ABSTRACT
In the last two years, billions of individuals worldwide have been safely vaccinated against SARS-CoV-2, the virus that causes COVID-19. However, a substantial number of people experience mild to moderate side effects, which may hamper vaccine and booster uptake;understanding the processes underlying differential responses to these vaccines can help to improve global vaccination efforts. Variation in HLA has been linked to disease outcome in COVID-19, and HLA-A*03:01 has previously been reported to increase risk for side effects following vaccination. Here, we expand on those findings, examining HLA variation for association with vaccine side effects in 6470 patients of European ancestry from the United States. In our cohort, ~30% of individuals experienced systemic side effects (e.g., fever, chills, headache) after their initial vaccination series, while that proportion climbed to >60% in individuals receiving booster doses. We confirm the association of HLA-A*03:01 with systemic side effects to COVID-19 vaccines, particularly the Pfizer-BioNTech vaccine (OR = 1.52 [95% CI 1.23-1.97], p = 0.002). We observed similar effect size of this allele in individuals reporting side effects from the initial series or boosters (OR = 1.25 [95% CI 1.15-1.53];p>0.0001), but comparatively higher effect size in individuals who subsequently experienced breakthrough infections (OR = 2.11 [95% CI 1.12-4.31];p = 0.04). Our results confirm prior reports regarding HLA association with vaccine side effects, and suggest that the immunopathology underlying the HLAA* 03:01 association with side effects may increase those individuals' propensity for breakthrough infections after vaccination. Our results highlight the need to explore the functional mechanisms underlying this association to improve vaccine design and implementation strategies against emergent SARS-CoV-2 variants.
ABSTRACT
Extreme polymorphism of HLA and Killer-cell Immunoglobulin-like Receptors (KIR) differentiates immune responses across individuals. Additional to Tcell receptor interactions, subsets of HLA class I act as ligands for inhibitory and activating KIR, allowing natural killer (NK) cells to detect and kill infected cells. We investigated the impact of HLA and KIR polymorphism on the severity of COVID-19. High resolution HLA class I and II and KIR genotypes were determined from 403 non-hospitalized and 1,575 hospitalized SARS-CoV-2 infected patients from Italy collected in 2020. We observed that the activating KIR2DS4*001 allotype is associated with severe disease (OR = 3.74, 95% CI 1.75-9.29, pc = 0.003). KIR2DS4*001 in presence of its specific HLA ligands and inhibitory KIR3DL2*002 in absence its HLA ligand are also enriched in severe COVID-19 patients (OR = 1.64, 95% CI 1.09-2.50, p = 0.019), suggesting this combination acts in tandem to increase risk of developing severe COVID-19. We also observed the HLA class II allotype, HLA-DPB1*13:01 protects SARS-CoV-2 infected patients from hospitalization (OR = 0.49, 95% CI 0.33-0.74, pc = 0.019). These association analyses were replicated using logistic regression with sex and age as covariates. Autoantibodies against IFN-alpha associated with COVID-19 severity were detected in 26% of hospitalized patients. HLA-C*08:02 was more frequent in patients with IFN-alpha autoantibodies than those without, and KIR3DL1*01502 was only present in patients lacking IFN- alpha antibodies. We intend to expand this analysis in Greek and Spanish COVID-19 cohorts. These findings show that KIR and HLA polymorphism may play important roles in determining the clinical outcome following SARS-CoV-2 infection, by influencing the course both of innate and adaptive immunity.
ABSTRACT
Background: Prospective, deeply phenotyped research cohorts monitoring people with multiple sclerosis (MS) depend on careful participant engagement that was threatened by COVID19- related restrictions to in-clinic visits. Coincidentally, there was forced adoption of televideo-enabled care. Objective(s): To leverage a natural experiment of "going virtual" during the pandemic to evaluate two hypotheses pertaining to remote MS research: that (1) global costs of remote visits are lower, and (2) disability evaluations are non-inferior. Method(s): Between 3/2020 and 12/2021, 207 UCSF EPIC/ ORIGINS MS cohort participants underwent hybrid in-clinic and virtual research visits. Among these, 96 contributed 100 'matched visits', i.e. in-clinic (Neurostatus, NS-EDSS) and remote (televideo-, tele-EDSS;electronic patient-reported, ePR-EDSS) evaluations within 14 days. Clinical and socio/ demographic characteristics were collected. First, visit costs were compared. Then, the quality of data extracted was compared using non-inferiority design with NS-EDSS as primary outcome. Result(s): The 96 participants contributing 100 matched visits had mean age 41.4 years (SD 11.7) and MS duration 1.4 years (SD 3.4);69% were female and 72% White, 8% lived in lowincome zip codes;median driving distance was 70 miles (mean 545). The costs of remote visits to participants (travel, caregiver time), to research (facilities, personnel, parking, participant compensation), and carbon footprint were all lower than in-person visits (p<0.05 for each). Median cohort EDSS was similar, whether evaluated using NS-EDSS (2), tele-EDSS (1.5) or ePREDSS (2), with range 0-6.5. Utilizing a TOST for Non-inferiority, both remote evaluations were non-inferior to NS-EDSS within+/-0.5 EDSS point (p<0.01 for each). Year-to-year, the % of participants with worsening/stable/improved EDSS scores was similar, whether the annual evaluations both used NS-EDSS, or whether the annual evaluation switched from NS-EDSS to tele-EDSS. Discussion(s): "Going virtual" during the pandemic represented a natural experiment in which to test hypotheses about remote research visits. These visits lowered costs for investigators and participants. Further, remote assessments were non-inferior to NS-EDSS and for more precision, could be supplemented with biosensors. Together, these insights support the conduct of research that is more inclusive to participants regardless of geography, race, income, opportunity costs or ability level.
ABSTRACT
Rationale: Exposure to respiratory pathogens, aeroallergens, and air pollution can lead to asthma exacerbations. The SarsCoV2 (COVID-19) pandemic led to widespread public health mandates including mask-wearing. We hypothesize that mask-wearing sequesters respiratory pathogens, leading to observed reduction in asthma exacerbations. The goal of this study was to characterize the bacterial microbiome from surgical masks in a cohort of school children with and without asthma. By identifying what is on both inside and outside the masks, we will be able to build a catalogue as a baseline for future analyses. Methods: We performed a cross-sectional study of children (4-18 years) attending an inner-city public school district. Students wore a surgical mask for a minimum of one school day. Parents completed a questionnaire about their child's demographics, respiratory history, and level of asthma impairment. To establish the protocol, we piloted the extraction and sequencing procedures among a sample of used masks from a hospital clinical personnel. DNA was extracted using a commercial DNA extraction kit on separated mask layers: inner, middle, and outer. 16S rRNA gene sequencing was then performed and then mapped against the most recent Greengene 16S rRNA gene database.Results: Recruitment and mask wearing occurred during an 8-week period (May 2021-July 2021). 34 students (18 with asthma;16 without asthma) from four schools were enrolled and completed the study. 74% of participants were in grades K-4, mean age was 8.4 years, and 53% identified as Hispanic/Puerto Rican. 59% of participants wore the mask one school day. 44% reported an asthma-related ED visit in their lifetime, while only 16% reported an ED visit in the past 12-months;53% of participants reported asthma symptoms with upper respiratory infections, however 77% reported zero respiratory infections in the past 12-months. In the masks worn by medical staff, bacterial genera including Staphyloccus, Haemophilus, Lawsonella, Streptococcus as well as Actinomyces, were identified similarly on inner and outer layers in the masks worn by clinicians. (Figure 1).Conclusions: We have demonstrated that recruiting and enrolling students from a medium-sized, inner-city public school district and obtaining facial mask samples is feasible. We demonstrate that self-reported rates of asthmarelated ED visits and respiratory infections differed pre-pandemic as compared to during. In addition, identifying the microbiome from surgical masks is possible. Bacteria genera identified were similar to known human nasal, oral and skin microbiomes. Current work is now in process characterizing and comparing the mask microbiomes among students with and without asthma.
ABSTRACT
Introduction: MS disease-modifying therapies (DMTs) lead to distinct effects on humoral and cellular immunity. Effective vaccine- elicited immunity to severe acute respiratory syndrome coronavirus- 2 (SARS-CoV-2), the causative agent of the ongoing COVID-19 pandemic, requires robust antibody and CD4+ and CD8+ T cell responses against the SARS-CoV-2 spike protein. Understanding how different MS DMTs affect COVID-19 vaccine immunity is a vital clinical gap that needs to be urgently addressed. Objectives: The goal of this study is to assess COVID-19 vaccine- elicited antibody and T cell responses in MS patients on different of DMTs. Aims: To measure SARS-CoV-2 spike antigen-specific antibody and CD4+ and CD8+ T cell responses before and after COVID- 19 vaccination of MS patients on different DMTs. Methods: Enrolment included MS patients on no therapy, or treated with glatiramer acetate (GA), dimethyl fumarate (DMF), natalizumab (NAT), sphingosine-1-phosphate receptor (S1P) modulator, or anti-CD20 monoclonal antibody (mAb). Serum and peripheral blood mononuclear cells (PBMCs) were collected from all patients before and 2-4 weeks following final COVID-19 vaccination. Patient serum was tested on a Luminex bead-based assay to quantitatively measure IgG levels against the whole SARSCoV- 2 spike protein and the spike receptor binding domain (RBD). PBMCs were stimulated with pools of SARS-CoV-2 spike peptides to measure the frequencies of spike-specific CD4+ and CD8+ T cells by activation-induced marker expression. Results: Following COVID-19 vaccination, all untreated MS patients and patients on GA, DMF, and NAT were seropositive with similar high IgG titres to total spike and spike RBD. MS patients on S1P modulators and anti-CD20 mAb exhibited significantly reduced IgG titres to total spike and spike RBD antigens, with only a fraction of patients reaching seropositivity. Spike antigen-specific CD4+ and CD8+ T cell responses were present at similar levels across all DMT categories following COVID-19 vaccination. Conclusions: MS DMTs exhibited differential effects on COVID- 19 vaccine-elicited humoral, but not T cell immunity. Whereas IgG responses were unaffected in MS patients on GA, DMF, and NAT, IgG levels were reduced in MS patients on S1P modulators and anti-CD20 mAb. The findings of this study have important clinical implications for assessing potential risk of COVID-19 infection in vaccinated MS patients on specific DMTs.