Behind the wave
BY
Amber Bennet, et al.
Introduction
The world has become engrossed in the vaccine development process since the world’s researchers began their race to provide a vaccine against the SARS-CoV-2 virus. To expedite the development of herd immunity through rapid and widespread vaccination, the COVID-19 vaccine development timeline has been compressed from a decades-long process into 1 – 2 years (Shah et al., 2020; Kamble et al, 2020). Understandably, this has incited public anxiety about potential compromises in safety and effectiveness (Dhanda et al., 2020).
Regulatory bodies recognise the possibility of rare adverse events going undetected in small clinical trials; thus, implementation of post-marketing surveillance strategies, as well as public accessibility of safety data is vital for benefit-risk decision making and alleviating public mistrust and vaccine hesitancy (Larson et al, 2016; Lane et al, 2018).
Background
Vaccination is the most effective method of preventing infectious diseases and is largely responsible for the eradication or minimisation of the incidence of many debilitating illnesses, including smallpox polio, measles, and tetanus (World Health Organisation, 2019). Vaccines are biological preparations that provide host immunity to infectious particles. A vaccine has traditionally been made from weakened or non-infectious forms of a pathogen, its toxins, or surface proteins to produce an agent that stimulates the body’s immune system. Modern vaccines, including those developed for the current pandemic have included the use of messenger RNA to directly induce the production of foreign proteins and responsive antibodies against it. For all vaccines, the goal is for the body to recognise foreign particles and activate a sustained immune response to remove it (CDC, 2012).
As the name suggests, post-market surveillance refers to the practice of monitoring the safety of a pharmaceutical drug/device after it has been released on the market and is an important part of the science of pharmacovigilance. Like other pharmaceutical drugs, vaccines are thoroughly tested and reviewed for safety, immunogenicity, and efficacy by animal testing, and three phases of clinical trials in humans before they can be marketed. Once a vaccine has been approved for public use, post-market surveillance of the vaccine is critical and its assessment is used to either refine, confirm or deny the safety of a drug. The parameters for safety monitoring change following market approval as the vaccines are now being used in the general population and are no longer monitored in a clinical trial with narrow inclusion/exclusion criteria. It is important to ensure safety and efficacy standards are continually achieved, especially in subpopulations that are frequently excluded in clinical trials.
Once the vaccine becomes widely used, and the infection rate of the target disease falls, the benefits of vaccination may not be immediately visible. Therefore, it is important that the immune response (i.e. antibody levels) is monitored to ensure the vaccine is providing sufficient immunisation to disease. For example, in patients receiving a vaccine targeting another coronavirus, Middle East Respiratory Disease (MERS), showed that after 6 months, antibodies specific to the viral spike protein had completely diminished (Dhanda et al, 2020).
A critical tool in the post-marketing landscape remains serological testing, which profiles production of disease-specific antibodies in vaccinated individuals. In addition, much of the critical research surrounding the COVID-19 pandemic still centres on understanding differences in the immune responses of asymptomatic, mild and severe infections and how such factors influence the duration of seroprevalence. Asymptomatic and mild cases most often result in low levels of antibody-mediated immunity. High levels of neutralizing antibody titres are detected in convalescent individuals and are positively correlated with disease severity. COVID-19 vaccines in development therefore aim to improve the immune response and maintain the levels of neutralizing antibodies for longer periods.
Importance of Post-Market Surveillance
Vaccines routinely undergo phase IV clinical trials (post-market surveillance) to assess the effects of minor changes to the formulation or vaccine strain. These trials are used to further optimise parameters such as age at vaccination, number and timing of vaccine doses, and simultaneous administration and interchangeability of vaccines on safety and efficacy (Pharmacovigilance, 2020). Adverse drug reactions (ADRs) or adverse events of special interest (AESIs) are likely to include allergic, inflammatory, and immune-mediated reactions. The incidence rates are typically low for severe vaccine-associated ADRs, e.g. Guillain-Barré Syndrome (2 cases per 100,000 person-years) and narcolepsy (1 case per 100,000 person-years)); however, while safety clinical trials can detect more frequent events (e.g. fever, headaches, rashes, etc.), they are not sized to detect ADRs with a frequency of <1/10,000 person-years (Fontanarosa et al, 2004; Sturkenboom et al, 2019). Although seemingly rare, it is important to note that an increased or disproportionate focus on adverse events, which is often identified by media reports on one or few case reports, may lead to a loss in confidence in vaccines, increasing costs and delays in future trials, often reducing the number of vaccine developers.
Post-marketing surveillance is intended to detect rare and/or delayed ADRs once vaccine candidates are publicly available and to allow for representation of larger populations, racial and ethnic minorities, older persons, and individuals with medical comorbidities that may not have been included in the preceding clinical trials.
Furthermore, pharmaceutical drugs targeting respiratory diseases, such as COVID-19, require additional safety considerations related to inflammatory ADRs linked to antibody-dependent enhancement. Historically, this system relied on passive collection of spontaneous patient reports of ADRs to ensure safety. This allows adverse events to slip through the cracks, with reports of poor quality, with inadequate documentation and detail. This creates difficulty in calculating the incidence of ADRs and establishing causal relationships. Post-marketing surveillance trials carried out by physicians around the world, with technical aid from pharmaceutical companies and accredited bioanalysis facilities, would allow for accurate collection and analysis of patient samples and supporting data.
How is Post-Market Surveillance conducted?
Passive surveillance (spontaneous reporting) systems, such as the FDA and CDC comanaged Vaccine Adverse Event Reporting System (VAERS), are the most commonly used form of post-marketing safety monitoring and relies on the cooperation of healthcare professionals, manufacturers, and/or patient contacts to report the occurrence of safety and efficacy outcomes. Furthermore, capabilities for enhanced monitoring of vaccine recipients, through smartphone and web-based surveys are also being developed to help capture potential adverse events and the role of individual variation (Lee et al, 2020). However, in cases such as the COVID-19 vaccine where rapid evaluation of safety signals is essential, it would be implausible to rely solely on passive systems of safety monitoring and therefore active surveillance methods would need to be considered.
Active methods such as these were successfully implemented in China, by the National Adverse Events Following Immunization (AEFI), during the 2009-2010 H1N1 influenza A (swine influenza) pandemic and involved organised data collection at specific time points on all participants in the vaccine study, irrespective of adverse outcomes. Data captured in health care encounter data and electronic medical records collected on large-linked databases (e.g. Vaccine Safety Datalink) provides a near real-time means of collating, tracking and monitoring of vaccine safety signals and adverse events on a large scale in order to support timely, educated decision-making (Lee et al, 2020). In the case of the H1N1 pandemic, data showed that 90 adverse events per million doses were detected. Of these, 81.2% were verified as vaccine-specific reactions, most of which were allergic reactions while 11 cases (0.1 per million doses) were related to Guillain-Barré Syndrome (Liang et al, 2011, NEJM). Therefore, the implementation of active surveillance methods such as this provides a scientifically robust approach to identifying potential safety or effectiveness concerns with real-world use and a means of pre-emptively detecting adverse events that were not detected during pre-marketing trials (Dhanda et al, 2020). Ultimately, the data collected during post-marketing surveillance is used to conduct real-time risk/benefit assessment of the pharmaceutical drug/vaccine, where the need for urgent action should be weighed against the need for further investigation.
Concluding Remarks
Post-marketing surveillance systems allow for the safety and efficacy assessment of pharmaceutical drugs in real world settings by the public. The urgent, global demand and expedited development of the current COVID-19 vaccine candidates merits a rigorous past-marketing surveillance strategy which will require more than conventional passive surveillance strategies, but rather active, integrative collaborations to compile a comprehensive, near real-time database to guide regulatory decision-making and public health practice to maintain a positive benefit-risk balance.
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