Publications

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.

Long COVID (LC) involves a spectrum of chronic symptoms after acute severe acute respiratory syndrome coronavirus 2 infection. Current hypotheses for the pathogenesis of LC include persistent virus, tissue damage, autoimmunity, endocrine insufficiency, immune dysfunction and complement activation. We performed immunological, virological, transcriptomic and proteomic analyses from a cohort of 142 individuals between 2020 and 2021, including uninfected controls (n = 35), acutely infected individuals (n = 54), convalescent controls (n = 24) and patients with LC (n = 28). The LC group was characterized by persistent immune activation and proinflammatory responses for more than 180 days after initial infection compared with convalescent controls, including upregulation of JAK-STAT, interleukin-6, complement, metabolism and T cell exhaustion pathways. Similar findings were observed in a second cohort enrolled between 2023 and 2024, including convalescent controls (n = 20) and patients with LC (n = 18). These data suggest that LC is characterized by persistent activation of chronic inflammatory pathways, suggesting new therapeutic targets and potential biomarkers of disease.

IMPORTANCE: The US Preventive Services Task Force (USPSTF) guidelines on preeclampsia risk assessment and aspirin prophylaxis (AP) have not been evaluated for clinical utility.

OBJECTIVE: To evaluate which characteristics in the USPSTF guidelines identify risk status and the association of preeclampsia risk with AP recommendations.

DESIGN, SETTING, AND PARTICIPANTS: This observational cohort study enrolled from July 2020 to March 2023 with data analysis performed from October to December 2024. Enrollment occurred at 11 centers throughout the US or via direct-to-participant recruitment. Pregnant participants aged 18 years or older with a singleton pregnancy less than 22 weeks' gestation were selected via convenience sampling.

EXPOSURE: The exposures were clinical factors abstracted from medical records by research coordinators, which were stratified according to USPSTF definitions of low, moderate (parity, advanced maternal age [AMA], race, and body mass index), and high (chronic hypertension, prior preeclampsia, type 1 or 2 diabetes, kidney disease, and/or autoimmune conditions) risk.

MAIN OUTCOMES AND MEASURES: Data collected included AP recommendation, presence of USPSTF-defined moderate risk factors or high risk factors, and any preeclampsia diagnosis. Effect sizes and relative risk (RR) were calculated within risk strata.

RESULTS: Of 5684 participants (median [IQR] age, 30.9 [26.4-34.6] years; 267 [4.1%] Asian; 1191 [21.0%] Black; 990 Hispanic [17.4%]; 2764 [48.6%] White; and 472 [8.3%] with other race or ethnicity), 5046 (88.8%) were at increased risk of preeclampsia (3996 [70.3%] at moderate risk and 1050 [18.5%] at high risk). A total of 2438 participants (43.1%) received an AP recommendation. The overall preeclampsia rate was 12.1% (685 participants). The PE rates specific to USPSTF categories were 3.0% for those at low risk (19 of 638 participants), 10.5% for those at moderate risk (419 of 3996 patients), and 23.5% for those at high risk (247 of 1050 participants). Among individuals with 2 or more moderate risk factors but without any high risk factor, nulliparity was associated with significantly increased risk of preeclampsia (RR, 1.48; 95% CI, 1.35-1.62; P < .001), while AMA was associated with decreased risk (RR, 0.79; 95% CI, 0.65-0.96; P = .02); there was no association with obesity (RR, 1.11; 95% CI, 1.01-1.22; P = .048) or Black race (RR, 0.95; 95% CI, 0.80-1.14; P = .63). Of 1044 participants with any high risk factors, 856 (82.0%) were recommended AP and of 634 at low risk, 538 (85.9%) were not recommended AP. In contrast, of 1942 participants with 1 moderate risk factor, 463 (23.8%) were recommended AP, and of 2032 with 2 or more moderate risk factors, 1024 (50.4%) were recommended AP.

CONCLUSIONS AND RELEVANCE: In this prospective cohort study of 5684 singleton pregnancies, 89% of the population was assessed as having increased risk (moderate or high) of preeclampsia by USPSTF criteria. These findings suggest that moderate risk factors in the absence of high risk factors show no or low value for estimating the risk of developing preeclampsia, leading to nonspecific recommendations of AP in the moderate risk category.

Messenger RNA (mRNA) vaccines were highly effective against the ancestral SARS-CoV-2 strain, but the efficacy of bivalent mRNA boosters against XBB variants was substantially lower. Here, we show limited durability of neutralizing antibody (NAb) responses against XBB variants and isotype switching to immunoglobulin G4 (IgG4) responses following bivalent mRNA boosting. Bivalent mRNA boosting elicited modest XBB.1-, XBB.1.5-, and XBB.1.16-specific NAbs that waned rapidly within 3 months. In contrast, bivalent mRNA boosting induced more robust and sustained NAbs against the ancestral WA1/2020 strain, suggesting immune imprinting. Following bivalent mRNA boosting, serum antibody responses were primarily IgG2 and IgG4 responses with poor Fc functional activity. In contrast, a third monovalent mRNA immunization boosted all isotypes including IgG1 and IgG3 with robust Fc functional activity. These data show substantial immune imprinting for the ancestral spike and isotype switching to IgG4 responses following bivalent mRNA boosting, with important implications for future booster designs and boosting strategies.

The COVID-19 Biorepository at Beth Israel Deaconess Medical Center in Boston was initiated in 2020 to address questions about COVID-19 infection and vaccination in a time of urgent need. From April 2020 through July 2024, we enrolled 1018 participants and collected thousands of biospecimens. We enrolled participants from the general population as well as from specific populations that were not well represented in clinical trials, including immunosuppressed, pregnant, and lactating individuals. Our observational study was designed to accommodate the rapidly changing landscape of the pandemic, including the introduction of new vaccines and boosters, breakthrough infections, and emerging variants. Reflecting on the past four years of this experience, we believe that teamwork, collaboration, and flexibility were key factors for the success of this effort, which generated data in real time about COVID-19 vaccine responses in multiple populations, hybrid immunity following breakthrough infections, immune evasion of emerging variants, and immune imprinting following booster immunizations. Rapid dissemination of data through preprints, peer-reviewed publications, and public communications allowed for the real time use of our findings to address public health issues and to inform vaccine policies. The dedication of the study participants, clinical investigators, and laboratory investigators made this research program possible.