The news is filled with stories about the novel 2019 coronavirus (2019-nCov or SARS-CoV-2). Emerging infectious diseases are part of the reality of a globalized civilization. Developing vaccines that can address new infectious agents is important to all of us.
How do we develop those vaccinations? That’s where clinical research involving human participants comes in. The current coronavirus outbreak has led to a surge of interest in coronavirus research and concern about the risks associated with coronaviruses. Let’s take a look at the basics of coronaviruses, strategies for developing medical countermeasures against the current outbreak, and key ethical and biosafety considerations for research involving the novel 2019 coronavirus and other emergent infectious diseases.
Note: For simplicity, in this article we’ll refer to the novel 2019 coronavirus as 2019-nCoV and the pneumonia associated with the viral infection as COVID-19.
Coronavirus: The Basics
Coronavirus (CoV) is a family of viruses that cause disease in mammals and birds. Most coronaviruses capable of infecting humans cause mild to moderate respiratory tract infections which are transmitted by respiratory droplets (e.g., coughing, sneezing). Certain notable coronavirus species can cause more virulent infections, including SARS, MERS, and 2019-nCoV.
An important early victory in the fight against the 2019-nCoV was the sequencing of the viral genome, which led to genetic tests/molecular diagnostics allowing for confirmation of infected individuals. The CDC also made molecular diagnostic kits available to authorized labs so a suspected case can be assessed within hours, rather than waiting days for analysis at the CDC central lab.
IRB Considerations for New Emerging Infectious Disease Research
Emerging infectious diseases can raise unique issues for institutional review board (IRB) review and research informed consent. The risks and benefits of any research involving human participants must be evaluated by the IRB and carefully explained in the informed consent form (ICF). But what if we don’t yet fully know the risks and benefits of a vaccination or other treatment because it is just being developed? At the very least, the researchers should understand the spectrum of risks and present that information in the research ICF. Disclosure is key.
IRBs are cautious about including vulnerable populations in research because of historical abuses of vulnerable groups such as children, prisoners, and individuals with cognitive impairment. However, many populations may be impacted by an emerging infectious disease; accordingly, eliminating certain groups from the inclusion criteria might skew the results of the research. Researchers utilizing unique inclusion and exclusion strategies should discuss the potential benefits and risks with the IRB in advance so that any potential concerns can be addressed prior to IRB review.
A protocol that reimburses participants for travel and other expenses, but describes the reimbursement too narrowly, may result in unnecessary delays when it becomes apparent that changes must be made to accommodate an ever-changing landscape. In the case of an outbreak like COVID-19, participant travel preferences may change over the course of the study based on the local/national infection rates. A participant who typically flies to a research site may decide instead to drive and stay in hotels even though the travel is substantially longer. Consider writing reimbursement provisions to cover several different travel scenarios that could arise.
To the extent reasonable, appropriate, and allowed under applicable law, researchers should consider the use of digital technology as a tool for participants to report symptoms as an alternative to check-ups at the site. Video technology provides a means to see and talk to a participant without the need to travel. If in-person assessments are necessary, consider whether in-home evaluations with visiting medical personnel would be sufficient.
Minimizing Risks Associated With Researching Genetically Engineered Vaccines
Research is currently underway to identify safe and effective medical countermeasures against COVID-19. While antivirals and antibodies can be utilized to treat viral infections, vaccines are the best way to prevent infection and control outbreaks. An effective vaccine can create an immune population no longer susceptible to infection and prevents the virus from spreading. A ring of vaccination around an outbreak can contain it and allow it to burn itself out without spreading to new hosts.
Currently available genetic engineering techniques and the 2019-nCoV genome sequence provide opportunities for vaccine research and development. Scientists can easily introduce single genes from 2019-nCoV into expression systems to produce subunit vaccines. Introducing 2019-nCoV genes into weakened vaccine strains of existing viruses also serves as a means of delivering both the 2019-nCoV antigen and an adjuvant to spur the immune response.
There are risks when utilizing genetic engineering technology. Introducing a coronavirus gene into another virus may have unintended consequences and pose occupational safety risks, as well as risks to the community and environment surrounding the research site. It is also important to mention that using the complete genetic sequence can enable creation of the virus in the laboratory setting. While a typical Biosafety Level 2 (BSL-2) laboratory provides adequate containment for expression of subunits, Biosafety Level 3 (BSL-3) containment is required for culturing and characterizing the virus as well as assaying vaccine efficacy in a challenge model utilizing laboratory animals.
BSL-3 laboratories are designed to contain aerosol transmissible pathogens. Laboratory design criteria include a double doorway entry system to provide security at the outer door and an anteroom between the doorways for donning and doffing personal protective equipment (PPE) including respiratory protection before entering the laboratory. The laboratory must have unidirectional, inward flowing, single pass air that is exhausted through a HEPA filter. All work must be performed within a negative pressured and HEPA filtered biosafety cabinet or another aerosol containment device. The facility must contain an autoclave for sterilizing infectious waste.
The role of an institutional biosafety committee (IBC) is to conduct risk assessments for research involving engineered genetic material to ensure an appropriate risk mitigation plan is in place. IBC review is required when the research or the site/institution has ties to NIH funding. Even if there are no ties to NIH funding, IBC review is considered a best practice, and the NIH recommends voluntary compliance.
Institutions embarking on coronavirus research should consult IBCs with adequate expertise to understand the science, risks, necessary safety practices, and regulatory requirements. There may be additional regulatory constraints depending on the coronavirus species: for example, the CDC has tightly regulated the 2012 SARS coronavirus as a select agent for its ability to pose a severe threat to public health and safety.
IRB Considerations for Ongoing Research During an Outbreak
Whether your research involves COVID-19 or not, the pandemic has undoubtedly impacted your research program. For ongoing research, investigators should always submit an amendment to the IRB to obtain prior review of changes to the research. The only exception to this is when changes are necessary to eliminate an immediate hazard to subject safety—only in that situation may an investigator implement changes prior to IRB review, and such changes must still be promptly reported to the IRB.
When changes necessary to eliminate apparent immediate hazards to participants are implemented prior to IRB review, no new consent is required unless the change fundamentally alters what the participants consented to. While the phrase “re-consent” is widely used, it does not exist in the regulations. If someone consents to participate in research, they only need to consent again if something changes that essentially negates their consent to participate. Participants can be informed of changes by way of a notification that is not a new consent document.
Researchers may want to incorporate a short screening to assess participants for exposure to the infectious disease before in-person interactions. The incorporation of this screening procedure does not require IRB approval. If a participant says yes to any of the screening questions, it is recommended that study staff identify a resource to direct the participant to.
It is a good idea to evaluate remote or virtual options for certain study activities. Review the study to determine if any procedures requiring participants to come to a hospital or a clinic can be eliminated or managed remotely through telemedicine or home visits. This would require an IRB determination stating that changes in these procedures would not impact the integrity of the research. If research participants cannot come to hospitals or clinics because of infection, self-quarantines, or travel restrictions, consider amending the protocol to identify alternative processes, such as digital technology to record symptoms, telemedicine options to provide virtual visits, and visits from visiting nurses or home health aides to conduct study related procedures. Please note that shipping study agents to participants is subject to state and federal laws.
In this kind of fast-paced environment, appropriately managing risks is critical to minimizing the current outbreak’s impact as well as to developing medical countermeasures to combat the outbreak. If you are unsure about something, don’t hesitate to contact the IRB and/or IBC overseeing the research. We are all in this together.