Standing in a queue outside the Chinese Embassy in Dublin, on a cold Tuesday morning, sheets of rain being blasted into your right ear by the unique Irish weather phenomenon of ‘sideways rain’, is not where most of us would choose to be. Particularly when it’s your second time there in the past two weeks because you brought the wrong documents the first time! However, such hardships must be endured when one’s parents-in-law haven’t seen their only granddaughter in half a year. And then, while patiently waiting and hoping your visa is approved without issue, the news breaks…
The outbreak of novel Coronavirus (2019-nCoV) has prompted increased attention to vaccines and vaccine studies. Biotech companies are working to tackle the current outbreak, but previous efforts to race forward with new vaccines during epidemics have hit unanticipated speed bumps. Vaccine trials entail unique ethical, logistical, and organizational challenges that stakeholders must understand before a study starts. This post discusses some of these operational aspects and why understanding them is critical to trial success.
Overview of Vaccine Trials
The objectives and uses of vaccines versus drugs affect the way they are researched and developed, supplied, financed, and accessed (Table 1). However, both vaccines and drugs are subject to the same rigorous regulatory scrutiny and require trials and approval by regulatory agencies.
The World Health Organization (WHO) estimated that at least 10 million deaths were prevented between 2010 and 2015 because of successful immunization programs. However, an unmet medical need remains, particularly in low- and lower-middle income countries, where diseases such as malaria, dengue, pneumococcal disease, HIV, and Ebola cause substantial mortality and morbidity. In countries where research is less common and where resources to conduct the clinical trial are low, large trials face many practical logistical and organizational obstacles that make it more difficult to run a trial to GCP standards.
These challenges are highlighted in publications describing large-scale trials of a pneumococcal vaccine in Gambia, a TB vaccine in Uganda, and a typhoid vaccine in Nepal, to name but a few. Moreover, with increased interest in “human challenge trials” (in which healthy individuals are deliberately infected with the disease-causing pathogens), vaccine trials involve unique issues.
Unique Challenges of Vaccine Trials
A report discussing the barriers to conducting vaccine trials in Asia and Africa notes that important factors to consider include working with local experts and investigators and awareness of cultural differences. Cultural differences must be taken into account even if they are not viewed as scientifically valid. Other factors include:
- Ethical concerns. Vaccines are usually given to healthy individuals, including children. Consequently, the ethical and safety standards of vaccine trials are especially high. For human challenge trials, additional ethical considerations include clear informed consent, effective treatment(s) for infection, and a strictly controlled environment.
- Reduced start-up time. Developing a vaccine during a health epidemic/crisis, e.g. Ebola, complicates traditional trial timelines. Experience is key in knowing what basics are essential while implementing processes and procedures in a rapidly changing environment. The same also applies to seasonal diseases, whereby the success of the trial hinges on operationalizing within time constraints.
- Representation. It’s well known that certain populations are underrepresented in vaccine trials, e.g. racial and ethnic minority groups for HIV or HPV vaccine trials in the United States. Reasons for under representation are complex, but include issues such as culture and language, logistics (e.g. getting to and from trial sites), and lack of information (i.e. not knowing about the trial in the first place). Understanding such barriers is the starting point to overcoming them.
- Vaccine mistrust/misinformation. A huge barrier to recruiting candidates to vaccine trials is the fact that the target population doesn’t have a clear understanding of the aims of the vaccine. This is compounded by alarmist, and usually unfounded, stories shared on social media. Impacts of such lack of trust range from reluctance to enroll to deadly attacks on health workers and patients. A concerted, tiered-level approach to community engagement and dissemination of information facilitates trust and confidence among stakeholders.
Community engagement can’t be underestimated, particularly as vaccine trials are large or may require long-term monitoring. Also, as vaccines are given to healthy individuals, maintaining “patient” engagement is particularly important because less face-to-face time with doctors may reduce the incentive of individuals to attend follow-up sessions.
Understanding patterns of pathogen circulation is also vital for interpreting data. For example, a 3-year study of a flu vaccine in rural India noted that
“prevention of influenza virus infection in India and similar tropical climates requires innovative approaches and recognition that optimal timing of vaccination differs from temperate parts of the world.”
Staff training and active monitoring of skills and set-up of infrastructure (e.g. cold-chain storage), especially in resource-limited regions and in times of health crises, are additional challenging aspects of vaccine trials. Chronic and highly infectious diseases, such as Ebola, introduce further logistical barriers. Obtaining Informed Consent can be challenging in any trial but consider the difficulty in an Emergency Treatment Center high-risk zone with medical staff wearing full personal protective equipment!
As with drug trials, comprehensive research and planning (e.g. early community engagement) are essential to ensure the successful conduct of vaccine trials. Many resources are available to help with the nuts and bolts of vaccine trial planning and to facilitate the meeting of international standards and good clinical practice requirements. For example, this report summarizes the development path of a novel vaccine candidate, and the WHO has published a guide on “Design of Vaccine Efficacy Trials To Be Used During Public Health Emergencies.”
Vaccine trials have unique, but not insurmountable challenges. The publications detailing vaccine trial challenges indicate that proper planning, clear protocols, and close communication among ALL stakeholders are keys to success.
The search for a 2019-nCoV vaccine continues, but researchers have somewhat of a head start – it belongs to the same family as the severe acute respiratory syndrome (SARS), for which a vaccine was developed following the 2002 outbreak. Progress is swift, with Australian scientists from the Peter Doherty Institute for Infection and Immunity in Melbourne claiming first re-creation of Coronavirus outside China as recently as 29th of January, less than a month from when the epidemic was first identified. According to Dr. Julian Druce, the Doherty Institute's virus identification laboratory head,
"having the real virus means we now have the ability to actually validate and verify all test methods, and compare their sensitivities and specificities".
With this speed of research and development, a vaccine may soon be available to us. Unfortunately, however, with the virus continuing to spread, and a travel warning in place advising against any non-essential travel to China, my newly acquired visa is looking more and more likely to go un-used.
Table 1 | Vaccine vs Drug Development
Source: Han, S. Clinical vaccine development. Clin Exp Vaccine Res. 2015; 4(1):46-53.