Faculty Bibliography

The immune response to COVID-19 booster vaccinations during pregnancy for mothers and their newborns and the functional response of vaccine-induced antibodies against Omicron variants are not well characterized. We conducted a prospective, multicenter cohort study of participants vaccinated during pregnancy with primary or booster mRNA COVID-19 vaccines from July 2021 to January 2022 at 9 academic sites. We determined SARS-CoV-2 binding and live virus and pseudovirus neutralizing antibody (nAb) titers pre- and post-vaccination, and at delivery for both maternal and infant participants. Immune responses to ancestral and Omicron BA.1 SARS-CoV-2 strains were compared between primary and booster vaccine recipients in maternal sera at delivery and in cord blood, after adjusting for days since last vaccination. A total of 240 participants received either Pfizer or Moderna mRNA vaccine during pregnancy (primary 2-dose series: 167; booster dose: 73). Booster vaccination resulted in significantly higher binding and nAb titers, including to the Omicron BA.1 variant, in maternal serum at delivery and in cord blood compared to a primary 2-dose series (range 0.44-0.88 log₁₀ higher, p < 0.0001 for all comparisons). Live virus nAb to Omicron BA.1 were present at delivery in 9 % (GMT ID50 12.7) of Pfizer and 22 % (GMT ID50 14.7) of Moderna primary series recipients, and in 73 % (GMT ID50 60.2) of mRNA boosted participants (p < 0.0001), although titers were significantly lower than to the D614G strain. Transplacental antibody transfer was efficient for all regimens with median transfer ratio range: 1.55-1.77 for IgG, 1.00-1.78 for live virus nAb and 1.79-2.36 for pseudovirus nAb. COVID-19 mRNA vaccination during pregnancy elicited robust immune responses in mothers and efficient transplacental antibody transfer to the newborn. A booster dose during pregnancy significantly increased maternal and cord blood binding and neutralizing antibody levels, including against Omicron BA.1. Findings support the use of a booster dose of COVID-19 vaccine during pregnancy.

BACKGROUND:Hepatitis C virus (HCV) treatment can effectively cure HCV among people who inject drugs (PWID). Perspectives of PWID treated in innovative models can reveal program features that address barriers to treatment, and guide implementation of similar models. METHODS:We interviewed 29 participants in the intervention arm of a randomized trial. The trial enrolled PWID with HCV in New York City from 2017 to 2020 and tested the effectiveness of a low-threshold HCV treatment model at a syringe services program. Participants were purposively sampled and interviewed in English or Spanish. The interview guide focused on prior experiences with HCV testing and treatment, and experiences during the trial. Interviews were inductively coded and analyzed using thematic analysis. RESULTS:Before enrollment, participants reported being tested for HCV in settings such as prison, drug treatment, and emergency rooms. Treatment was delayed because of not being seen as urgent by providers. Participants reported low self-efficacy, competing priorities, and systemic barriers to treatment such as insurance, waiting lists, and criminal-legal interactions. Stigma was a major factor. Treatment during the trial was facilitated through respect from staff, which overcame stigma. The flexible care model (allowing walk-ins and missed appointments) helped mitigate logistical barriers. The willingness of the staff to address social determinants of health was highly valued. CONCLUSION:Our findings highlight the need for low-threshold programs with nonjudgmental behavior from program staff, and flexibility to adapt to participants' needs. Social determinants of health remain a significant barrier, but programs' efforts to address these factors can engender trust and facilitate treatment. Trial registration NCT03214679.

As part of a multicenter study evaluating homologous and heterologous COVID-19 booster vaccines, we assessed the magnitude, breadth, and short-term durability of binding and pseudovirus-neutralizing antibody (PsVNA) responses following a single booster dose of NVX-CoV2373 in adults primed with either Ad26.COV2.S, mRNA-1273, or BNT162b2 vaccines. NVX-CoV2373 as a heterologous booster was immunogenic and associated with no safety concerns through Day 91. Fold-rises in PsVNA titers from baseline (Day 1) to Day 29 were highest for prototypic D614G variant and lowest for more recent Omicron sub-lineages BQ.1.1 and XBB.1. Peak humoral responses against all SARS-CoV-2 variants were lower in those primed with Ad26.COV2.S than with mRNA vaccines. Prior SARS CoV-2 infection was associated with substantially higher baseline PsVNA titers, which remained elevated relative to previously uninfected participants through Day 91. These data support the use of heterologous protein-based booster vaccines as an acceptable alternative to mRNA or adenoviral-based COVID-19 booster vaccines. This trial was conducted under ClinicalTrials.gov: NCT04889209.

High error rates of viral RNA-dependent RNA polymerases lead to diverse intra-host viral populations during infection. Errors made during replication that are not strongly deleterious to the virus can lead to the generation of minority variants. However, accurate detection of minority variants in viral sequence data is complicated by errors introduced during sample preparation and data analysis. We used synthetic RNA controls and simulated data to test seven variant-calling tools across a range of allele frequencies and simulated coverages. We show that choice of variant caller and use of replicate sequencing have the most significant impact on single-nucleotide variant (SNV) discovery and demonstrate how both allele frequency and coverage thresholds impact both false discovery and false-negative rates. When replicates are not available, using a combination of multiple callers with more stringent cutoffs is recommended. We use these parameters to find minority variants in sequencing data from SARS-CoV-2 clinical specimens and provide guidance for studies of intra-host viral diversity using either single replicate data or data from technical replicates. Our study provides a framework for rigorous assessment of technical factors that impact SNV identification in viral samples and establishes heuristics that will inform and improve future studies of intra-host variation, viral diversity, and viral evolution. IMPORTANCE When viruses replicate inside a host cell, the virus replication machinery makes mistakes. Over time, these mistakes create mutations that result in a diverse population of viruses inside the host. Mutations that are neither lethal to the virus nor strongly beneficial can lead to minority variants that are minor members of the virus population. However, preparing samples for sequencing can also introduce errors that resemble minority variants, resulting in the inclusion of false-positive data if not filtered correctly. In this study, we aimed to determine the best methods for identification and quantification of these minority variants by testing the performance of seven commonly used variant-calling tools. We used simulated and synthetic data to test their performance against a true set of variants and then used these studies to inform variant identification in data from SARS-CoV-2 clinical specimens. Together, analyses of our data provide extensive guidance for future studies of viral diversity and evolution.

COVID-19 vaccines were developed at unparalleled speed, but racial disparities persist in vaccine uptake. This is a cross-sectional survey that was conducted in mid-2021 in ambulatory clinics across Brooklyn, New York. The objectives of the study were to assess: knowledge of COVID-19, healthcare communication and access, attitudes including trust in the process of vaccine development and mistrust due to racial discrimination, and to determine the relationship of the above to vaccine receipt. 58 respondents self-identified as Black non-Hispanic and completed the survey: the majority were women (79%), <50 years old (65%), employed (66%), and had annual household income <$75,000 (59%). The majority reported having some health insurance (97%) and a regular place of healthcare (95%). 60% of respondents reported COVID-19 vaccination receipt. A significant percentage of the vaccinated group compared to the unvaccinated group scored higher on knowledge questions (91% vs. 65%; p = 0.018), felt it was important that others in the community get vaccinated (89% vs. 65%, p = 0.04), and trusted vaccine safety (86% vs. 35%; p < 0.0001) and effectiveness (88% vs. 48%; p < 0.001). The unvaccinated group reported a lower annual household income of <$75,000 (72% vs. 50%; p = 0.0002) and also differed by employment status (p = 0.04). Majority in both groups agreed that racial discrimination interferes with healthcare (78%). In summary, unvaccinated Black non-Hispanic respondents report significant concerns about vaccine safety and efficacy and have greater mistrust in the vaccine development process. The relationship between racial discrimination, mistrust, and vaccine hesitancy needs further study in order to improve vaccine uptake in this population.

The Infectious Diseases Society of America (IDSA) has set clear priorities in recent years to promote inclusion, diversity, access, and equity (IDA&E) in infectious disease (ID) clinical practice, medical education, and research. The IDSA IDA&E Task Force was launched in 2018 to ensure implementation of these principles. The IDSA Training Program Directors Committee met in 2021 and discussed IDA&E best practices as they pertain to the education of ID fellows. Committee members sought to develop specific goals and strategies related to recruitment, clinical training, didactics, and faculty development. This article represents a presentation of ideas brought forth at the meeting in those spheres and is meant to serve as a reference document for ID training program directors seeking guidance in this area.

UNLABELLED:Adaptive immune responses are induced by vaccination and infection, yet little is known about how CD4+ T cell memory differs between these two contexts. Notable differences in humoral and cellular immune responses to primary mRNA vaccination were observed and associated with prior COVID-19 history, including in the establishment and recall of Spike-specific CD4+ T cells. It was unclear whether CD4+ T cell memory established by infection or mRNA vaccination as the first exposure to Spike was qualitatively similar. To assess whether the mechanism of initial memory T cell priming affected subsequent responses to Spike protein, 14 people who were receiving a third mRNA vaccination, referenced here as the booster, were stratified based on whether the first exposure to Spike protein was by viral infection or immunization (infection-primed or vaccine-primed). Using multimodal scRNA-seq of activation-induced marker (AIM)-reactive Spike-specific CD4+ T cells, we identified 220 differentially expressed genes between infection- and vaccine-primed patients at the post-booster time point. Infection-primed participants had greater expression of genes related to cytotoxicity and interferon signaling. Gene set enrichment analysis (GSEA) revealed enrichment for Interferon Alpha, Interferon Gamma, and Inflammatory response gene sets in Spike-specific CD4+ T cells from infection-primed individuals, whereas Spike-specific CD4+ T cells from vaccine-primed individuals had strong enrichment for proliferative pathways by GSEA. Finally, SARS-CoV-2 breakthrough infection in vaccine-primed participants resulted in subtle changes in the transcriptional landscape of Spike-specific memory CD4+ T cells relative to pre-breakthrough samples but did not recapitulate the transcriptional profile of infection-primed Spike-specific CD4+ T cells. Together, these data suggest that CD4+ T cell memory is durably imprinted by the inflammatory context of SARS-CoV-2 infection, which has implications for personalization of vaccination based on prior infection history. ONE SENTENCE SUMMARY/UNASSIGNED:SARS-CoV-2 infection and mRNA vaccination prime transcriptionally distinct CD4+ T cell memory landscapes which are sustained with subsequent doses of vaccine.

BACKGROUND:People who inject drugs are at increased risk for several bacterial infections such as bacteremia, endocarditis, and osteomyelitis resulting in severe morbidity and high care costs. Limited data exist surrounding the injection drug use practices and behaviors that may increase the risk of these infections. METHODS:Individuals admitted to a single hospital in New York City with severe bacterial infection, between August 2020 and June 2021, were recruited to partake in an in-depth survey examining potential factors, both demographic and injection drug use behavioral, associated with severe bacterial infections. RESULTS:Thirty-four participants were recruited with injection drug use-associated severe bacterial infection. The mean age was 36.5 years; 21 (62%) were currently homeless, with 19 (56%) patients admitted for infective endocarditis. The mean length of hospital stay of all participants was 32.2 days; 94% received medication for opioid use disorder while admitted, whereas 35% left before treatment completion with a patient-directed discharge or elopement. Eight-two percent of participants were injected daily in the prior 30 days, with an average of 276 injections per participant. Fifty percent of participants reported requiring multiple sticks per injection event "always" or "very often," with 94% reporting reuse of syringes in the prior month. CONCLUSIONS:Severe bacterial infections in people who inject drugs resulted in prolonged and complex hospitalization that culminate in suboptimal outcomes despite aggressive measures to engage patients in medication for opioid use disorder. Numerous nonsterile injection drug use practices were identified, indicating a gap in current infection prevention harm reduction messaging.

BACKGROUND:Lower respiratory tract infections are frequently treated with antibiotics, despite a viral cause in many cases. It remains unknown whether low procalcitonin concentrations can identify patients with lower respiratory tract infection who are unlikely to benefit from antibiotics. We aimed to compare the efficacy and safety of azithromycin versus placebo to treat lower respiratory tract infections in patients with low procalcitonin. METHODS:We conducted a randomised, placebo-controlled, double-blind, non-inferiority trial at five health centres in the USA. Adults aged 18 years or older with clinically suspected non-pneumonia lower respiratory tract infection and symptom duration from 24 h to 28 days were eligible for enrolment. Participants with a procalcitonin concentration of 0·25 ng/mL or less were randomly assigned (1:1), in blocks of four with stratification by site, to receive over-encapsulated oral azithromycin 250 mg or matching placebo (two capsules on day 1 followed by one capsule daily for 4 days). Participants, non-study clinical providers, investigators, and study coordinators were masked to treatment allocation. The primary outcome was efficacy of azithromycin versus placebo in terms of clinical improvement at day 5 in the intention-to-treat population. The non-inferiority margin was -12·5%. Solicited adverse events (abdominal pain, vomiting, diarrhoea, allergic reaction, or yeast infections) were recorded as a secondary outcome. This trial is registered with ClinicalTrials.gov, NCT03341273. FINDINGS/RESULTS:Between Dec 8, 2017, and March 9, 2020, 691 patients were assessed for eligibility and 499 were enrolled and randomly assigned to receive azithromycin (n=249) or placebo (n=250). Clinical improvement at day 5 was observed in 148 (63%, 95% CI 54 to 71) of 238 participants with full data in the placebo group and 155 (69%, 61 to 77) of 227 participants with full data in the azithromycin group in the intention-to-treat analysis (between-group difference -6%, 95% CI -15 to 2). The 95% CI for the difference did not meet the non-inferiority margin. Solicited adverse events and the severity of solicited adverse events were not significantly different between groups at day 5, except for increased abdominal pain associated with azithromycin (47 [23%, 95% CI 18 to 29] of 204 participants) compared with placebo (35 [16%, 12 to 21] of 221; between-group difference -7% [95% CI -15 to 0]; p=0·066). INTERPRETATION/CONCLUSIONS:Placebo was not non-inferior to azithromycin in terms of clinical improvement at day 5 in adults with lower respiratory tract infection and a low procalcitonin concentration. After accounting for both the rates of clinical improvement and solicited adverse events at day 5, it is unclear whether antibiotics are indicated for patients with lower respiratory tract infection and a low procalcitonin concentration. FUNDING/BACKGROUND:National Institute of Allergy and Infectious Diseases, bioMérieux.

While effective at preventing Zaire ebolavirus (ZEBOV) disease, cellular immunity to ZEBOV and vector-directed immunity elicited by the recombinant vesicular stomatitis virus expressing ZEBOV glycoprotein (rVSVΔG-ZEBOV-GP) vaccine remain poorly understood. Sera and peripheral blood mononuclear cells were collected from 32 participants enrolled in a prospective multicenter study [ClinicalTrials.gov NCT02788227] before vaccination and up to six months post-vaccination. IgM and IgG antibodies, IgG-producing memory B cells (MBCs), and T cell reactivity to ZEBOV glycoprotein (ZEBOV-GP), vesicular stomatitis virus-Indiana strain (VSV-I) matrix (M) protein, and VSV-I nucleoprotein (NP) were measured using ELISA, ELISpot, and flow cytometry, respectively. 11/32 (34.4%) participants previously received a different investigational ZEBOV vaccine prior to enrollment and 21/32 (65.6%) participants were ZEBOV vaccine naïve. Both ZEBOV vaccine naïve and experienced participants had increased ZEBOV-GP IgG optical densities (ODs) post-rVSVΔG-ZEBOV-GP vaccination while only ZEBOV vaccine naïve participants had increased ZEBOV-GP IgM ODs. Transient IgM and IgG antibody responses to VSV-I M protein and NP were observed in a minority of participants. All participants had detectable ZEBOV-GP specific IgG-producing MBCs by 6 months post-vaccination while no changes were observed in the median IgG-producing MBCs to VSV-I proteins. T cell responses to ZEBOV-GP differed between ZEBOV vaccine experienced and ZEBOV vaccine naïve participants. T cell responses to both VSV-I M protein and VSV-I NP were observed, but were of a low magnitude. The rVSVΔG-ZEBOV-GP vaccine elicits robust humoral and memory B cell responses to ZEBOV glycoprotein in both ZEBOV vaccine naïve and experienced individuals and can generate vector-directed T cell immunity. Further research is needed to understand the significance of pre-existing vector and target antigen immunity on responses to booster doses of rVSVΔG-ZEBOV-GP and other rVSV-vectored vaccines.