Cassie and Len Calabrese’s COVID-19 Corner: Issue #9

Well, our COVID-19 Corner must be working as many states and municipalities are getting on the mask wagon. We have labeled it the “Save the economy and save your grandmother” initiative. Let’s keep it up. Maybe POTUS will start reading our Corner in his briefing? You never know. Recently many states in the US have been hitting daily records for case counts, and this is in direct correlation with lack of masking and opening back up society. The importance of masking and maintaining social distancing cannot be stressed enough.

Today we are now turning our thoughts down the road a bit and thinking about immune response, immune memory, and host defense in an effort to understand the issue and opportunities for vaccine development.

Mutual pick:

This week we are interested in several commentaries published in Nature Reviews Immunology that discuss what we know and don’t know about antibody-mediated protection from SARS-CoV-2 and potential vaccine targets.

In a previous issue of COVID-19 Corner (issue #2) we discussed our understanding of SARS-CoV-2 lab diagnosis and immunity, highlighting a JAMA article that sheds light on the interpretation of antibody tests (, informing us that IgM antibodies typically appear after 5-7 days, and IgG antibodies following the second week. It was in this issue that we introduced the concept that not all antibodies are created equal, which has implications for SARS-CoV-2 vaccine development. Numerous drug companies are in a race to find an effective vaccine against COVID-19 using a wide array of vaccine technologies at a pace never before seen in the history of vaccine development.  What they are hoping to generate are neutralizing antibodies or antibodies that will bind to specific viral domains and prevent entry into the cell- the type of antibody interaction desired for long-term immunity. There already exist many questions surrounding neutralizing antibodies in COVID-19 infection, and it remains unclear how humoral immunity effects the severity of and recovery from infection. As outlined above, antibodies to SARS-CoV-2 develop soon after infection, and there are data to suggest that antibody titers are higher in patients with more severe disease. Population level studies show that the majority of patients recovered from COVID-19 develop low levels of neutralizing antibodies. These findings fuel uncertainty about the role of the antibody response in this disease. We encourage you to read this commentary by Tomer Zohar and Galit Alter called “Dissecting antibody-mediated protection against SARS-CoV-2”, published in Nature Reviews Immunology (, wherein the authors discuss various antibody functions and implications in protection.

Only a portion of the antibodies formed against SARS-CoV-2 will be neutralizing, and antibodies can have numerous other effects, both positive and negative. One of the most feared outcomes of non-neutralizing antibodies is antibody dependent enhancement (ADE), which is nicely outlined in the Nature Reviews Immunology commentary by Peter Hotez, et al. ( ADE involves antibodies binding to virus and facilitating their entry into cells via Fcϒ receptors – even into cells that do not have the right receptor for viral entry.  This interaction has been documented in other viral infections, in particular Dengue, wherein dengue vaccine trials it was found that some recipients who had been previously exposed to Dengue experienced severe disease after vaccination due to ADE. Fortunately, ADE has yet to be observed in SARS-CoV-2 infection, but clearly there is much we have yet to learn.

We also want to point out a third short piece in the same issue of Nature Reviews by Peter Hotez, et al. proposes that aluminum-based adjuvants may be the answer to an effective vaccine ( Sometimes ‘old stuff’ may outperform and be better than new stuff in terms of bioengineering. The use of aluminum, a time-honored and safe adjuvant, is categorized in our thinking as one of Janeway’s immunologist’s dirty little secrets, a phrase that if you have not heard it before is a legend in the modern history of immunology.  Dr. Hotez is a brilliant guy and outspoken in his efforts to fight epidemic after epidemic. Check him out.

Each of these three Nature Review pieces are short, barely two pages each, and are insightful reads that spark lots of questions and deep thought.

Finally, what about T cells and immunity? Surprisingly we are just starting to learn more about this important pillar of adaptive immunity and it appears that our immune system is actually quite creative and capable of mounting an effective cell mediated immune response against SARS-CoV-2. Gifroni and colleagues examined a cohort of patients recovering from COVID-19 and detected elements of T cell recognition by CD4 cells in 100% and CD8 cells in 70%. The details can be found in this link to a nice summary in Science Daily The paper itself has some heavy stepping but it’s a great read, per Len.  This type of study is absolutely critical to benchmarking vaccine trials in an effort to determine whether candidates can mimic and achieve some sort of immune protection. Mind you it’s merely an important first step. Also of interest, they found evidence of what appears to be some immune memory for COVID viruses pre SARS-CoV-2 meaning that common cold Corona may contribute to our immune profile in some, as of yet, not clearly understandable way. Could be important!

With cases on the rise, the coming weeks will likely be challenging. Counsel your loved ones as you would your patients – always wear a mask when outside your home or around anyone who is not your immediate family. Maintain social distancing, and if socializing, be sure to socialize with others who have been masking and social distancing. Outdoor activities are safer than indoors in terms of transmission. Be smart. Be safe.

Please give us a shout out with any questions!


Leonard H. Calabrese, DO, is the head of the RJ Fasenmyer Center for Clinical Immunology and Vice-Chair of the Department of Rheumatic and Immunologic Diseases at Cleveland Clinic  Dr. Calabrese has lectured nationally and internationally on the subjects of immunology, rheumatology, and viral diseases. He is the author of more than 400 published peer-reviewed articles, book chapters, and reviews. @LCalabreseDO

Cassandra Calabrese, DO, is a staff physician in the Department of Rheumatic and Immunologic Diseases and the Department of Infectious Diseases at Cleveland Clinic and directs the combined Rheumatology-Infectious Disease training program. She also directs the Clinic for immune-related adverse events form cancer immunotherapy within the department of Rheumatic and Immunologic Diseases. @CCalabreseDO

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