 1999¹⁷ and by the Food and Drug Administration in 2000¹⁸ is gonadotropin-releasing hormone (GnRH) antagonist, used to prevent ovulation in women going through fertility procedures.
The second most common side effect reported are “reactions at the injection site, such as redness, swelling and itching”¹⁹.
(Read our case study here.)

Finally, it is well-understood that medication non-compliance, including that due to ISRs, has significant economic and health consequences for both patients and the healthcare system as a whole. These complications can result in increased healthcare costs, decreased quality of life, and increased morbidity and mortality.

Genoskin provides valuable expertise to pharmaceutical and biotechnology companies by characterizing, before clinical trials, human immune responses to their drug candidates or other biological agents in bio-stabilized and immunocompetent human skin platforms (HypoSkin human skin models). This approach significantly reduces the risk of unexpected adverse events and accelerates the drug development process.

Genoskin’s ISR Platform^® is an ideal tool for non-clinical testing, enabling drug candidates to be assessed before proceeding to clinical phases. By using this platform, pharmaceutical and biotechnology companies can also identify and understand local adverse reactions and take steps to mitigate any safety concerns that arise during clinical trials.

Overall, Genoskin’s human skin models and ISR Platform^® offer a powerful combination of tools that can help to speed up drug development, improve safety and efficacy testing, and ultimately bring safer and more effective drugs to market.