The role of host genetics in the immune response to SARS-CoV-2 and COVID-19 susceptibility and severity.

This article provides a review of studies evaluating the role of host (and viral) genetics (including variation in HLA genes) in the immune response to coronaviruses, as well as the clinical outcome of coronavirus-mediated disease. The initial sections focus on seasonal coronaviruses, SARS-CoV, and MERS-CoV. We then examine the state of the knowledge regarding genetic polymorphisms and SARS-CoV-2 and COVID-19. The article concludes by discussing research areas with current knowledge gaps and proposes several avenues for future scientific exploration in order to develop new insights into the immunology of SARS-CoV-2.

Distinct Homologous and Variant-Specific Memory B-Cell and Antibody Response Over Time After Severe Acute Respiratory Syndrome Coronavirus 2 Messenger RNA Vaccination.

The durability of protective humoral immunity after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and infection is largely dependent on the generation and persistence of antigen-specific isotype-switched memory B cells (MBCs) and long-lived plasma cells that reside in the bone marrow and secrete high-affinity neutralizing antibodies. The reactivity of vaccine-induced MBCs to emerging clinically significant SARS-CoV-2 variants of concern (VoCs) is largely unknown. In a longitudinal cohort study (up to 6 months following coronavirus disease 2019 messenger RNA vaccination), we measured MBCs in concert with other functional antibody measures. We found statistically significant differences between the frequencies of MBCs responding to homologous and VoC (Beta, Gamma, and Delta) receptor-binding domains after vaccination that persisted over time. In concert with a waning antibody response, the reduced MBC response to VoCs could translate to a weaker subsequent recall immune response and increased susceptibility to the emerging SARS-CoV-2 variant strains after vaccination.

The Influence of Sex, Body Mass Index, and Age on Cellular and Humoral Immune Responses Against Measles After a Third Dose of Measles-Mumps-Rubella Vaccine.

BACKGROUND: A third dose of measles-mumps-rubella vaccine (MMR3) is recommended in mumps outbreak scenarios, but the immune response and the need for widespread use of MMR3 remain uncertain. Herein, we characterized measles-specific immune responses to MMR3 in a cohort of 232 healthy subjects. METHODS: Serum and peripheral blood mononuclear cells (PBMCs) were sampled at day 0 and day 28 after MMR3. Measles-specific binding and neutralizing antibodies were quantified in sera by enzyme-linked immunosorbent assay and a microneutralization assay, respectively. PBMCs were stimulated with inactivated measles virus, and the release of cytokines/chemokines was assessed by a multiplex assay. Demographic variables of subjects were examined for potential correlations with immune outcomes. RESULTS: Of the study participants, 95.69% and 100% were seropositive at day 0 and day 28, respectively. Antibody avidity significantly increased from 38.08% at day 0 to 42.8% at day 28 (P = .00026). Neutralizing antibodies were significantly enhanced, from 928.7 at day 0 to 1289.64 mIU/mL at day 28 (P = .0001). Meanwhile, cytokine/chemokine responses remained largely unchanged. Body mass index was significantly correlated with the levels of inflammatory cytokines/chemokines. CONCLUSIONS: Measles-specific humoral immune responses, but not cellular responses, were enhanced after MMR3 receipt, extending current understanding of immune responses to MMR3 and supporting MMR3 administration to seronegative or high-risk individuals.

Advancing the Science of Vaccine Safety During the Coronavirus Disease 2019 (COVID-19) Pandemic and Beyond: Launching an International Network of Special Immunization Services.

Within 2 years after the start of the coronavirus disease 2019 (COVID-19) pandemic, novel severe acute respiratory syndrome coronavirus 2 vaccines were developed, rigorously evaluated in large phase 3 trials, and administered to more than 5 billion individuals globally. However, adverse events of special interest (AESIs) have been described post-implementation, including myocarditis after receipt of messenger RNA (mRNA) vaccines and thrombosis with thrombocytopenia syndrome after receipt of adenoviral vector vaccines. AESIs are rare (<1 to 10/100 000 vaccinees) and less frequent than COVID-19 complications, though they have associated morbidity and mortality. The diversity of COVID-19 vaccine platforms (eg, mRNA, viral vector, protein) and rates of AESIs both between and within platforms (eg, higher rate of myocarditis after mRNA-1273 vs BNT162b2 vaccines) present an important opportunity to advance vaccine safety science. The International Network of Special Immunization Services has been formed with experts in vaccine safety, systems biology, and other relevant disciplines to study cases of AESIs and matched controls to uncover the pathogenesis of rare AESIs and inform vaccine development.

Mumps virus-specific immune response outcomes and sex-based differences in a cohort of healthy adolescents.

Despite high levels of MMR-II usage in the US, mumps outbreaks continue to occur. Evidence suggests that mumps vaccine-induced humoral immunity wanes over time. Relatively few studies have examined cell-mediated immunity or reported on sex-based differences. To better understand sex-based differences in the immune response to mumps vaccine, we measured neutralizing antibody titers and mumps-specific cytokine/chemokine responses in a cohort of 748 adolescents and young adults after two doses of MMR vaccine. We observed significantly higher neutralizing antibody titers in females than in males (120.8 IU/mL, 98.7 IU/mL, p = 0.038) but significantly higher secretion levels of MIP-1α, MIP-1ß, TNFα, IL-6, IFNγ, and IL-1ß in males compared to females. These data demonstrate that sex influences mumps-specific humoral and cell-mediated immune response outcomes, a phenomenon that should be considered during efforts to improve vaccines and prevent future outbreaks.

Transcriptional signatures associated with rubella virus-specific humoral immunity after a third dose of MMR vaccine in women of childbearing age.

Multiple factors linked to host genetics/inherent biology play a role in interindividual variability in immune response outcomes after rubella vaccination. In order to identify these factors, we conducted a study of rubella-specific humoral immunity before (Baseline) and after (Day 28) a third dose of MMR-II vaccine in a cohort of 109 women of childbearing age. We performed mRNA-Seq profiling of PBMCs after rubella virus in vitro stimulation to delineate genes associated with post-vaccination rubella humoral immunity and to define genes mediating the association between prior immune response status (high or low antibody) and subsequent immune response outcome. Our study identified novel genes that mediated the association between prior immune response and neutralizing antibody titer after a third MMR vaccine dose. These genes included the following: CDC34; CSNK1D; APOBEC3F; RAD18; AAAS; SLC37A1; FAS; and JAK2. The encoded proteins are involved in innate antiviral response, IFN/cytokine signaling, B cell repertoire generation, the clonal selection of B lymphocytes in germinal centers, and somatic hypermutation/antibody affinity maturation to promote optimal antigen-specific B cell immune function. These data advance our understanding of how subjects' prior immune status and/or genetic propensity to respond to rubella/MMR vaccination ultimately affects innate immunity and humoral immune outcomes after vaccination.

Distorted Human Decision-Making as a Critical Aspect of Pandemic Planning and Preparedness.

The United States continues to experience lower than expected vaccination rates against COVID-19 due to a variety of barriers such as lack of trust, lack of planning, cultural perspectives and issues, suboptimal communication, and political/economic conflicts of interest. In this paper issues of human behavior and decision-making are highlighted as integral to understanding the generally poor US response to the SARS-CoV-2 pandemic. In particular, the US pandemic response was significantly distorted through a combination of cultural and human behavior issues related to conflicting leadership, cultural individualism, the prevalent idea of the democratization of expertise, and a false epistemological lens for decision-making. Including experts from multiple disciplines reveals how to address the human behavioral side of pandemic planning and operations to increase vaccine coverage rates. Including content experts from psychology and the social sciences allows the explicit recognition and preparation for distorted human behavior in planning for future pandemic response.

SARS-CoV-2 immunity: review and applications to phase 3 vaccine candidates.

Understanding immune responses to severe acute respiratory syndrome coronavirus 2 is crucial to understanding disease pathogenesis and the usefulness of bridge therapies, such as hyperimmune globulin and convalescent human plasma, and to developing vaccines, antivirals, and monoclonal antibodies. A mere 11 months ago, the canvas we call COVID-19 was blank. Scientists around the world have worked collaboratively to fill in this blank canvas. In this Review, we discuss what is currently known about human humoral and cellular immune responses to severe acute respiratory syndrome coronavirus 2 and relate this knowledge to the COVID-19 vaccines currently in phase 3 clinical trials.

Prediction of post-vaccination Guillain-Barré syndrome using data from a passive surveillance system.

PURPOSE: Severe adverse events (AEs), such as Guillain-Barré syndrome (GBS) occur rarely after influenza vaccination. We identify highly associated AEs with GBS and develop prediction models for GBS using the US Vaccine Adverse Event Reporting System (VAERS) reports following trivalent influenza vaccination (FLU3). METHODS: This study analyzed 80 059 reports from the US VAERS between 1990 and 2017. Several AEs were identified as highly associated with GBS and were used to develop the prediction model. Some common and mild AEs that were suspected to be underreported when GBS occurred simultaneously were removed from the final model. The analyses were validated using European influenza vaccine AEs data from EudraVigilance. RESULTS: Of the 80 059 reports, 1185 (1.5%) were annotated as GBS related. Twenty-four AEs were identified as having strong association with GBS. The full prediction model, using age, sex, and all 24 AEs achieved an area under the receiver operating characteristic (ROC) curve (AUC) of 85.4% (90% CI: [83.8%, 86.9%]). After excluding the nine (e.g., pruritus, rash, injection site pain) likely underreported AEs, the final AUC became 77.5% (90% CI: [75.5%, 79.6%]). Two hundred and one (0.25%) reports were predicted as of high risk of GBS (predicted probability >25%) and 84 actually developed GBS. CONCLUSION: The prediction performance demonstrated the potential of developing risk-prediction models utilizing the VAERS cohort. Excluding the likely underreported AEs sacrificed some prediction power but made the model more interpretable and feasible. The high absolute risk of even a small number of AE combinations suggests the promise of GBS prediction within the VAERS dataset.

Immunosenescence and human vaccine immune responses.

The age-related dysregulation and decline of the immune system-collectively termed "immunosenescence"-has been generally associated with an increased susceptibility to infectious pathogens and poor vaccine responses in older adults. While numerous studies have reported on the clinical outcomes of infected or vaccinated individuals, our understanding of the mechanisms governing the onset of immunosenescence and its effects on adaptive immunity remains incomplete. Age-dependent differences in T and B lymphocyte populations and functions have been well-defined, yet studies that demonstrate direct associations between immune cell function and clinical outcomes in older individuals are lacking. Despite these knowledge gaps, research has progressed in the development of vaccine and adjuvant formulations tailored for older adults in order to boost protective immunity and overcome immunosenescence. In this review, we will discuss the development of vaccines for older adults in light of our current understanding-or lack thereof-of the aging immune system. We highlight the functional changes that are known to occur in the adaptive immune system with age, followed by a discussion of current, clinically relevant pathogens that disproportionately affect older adults and are the central focus of vaccine research efforts for the aging population. We conclude with an outlook on personalized vaccine development for older adults and areas in need of further study in order to improve our fundamental understanding of adaptive immunosenescence.

Polymorphisms in the Wilms Tumor Gene Are Associated With Interindividual Variations in Rubella Virus-Specific Cellular Immunity After Measles-Mumps-Rubella II Vaccination.

Rubella vaccination induces widely variable immune responses in vaccine recipients. While rubella vaccination is effective at inducing immunity to rubella infection in most subjects, up to 5% of individuals do not achieve or maintain long-term protective immunity. To expand upon our previous work identifying genetic polymorphisms that are associated with these interindividual differences in humoral immunity to rubella virus, we performed a genome-wide association study in a large cohort of 1843 subjects to discover single-nucleotide polymorphisms (SNPs) associated with rubella virus-specific cellular immune responses. We identified SNPs in the Wilms tumor protein gene (WT1) that were significantly associated (P < 5 × 10-8) with interindividual variations in rubella-specific interleukin 6 secretion from subjects' peripheral blood mononuclear cells postvaccination. No SNPs were found to be significantly associated with variations in rubella-specific interferon-γ secretion. Our findings demonstrate that genetic polymorphisms in the WT1 gene in subjects of European ancestry are associated with interindividual differences in rubella virus-specific cellular immunity after measles-mumps-rubella II vaccination.

Prevalence and Morbidity of Undiagnosed Celiac Disease From a Community-Based Study.

BACKGROUND & AIMS: Little is known about the prevalence and burden of undiagnosed celiac disease in individuals younger than age 50. We determined the prevalence and morbidity of undiagnosed celiac disease in individuals younger than age 50 in a community. METHODS: We tested sera from 31,255 residents of Olmsted County, Minnesota (<50 y), without a prior diagnosis of celiac disease assay using an assay for IgA against tissue transglutaminase; in subjects with positive test results, celiac disease was confirmed using an assay for endomysial IgA. We performed a nested case-control study to compare the proportion of comorbidities between undiagnosed cases of celiac disease and age- and sex-matched seronegative controls (1:2). Medical records were abstracted to identify potential comorbidities. RESULTS: We identified 338 of 30,425 adults with positive results from both serologic tests. Based on this finding, we estimated the prevalence of celiac disease to be 1.1% (95% confidence interval, 1.0%-1.2%); 8 of 830 children tested positive for IgA against tissue transglutaminase (1.0%; 95% confidence interval, 0.4%-1.9%). No typical symptoms or classic consequences of diagnosed celiac disease (diarrhea, anemia, or fracture) were associated with undiagnosed celiac disease. Undiagnosed celiac disease was associated with increased rates of hypothyroidism (odds ratio, 2.2; P < .01) and a lower than average cholesterol level (P = .03) and ferritin level (P = .01). During a median follow-up period of 6.3 years, the cumulative incidence of a subsequent diagnosis with celiac disease at 5 years after testing was 10.8% in persons with undiagnosed celiac disease vs 0.1% in seronegative persons (P < .01). Celiac disease status was not associated with overall survival. CONCLUSIONS: Based on serologic tests of a community population for celiac disease, we estimated the prevalence of undiagnosed celiac disease to be 1.1%. Undiagnosed celiac disease appeared to be clinically silent and remained undetected, but long-term outcomes have not been determined.

Genome-wide associations of CD46 and IFI44L genetic variants with neutralizing antibody response to measles vaccine.

Population-based studies have revealed 2-10% measles vaccine failure rate even after two vaccine doses. While the mechanisms behind this remain unknown, we hypothesized that host genetic factors are likely to be involved. We performed a genome-wide association study of measles specific neutralizing antibody and IFNγ ELISPOT response in a combined sample of 2872 subjects. We identified two distinct chromosome 1 regions (previously associated with MMR-related febrile seizures), associated with vaccine-induced measles neutralizing antibody titers. The 1q32 region contained 20 significant SNPs in/around the measles virus receptor-encoding CD46 gene, including the intronic rs2724384 (p value = 2.64 × 10-09) and rs2724374 (p value = 3.16 × 10-09) SNPs. The 1q31.1 region contained nine significant SNPs in/around IFI44L, including the intronic rs1333973 (p value = 1.41 × 10-10) and the missense rs273259 (His73Arg, p value = 2.87 × 10-10) SNPs. Analysis of differential exon usage with mRNA-Seq data and RT-PCR suggests the involvement of rs2724374 minor G allele in the CD46 STP region exon B skipping, resulting in shorter CD46 isoforms. Our study reveals common CD46 and IFI44L SNPs associated with measles-specific humoral immunity, and highlights the importance of alternative splicing/virus cellular receptor isoform usage as a mechanism explaining inter-individual variation in immune response after live measles vaccine.

Vaccinomics, adversomics, and the immune response network theory: individualized vaccinology in the 21st century.

Vaccines, like drugs and medical procedures, are increasingly amenable to individualization or personalization, often based on novel data resulting from high throughput "omics" technologies. As a result of these technologies, 21st century vaccinology will increasingly see the abandonment of a "one size fits all" approach to vaccine dosing and delivery, as well as the abandonment of the empiric "isolate-inactivate-inject" paradigm for vaccine development. In this review, we discuss the immune response network theory and its application to the new field of vaccinomics and adversomics, and illustrate how vaccinomics can lead to new vaccine candidates, new understandings of how vaccines stimulate immune responses, new biomarkers for vaccine response, and facilitate the understanding of what genetic and other factors might be responsible for rare side effects due to vaccines. Perhaps most exciting will be the ability, at a systems biology level, to integrate increasingly complex high throughput data into descriptive and predictive equations for immune responses to vaccines. Herein, we discuss the above with a view toward the future of vaccinology.

The composition of immune cells serves as a predictor of adaptive immunity in a cohort of 50- to 74-year-old adults.

Influenza causes significant morbidity and mortality annually. Although vaccination offers a considerable amount of protection, it is far from perfect, especially in aging populations. This is due to age-related defects in immune function, a process called immunosenescence. To date, there are no assays or methods to predict or explain variations in an individual's level of response to influenza vaccination. In this study, we measured levels of several immune cell subsets at baseline (Day 0) and at Days 3 and 28 post-vaccination using flow cytometry. Statistical modelling was performed to assess correlations between levels of cell subsets and Day 28 immune responses - haemagglutination inhibition (HAI) assay, virus neutralizing antibody (VNA) assay, and memory B cell ELISPOT. Changes in several groups of cell types from Day 0 to Day 28 and Day 3 to Day 28 were found to be significantly associated with immune response. Baseline levels of several immune cell subsets, including B cells and regulatory T cells, were able to partially explain variation in memory B-cell ELISPOT results. Increased expression of HLA-DR on plasmacytoid dendritic cells after vaccination was correlated with increased HAI and VNA responses. Our data suggest that the expression of activation markers (HLA-DR and CD86) on various immune cell subsets, as well as the relative distribution of cell subsets, both have value in predicting immune responses to influenza vaccination in older individuals.

Rubella.

Rubella remains an important pathogen worldwide, with roughly 100,000 cases of congenital rubella syndrome estimated to occur every year. Rubella-containing vaccine is highly effective and safe and, as a result, endemic rubella transmission has been interrupted in the Americas since 2009. Incomplete rubella vaccination programmes result in continued disease transmission, as evidenced by recent large outbreaks in Japan and elsewhere. In this Seminar, we provide present results regarding rubella control, elimination, and eradication policies, and a brief review of new laboratory diagnostics. Additionally, we provide novel information about rubella-containing vaccine immunogenetics and review the emerging evidence of interindividual variability in humoral and cell-mediated innate and adaptive immune responses to rubella-containing vaccine and their association with haplotypes and single-nucleotide polymorphisms across the human genome.