Vaccine safety: An evolving evidence‐based science

Immunizations are undeniably one of the greatest achievements in medicine, saving countless lives and preventing diseases that were previously commonplace.1, 2 However, because vaccines are universally administered, largely to healthy individuals, often young infants, they must be extremely safe. In fact, before vaccines are licensed for use, they must be proven both effective for the prevention of disease and must meet a high mark for safety. A number of nations have established vaccine safety systems, and the World Health Organization has established vaccine safety initiatives such as the Global Advisory Committee on Vaccine Safety (GACVS) and the Vaccine Safety Net.3 The former being a scientific body tasked to provide independent advice on issues related to immunization safety and the latter being a global network of websites that provides reliable, scientifically based information from a vast array of sources to include academic experts and key non‐governmental organizations on vaccine safety. In the United States, the Food and Drug Administration (FDA) requires that manufacturers provide the appropriate level of evidence that vaccines are safe and efficacious prior to approval and has a mandated post‐licensure monitoring process.4 The Center for Disease Control's (CDC) Immunization Safety Office (ISO) proactively monitors vaccine safety through many different mechanisms, including a large surveillance network associated with multiple health maintenance organizations called the Vaccine Safety Datalink (VSD).5 The current process in the United Kingdom is quite similar and includes expert review of all vaccine trial data by the Medicines and Healthcare products Regulatory Agency (MHRA) or the European Medicines Agency (EMA). In addition, the United Kingdom requires that vaccine safety be monitored on an ongoing basis which is accomplished through the MHRA Yellow Card Scheme which has been in place since 1964.6 Additionally, the United Kingdom has also started to implement a near real‐time vaccine safety surveillance system using the UK Clinical Practice Research Datalink (CPRD) to rapidly detect vaccine safety signals.7 Furthermore, since 2005, the European Center for Disease Prevention and Control (ECDC) has promoted immunization best practices, vaccine preventable disease surveillance, and vaccine safety initiatives. Many individual European Union member states also have vaccine safety programs.8

We are currently in the midst of a global outbreak of measles. In the United States alone, there have been 1109 cases as of 3 July 2019 which is the largest number since measles was declared an eliminated disease in 2000. This is a harsh reminder that having safe and effective vaccines does not ensure that they are administered. When queried about their reasons for vaccine refusal, parents frequently cite that they have concerns about the safety of the vaccines. Unfortunately, the public remains largely uninformed about the vaccine evaluation process and its scientific rigour, leading to a lack of confidence in vaccine safety.

One of the other vaccine safety groups that is funded by the CDC ISO is the Clinical Immunization Safety Assessment (CISA) Network. The CISA project was established in 2001 to address specific adverse events encountered by individual patients who have received or plan to receive a specific vaccine. The network consists of vaccine safety experts from ISO and several academic medical centres, and other subject matter experts who focus on understanding adverse events associated with vaccines. One of us (K.M.E.) has been part of this network since its inception and has seen the importance of the skilled input of allergists and immunologists in the process of evaluating adverse events that have temporally been associated with vaccination. The meticulous approach to understanding adverse events must be built on a strong scientific infrastructure with the ability to dissect the origin of the immune responses generated, both protective and detrimental.

In this issue of the British Journal of Clinical Pharmacology, Stone and colleagues provide a systematic literature search and narrative review of immune‐mediated adverse events associated with vaccines and their documented or proposed mechanisms of action. They also outline directions for future research to expand our knowledge regarding these events. Several well‐known mechanisms of hypersensitivity to vaccines are outlined, including IgE‐mediated immediate hypersensitivity reactions to vaccines or their excipients. They also provide an interesting discussion on a newer mechanism of an IgE‐mediated adverse reaction to vaccinations that is unique to gelatin‐containing vaccines known as galactose‐alpha‐1,3 galactose or “alpha‐gal” hypersensitivity. Alpha‐gal allergy, first described in 2009, is now identified as a global problem.9, 10 It is currently understood to be a tick‐induced allergic disease where bites from several species of ticks stimulate IgE antibodies against the cross‐reactive carbohydrate determinant galactose‐alpha‐1,3 galactose. This carbohydrate is also found in several mammalian meats such as beef, pork, lamb, and mutton, and the hypersensitivity can present as a delayed reaction after consumption of red meats and meat‐derived gelatin, as well as topical and intraoperative meat‐derived gelatin colloid.11 More recently, gelatin containing vaccines have been shown to cause immediate onset anaphylaxis in both an adult and paediatric patients with known alpha‐gal hypersensitivity.12, 13 Stone and colleagues highlight this unique hypersensitivity syndrome and emphasize that clinicians should be aware of the risk of anaphylaxis with gelatin‐containing vaccines in those with alpha gal hypersensitivity. They also suggest that providers should perform alpha gal allergy testing in those presenting with anaphylaxis temporally associated with gelatin‐containing vaccines.

Mechanisms of delayed‐type hypersensitivity are also reviewed, as well as a section on the safety of vaccines in the immunocompromised. Safety concerns in the latter group have become more important as a growing segment of the population is immunocompromised by medications or biologics to control their basic disease processes.

Why is it so important to understand the specific basis of adverse events temporally associated with vaccines? First, it is important that such events be carefully reviewed for their potential causality and in particular whether the adverse event following immunization (AEFI) has a biologically plausible mechanism of action. Establishing causality can be particularly challenging. Causality assessment tools that are largely applied to small molecule drugs with defined half‐lives, temporary effects, and a defined causality window such as the Naranjo drug reaction probability score do not easily translate to use for vaccine AEFI.14 Experts who are dissecting adverse events from other pharmacologic agents, such as antibiotics and antivirals, can and should add expertise to this search for mechanisms associated with AEFI. Investigative allergists, immunologists, and other scientists should be engaged in uncovering mechanisms associated with vaccine adverse events. The development of biological repositories to store PBMC, plasma, serum, and potentially other samples from individuals who have experienced well defined adverse events would be an important resource to help us move forward down the path toward understanding and preventing rare immune‐mediated vaccine adverse events.

Second, it is also very important to establish the frequency of the adverse events associated with vaccines. The VSD in the United States, as mentioned earlier, is a large vaccine safety surveillance network that can be used to determine the absolute risk of an AEFI. An example of the effective use of this system was demonstrated in the occurrence of intussusception associated with the former rotavirus vaccine RotaShield. This AEFI was first identified in clinical trials conducted prior to licensure. Then, at the time of licensure, a diagnostic code was assigned to intussusception following rotavirus vaccine, and the event was included in the vaccine package insert. After the vaccine was licensed, vaccine‐associated cases of intussusception were identified and further assessed through these large surveillance networks, ultimately demonstrating an increased risk of the event in vaccinated persons. Much larger sample sizes to assess safety were also required for the licensure of subsequent rotavirus vaccines.

However, there are limitations to this current approach. Some critics argue that safety concerns in “at‐risk subpopulations” might escape detection in our current systems that are designed to detect more common and well‐characterized events. They posit that advances in machine learning and systems immunology could enable us to better “understand the heterogeneity of responses and to optimize vaccines and their use.”15, 16

New and improved scientific techniques are always evolving and should be applied to addressing safety concerns. The public needs to know that we take their safety concerns seriously and that all serious vaccine events are reviewed case by case to determine which adverse events are likely causal and which are only temporally associated. In addition, the public needs to understand that there are complications associated with natural infections and the devastating cases of subacute sclerosing panencephalitis after convalescence from natural measles are relevant and timely examples of the benefits to being immunized.17

While adverse events following immunizations (AEFIs) are rare, when they occur, they should be evaluated, their frequency quantified, and their mechanism investigated. One of the particular strengths of the CISA network is the ability to investigate specific AEFIs with careful review of the medical records from the individual patients, an extensive literature search to find other similar reports, and with the performance of specific tests that might shed light on the mechanisms of adverse events with a goal of prevention in the future.

As Stone et al suggest, we need to be intentional and strategic in understanding the mechanisms of AEFIs. Many other investigative fields in medicine are utilizing precision medicine “an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person”.18, 19 It can often appear that “one size fits all with immunizations.” However, the field of vaccinology needs to consider individual variation when dealing with AEFIs.20 It needs to understand the genomics, metabolomics, proteomics, and the microbiome associated with AEFI. Perhaps then we can be more precise on dosages, boosters, and schedules that ultimately may afford a tailored approach to an individual while still preventing disease.20 The field of vaccinology needs to move forward into the 21st century and embrace precision medicine as well particularly as more vaccines become available to prevent diseases, and newer adjuvants become mainstream.

COMPETING INTEREST

There are no competing interests to declare.

McClenathan BM, Edwards KM. Vaccine safety: An evolving evidence‐based science. Br J Clin Pharmacol. 2019;85:2649–2651. 10.1111/bcp.14080