The FDA and Scientific Experts Discuss Infectious Disease Risk

On February 8-9, 2017 the Food and Drug Administration (FDA) organized a public workshop entitled ‘Identification and Characterization of the Infectious Disease Risks of Human Cells, Tissues, and Cellular and Tissue-based Products’. The purpose of this workshop was to gather scientific experts to discuss the methods available to identify and characterize infectious disease risks associated with human cells, tissues, and cellular and tissue-based products (HCT/Ps).

Experts from the FDA, the Centers for Disease Control and Prevention, the industry and several academic institutions discussed the challenges associated with preventing infectious disease transmission in the HCT/P donor population, and the complexity associated with assessing the risks and benefits. Discussions about emerging diseases and testing methods currently used brought light into what improvements should be made.

The global ease of human movement is at the origin of a rapid spread of zoonotic infections and other emerging diseases. Indeed, an epidemic can easily spread and requires a global response to identify the causing agent, the reservoir and determine ways to produce vaccines for global supply.

Another factor affecting the spread of emerging diseases is when herd immunity is compromised. Infectious diseases such as measles can predictably re-emerge, an example provided during the workshop was the 2014 measles epidemic in the US. Experts also discussed the widespread of yellow fever, Zika and other vector-borne diseases and the threat caused by the presence of their vectors such as Aedes albopictus and Aedes aegypti mosquitos on the US territory. Presenters have particularly stressed the need for a global supply of yellow fever vaccine.

Modeling methods are now available and allow to simulate and predict the potential impact of emerging diseases in specific populations, as those can be influenced by various factors including vaccination and resistance to antibiotics. It has been shown that statistical analysis of the incidence and prevalence of these diseases can be influenced by the population, the vector, the geography and surveillance methods used. These parameters can be used for scaling to estimate the potential risk.

Estimating the disease incidence in the blood donor population using recently developed assays to identify recent and long-standing infections can allow the prevention of transmission to occur. Nucleic acid tests allow a determination of early infections when antibodies are not yet detected and serological assays allow a determination in older infections. But these frames vary according to the virus and test used. Experts at the workshop have discussed the importance of improving the data collection and making the use of a confirmatory test for positive results consistent to facilitate modeling. Reliability of the data, specificity, and sensitivity of the assays used together with a consistency of the methods used across the US would improve the incidence estimation. Challenges associated with emerging infections such as Ebola are the uncertain period of time of asymptomatic viremia which can have brutal consequences. Ebola had a 90% mortality in some outbreaks.

The data obtained from blood donors can be used to estimate the incidence and prevalence in the HCT/P donor population. However, variables such as the diseases tested, the gathering of donor medical behavior history from interview information, which is not possible with deceased donors, and the lack of follow-up testing of most donors will affect this estimation. An integrated approach to monitor zoonotic diseases in the US may be beneficial to identifying emerging diseases. The modeling of incidence and prevalence is also challenged by the donor types such as reproductive HCT/Ps or conventional tissues from deceased patients. There are many challenges associated with post-mortem detection of infectious diseases which can make the detection unreliable such a changes in plasma samples that can interfere with the nucleic acid amplification process.

Nevertheless, without close surveillance data, the risk for the donor population is difficult to quantify. Experts have discussed the presence of Ebola in aqueous humor of patients who have survived even nine weeks after clearance of the viremia. Zika RNA was found by RT-PCR in aqueous humor although the corneal tissue is avascular and less prone to disease transmission. Scientists also discussed fungal contamination of ocular tissue and the possibility of potentially adding antifungals to corneal storage media.

Many pathogens can be transmitted through HCT/Ps and the risk of transmission is variable according to the pathogen tropism, tissue type, tissue processing and preservation.

Furthermore, to follow-up on sample storage and treatment, past experience have shown that freeze-drying of Factor VIII for hemophiliacs did not stop HCV and HIV transmissions. Regarding repeat sperm donors, storage of the samples can allow a timeframe to test for infectious diseases but the storage treatment itself does not prevent transmission. However, for other types of transplant such as Bone grafts, presenters gave an example of recipients of irradiated bone from an HCV-positive donor not being infected, showing that tissue processing can affect transmission.

Experts also discussed risks and benefits, that varies for different types of tissues. For instance, when a patient requires a transplantation for survival, the options to mitigate infectious disease are limited leading to a life and death decision.

Although rare, transmission of disease to HCT/P recipients have occurred.

To reduce the risk, a multistep process is recommended to select a safe donor and reduce the bioburden. For instance, by the time a tissue is tested for CJD (brain biopsy processed etc), the tissue would have already been transplanted. Better surveillance is key for organ transplant.

Challenges of traditional screening and testing approaches for donors of HCT/Ps, correlation of positive and negative serology and nucleic acid test results with the medical history interview is affected by a number of influences including the interviewee relationship to the deceased donor. Testing needs to HCT/P donors differs from testing performed for blood donors and participants highlighted the importance of the collaboration needed between tissue bank and test kit manufacturers to advance the scientific knowledge. Finally, to model better the benefit-risk assessment of a medical product, the FDA pointed out two aspects: the risk management and risk communication. The risk management consists of ways to decide if the used of the product affect the benefit-risk and risk communication makes sure that people are aware of the scientific base of knowledge on how to use a product effectively.

This FDA workshop allowed to have an insight into the methods currently used but also those being developed to prepare for emerging diseases in the donor population.

In the recent years, scientists have also studied the importance of innate immunity in the tolerance and rejection of transplants, the emergence of diseases in the recipient following transplantation and the outcome of viral infection in patients with active infections. New methods such as CRISPR for gene editing allow an insight into personalized therapeutic transplant and potential applications to introduce or edit genes to prevent viral infections. For instance, CCR5-Δ32 mutation provides resistance to HIV infection after transplantation with CCR5Δ32/Δ32 stem cells. These new methods evolve rapidly and will hopefully help prevent the emergence of infectious diseases in the donor population.

Nitisha Pyndiah - Biotech Consulting Services

Nitisha Pyndiah, PhD, is a Consultant where she provides advice for the development of biological, biotechnological, and biosimilar products.

Nitisha provides expertise in the areas of virology, molecular biology, microbiology, immunology, immunogenicity, quality control, GLP and GMP. She prepares and evaluates CMC sections, including FDA meeting documents; and conducts scientific and regulatory gap analyses. She supports technical, strategic, and operational regulatory affairs for recombinant proteins, monoclonal antibodies, and vaccines.