Publications

Antibodies and helper T cells play important roles in SARS-CoV-2 infection and vaccination. We sequenced B- and T-cell receptor repertoires (BCR/TCR) from the blood of 251 infectees, vaccinees, and controls to investigate whether features of these repertoires could predict subjects' SARS-CoV-2 neutralizing antibody titer (NAbs), as measured by enzyme-linked immunosorbent assay (ELISA). We sequenced recombined immunoglobulin heavy-chain (IGH), TCRβ (TRB), and TCRδ (TRD) genes in parallel from all subjects, including select B- and T-cell subsets in most cases, with a focus on their hypervariable CDR3 regions, and correlated this AIRRseq data with demographics and clinical findings from subjects' electronic health records. We found that age affected NAb levels in vaccinees but not infectees. Intriguingly, we found that vaccination and infection are associated with longer non-productively recombined IGHs, suggesting an effect that precedes clonal selection. We found that TRB repertoires' binding capacity to known SARS-CoV-2-specific CD4+ TRBs performs as well as the best hand-tuned approximate or "fuzzy" matching at predicting a protective level of NAbs, while also being more robust to repertoire sample size and not requiring hand-tuning. The overall conclusion from this large, unbiased, clinically well annotated dataset is that B- and T-cell adaptive responses to SARS-CoV-2 infection and vaccination are surprising, subtle, and diffuse. We discuss methodological and statistical challenges faced in attempting to define and quantify such strong-but-diffuse repertoire signatures and present tools and strategies for addressing these challenges.

An open label Phase-1 proof-of-concept study evaluated the safety and immunogenicity of IMNN-101, a DNA vaccine based on an expression plasmid and a synthetic delivery carrier (the PlaCCine vaccine), in healthy human adults previously vaccinated or infected with SARS-CoV-2. Study participants received a single intramuscular dose of 0.5 mg, 1.0 mg, or 2.0 mg of IMNN-101 DNA vaccine (n = 8 participants per group). Mild to moderate reactogenicity events were observed in 67% (16/24) of participants, including tenderness, hardening, pain, redness, swelling, and itching at the injection site, as well as fatigue, muscle aches, headache, and nausea/vomiting. Fourteen grade 1 or 2 treatment-emergent adverse events were reported: none of those attributed to IMNN-101. There were no reports of myocarditis or pericarditis. The immunization with IMNN-101 resulted in an increase in neutralizing antibody (NAb) titers against XBB.1.5 and other circulating variants of SARS-CoV-2, with 2-3-fold increase in NAb titers that were maintained during the 6-month follow up. This first-in-human evaluation of a PlaCCine-based DNA vaccine demonstrates a favorable safety profile and durable humoral immune response. The PlaCCine vaccine is thermostable, does not require a device or virus for delivery, and offers a viable alternative approach to immunization.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to evolve five years after the initial outbreak. Although mRNA vaccines encoding the JN.1 and KP.2 Spike proteins were authorized in fall 2024, it remains unclear whether vaccine updates will be necessary for variants containing antigenically closely related Spike proteins. In this study, we evaluated the immunogenicity of JN.1 and KP.2 mRNA boosters in participants from Germany and the United States, respectively. Both vaccines induced robust and similar neutralizing antibody responses against JN.1, KP.2, and other globally relevant variants such as LP.8.1.1 and NB.1.8.1. These data suggest that updating the vaccine formulation to closely related strains will likely offer only modest additional benefits against currently circulating variants.

Antibodies and helper T cells play important roles in SARS-CoV-2 infection and vaccination. We sequenced B- and T-cell receptor repertoires (BCR/TCR) from the blood of 251 infectees, vaccinees, and controls to investigate whether features of these repertoires could predict subjects' SARS-CoV-2 neutralizing antibody titer (NAbs), as measured by enzyme-linked immunosorbent assay (ELISA). We sequenced recombined immunoglobulin heavy-chain (IGH), TCRβ (TRB), and TCRδ (TRD) genes in parallel from all subjects, including select B- and T-cell subsets in most cases, with a focus on their hypervariable CDR3 regions, and correlated this AIRRseq data with demographics and clinical findings from subjects' electronic health records. We found that age affected NAb levels in vaccinees but not infectees. Intriguingly, we found that vaccination and infection have an effect on non-productively recombined IGHs, suggesting an effect that precedes clonal selection. We found that repertoires' binding capacity to known SARS-CoV-2-specific CD4+ TRBs performs as well as the best hand-tuned approximate or "fuzzy" matching at predicting a protective level of NAbs, while also being more robust to repertoire sample size and not requiring hand-tuning. The overall conclusion from this large, unbiased, clinically well annotated dataset is that B- and T-cell adaptive responses to SARS-CoV-2 infection and vaccination are surprising, subtle, and diffuse. We discuss methodological and statistical challenges faced in attempting to define and quantify such strong-but-diffuse repertoire signatures and present tools and strategies for addressing these challenges.

Borrelia miyamotoi disease (BMD), also known as hard-tick relapsing fever, is an emerging tick-borne illness caused by the bacterium Borrelia miyamotoi. This pathogen is transmitted primarily by Ixodes ticks, also known as deer ticks or black-legged ticks. BMD poses significant public health concerns because of its potential to cause severe hemodynamic and hematologic disturbances, particularly in vulnerable populations such as pregnant individuals. BMD often presents with symptoms like other tick-borne infections, including fever, chills, headache, and muscle aches, but often lacks the characteristic rash seen in Lyme disease and does not typically have a greater-than-24-hour tick attachment period for transmission. A high index of suspicion in the late spring and summer months in the Northern hemisphere is essential for early diagnosis of BMD and treatment to prevent maternal and neonatal morbidity and mortality.

Hypertensive disorders of pregnancy (HDP), including preeclampsia, affect 1 in 6 pregnancies, are major contributors to maternal morbidity and mortality, yet lack precision medicine strategies. Analyzing transcriptomic data from a prospectively-collected diverse cohort (n = 9102), this study reveals distinct RNA subtypes in maternal blood, reclassifying clinical HDP phenotypes like early/late-onset preeclampsia. The placental gene PAPPA2 strongly predicts the most severe forms of preeclampsia in individuals without pre-existing high risk factors, months before symptoms, and its overexpression correlates with earlier delivery in a dose-dependent manner. Further, molecular subtypes characterized by immune genes are upregulated in less severe forms of HDP. These results reclassify HDP clinical phenotypes into two distinct molecular subtypes, placental-associated or immune-associated. Validation performance for placental-associated HDP yields an AUC of 0.88 in the advanced maternal age population without pre-existing high risk factors. Molecular subtypes create new opportunities to apply precision-based medicine in maternal health.