Search

Background: Cytokines and chemokines play a critical role in the response to infection and vaccination. We aimed to assess the longitudinal association of COVID-19 vaccination with cytokine and chemokine concentrations and trajectories among people with SARS-CoV-2 infection., Methods: In this longitudinal, prospective cohort study, blood samples were used from participants enrolled in a multi-centre randomised trial assessing the efficacy of convalescent plasma therapy for ambulatory COVID-19. The trial was conducted in 23 outpatient sites in the USA. In this study, participants (aged ≥18 years) were restricted to those with COVID-19 before vaccination or with breakthrough infections who had blood samples and symptom data collected at screening (pre-transfusion), day 14, and day 90 visits. Associations between COVID-19 vaccination status and concentrations of 21 cytokines and chemokines (measured using multiplexed sandwich immunoassays) were examined using multivariate linear mixed-effects regression models, adjusted for age, sex, BMI, hypertension, diabetes, trial group, and COVID-19 waves (pre-alpha or alpha and delta)., Findings: Between June 29, 2020, and Sept 30, 2021, 882 participants recently infected with SARS-CoV-2 were enrolled, of whom 506 (57%) were female and 376 (43%) were male. 688 (78%) of 882 participants were unvaccinated, 55 (6%) were partly vaccinated, and 139 (16%) were fully vaccinated at baseline. After adjusting for confounders, geometric mean concentrations of interleukin (IL)-2RA, IL-7, IL-8, IL-15, IL-29 (interferon-λ), inducible protein-10, monocyte chemoattractant protein-1, and tumour necrosis factor-α were significantly lower among the fully vaccinated group than in the unvaccinated group at screening. On day 90, fully vaccinated participants had approximately 20% lower geometric mean concentrations of IL-7, IL-8, and vascular endothelial growth factor-A than unvaccinated participants. Cytokine and chemokine concentrations decreased over time in the fully and partly vaccinated groups and unvaccinated group. Log 10 cytokine and chemokine concentrations decreased faster among participants in the unvaccinated group than in other groups, but their geometric mean concentrations were generally higher than fully vaccinated participants at 90 days. Days since full vaccination and type of vaccine received were not correlated with cytokine and chemokine concentrations., Interpretation: Initially and during recovery from symptomatic COVID-19, fully vaccinated participants had lower concentrations of inflammatory markers than unvaccinated participants suggesting vaccination is associated with short-term and long-term reduction in inflammation, which could in part explain the reduced disease severity and mortality in vaccinated individuals., Funding: US Department of Defense, National Institutes of Health, Bloomberg Philanthropies, State of Maryland, Mental Wellness Foundation, Moriah Fund, Octapharma, HealthNetwork Foundation, and the Shear Family Foundation., Competing Interests: Declaration of interests KAG reports consultancy work for the Aspen Institute, Teach for America, serving as a non-paid member of a scientific advisory board for Pfizer, and writing COVID-19 management guidelines for UpToDate. AGA reports consultancy work for Implementation Group, Hirslanden Klinik, and Elsevier. ERC reports receiving unrestricted research grants from Gilead and Merck paid to the Regents of the University of California and participating in an advisory board to Theratechnologies for an unrelated topic. JSC reports consultancy work for Merck and Company in 2021. TJG reports employment by Fenwal, a Fresenius Kabi Company. LLH reports research funding to Johns Hopkins Center of American Indian Health from AstraZeneca, US Centers for Disease Control and Prevention, Merck, NIH, and Pfizer. MAH reports contracts from Gilead Sciences, Insmed, and AN2 Therapeutics to the University of Cincinnati. GSM reports research grant support from Teva, Alk-Abello, Genentech, Novartis, GlaxoSmithKline, and Sanofi-Regeneron, serving as an immediate past president of the American Academy of Allergy Asthma and Immunology, and is co-chair of the Continuous Assessment Program Examination for the American Board of Allergy and Immunology. BP reports participating in part of the COVID-19 trials and pulmonary arterial hypertension trials. JHP reports research funding from MindRhythm. JSR is a consultant and advisor with Sanofi Genzyme, and a board of directors member with the American Society for Apheresis. SK reports helping to produce educational materials related to HIV with Integritas Communications and Vindico Medical Education. AC reports serving on the scientific advisory board of SAB Biotherapeutics. EMB reports personal fees and non-financial support from Terumo BCT, Abbott Laboratories, Tegus, and UptoDate, is a member of the US Food and Drug Administration Blood Products Advisory Committee, and served on a convalescent plasma guideline panel. DH reports personal fees from Neurelis, Neurotrope, and medicolegal consulting. DJS is a founder and board member with stock options (macrolide for malaria) for AliquantumRx and reports consulting for Hemex Health and royalties for malaria diagnostic test control standards to Alere. SLH reports serving on the data monitoring committee for Pfizer. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Biological sex and gender-based constructs contribute significantly to the diversity of disease outcomes and treatment responses across the life course. To promote research considering sex and gender, the National Institutes of Health (NIH) Office of Research on Women's Health (ORWH) launched the Specialized Centers of Research Excellence (SCORE) on sex differences program. The Career Enhancement Core (CEC) of the Johns Hopkins SCORE on Sex and Age Differences in Immunity to Influenza (SADII) partnered with the Foundation for Gender-Specific Medicine, which matched NIH funding to support seed grants. Over 3 years we awarded 12 (10 were women faculty) seed grants to early-stage investigators. One year after the award, the seed grant awardees highlighted their progress, including publications, grant applications, and abstracts. All awardees noted challenges with their progress related to the COVID-19 pandemic and supply chain delays and shared suggestions for improving the programming of the CEC. They also highlighted the multiple ways the awards had helped them gain pilot data toward larger grants, build collaborative relationships, and present at the annual SCORE symposium. We describe a model and evidence supporting a private-academic collaboration to support the careers of early-stage investigators conducting research related to sex and gender.

Background: Polyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset Covid-19 is uncertain., Methods: In this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19-related hospitalization within 28 days after transfusion., Results: Participants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P = 0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized., Conclusions: In participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalization. (Funded by the Department of Defense and others; CSSC-004 ClinicalTrials.gov number, NCT04373460.)., (Copyright © 2022 Massachusetts Medical Society.)

Benchmarks for protective immunity from infection or severe disease after SARS-CoV-2 vaccination are still being defined. Here, we characterized virus neutralizing and ELISA antibody levels, cellular immune responses, and viral variants in 4 separate groups: healthy controls (HCs) weeks (early) or months (late) following vaccination in comparison with symptomatic patients with SARS-CoV-2 after partial or full mRNA vaccination. During the period of the study, most symptomatic breakthrough infections were caused by the SARS-CoV-2 Alpha variant. Neutralizing antibody levels in the HCs were sustained over time against the vaccine parent virus but decreased against the Alpha variant, whereas IgG titers and T cell responses against the parent virus and Alpha variant declined over time. Both partially and fully vaccinated patients with symptomatic infections had lower virus neutralizing antibody levels against the parent virus than the HCs, similar IgG antibody titers, and similar virus-specific T cell responses measured by IFN-γ. Compared with HCs, neutralization activity against the Alpha variant was lower in the partially vaccinated infected patients and tended to be lower in the fully vaccinated infected patients. In this cohort of breakthrough infections, parent virus neutralization was the superior predictor of breakthrough infections with the Alpha variant of SARS-CoV-2.

Background: An antigenic mismatch between the vaccine and circulating H3N2 strains was hypothesized to contribute to the severity of the 2017-2018 season in North America., Methods: Serum and nasal washes were collected from influenza positive and negative patients during the 2017-2018 season to determine neutralizing antibody (nAb) titers and for influenza virus sequencing, respectively., Results: The circulating and vaccine H3N2 virus strains were different clades, with the vaccine strain being clade 3C.2a and the circulating viruses being 3C.2a2 or 3C.3a. At enrollment, both the H3N2 negative and positive patients had greater nAb titers to the egg-adapted vaccine virus compared to the cell-grown vaccine but the H3N2-negative population had significantly greater titers to the circulating 3C.2a2. Among H3N2-positive patients, vaccination, younger age, and female sex were associated with greater nAb responses to the egg-adapted vaccine H3N2 virus but not to the cell-grown vaccine or circulating viruses., Conclusions: For the 2017-2018 circulating viruses, mutations introduced by egg adaptation decreased vaccine efficacy. No increased protection was afforded by vaccination, younger age, or female sex against 2017-2018 circulating H3N2 viruses., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

The current novel coronavirus disease 2019 (COVID-19) pandemic is revealing profound differences between men and women in disease outcomes worldwide. In the United States, there has been inconsistent reporting and analyses of male-female differences in COVID-19 cases, hospitalizations, and deaths. We seek to raise awareness about the male-biased severe outcomes from COVID-19, highlighting the mechanistic differences including in the expression and activity of angiotensin-converting enzyme 2 (ACE2) as well as in antiviral immunity. We also highlight how sex differences in comorbidities, which can be associated with both age and race, impact male-biased outcomes from COVID-19., Competing Interests: The authors have declared that no competing interests exist.

The continual emergence of novel influenza A strains from non-human hosts requires constant vigilance and the need for ongoing research to identify strains that may pose a human public health risk. Since 1999, canine H3 influenza A viruses (CIVs) have caused many thousands or millions of respiratory infections in dogs in the United States. While no human infections with CIVs have been reported to date, these viruses could pose a zoonotic risk. In these studies, the National Institutes of Allergy and Infectious Diseases (NIAID) Centers of Excellence for Influenza Research and Surveillance (CEIRS) network collaboratively demonstrated that CIVs replicated in some primary human cells and transmitted effectively in mammalian models. While people born after 1970 had little or no pre-existing humoral immunity against CIVs, the viruses were sensitive to existing antivirals and we identified a panel of H3 cross-reactive human monoclonal antibodies (hmAbs) that could have prophylactic and/or therapeutic value. Our data predict these CIVs posed a low risk to humans. Importantly, we showed that the CEIRS network could work together to provide basic research information important for characterizing emerging influenza viruses, although there were valuable lessons learned., Competing Interests: AG-S. is inventor of patents on influenza virus vaccines owned by the Icahn School for Medicine at Mount Sinai and licensed to Medimmune, BI Vetmedica, Vivaldi Biosciences, Zoetis and Avimex.

The National Institutes of Health Xenopus Initiative is a concerted effort to interact with the Xenopus research community to identify the community's needs; to devise strategies to meet those needs; and to support, oversee, and coordinate the resulting projects. This chapter provides a brief description of several genetic and genomic resources generated by this initiative and explains how to access them. The resources described in this chapter are (1) complementary deoxyribonucleic acid (cDNA) libraries and expressed sequence tag (EST) sequences; (2) UniGene clusters; (3) full-insert cDNA sequences; (4) a genetic map; (5) genomic libraries; (6) a physical map; (7) genome sequence; (8) microarrays; (9) mutagenesis and phenotyping; and (10) bioinformatics. The descriptions presented here were based on data that were available at the time of manuscript submission. Because these are ongoing projects, they are constantly generating new data and analyses. The Web sites cited in each subheading present current data and analyses.

The National Institutes of Health's Mammalian Gene Collection (MGC) project was designed to generate and sequence a publicly accessible cDNA resource containing a complete open reading frame (ORF) for every human and mouse gene. The project initially used a random strategy to select clones from a large number of cDNA libraries from diverse tissues. Candidate clones were chosen based on 5'-EST sequences, and then fully sequenced to high accuracy and analyzed by algorithms developed for this project. Currently, more than 11,000 human and 10,000 mouse genes are represented in MGC by at least one clone with a full ORF. The random selection approach is now reaching a saturation point, and a transition to protocols targeted at the missing transcripts is now required to complete the mouse and human collections. Comparison of the sequence of the MGC clones to reference genome sequences reveals that most cDNA clones are of very high sequence quality, although it is likely that some cDNAs may carry missense variants as a consequence of experimental artifact, such as PCR, cloning, or reverse transcriptase errors. Recently, a rat cDNA component was added to the project, and ongoing frog (Xenopus) and zebrafish (Danio) cDNA projects were expanded to take advantage of the high-throughput MGC pipeline.

The NIH Xenopus Initiative is establishing many of the genetic and genomic resources that have been recommended by the Xenopus research community. These resources include cDNA libraries, expressed sequence tags, full-length cDNA sequences, genomic libraries, pilot projects to mutagenize and phenotype X. tropicalis, and sequencing the X. tropicalis genome. This review describes the status of these projects and explains how to access their data and resources. Current information about these activities is available on the NIH Xenopus Web site (http://www.nih.gov/science/models/xenopus/).