We have benefited from an incredible collaboration, primarily other parts of NIH and the Department of Health and Human Services, NIAID, FDA, CDC and BARDA, and also Mount Sinai, where Ramon Parsons, Florian Krammer and their colleagues have really been very helpful, and in addition, other cancer centers as well.
The shorter-term goals have been to characterize the performance of different serological assays, correlate them with neutralization, and understand possible cross-reacting sera from prior to the epidemic, and to correlate this with serological tests submitted to the FDA.
The longer term goals are to understand implications of being seropositive. Does this really mean resistance to reinfection and duration of seropositivity?
FDA and commercial serology devices
The FDA had issued a number of press releases, first on March 16. They permitted the sale of commercial laboratory-based, rapid lateral flow SARS-CoV-2 serology devices without actually assessing the performance. The serology devices, importantly, are not used to diagnose current infection. That’s measuring the viral RNA or viral protein. This instead is measuring antibodies.
During this initial period, there was a lot of heterogeneity in the quality of the devices that were available, but at the beginning of May, the FDA gave emergency use authorization to several commercial devices and required that all other manufacturers would submit emergency use authorizations or EUA requests within 10 business days, and some of the Emergency Use Authorizations, they took advantage of data that had been developed at the Frederick National Laboratory and the serology laboratory.
Then about 10 days ago, the FDA gave emergency use authorizations for several additional devices. [Here are] the results of the initial 40 commercial serology devices that have been evaluated by the Frederick National Laboratory serology laboratory:
We have tested both IgM and IgG antibody tests, but I think that people should be focused more on the IgG antibody tests, because IgM and IgG in this disease become positive at about the same time, but IgM goes down faster than IgG.
What we have found in this analysis is that the sensitivity for the various devices, the ability to detect true positives, vary enormously. Some of them were extraordinarily good, being in the 90% to 100% range, but some of the devices were not very good and had sensitivity that was well below that, and one as low as 30%.
Specificity was also quite variable, and I’ll have something to say about that in a subsequent slide. The specificity, it’s the efficiency with which you don’t detect false positives, and again, it varied from a high of 100% to a low of 87%.
The results, we then sent them to the FDA to help FDA determine suitability for Emergency Use Authorization, and as I mentioned, the FDA has made some of their NCI evaluation results publicly available, and others will be released in the near future, and my expectation is that because of the increased stringency of the authorizations, that in the very near future, only devices with high sensitivity and high specificity should be available in the United States.
Low rates of seroprevalence
The vast majority of the United States, with the possible exception of perhaps first responders or healthcare workers in New York and a few other places, the seroprevalence is actually quite low, well below 10% in virtually all areas of the United States, when you look on a state-wide level, rather than looking at specific populations, such as nursing homes or meat processing plants, but if you look at this slide, if a test has 99% specificity, which we would consider a very good test, and the seroprevalence is found to be at 5%, 20% of the positive will be false positive. In other words, one out of five of the positives will be false positives.
If a test has 95% sensitivity, which you usually would think about as being quite good, and the seroprevalence was found to be 5%, at that point, 50% of the positives will be false positives, which means that there’s a tremendous false error rate. That is why it’s so important for the current tests to have very high specificity.
So, I want to go over with you some of the questions that currently are unknown and being addressed by research. First, being antibody positive means either the person is currently infected with SARS-CoV-2 or has been previously infected. Second, you can now use the test for seroprevalence studies. It should identify most people who had asymptomatic or symptomatic infection. However, a small minority of people, mainly those with asymptomatic infection, may remain antibody negative.
Third, it’s not currently known whether being antibody positive is associated with protection against re-infection, what antibody levels may be associated with protection, and how long protection and antibody levels will last. And therefore, we think that antibody titers are likely to become important, and we are in the process of developing quantitative assays, and I think in the near future that the FDA will also be evaluating quantitative assays.
For candidate polyclonal antibodies, from convalescent sera and neutralizing antibodies, which are currently being initiated in clinical trials, will they reduce the risk of serious disease? It remains to be seen. If they do, it will imply that the candidate SARS-CoV-2 vaccines, which mainly we think will function by inducing neutralizing antibodies, would be more likely to confer protection.
The phase III trials for the vaccines will be starting sometime next month, as many of you have heard, but they will be randomized controlled trials that will look at evaluating whether there are enough events in the control group and the vaccine group to be able to identify a clear cut benefit.
I just want you to see how many different people have been involved in making this effort possible. I, of course, want to acknowledge the people at the Frederick Serology Laboratory, Ligia Pinto, Troy Kemp and Jim Cherry.
This is setting up a data resource for strategic assessment of serology. It will be a COVID-19 sero-track. We are setting this up with the strong collaboration with NIAID and CDC.
The reason we are doing it is that both the NIAID and CDC asked us if we could do it, they were so strapped for their various resources. So Tony Kerlavage and Stephen Chanock have been extraordinarily proactive in setting this up over a very recent period, and Neal Freedman from NCI is going to be the subject matter expert at NCI, and they will be subject matter experts from NIAID and CDC, and the idea for the warehouse is to collect and manage COVID-19 serological test results and serve as a research resource to NCI, NIAID, CDC and the broader research community.
The dashboard, the goal will be to be a summary of global serological studies, assay types and results generated, and antibody prevalence in the U.S. For the ability to filter results by geography and demographics. If you look on the right, the prototype would be in two stages. We hope that the summary dashboard will be able to be set up sometime this summer, and the larger prototype to be a prototype to be working in the fall. So stay tuned for this.
Proposed Serological Sciences Network
I want to now, for the remainder of the time, talk about the proposed Serological Sciences Network for SARS-CoV-2. The announcement for this network came out 10 days ago, and the due date is going to be by July 22.
So, there will be Serological Sciences Capacity Building Centers. The goal is to expand the testing capacity and practice in the community, implementing standardization for serology development, and using these tests and scale up as necessary for testing, and to acquire convalescent sera from recovered patients who are seropositive, and to conduct surveillance trials, and to pursue focused serological science.
There will also be the Serological Sciences Centers of Excellence, and their goals are to understand the mechanisms driving serological, humoral, and cellular immune responses to SARS-CoV-2 viral infection, and to inform the development of novel serological tests, to determine the serological correlates with disease, pathogenesis, and protection against future infection, and improve population-based models of outbreak and susceptibility through serological focused studies. There will be a preference for cancer relevant components, and each center will have several projects and administrative core and the possibility of a technical core, and these will be U54 awards.
The third component will be the serological sciences projects, and the goals will be to understand the mechanisms driving the serological, humoral, and cellular immune responses to infection, to inform the development of tests, determine the serological correlates, improve population-based models, and again, preference for cancer relevant component. These will be five to 10 U01 awards, and up to $500,000 cost per year and up to five years.
There will also be a Network Coordinating Center at the Frederick National Lab. It will be distinct from the dashboard that I mentioned, and the goals will be to provide program management, coordination and communication across the network.
Coordination for sharing of data, reagents, samples, assays and coordinate comparison of results among different centers and assays through inter-center collaborative studies leading to international serological standardization. And to coordinate the partnerships with national and international associates, such as FDA, CDC, World Health Organization, the National Institute for Biological Standards of Control, and others, and to work in collaboration with the program staff.
There was a request for information, an RFI, for strategy for the coronavirus testing and that was to seek input from the research community. It closed about three weeks ago and some of the responses are being incorporated into the scope of the network.
To summarize the hub-and-spoke notion of the Serological Sciences networks, and importantly, to acknowledge the many people who have been instrumental in putting this aspect together. Particularly, I’d like to acknowledge Dinah Singer, Crystal Wolfrey, and Sara Hook at NCI and at NIAID Carl Dieffenbach, Emily Erbelding, and Cristina Cassetti.