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Principal Investigator: KENNETH M KAUFMAN
Organization: CINCINNATI VA MEDICAL CENTER RESEARCH
Fiscal Year: 2022
Funding agency: Veterans Affairs
The new Covid-19 virus is deadly for 0.2% to 4% of people infected, with older men the most severely afflicted
with this scourge, being mortal to ~15% of those infected over 80 years, making the US Veteran population
especially vulnerable. It is critically important to understand the mechanisms of this lethal pathophysiology in
order to design interventions that will save lives. MERS, SARS-CoV, and now the new human Covid-19 mean
that three coronaviruses have threatened to become horrific public health problems for the entire world; this
last and most recent one, Covid-19, has succeeded.
Some of the antibodies formed against this virus appear to accentuate the clinical severity of disease, possibly
making the specific details of the immune response responsible for the demise of many infected patients. We
have had more than two decades of experience as VA Merit supported investigators exploring the antigenic
structure of the lupus autoantigens, leading us to the theory that Epstein-Barr virus causes lupus, which is a
hypothesis now supported by convincing circumstantial evidence. We propose to apply our experience to
exploring the details of the fine antigenic specificity of the anti-Covid-19 antibody response in order to
understand what specific antibodies are dangerous. We propose to explore two hypotheses:
Hypothesis 1. Specific and detailed knowledge of antibody immune responses to Covid-19 will be
useful for elucidating pathogenic mechanisms, predicting disease severity, designing vaccines,
selecting therapeutic plasmas, making patient care decisions, informing population epidemiology,
determining infection dynamics, and choosing individual behaviors in the face of the Covid-19
pandemic.
Hypothesis 2. Anti-Covid-19 antibody fine antigenic specificity will correlate with clinical
manifestations and infection severity.
We propose two aims:
Aim 1. Develop and apply assays to dissect the antigenic fine specificity of antibodies forming against shared
and sub-strain specific Covid-19 antigens in the natural human Covid-19 infection.
Aim 2. Isolate and purify anti-Covid-19 antibodies against the major epitopes and any specific antibodies that
are associated with severe pulmonary disease.
We will use Western blotting, solid phase assays (ELISAs), phage display libraries expressing 30-mer amino
acid peptides, and synthesized overlapping fmoc peptides to fully characterize the fine specificity antibody
response to the Covid-19 virus. We will obtain plasma and serum from Veterans and others which we will
evaluate for correlates with clinical outcome. We will isolate individual specificities and characterize their
properties with respect to type, isotype, glycosylation, and activity. We will perform pseudotype assays on
whole repertoires and individual antibody specificities in BSL2 and test for confirmation with neutralization with
collaborators with BSL3 facilities. From these studies we hope to learn how to identify Veterans who are likely
to have a more severe illness and provide clues for developing approaches that could succeed in ameliorating
infection severity and prevent severe disease.
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