Immunogenicity of quadrivalent meningococcal conjugate vaccine in frequent platelet donors.

Frequent plateletpheresis is associated with severe lymphopenia of uncertain clinical significance. We assessed the functional impact of frequent platelet donations and associated lymphopenia on the response to neoantigens. We conducted a prospective study of 102 platelet donors (HIV uninfected) who were naive to meningococcal vaccination recruited at Brigham and Women's Hospital. One dose of quadrivalent meningococcal conjugate vaccine was administered. Seroresponse was defined as a fourfold increase of serum bactericidal antibody titers and seroprotection was defined as postvaccination titers of ≥1:8, for each of the 4 vaccine antigens (A, C, W, and Y). Mean age of participants was 61 years, 69% were male, and medial number of platelet donations in prior year was 14 (interquartile range, 4-20). Frequent platelet donors had a low CD4 count (14% with ≤200/µL and 34% with ≤350/µL). Seroresponse rates varied from 68% for serogroup Y to 86% for serogroup A and were higher for participants with baseline titers of <1:8. Postvaccination seroprotection rates varied from 76% for serogroup Y to 96% for serogroup A. After adjustments for age, sex, and frequent donations, lower total lymphocyte or lower CD4 counts were not associated with lower responses. These data suggest no impairment by plateletpheresis-associated lymphopenia on response to these neoantigens. This trial was registered at www.clinicaltrials.gov as #NCT04224311.

A Phase 2 Clinical Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of Different Prime-Boost Vaccination Schedules of 2013 and 2017 A(H7N9) Inactivated Influenza Virus Vaccines Administered With and Without AS03 Adjuvant in Healthy US Adults.

INTRODUCTION: A surge of human influenza A(H7N9) cases began in 2016 in China from an antigenically distinct lineage. Data are needed about the safety and immunogenicity of 2013 and 2017 A(H7N9) inactivated influenza vaccines (IIVs) and the effects of AS03 adjuvant, prime-boost interval, and priming effects of 2013 and 2017 A(H7N9) IIVs. METHODS: Healthy adults (n = 180), ages 19-50 years, were enrolled into this partially blinded, randomized, multicenter phase 2 clinical trial. Participants were randomly assigned to 1 of 6 vaccination groups evaluating homologous versus heterologous prime-boost strategies with 2 different boost intervals (21 vs 120 days) and 2 dosages (3.75 or 15 µg of hemagglutinin) administered with or without AS03 adjuvant. Reactogenicity, safety, and immunogenicity measured by hemagglutination inhibition and neutralizing antibody titers were assessed. RESULTS: Two doses of A(H7N9) IIV were well tolerated, and no safety issues were identified. Although most participants had injection site and systemic reactogenicity, these symptoms were mostly mild to moderate in severity; injection site reactogenicity was greater in vaccination groups receiving adjuvant. Immune responses were greater after an adjuvanted second dose, and with a longer interval between prime and boost. The highest hemagglutination inhibition geometric mean titer (95% confidence interval) observed against the 2017 A(H7N9) strain was 133.4 (83.6-212.6) among participants who received homologous, adjuvanted 3.75 µg + AS03/2017 doses with delayed boost interval. CONCLUSIONS: Administering AS03 adjuvant with the second H7N9 IIV dose and extending the boost interval to 4 months resulted in higher peak antibody responses. These observations can broadly inform strategic approaches for pandemic preparedness. Clinical Trials Registration. NCT03589807.

COVID-19 vaccine efficacy in participants with weakened immune systems from four randomized-controlled trials.

BACKGROUND: Although the SARS-CoV-2 vaccines are highly efficacious at preventing severe disease in the general population, current data are lacking regarding vaccine efficacy (VE) for individuals with mild immunocompromising conditions. METHODS: A post-hoc, cross-protocol analysis of participant-level data from the blinded phase of four randomized, placebo-controlled, COVID-19 vaccine phase 3 trials (Moderna, AstraZeneca, Janssen, and Novavax) was performed. We defined a "tempered immune system" (TIS) variable via a consensus panel based on medical history and medications to determine VE against symptomatic and severe COVID-19 cases in TIS participants versus non-TIS (NTIS) individuals starting at 14 days after completion of the primary series through the blinded phase for each of the four trials. An analysis of participants living with well-controlled HIV was conducted using the same methods. RESULTS: 3,852/30,351 (12.7%) Moderna participants, 3,088/29,868 (10.3%) Novavax participants, 3,549/32,380 (11.0%) AstraZeneca participants, and 5,047/43,788 (11.5%) Janssen participants were identified as having a TIS. Most TIS conditions (73.9%) were due to metabolism and nutritional disorders. Vaccination (versus placebo) significantly reduced the likelihood of symptomatic and severe COVID-19 for all participants for each trial. VE was not significantly different for TIS participants vs NTIS for either symptomatic or severe COVID-19 for each trial, nor was VE significantly different in the symptomatic endpoint for participants with HIV. CONCLUSIONS: For individuals with mildly immunocompromising conditions, there is no evidence of differences in VE against symptomatic or severe COVID-19 compared to those with non-tempered immune systems in the four COVID-19 vaccine randomized controlled efficacy trials.

Pediatric Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccines: Perceptions and Attitudes From the Food and Drug Administration Public Commentary.

Authorization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines for children has ushered in a new phase of the immunization campaign to address the pandemic but has been received with mixed responses from parents, children, and opinion leaders. Herein we consider perceptions and attitudes towards pediatric SARS-CoV-2 vaccines from a Food and Drug Administration (FDA) public commentary reflecting more than 63 000 comments.

Coronavirus Disease 2019 Vaccine Trials (and Tribulations): How to Improve the Process of Clinical Trials in a Pandemic.

Vaccine clinical trials have been essential to developing effective severe acute respiratory syndrome coronavirus 2 vaccines. The challenges of supply chain disruptions, infection control, study designs, and participant factors that affect trial procedures are reviewed, with specific solutions to streamline the clinical trial process.

Circulating Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccine Antigen Detected in the Plasma of mRNA-1273 Vaccine Recipients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins were measured in longitudinal plasma samples collected from 13 participants who received two doses of mRNA-1273 vaccine. Eleven of 13 participants showed detectable levels of SARS-CoV-2 protein as early as day 1 after first vaccine injection. Clearance of detectable SARS-CoV-2 protein correlated with production of immunoglobulin G (IgG) and immunoglobulin A (IgA).

Severe Acute Respiratory Syndrome Coronavirus 2 Messenger RNA Vaccines in Allogeneic Hematopoietic Stem Cell Transplant Recipients: Immunogenicity and Reactogenicity.

The severe acute respiratory syndrome coronavirus 2 messenger RNA vaccine-induced humoral response and reactogenicity profile are described in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Findings showed that 75.0% (by Simoa assay) or 80.0% (by Roche assay) of the HSCT cohort had a positive antibody response on series completion, compared with 100% in the healthy cohort.

The Effect of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Mitigation Strategies on Seasonal Respiratory Viruses: A Tale of 2 Large Metropolitan Centers in the United States.

To assess the impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic on seasonal respiratory viruses, absolute case counts and viral reproductive rates from 2019-2020 were compared against previous seasons. Our findings suggest that the public health measures implemented to reduce SARS-CoV-2 transmission significantly reduced the transmission of other respiratory viruses.

Clinical Effectiveness of the Queen Square Intensive Comprehensive Aphasia Service for Patients With Poststroke Aphasia.

Background and Purpose: Poststroke aphasia has a major impact on peoples' quality of life. Speech and language therapy interventions work, especially in high doses, but these doses are rarely achieved outside of research studies. Intensive Comprehensive Aphasia Programs (ICAPs) are an option to deliver high doses of therapy to people with aphasia over a short period of time. Methods: Forty-six people with aphasia in the chronic stage poststroke completed the ICAP over a 3-week period, attending for 15 days and averaging 6 hours of therapy per day. Outcome measures included the Comprehensive Aphasia Test, an impairment-based test of the 4 main domains of language (speaking, writing, auditory comprehension, and reading) which was measured at 3 time points (baseline, immediately posttreatment at 3 weeks and follow-up at 12-week post-ICAP); and, the Communicative Effectiveness Index, a carer-reported measure of functional communication skills collected at baseline and 12 weeks. Results: A 2-way repeated measures multivariate ANOVA was conducted. We found a significant domain-by-time interaction, F=12.7, P<0.0005, indicating that the ICAP improved people with aphasia's language scores across all 4 domains, with the largest gains in speaking (Cohen's d=1.3). All gains were maintained or significantly improved further at 12-week post-ICAP. Importantly, patients' functional communication, as indexed by changes on the Communicative Effectiveness Index, also significantly improved at 12-week post-ICAP, t=5.4, P<0.0005, also with a large effect size (Cohen's d=0.9). Conclusions: People with aphasia who participated in the Queen Square ICAP made large and clinically meaningful gains on both impairment-based and functional measures of language. Gains were sustained and in some cases improved further over the subsequent 12 weeks.

Clinical characteristics and outcomes of toxoplasmosis among transplant recipients at two US academic medical centers.

Toxoplasma gondii can cause severe opportunistic infection in immunocompromised individuals, but diagnosis is often delayed. We conducted a retrospective review of solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients with toxoplasmosis between 2002 and 2018 at two large US academic transplant centers. Patients were identified by ICD-9 or ICD-10 toxoplasmosis codes, positive Toxoplasma polymerase chain reaction test result, or pathologic diagnosis. Data were collected regarding transplant type, time from transplant to toxoplasmosis diagnosis, clinical and radiographic features, and mortality at 30 and 90 days. Twenty patients were identified: 10 HSCT recipients (80% allogeneic HSCT) and 10 SOT recipients (60% deceased donor renal transplants). Rejection among SOT recipients (70%) and graft-versus-host disease (GVHD) prophylaxis among HSCT recipients (50%) were frequent. Median time from transplant to toxoplasmosis diagnosis was longer for SOT than HSCT (1385 vs. 5 days, P-value .002). Clinical manifestations most commonly were encephalitis (65%), respiratory failure (40%), renal failure (40%), and distributive shock (40%). Cohort 30-day mortality was 45%, and 90-day mortality was 55%. Diagnosis was postmortem in 25% of the cohort. Further evaluation of toxoplasmosis screening is needed for noncardiac SOT recipients, HSCT recipients with GVHD, and periods of increased net immunosuppression.

COVID-19 Serology at Population Scale: SARS-CoV-2-Specific Antibody Responses in Saliva.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of an ongoing pandemic that has infected over 36 million and killed over 1 million people. Informed implementation of government public health policies depends on accurate data on SARS-CoV-2 immunity at a population scale. We hypothesized that detection of SARS-CoV-2 salivary antibodies could serve as a noninvasive alternative to serological testing for monitoring of SARS-CoV-2 infection and seropositivity at a population scale. We developed a multiplex SARS-CoV-2 antibody immunoassay based on Luminex technology that comprised 12 CoV antigens, mostly derived from SARS-CoV-2 nucleocapsid (N) and spike (S). Saliva and sera collected from confirmed coronavirus disease 2019 (COVID-19) cases and from the pre-COVID-19 era were tested for IgG, IgA, and IgM to the antigen panel. Matched saliva and serum IgG responses (n = 28) were significantly correlated. The salivary anti-N IgG response resulted in the highest sensitivity (100%), exhibiting a positive response in 24/24 reverse transcription-PCR (RT-PCR)-confirmed COVID-19 cases sampled at >14 days post-symptom onset (DPSO), whereas the salivary anti-receptor binding domain (RBD) IgG response yielded 100% specificity. Temporal kinetics of IgG in saliva were consistent with those observed in blood and indicated that most individuals seroconvert at around 10 DPSO. Algorithms employing a combination of the IgG responses to N and S antigens result in high diagnostic accuracy (100%) by as early as 10 DPSO. These results support the use of saliva-based antibody testing as a noninvasive and scalable alternative to blood-based antibody testing.

Extrahepatic manifestations of hepatitis C infection: navigating CHASM.

This article describes the importance of extrahepatic systemic manifestations of chronic hepatitis C virus (HCV) infection. While most HCV literature focuses on liver injury and fibrosis progression, a spectrum of systemic disease processes, collectively called C hepatitis-associated systemic manifestations (CHASMs), are present in a high proportion of infected persons. These include thyroid disease (Hashimoto's thyroiditis, Graves disease, and thyroid cancer), cardiovascular disease (atherosclerosis, carotid artery disease, and coronary artery disease), renal disease (MPGN and glomerulosclerosis), eye disease (Mooren's ulcers and sicca syndrome), skin disease (PCT, vasculitis, and lichen planus), lymphomas (NHL and splenic T-cell), and diabetes. Mechanistic understanding of how HCV leads to CHASM processes could lead to development of new interventions. The role of early HCV treatment and cure may result in preventive strategies for a variety of complex disease states. Key Points • Systemic extrahepatic complications of HCV comprise a spectrum of disease states in many organs and systems.• Effective treatment of HCV may reduce or eliminate some but not all of these systemic complications.• Further research into early treatment intervention as a prevention strategy for systemic disease is warranted.

Treatment of hepatitis C: a systematic review.

IMPORTANCE: Hepatitis C virus (HCV) infects more than 185 million individuals worldwide. Twenty percent of patients chronically infected with HCV progress to cirrhosis. New, simpler therapeutics using direct-acting antivirals that target various stages of the HCV life cycle are in development to eradicate HCV without concomitant interferon. OBJECTIVES: To summarize published evidence on safety, efficacy (measured by a sustained virologic response [SVR], which is the treatment goal of undetectable plasma HCV RNA 12 or 24 weeks after therapy completion), and tolerability of current US Food and Drug Administration-approved interferon-based regimens and oral interferon-free regimens used for treating HCV infection and coinfection with human immunodeficiency virus (HIV) and HCV; to provide treatment recommendations for specialists and generalists based on published evidence. EVIDENCE REVIEW: A literature search of Web of Science, Scopus, Embase, Agricola, Cochrane Library, Cinahl Plus, ClinicalTrials.gov, Conference Papers Index, Gideon, PsycINFO, Google Scholar, and Oaister was conducted from January 1, 2009, to May 30, 2014. Publications describing phase 2, 3, and 4 studies evaluating the treatment of HCV were included. Forty-one studies involving 19,063 adult patients were included. Strength of clinical data and subsequent HCV treatment recommendations were graded according to the Oxford Centre for Evidence-Based Medicine. FINDINGS: Patients infected with HCV genotype 1 represent 60% to 75% of HCV infections in the United States. Hepatitis C virus genotype 1 is more difficult to cure than genotype 2 or genotype 3. Patients with HCV genotype 1 should receive treatment with sofosbuvir + pegylated interferon + ribavirin because of the shorter duration of therapy and high rates of SVR (89%-90%). Simeprevir + pegylated interferon + ribavirin is an alternative for patients with HCV genotype 1 (SVR, 79%-86%). Patients with HCV genotypes 2 and 3, representing 20% to 29% of US HCV infections, should receive therapy with sofosbuvir + ribavirin alone (SVR for genotype 2, 12 weeks' duration: 82%-93%; SVR for genotype 3, 24 weeks' duration, 80%-95%). Patients with HIV-HCV coinfection and patients with compensated cirrhosis (ie, cirrhosis but preserved synthetic liver function) should receive the same treatment as HCV-monoinfected patients. CONCLUSIONS AND RELEVANCE: New, short-duration, simpler therapies result in high SVR rates for HCV-infected patients. In conjunction with increased screening for HCV as suggested by recent Centers for Disease Control and Prevention guidelines, availability of new therapies may lead to the treatment of many more people with chronic HCV infection.

Heterologous SARS-CoV-2 booster vaccine for individuals with hematological malignancies after a primary SARS-CoV-2 mRNA vaccine series.

Heterologous COVID-19 vaccine boosters have not been evaluated for patients with hematological malignancies. A Novavax booster was administered for 56 individuals with hematological malignancies who had received a primary COVID-19 series and prior boosters with mRNA vaccines only. Blood specimens were obtained at baseline (pre-vaccine), 28 days, and 168 days after vaccination with the Novavax booster. The median fold change of anti-Spike IgG was 1.02 (IQR 0.79, 1.3) between baseline and Day 28. Circulating Spike protein-specific B cells increased 1.4-fold at Day 28 (p < 0.05). Increases in antibody and T cell responses were modest without significance, with a waning of humoral and cellular responses at 168 days after vaccination.

Neuroinvasive Bacillus cereus Infection in Immunocompromised Hosts: Epidemiologic Investigation of 5 Patients With Acute Myeloid Leukemia.

Background: Bacillus cereus is a ubiquitous gram-positive rod-shaped bacterium that can cause sepsis and neuroinvasive disease in patients with acute leukemia or neutropenia. Methods: A single-center retrospective review was conducted to evaluate patients with acute leukemia, positive blood or cerebrospinal fluid test results for B cereus, and abnormal neuroradiographic findings between January 2018 and October 2022. Infection control practices were observed, environmental samples obtained, a dietary case-control study completed, and whole genome sequencing performed on environmental and clinical Bacillus isolates. Results: Five patients with B cereus neuroinvasive disease were identified. All patients had acute myeloid leukemia (AML), were receiving induction chemotherapy, and were neutropenic. Neurologic involvement included subarachnoid or intraparenchymal hemorrhage or brain abscess. All patients were treated with ciprofloxacin and survived with limited or no neurologic sequelae. B cereus was identified in 7 of 61 environmental samples and 1 of 19 dietary protein samples-these were unrelated to clinical isolates via sequencing. No point source was identified. Ciprofloxacin was added to the empiric antimicrobial regimen for patients with AML and prolonged or recurrent neutropenic fevers; no new cases were identified in the ensuing year. Conclusions: B cereus is ubiquitous in the hospital environment, at times leading to clusters with unrelated isolates. Fastidious infection control practices addressing a range of possible exposures are warranted, but their efficacy is unknown and they may not be sufficient to prevent all infections. Thus, including B cereus coverage in empiric regimens for patients with AML and persistent neutropenic fever may limit the morbidity of this pathogen.

Impact of Donor and Recipient SARS-CoV-2 Vaccination or Infection on Immunity after Hematopoietic Cell Transplantation.

The role of donor and recipient Coronavirus disease 2019 (COVID-19) immunologic status pre-transplantation has not been fully investigated in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. Given the poor immunogenicity to vaccines in this population and the serious outcomes of COVID-19, adoptive transfer of immunity may offer important insight into improving protection for this vulnerable population. In this study, we evaluated the role of adoptive transfer of immunity at 1 month post-transplantation and 6 months post-transplantation after vaccination of recipients, based on pre-transplantation severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and infection exposures of both recipient and donor. Using banked specimens from related donor allogeneic HSCT recipients and clinical data from both donors and recipients, anti-Spike (S) IgG titers were analyzed at 1, 3, and 6 months post-transplantation according to prior SARS-CoV-2 immunologic exposures. Recipients were excluded if they had received SARS-CoV-2 monoclonal antibodies or had infection in the first 6 months post-transplantation. Of the 53 recipient-donor pairs, 29 donors and 24 recipients had prior SARS-CoV-2 immunologic exposure. Recipient-donor pairs with no prior SARS-CoV-2 exposure (D0R0) had significantly lower anti-S IgG titers at 1 month compared to those with prior exposures (D1R1) (D0R0: median, 2.43 [interquartile range (IQR), .41 to 3.77]; D1R1: median, 8.42; IQR, 5.58 to 12.20]; P = .008). At 6 months, anti-S IgG titers were higher in recipients who were vaccinated at 3 months post-transplantation in the D1R1 cohort (median IgG, 148.34; IQR, 92.36 to 204.33) compared with the D0R0 cohort (median IgG, 38.74; IQR, 8.93 to 119.71). Current strategies should be optimized to enhance SARS-CoV-2 protection for HSCT recipients, including augmentation of the immune response for both donors and recipients prior to transplantation.

More than one way to improve a CAT: Outcomes and reflections on two iterations of the Queen Square Intensive Comprehensive Aphasia Programme.

Background: The field of human expert performance teaches us that high quality, high-dose guided practice is required to make large gains in cognitively driven acts. The same also seems to be true for people with acquired brain injury, yet therapy services for people with aphasia (PWA) have traditionally not been designed with this in mind. Intensive Comprehensive Aphasia Programmes (ICAPs) are one way to address the chronic under-dosing of therapy that most PWA experience. Aims: There are several ways to deliver an ICAP; here we describe two iterations of our Queen Square ICAP. There was a 20-month COVID-induced pause between the Year 1 (Y1) and Year 2 (Y2) ICAP groups. We analyse ICAP-induced changes in both groups of PWA on a series of key outcome measures that span the International Classification of Functioning, Disability and Health, covering language impairment and function as well as mood and social participation. Methods & Procedures: Forty-six PWA took part in Y1 and 44 in Y2. The PWA were all in the chronic stage post stroke and varied in aphasia severity from mild to severe, with the Y2 group being more impaired than Y1. Quantitative data was collected before and after the ICAP. The Y2 therapy team provided independent reflections on their experiences of delivering an ICAP. Outcomes & Results: ICAP-related changes in outcome measures (impairment, function and goal attainment) were generally comparable for the Y1 and Y2 groups, with both groups' speech production abilities improving the most. Both groups made clinically and statistically significant gains on the main quality of life measure. Participation in the ICAP made a big difference to PWAs' self-confidence ratings. Their mood ratings also improved significantly, although they were not, on average, in the depressed range at baseline (directly pre-ICAP). All improvements achieved in both groups were maintained at the 3-month follow-up, highlighting the lasting effects that ICAPs can provide. Conclusions: Evidence continues to accrue that ICAPs are an efficient way of increasing the dose of expert coaching required for people with chronic aphasia to make clinically meaningful improvements in their communicative abilities and quality of life. The main challenge remaining is convincing health-care providers to invest in them.

SARS-CoV-2 Vaccine-Induced Immune Responses Among Hematopoietic Stem Cell Transplant Recipients.

Background: Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination reduces the risk and severity of coronavirus disease 2019 (COVID-19), several variables may impact the humoral response among patients undergoing hematopoietic stem cell transplantation (HSCT). Methods: A retrospective chart review was conducted among SARS-CoV-2-vaccinated HSCT recipients between 2020 and 2022 at a single center in Boston, Massachusetts. Patients age ≥18 years who received doses of Pfizer, Moderna, or J&J vaccines were included. Anti-spike (S) immunoglobulin G (IgG) titer levels were measured using the Roche assay. Responders (≥0.8 U/mL) and nonresponders (<0.8 U/mL) were categorized and analyzed. Multivariable linear and logistic regression were used to estimate the correlation coefficient and odds ratio of response magnitude and status. Results: Of 152 HSCT recipients, 141 (92.8%) were responders, with a median (interquartile range [IQR]) anti-S IgG titer of 2500 (107.9-2500) U/mL at a median (IQR) of 80.5 (36-153.5) days from last dose, regardless of the number of doses received. Higher quantitative titers were associated with receipt of more vaccine doses (coeff, 205.79; 95% CI, 30.10 to 381.47; P = .022), being female (coeff, 343.5; 95% CI, -682.6 to -4.4; P = .047), being younger (<65 years; coeff, 365.2; 95% CI, -711.3 to 19.1; P = .039), and not being on anti-CD20 therapy (coeff, -1163.7; 95% CI, -1717.7 to -609.7; P = .001). Being male (odds ratio [OR], 0.11; 95% CI, 0.01 to 0.93; P = .04) and being on anti-CD20 therapy (OR, 0.16; 95% CI, 0.03 to 0.70; P = .016) were associated with nonresponse. Conclusions: Overall, most HSCT recipients had high SARS-CoV-2 antibody responses. More vaccine doses improved the magnitude of immune responses. Anti-S IgG monitoring may be useful for identifying attenuated vaccine-induced responses.