Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:The purpose of this focused review is to discuss unusual presentations of viral infections in the context of specific inborn errors of immunity. We will discuss hyper immunoglobulin E (IgE) syndromes, epidermodysplasia verruciformis, and X-linked agammaglobulinemia as examples of inborn errors of immunity associated with specific presentations of viral infection and disease. RECENT FINDINGS/RESULTS:Advances in both genetic and viral diagnostics have broadened our understanding of viral pathogenesis in the setting of immune dysfunction and the variable phenotype of inborn errors of immunity. Dedicator of cytokinesis 8 (DOCK8) deficiency is now recognized as an inborn error of immunity within the hyper IgE syndrome phenotype and is associated with unusually aggressive cutaneous disease caused by herpes simplex and other viruses. Studies of patients with epidermodysplasia verruciformis have proven that rarely detected human papillomavirus subtypes may cause malignancy in the absence of adequate host defenses. Finally, patients with X-linked agammaglobulinemia may remain at risk for severe and chronic viral infections, even as immune globulin supplementation reduces the risk of bacterial infection. SUMMARY/CONCLUSIONS:Susceptibility to viral infections in patients with inborn errors of immunity is conferred by specific, molecular defects. Recurrent, severe, or otherwise unusual presentations of viral disease should prompt investigation for an underlying genetic defect.

IMPORTANCE:SARS-CoV-2 viral load (VL) in the nasopharynx is difficult to quantify and standardize across settings, but it may inform transmission potential and disease severity. OBJECTIVE:To characterize VL at COVID-19 diagnosis among previously uninfected and unvaccinated individuals by evaluating the association of demographic and clinical characteristics, viral variant, and trial with VL, as well as the ability of VL to predict severe disease. DESIGN, SETTING, AND PARTICIPANTS:This secondary cross-protocol analysis used individual-level data from placebo recipients from 4 harmonized, phase 3 COVID-19 vaccine efficacy trials sponsored by Moderna, AstraZeneca, Janssen, and Novavax. Participants were SARS-CoV-2 negative at baseline and acquired COVID-19 during the blinded phase of the trials. The setting included the US, Brazil, South Africa, Colombia, Argentina, Peru, Chile, and Mexico; start dates were July 27, 2020, to December 27, 2020; data cutoff dates were March 26, 2021, to July 30, 2021. Statistical analysis was performed from November 2022 to June 2023. MAIN OUTCOMES AND MEASURES:Linear regression was used to assess the association of demographic and clinical characteristics, viral variant, and trial with polymerase chain reaction-measured log10 VL in nasal and/or nasopharyngeal swabs taken at the time of COVID-19 diagnosis. RESULTS:Among 1667 participants studied (886 [53.1%] male; 995 [59.7%] enrolled in the US; mean [SD] age, 46.7 [14.7] years; 204 [12.2%] aged 65 years or older; 196 [11.8%] American Indian or Alaska Native, 150 [9%] Black or African American, 1112 [66.7%] White; 762 [45.7%] Hispanic or Latino), median (IQR) log10 VL at diagnosis was 6.18 (4.66-7.12) log10 copies/mL. Participant characteristics and viral variant explained only 5.9% of the variability in VL. The independent factor with the highest observed differences was trial: Janssen participants had 0.54 log10 copies/mL lower mean VL vs Moderna participants (95% CI, 0.20 to 0.87 log10 copies/mL lower). In the Janssen study, which captured the largest number of COVID-19 events and variants and used the most intensive post-COVID surveillance, neither VL at diagnosis nor averaged over days 1 to 28 post diagnosis was associated with COVID-19 severity. CONCLUSIONS AND RELEVANCE:In this study of placebo recipients from 4 randomized phase 3 trials, high variability was observed in SARS-CoV-2 VL at the time of COVID-19 diagnosis, and only a fraction was explained by individual participant characteristics or viral variant. These results suggest challenges for future studies of interventions seeking to influence VL and elevates the importance of standardized methods for specimen collection and viral load quantitation.

BACKGROUND:While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. METHODS:In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7-15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. FINDINGS/RESULTS:Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05-0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01-0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. INTERPRETATION/CONCLUSIONS:Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. FUNDING/BACKGROUND:National Institutes of Health.

IMPORTANCE/UNASSIGNED:Current data identifying COVID-19 risk factors lack standardized outcomes and insufficiently control for confounders. OBJECTIVE/UNASSIGNED:To identify risk factors associated with COVID-19, severe COVID-19, and SARS-CoV-2 infection. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This secondary cross-protocol analysis included 4 multicenter, international, randomized, blinded, placebo-controlled, COVID-19 vaccine efficacy trials with harmonized protocols established by the COVID-19 Prevention Network. Individual-level data from participants randomized to receive placebo within each trial were combined and analyzed. Enrollment began July 2020 and the last data cutoff was in July 2021. Participants included adults in stable health, at risk for SARS-CoV-2, and assigned to the placebo group within each vaccine trial. Data were analyzed from April 2022 to February 2023. EXPOSURES/UNASSIGNED:Comorbid conditions, demographic factors, and SARS-CoV-2 exposure risk at the time of enrollment. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Coprimary outcomes were COVID-19 and severe COVID-19. Multivariate Cox proportional regression models estimated adjusted hazard ratios (aHRs) and 95% CIs for baseline covariates, accounting for trial, region, and calendar time. Secondary outcomes included severe COVID-19 among people with COVID-19, subclinical SARS-CoV-2 infection, and SARS-CoV-2 infection. RESULTS/UNASSIGNED:A total of 57 692 participants (median [range] age, 51 [18-95] years; 11 720 participants [20.3%] aged ≥65 years; 31 058 participants [53.8%] assigned male at birth) were included. The analysis population included 3270 American Indian or Alaska Native participants (5.7%), 7849 Black or African American participants (13.6%), 17 678 Hispanic or Latino participants (30.6%), and 40 745 White participants (70.6%). Annualized incidence was 13.9% (95% CI, 13.3%-14.4%) for COVID-19 and 2.0% (95% CI, 1.8%-2.2%) for severe COVID-19. Factors associated with increased rates of COVID-19 included workplace exposure (high vs low: aHR, 1.35 [95% CI, 1.16-1.58]; medium vs low: aHR, 1.41 [95% CI, 1.21-1.65]; P < .001) and living condition risk (very high vs low risk: aHR, 1.41 [95% CI, 1.21-1.66]; medium vs low risk: aHR, 1.19 [95% CI, 1.08-1.32]; P < .001). Factors associated with decreased rates of COVID-19 included previous SARS-CoV-2 infection (aHR, 0.13 [95% CI, 0.09-0.19]; P < .001), age 65 years or older (aHR vs age <65 years, 0.57 [95% CI, 0.50-0.64]; P < .001) and Black or African American race (aHR vs White race, 0.78 [95% CI, 0.67-0.91]; P = .002). Factors associated with increased rates of severe COVID-19 included race (American Indian or Alaska Native vs White: aHR, 2.61 [95% CI, 1.85-3.69]; multiracial vs White: aHR, 2.19 [95% CI, 1.50-3.20]; P < .001), diabetes (aHR, 1.54 [95% CI, 1.14-2.08]; P = .005) and at least 2 comorbidities (aHR vs none, 1.39 [95% CI, 1.09-1.76]; P = .008). In analyses restricted to participants who contracted COVID-19, increased severe COVID-19 rates were associated with age 65 years or older (aHR vs <65 years, 1.75 [95% CI, 1.32-2.31]; P < .001), race (American Indian or Alaska Native vs White: aHR, 1.98 [95% CI, 1.38-2.83]; Black or African American vs White: aHR, 1.49 [95% CI, 1.03-2.14]; multiracial: aHR, 1.81 [95% CI, 1.21-2.69]; overall P = .001), body mass index (aHR per 1-unit increase, 1.03 [95% CI, 1.01-1.04]; P = .001), and diabetes (aHR, 1.85 [95% CI, 1.37-2.49]; P < .001). Previous SARS-CoV-2 infection was associated with decreased severe COVID-19 rates (aHR, 0.04 [95% CI, 0.01-0.14]; P < .001). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this secondary cross-protocol analysis of 4 randomized clinical trials, exposure and demographic factors had the strongest associations with outcomes; results could inform mitigation strategies for SARS-CoV-2 and viruses with comparable epidemiological characteristics.

BACKGROUND:In 2018-2019, large outbreaks of measles occurred in Israel and in New York City, driven in part by travel of unimmunized children between the 2 communities. METHODS:A retrospective chart review was conducted for children tested for measles (March 2018-September 2019) at NYU Langone Health in New York, NY, and in Ramla subdistrict, Israel. Vaccination records were reviewed to determine vaccination status for measles, mumps, and rubella (MMR) at the time of measles testing and 1-year post-testing. RESULTS:A total of 264 children were tested for measles, and 102 (38.6%) had confirmed measles. Only 20 (19.6%) of measles-positive cases received a full 2-dose course of vitamin A. 82.4% of children with measles were ≥1 year at the time of diagnosis and fully eligible for MMR vaccine. Of the 100 measles-positive cases with available vaccine records, 63 were unvaccinated at testing, and 27 remained unimmunized against MMR 1 year later. At testing, measles-negative children were significantly more likely to have received MMR than measles-positive children (65.4% vs 37%, P < .01). One year later, 70.4% of measles-negative cases and only 57.1% of measles-positive cases had received MMR vaccine (P = .18). CONCLUSIONS:The majority of measles cases occurred in unimmunized children eligible for vaccination, and >25% of children in both measles-positive and -negative groups remained unimmunized for MMR 1-year post-outbreak. Our results suggest the need for novel, longitudinal vaccination strategies and increased awareness of the role of vitamin A.

The raccoon roundworm Baylisascaris procyonis (B. procyonis) may infect humans to cause severe or fatal meningoencephalitis, as well as ocular and visceral larva migrans. Young children are at greater risk for cerebral larva migrans with severe meningoencephalitis, and early empiric therapy may improve outcomes. Familiarity with characteristic brain imaging findings may prompt earlier diagnosis, particularly in the setting of CSF eosinophilia. We report a case of a 19-month-old boy who presented with truncal ataxia and was found to have peripheral and CSF eosinophilia. MRI demonstrated symmetric, confluent T2 hyperintense signal in the cerebral and cerebellar deep white mater, which helped differentiate B. procyonis meningoencephalitis from other infectious and non-infectious causes of eosinophilic meningoencephalitis. Early recognition and treatment of B. procyonis meningoencephalitis are important for improved outcomes, and careful review of neuroimaging can play a critical role in suggesting the diagnosis.

BACKGROUND:The safety and efficacy of the AZD1222 (ChAdOx1 nCoV-19) vaccine in a large, diverse population at increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United States, Chile, and Peru has not been known. METHODS:In this ongoing, double-blind, randomized, placebo-controlled, phase 3 clinical trial, we investigated the safety, vaccine efficacy, and immunogenicity of two doses of AZD1222 as compared with placebo in preventing the onset of symptomatic and severe coronavirus disease 2019 (Covid-19) 15 days or more after the second dose in adults, including older adults, in the United States, Chile, and Peru. RESULTS:A total of 32,451 participants underwent randomization, in a 2:1 ratio, to receive AZD1222 (21,635 participants) or placebo (10,816 participants). AZD1222 was safe, with low incidences of serious and medically attended adverse events and adverse events of special interest; the incidences were similar to those observed in the placebo group. Solicited local and systemic reactions were generally mild or moderate in both groups. Overall estimated vaccine efficacy was 74.0% (95% confidence interval [CI], 65.3 to 80.5; P<0.001) and estimated vaccine efficacy was 83.5% (95% CI, 54.2 to 94.1) in participants 65 years of age or older. High vaccine efficacy was consistent across a range of demographic subgroups. In the fully vaccinated analysis subgroup, no severe or critical symptomatic Covid-19 cases were observed among the 17,662 participants in the AZD1222 group; 8 cases were noted among the 8550 participants in the placebo group (<0.1%). The estimated vaccine efficacy for preventing SARS-CoV-2 infection (nucleocapsid antibody seroconversion) was 64.3% (95% CI, 56.1 to 71.0; P<0.001). SARS-CoV-2 spike protein binding and neutralizing antibodies increased after the first dose and increased further when measured 28 days after the second dose. CONCLUSIONS:AZD1222 was safe and efficacious in preventing symptomatic and severe Covid-19 across diverse populations that included older adults. (Funded by AstraZeneca and others; ClinicalTrials.gov number, NCT04516746.).

Antibody responses among immunocompromised solid organ transplant recipients (SOT) infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) may be diminished compared to the general population and have not been fully characterized. We conducted a cohort study at our transplant center to investigate the rate of seroconversion for SARS-CoV-2 IgG antibodies among SOT recipients who were diagnosed with Coronavirus disease 2019 (COVID-19) and underwent serum SARS-CoV-2 IgG enzyme-linked immunosorbent assay (ELISA) testing. The 61 patients who were included in the final analysis underwent initial SARS-CoV-2 IgG testing at a median of 62 days (Interquartile range 55.0-75.0) from symptom onset. Note that, 51 of 61 patients (83.6%) had positive SARS-CoV-2 IgG results, whereas 10 (16.4%) had negative IgG results. Six (60%) out of 10 seronegative patients underwent serial IgG testing and remained seronegative up to 17 weeks post-diagnosis. Use of belatacept in maintenance immunosuppression was significantly associated with negative IgG antibodies to SARS-CoV-2 both in univariate and multivariate analyses (Odds ratio 0.04, p = .01). In conclusion, the majority of organ transplant recipients with COVID-19 in our study developed SARS-CoV-2 antibodies. Further longitudinal studies of the durability and immunologic role of these IgG responses and the factors associated with lack of seroconversion are needed.