Mucosal Adenoviral-vectored Vaccine Boosting Durably Prevents XBB.1.16 Infection in Nonhuman Primates.

Waning immunity and continued virus evolution have limited the durability of protection from symptomatic infection mediated by intramuscularly (IM)-delivered mRNA vaccines against COVID-19 although protection from severe disease remains high. Mucosal vaccination has been proposed as a strategy to increase protection at the site of SARS-CoV-2 infection by enhancing airway immunity, potentially reducing rates of infection and transmission. Here, we compared protection against XBB.1.16 virus challenge 5 months following IM or mucosal boosting in non-human primates (NHP) that had previously received a two-dose mRNA-1273 primary vaccine regimen. The mucosal boost was composed of a bivalent chimpanzee adenoviral-vectored vaccine encoding for both SARS-CoV-2 WA1 and BA.5 spike proteins (ChAd-SARS-CoV-2-S) and delivered either by an intranasal mist or an inhaled aerosol. An additional group of animals was boosted by the IM route with bivalent WA1/BA.5 spike-matched mRNA (mRNA-1273.222) as a benchmark control. NHP were challenged in the upper and lower airways 18 weeks after boosting with XBB.1.16, a heterologous Omicron lineage strain. Cohorts boosted with ChAd-SARS-CoV-2-S by an aerosolized or intranasal route had low to undetectable virus replication as assessed by levels of subgenomic SARS-CoV-2 RNA in the lungs and nose, respectively. In contrast, animals that received the mRNA-1273.222 boost by the IM route showed minimal protection against virus replication in the upper airway but substantial reduction of virus RNA levels in the lower airway. Immune analysis showed that the mucosal vaccines elicited more durable antibody and T cell responses than the IM vaccine. Protection elicited by the aerosolized vaccine was associated with mucosal IgG and IgA responses, whereas protection elicited by intranasal delivery was mediated primarily by mucosal IgA. Thus, durable immunity and effective protection against a highly transmissible heterologous variant in both the upper and lower airways can be achieved by mucosal delivery of a virus-vectored vaccine. Our study provides a template for the development of mucosal vaccines that limit infection and transmission against respiratory pathogens.

Deep Phenotyping of Neurologic Postacute Sequelae of SARS-CoV-2 Infection.

BACKGROUND AND OBJECTIVES: SARS-CoV-2 infection has been associated with a syndrome of long-term neurologic sequelae that is poorly characterized. We aimed to describe and characterize in-depth features of neurologic postacute sequelae of SARS-CoV-2 infection (neuro-PASC). METHODS: Between October 2020 and April 2021, 12 participants were seen at the NIH Clinical Center under an observational study to characterize ongoing neurologic abnormalities after SARS-CoV-2 infection. Autonomic function and CSF immunophenotypic analysis were compared with healthy volunteers (HVs) without prior SARS-CoV-2 infection tested using the same methodology. RESULTS: Participants were mostly female (83%), with a mean age of 45 ± 11 years. The median time of evaluation was 9 months after COVID-19 (range 3-12 months), and most (11/12, 92%) had a history of only a mild infection. The most common neuro-PASC symptoms were cognitive difficulties and fatigue, and there was evidence for mild cognitive impairment in half of the patients (MoCA score <26). The majority (83%) had a very disabling disease, with Karnofsky Performance Status ≤80. Smell testing demonstrated different degrees of microsmia in 8 participants (66%). Brain MRI scans were normal, except 1 patient with bilateral olfactory bulb hypoplasia that was likely congenital. CSF analysis showed evidence of unique intrathecal oligoclonal bands in 3 cases (25%). Immunophenotyping of CSF compared with HVs showed that patients with neuro-PASC had lower frequencies of effector memory phenotype both for CD4+ T cells (p < 0.0001) and for CD8+ T cells (p = 0.002), an increased frequency of antibody-secreting B cells (p = 0.009), and increased frequency of cells expressing immune checkpoint molecules. On autonomic testing, there was evidence for decreased baroreflex-cardiovagal gain (p = 0.009) and an increased peripheral resistance during tilt-table testing (p < 0.0001) compared with HVs, without excessive plasma catecholamine responses. DISCUSSION: CSF immune dysregulation and neurocirculatory abnormalities after SARS-CoV-2 infection in the setting of disabling neuro-PASC call for further evaluation to confirm these changes and explore immunomodulatory treatments in the context of clinical trials.

Kinetics of the Antibody Response to Symptomatic SARS-CoV-2 Infection in Vaccinated and Unvaccinated Individuals in the Blinded Phase of the mRNA-1273 COVID-19 Vaccine Efficacy Trial.

Background: Hybrid immunity is associated with more durable protection against coronavirus disease 2019 (COVID-19). We describe the antibody responses following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vaccinated and unvaccinated individuals. Methods: The 55 vaccine arm COVID-19 cases diagnosed during the blinded phase of the Coronavirus Efficacy trial were matched with 55 placebo arm COVID-19 cases. Pseudovirus neutralizing antibody (nAb) activity to the ancestral strain and binding antibody (bAb) responses to nucleocapsid and spike antigens (ancestral and variants of concern [VOCs]) were assessed on disease day 1 (DD1) and 28 days later (DD29). Results: The primary analysis set was 46 vaccine cases and 49 placebo cases with COVID-19 at least 57 days post-first dose. For vaccine group cases, there was a 1.88-fold rise in ancestral antispike bAbs 1 month post-disease onset, although 47% had no increase. The vaccine-to-placebo geometric mean ratios for DD29 antispike and antinucleocapsid bAbs were 6.9 and 0.04, respectively. DD29 mean bAb levels were higher for vaccine vs placebo cases for all VOCs. DD1 nasal viral load positively correlated with bAb levels in the vaccine group. Conclusions: Following COVID-19, vaccinated participants had higher levels and greater breadth of antispike bAbs and higher nAb titers than unvaccinated participants. These were largely attributable to the primary immunization series.

Clinical outcomes and immune responses to SARS-CoV-2 vaccination in severe aplastic anaemia.

Patients with severe aplastic anaemia (SAA) are often not vaccinated against viruses due to concerns of ineffective protective antibody response and potential for pathogenic global immune system activation, leading to relapse. We evaluated the impact of COVID-19 vaccination on haematological indices and disease status and characterized the humoural and cellular responses to vaccination in 50 SAA patients, who were previously treated with immunosuppressive therapy (IST). There was no significant difference in haemoglobin (p = 0.52), platelet count (p = 0.67), absolute lymphocyte (p = 0.42) and neutrophil (p = 0.98) counts prior to and after completion of vaccination series. Relapse after vaccination, defined as a progressive decline in counts requiring treatment, occurred in three patients (6%). Humoural response was detectable in 90% (28/31) of cases by reduction in an in-vitro Angiotensin II Converting Enzyme (ACE2) binding and neutralization assay, even in patients receiving ciclosporin (10/11, 90.1%). Comparison of spike-specific T-cell responses in 27 SAA patients and 10 control subjects revealed qualitatively similar CD4+ Th1-dominant responses to vaccination. There was no difference in CD4+ (p = 0.77) or CD8+ (p = 0.74) T-cell responses between patients on or off ciclosporin therapy at the time of vaccination. Our data highlight appropriate humoural and cellular responses in SAA previously treated with IST and true relapse after vaccination is rare.

mRNA-1273 or mRNA-Omicron boost in vaccinated macaques elicits similar B cell expansion, neutralizing responses, and protection from Omicron.

SARS-CoV-2 Omicron is highly transmissible and has substantial resistance to neutralization following immunization with ancestral spike-matched vaccines. It is unclear whether boosting with Omicron-matched vaccines would enhance protection. Here, nonhuman primates that received mRNA-1273 at weeks 0 and 4 were boosted at week 41 with mRNA-1273 or mRNA-Omicron. Neutralizing titers against D614G were 4,760 and 270 reciprocal ID50 at week 6 (peak) and week 41 (preboost), respectively, and 320 and 110 for Omicron. 2 weeks after the boost, titers against D614G and Omicron increased to 5,360 and 2,980 for mRNA-1273 boost and 2,670 and 1,930 for mRNA-Omicron, respectively. Similar increases against BA.2 were observed. Following either boost, 70%-80% of spike-specific B cells were cross-reactive against WA1 and Omicron. Equivalent control of virus replication in lower airways was observed following Omicron challenge 1 month after either boost. These data show that mRNA-1273 and mRNA-Omicron elicit comparable immunity and protection shortly after the boost.

Visual, cognitive, and language assessments at 39 months: a follow-up study of children fed formulas containing long-chain polyunsaturated fatty acids to 1 year of age

Objective. Docosahexaenoic acid (DHA)and arachidonic acid (ARA) are long-chain polyunsaturated fatty acids found in breast milk and recently added to infant formulas...

Diversion of controlled substances: a catalyst for change.

A quality improvement team was formed in response to a controlled substance diversion by an employee. The team's objectives were to track controlled substances throughout the institution and to design a system that would eliminate inappropriate access to controlled substances without negatively affecting patient care. The team utilized flow charts, staff interviews, and auditing tools to identify weaknesses within the current system. Subcommittees were formed to evaluate access and to develop an education campaign. It is the institution's responsibility to keep patients and staff safe by designing, implementing, and monitoring systems to appropriately control access to controlled substances.

Visual, cognitive, and language assessments at 39 months: a follow-up study of children fed formulas containing long-chain polyunsaturated fatty acids to 1 year of age.

OBJECTIVE: Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are long-chain polyunsaturated fatty acids found in breast milk and recently added to infant formulas. Their importance in infant nutrition was recognized by the rapid accretion of these fatty acids in the brain during the first postnatal year, reports of enhanced intellectual development in breastfed children, and recognition of the physiologic importance of DHA in visual and neural systems from studies in animal models. These considerations led to clinical trials to evaluate whether infant formulas that are supplemented with DHA or both DHA and ARA would enhance visual and cognitive development or whether conversion of linoleic acid and alpha-linolenic acid, the essential fatty acid precursors of ARA and DHA, respectively, at the levels found in infant formulas is sufficient to support adequately visual and cognitive development. Visual and cognitive development were not different with supplementation in some studies, whereas other studies reported benefits of adding DHA or both DHA and ARA to formula. One of the first trials with term infants that were fed formula supplemented with DHA or both DHA and ARA evaluated growth, visual acuity (Visual Evoked Potential; Acuity Card Procedure), mental and motor development (Bayley Scales of Infant Development), and early language development (MacArthur Communicative Developmental Inventories). Growth, visual acuity, and mental and motor development were not different among the 3 formula groups or between the breastfed and formula-fed infants in the first year of life. At 14 months of age, infants who were fed the formula with DHA but no ARA had lower vocabulary production and comprehension scores than infants who were fed the unsupplemented control formula or who were breastfed, respectively. The present follow-up study evaluated IQ, receptive and expressive vocabulary, visual-motor function, and visual acuity of children from the original trial when they reached 39 months of age. METHODS: Infants were randomized within 1 week after birth and fed a control formula (n = 65), one containing DHA (n = 65), or one containing both ARA and DHA (n = 66) to 1 year of age. A comparison group (n = 80) was exclusively breastfed for at least 3 months after which the infants continued to be exclusively breastfed or were supplemented with and/or weaned to infant formula. At 39 months, standard tests of IQ (Stanford Binet IQ), receptive vocabulary (Peabody Picture Vocabulary Test-Revised), expressive vocabulary (mean length of utterance), visual-motor function (Beery Visual-Motor Index), and visual acuity (Acuity Card Procedure) were administered. Growth, red blood cell fatty acid levels, and morbidity also were evaluated. RESULTS: Results were analyzed using analysis of variance or linear regression models. The regression model for IQ, receptive and expressive language, and the visual-motor index controlled for site, birth weight, sex, maternal education, maternal age, and the child's age at testing. The regression model for visual acuity controlled for site only. A variable selection model also identified which of 22 potentially prognostic variables among different categories (feeding groups, the child and family demographics, indicators of illness since birth, and environment) were most influential for IQ and expressive vocabulary. A total of 157 (80%) of the 197 infants studied at 12 months participated in this follow-up study. Characteristics of the families were representative of US families with children up to 5 years of age, and there were no differences in the demographic or family characteristics among the randomized formula groups. As expected, the formula and breastfed groups differed in ethnicity, marital status, parental education, and the prevalence of smoking. Sex, ethnicity, gestational age at birth, and birth weight for those who participated at 39 months did not differ from those who did not. The 12-month Bayley mental and motor scores and 14-month vocabulary scores of the children who participated also were were not different from those who did not. At 39 months, IQ, receptive and expressive language, visual-motor function, and visual acuity were not different among the 3 randomized formula groups or between the breastfed and formula groups. The adjusted means for the control, ARA+DHA, DHA, and breastfed groups were as follows: IQ scores, 104, 101, 100, 106; Peabody Picture Vocabulary Test, 99.2, 97.2, 95.1, 97.4; mean length of utterance, 3.64, 3.75, 3.93, 4.08; the visual-motor index, 2.26, 2.24, 2.05, 2.40; and visual acuity (cycles/degree), 30.4, 27.9, 27.5, 28.6, respectively. IQ was positively associated with female sex and maternal education and negatively associated with the number of siblings and exposure to cigarette smoking in utero and/or postnatally. Expressive language also was positively associated with maternal education and negatively associated with the average hours in child care per week and hospitalizations since birth but only when the breastfed group was included in the analysis. The associations between maternal education and child IQ scores are consistent with previous reports as are the associations between prenatal exposure to cigarette smoke and IQ and early language development. Approximately one third of the variance for IQ was explained by sex, maternal education, the number of siblings, and exposure to cigarette smoke. Growth achievement, red blood cell fatty acid levels, and morbidity did not differ among groups. CONCLUSIONS: We reported previously that infants who were fed an unsupplemented formula or one with DHA or with both DHA and ARA through 12 months or were breastfed showed no differences in mental and motor development, but those who were fed DHA without ARA had lower vocabulary scores on a standardized, parent-report instrument at 14 months of age when compared with infants who were fed the unsupplemented formula or who were breastfed. When the infants were reassessed at 39 months using age-appropriate tests of receptive and expressive language as well as IQ, visual-motor function and visual acuity, no differences among the formula groups or between the formula and breastfed groups were found. The 14-month observation thus may have been a transient effect of DHA (without ARA) supplementation on early vocabulary development or may have occurred by chance. The absence of differences in growth achievement adds to the evidence that DHA with or without ARA supports normal growth in full-term infants. In conclusion, adding both DHA and ARA when supplementing infant formulas with long-chain polyunsaturated fatty acids supports visual and cognitive development through 39 months.