Suboptimal Immunity Research Articles

Multicomponent intranasal adjuvant for mucosal and durable systemic SARS-CoV-2 immunity in young and aged mice

Multiple FDA-approved SARS-CoV-2 vaccines currently provide excellent protection against severe disease. Despite this, immunity can wane relatively fast, particularly in the elderly and novel viral variants capable of evading infection- and vaccination-induced immunity continue to emerge. Intranasal (IN) vaccination more effectively induces mucosal immune responses than parenteral vaccines, which would improve protection and reduce viral transmission. Here, we developed a rationally designed IN adjuvant consisting of a combined nanoemulsion (NE)-based adjuvant and an RNA-based RIG-I agonist (IVT DI) to drive more robust, broadly protective antibody and T cell responses. We previously demonstrated this combination adjuvant (NE/IVT) potently induces protective immunity through synergistic activation of an array of innate receptors. We now demonstrate that NE/IVT with the SARS-CoV-2 receptor binding domain (RBD), induces robust and durable humoral, mucosal, and cellular immune responses of equivalent magnitude and quality in young and aged mice. This contrasted with the MF59-like intramuscular adjuvant, Addavax, which showed a decrease in immunogenicity with age. Robust antigen-specific IFN-γ/IL-2/TNF-α was induced in both young and aged NE/IVT-immunized animals, which is significant as their reduced production is associated with suboptimal protective immunity in the elderly. These findings highlight the potential of adjuvanted mucosal vaccines for improving protection against COVID-19.

Predictors of re-admission after COVID-19 hospitalizations in patients with underlying gastrointestinal malignancy.

e16327 Background: COVID-19 infections have been known to cause worse outcomes in patients with underlying co-morbid conditions. Currently, there is limited data regarding re-admissions in such patients after COVID-19 infection. So, we pursued to assess the rates, predictors, and causes of re-admission after COVID-19 infection in patients who had underlying gastrointestinal malignancy. Methods: The National Readmission Database for 2020 was analyzed to identify patients with COVID-19 hospitalizations who also had a co-diagnosis of GI malignancy. Data for re-admission was gathered, at 30 and 90 days after initial hospitalization. Multivariate logistic and linear regression analysis was used accordingly to adjust for possible confounders. Results: For 30 days: A total of 2,726 COVID-19 hospitalizations had a co-diagnosis of GI malignancy. The mean LOS (length of stay) for index admission was 8.7 days. The mean TOTCHG (total hospital charge) for index admission was $85,747. Within 30 days from discharge, 462 (21%) were re-admitted. The in-hospital mortality in re-admissions (18.4%) was quite similar to that for index hospitalization (18.5%). Positive predictors of re-admission include shorter length of stay during initial hospitalization (<3 days), anemia, renal insufficiency/chronic kidney disease, and atherosclerosis of the aorta. Females had a lower chance of re-admission compared to males. Among the top causes of re-admission were ongoing COVID-19 infection (27%), sepsis (16.3%), acute kidney injury (2.4%), and metabolic encephalopathy (1.2%). For 90 days: A total of 1,782 COVID-19 hospitalizations had a co-diagnosis of GI malignancy. The mean LOS (length of stay) for index admission was 9.2 days. The mean TOTCHG (total hospital charge) for index admission was $90,908. Within 90 days from discharge, 411 (29%) were re-admitted. The in-hospital mortality in readmissions (14%) was lower than that for index hospitalization (20.3%). Predictors of re-admissions include secured insurance, anemia, renal insufficiency/chronic kidney disease, and cerebrovascular accidents. Top causes of re-admission were ongoing COVID-19 infection (18.5%), aspiration pneumonitis (2.9%), pneumonia (2.3%), and acute kidney injury (1.4%). Conclusions: Infections were the leading cause of re-admission, which is an important factor to consider when managing patients with GI malignancies due to sub-optimal immunity. Among these patients, those with concomitant anemia and chronic kidney disease were more prone to being re-admitted. Patients with GI malignancies also tended to have a higher length of stay, leading to higher charges, more exposure to nosocomial infections, and delays in cancer treatment leading to worse cancer outcomes. Pre-mature discharges, without medical optimization, can also potentially predispose to higher rates of re-admissions.

Impact of age and comorbidities on SARS-CoV-2 vaccine-induced T cell immunity

BackgroundOlder age and chronic disease are important risk factors for developing severe COVID-19. At population level, vaccine-induced immunity substantially reduces the risk of severe COVID-19 disease and hospitalization. However, the relative impact of humoral and cellular immunity on protection from breakthrough infection and severe disease is not fully understood.MethodsIn a study cohort of 655 primarily older study participants (median of 63 years (IQR: 51–72)), we determined serum levels of Spike IgG antibodies using a Multiantigen Serological Assay and quantified the frequency of SARS-CoV-2 Spike-specific CD4 + and CD8 + T cells using activation induced marker assay. This enabled characterization of suboptimal vaccine-induced cellular immunity. The risk factors of being a cellular hypo responder were assessed using logistic regression. Further follow-up of study participants allowed for an evaluation of the impact of T cell immunity on breakthrough infections.ResultsWe show reduced serological immunity and frequency of CD4 + Spike-specific T cells in the oldest age group (≥75 years) and higher Charlson Comorbidity Index (CCI) categories. Male sex, age group ≥75 years, and CCI > 0 is associated with an increased likelihood of being a cellular hypo-responder while vaccine type is a significant risk factor. Assessing breakthrough infections, no protective effect of T cell immunity is identified.ConclusionsSARS-CoV-2 Spike-specific immune responses in both the cellular and serological compartment of the adaptive immune system increase with each vaccine dose and are progressively lower with older age and higher prevalence of comorbidities. The findings contribute to the understanding of the vaccine response in individuals with increased risk of severe COVID-19 disease and hospitalization.

Addressing Determinants of Immunization Inequities Requires Objective Tools to Devise Local Solutions.

Universal immunization substantially reduces morbidity and mortality from vaccine-preventable diseases. In recent years, routine immunization coverage has varied considerably among countries across the WHO European Region, and among different populations and districts within countries. It has even declined in some countries. Sub-optimal immunization coverage contributes to accumulations of susceptible individuals and can lead to outbreaks of vaccine-preventable diseases. The European Immunization Agenda 2030 (EIA2030) seeks to build better health in the WHO European Region by ensuring equity in immunization and supporting immunization stakeholders in devising local solutions to local challenges. The factors that influence routine immunization uptake are context specific and multifactorial; addressing immunization inequities will require overcoming or removing barriers to vaccination for underserved individuals or populations. Local level immunization stakeholders must first identify the underlying causes of inequities, and based on this information, tailor resources, or service provision to the local context, as per the organization and characteristics of the health care system in their countries. To do this, in addition to using the tools already available to broadly identify immunization inequities at the national and regional levels, they will need new pragmatic guidance and tools to address the identified local challenges. It is time to develop the necessary guidance and tools and support immunization stakeholders at all levels, especially those at the subnational or local health centre levels, to make the vision of EIA2030 a reality.

Communication strategies to improve human papillomavirus (HPV) immunisation uptake among adolescents in sub-Saharan Africa: a systematic review and meta-analysis

ObjectivesDeveloping countries face the greatest cervical cancer disease burden and mortality with suboptimal immunisation uptake. This review explores the communication strategies adopted, successes, challenges and lessons learnt in sub-Saharan countries...

Multi-method findings on COVID-19 vaccine acceptability among urban refugee adolescents and youth in Kampala, Uganda

ABSTRACT Scant studies have explored COVID-19 vaccine acceptability among refugees. However, contexts of forced migration may elevate COVID-19 vulnerabilities, and suboptimal refugee immunisation rates are reported for other vaccine-preventable diseases. We conducted a multi-methods study to describe COVID-19 vaccine acceptability among urban refugee youth in Kampala, Uganda. This study uses cross-sectional survey data from a cohort study with refugees aged 16–24 in Kampala to examine socio-demographic factors associated with vaccine acceptability. A purposively sampled cohort subset (n = 24) participated in semi-structured in-depth individual interviews, as did key informants (n = 6), to explore COVID-19 vaccine acceptance. Among 326 survey participants (mean age: 19.9; standard deviation 2.4; 50.0% cisgender women), vaccine acceptance was low (18.1% reported they were very likely to accept an effective COVID-19 vaccine). In multivariable models, vaccine acceptance likelihood was significantly associated with age and country of origin. Qualitative findings highlighted COVID-19 vaccine acceptability barriers and facilitators spanning social-ecological levels, including fear of side effects and mistrust (individual level), misinformed healthcare, community and family attitudes (community level), tailored COVID-19 services for refugees (organisational and practice setting), and political support for vaccines (policy environment). These data signal the urgent need to address social-ecological factors shaping COVID-19 vaccine acceptability among Kampala’s young urban refugees. Trial registration: ClinicalTrials.gov identifier: NCT04631367.

A looming epidemic: combating the recurrent outbreaks of diphtheria in Nigeria.

Nigeria has endured several diphtheria outbreaks over the last few decades, mirroring a suboptimal population immunity across several demographics within the country. The country's northern region has been affected mainly by this infectious disease; it directly depicts the effect of poor DPT vaccine uptake amongst children in this region compared to other geopolitical zones in Nigeria. Whilst pharmaceutical intervention and surveillance activities have commenced as directed by the NCDC, to combat this public health menace, top leaders of the Nigerian healthcare system - public and private sectors, must understudy the predisposing factors gearing the recurrence of diphtheria in Nigeria and provide robust, research-based and scientific mechanisms to arrest the root causes of the incessant outbreaks. This article discusses the factors promoting the recurrent diphtheria outbreaks in Nigeria, the preexisting interventions with their existential deterrents, and new strategies recommended to curb the further resurgence of the disease.

China has the momentum to eliminate measles

China has the momentum to eliminate measles

Human papillomavirus infection-related cancer risk for kidney transplant recipients during adult life can be reduced by vaccination during childhood and adolescence.

Malignancies are found between the first three reasons of mortality in pediatric and adult kidney transplant recipients, who overall have disproportionately higher rates of cancer compared to the general population, including human papillomavirus (HPV)-related genital, anal and oropharynx region cancers. Therefore, preventing HPV in this patient population is extremely important. HPV-vaccine was demonstrated to prevent HPV infection in individuals with intact immune systems. In addition, recent data reported less precancerous HPV lesions and cervical cancers with use of HPV vaccine. Since HPV is a sexually transmitted virus that is typically acquired shortly after the onset of sexual activity, it is best to administer the HPV vaccine immunization prior to the onset of sexual activity. This article reviews the epidemiology and pathophysiology of the HPV infection, as well as its role in the development of HPV-related pre-cancerous lesions and cancers in both general population and kidney transplant recipients. The focus is on the most effective primary prophylactic strategy, which is the HPV vaccination. The particularities of HPV vaccination strategies in kidney transplant recipients are compared to the general population. In addition, the article analyzes the various causes of suboptimal HPV immunization rates in kidney transplant candidates and recipients and discusses vaccination optimization strategies that can be applied during childhood and adolescence to reduce the burden of HPV-related disease states and cancer among adult kidney transplant recipients.

Factors contributing to vaccine hesitancy and reduced vaccine confidence in rural underserved populations

Vaccination remains one of the most effective ways to limit the spread of infectious diseases, and reduce mortality and morbidity in rural areas. Waning public confidence in vaccines, especially the COVID-19 vaccine, remains a cause for concern. A number of individuals in the US and worldwide remain complacent, choosing not to be vaccinated and/or delay COVID-19 vaccination, resulting in suboptimal herd immunity. The primary goal of this study is to identify modifiable factors contributing to COVID-19 vaccine hesitancy among vaccine-eligible individuals with access to vaccines in two under-resourced rural states, Alaska and Idaho. This qualitative study used semi-structured interviews with providers and focus groups with community participants in Alaska and Idaho. A moderator’s guide was used to facilitate interviews and focus groups conducted and recorded using Zoom and transcribed verbatim. Thematic, qualitative analysis was conducted using QDA Miner. Themes and subthemes that emerged were labeled, categorized, and compared to previously described determinants of general vaccine hesitancy: established contextual, individual and/or social influences, vaccine and vaccination-specific concerns. Themes (n = 9) and sub-themes (n = 51) identified during the qualitative analysis highlighted a factor’s contributing to COVID-19 vaccine hesitancy and poor vaccine uptake. Relevant influenceable factors were grouped into three main categories: confidence, complacency, and convenience. Vaccines are effective public health interventions to promote health and prevent diseases in rural areas. Practical solutions to engage healthcare providers, researchers, vaccine advocates, vaccine manufacturers, and other partners in local communities are needed to increase public trust in immunization systems to achieve community immunity.

The Outcomes of Covid-19 in Patients with CLL during the Omicron Sub-Variants Surge

Introduction: Patients with chronic lymphocytic leukemia (CLL) infected with SARS-CoV-2 are at increased risk of severe Covid-19 and death, because of an impaired immune system and suboptimal immunity after vaccination. Despite recent studies, the outcomes of patients with CLL infected with the Omicron sub-variants are not fully elucidated. Methods: In this single-center retrospective study, we analyzed the clinical outcomes of CLL patients infected with SARS-CoV-2 from December 2021 through July 2022. The entire cohort was divided into three groups according to the SARS-CoV-2 variants dominating periods in Israel; period #1, since December 15th, 2021 until March 13th, 2022 (B.1.1.529, BA.1), period #2, since March 14th until June 5th, 2022 (BA.2) and period #3, since June 6th until July 24th, 2022 (BA.5). Results: A total of 90 patients were included in this study (Table 1). The median age was 72 years (range 39-93) and 66 were males (73.3%). Thirty-four patients (37.8%) were treatment naïve, 45 (50.0%) on active treatment (28 treated with Bruton's tyrosine kinase inhibitors [BTKi], 16 with venetoclax+anti-CD20 therapy, and 1 with venetoclax monotherapy), and 11 (12.2%) previously treated. Eighty-seven patients (96.7%) had Covid-19-related symptoms, most commonly fatigue (n=50, 55.6%), followed by cough (n=43, 47.8%) and fever (n=37, 41.1%). Eighty-five patients (94.4%) were vaccinated with at least 3 doses of the BNT162b2 mRNA vaccine. During the study's follow-up period (median=120 days, range 4-221), 2 patients (2.2%) were re-infected with SARS-CoV-2. The severity of Covid-19 on detection was mild in 78 patients (86.7%) and moderate/severe in 12 patients (13.3%). Forty-eight patients (53.3%) were treated with oral antiviral drugs or monoclonal antibodies (40 with paxlovid, 7 with molnupiravir and 1 with casirivimab/imdevimab) outside the hospital. Nine patients developed mild Covid-19 despite administration of pre-exposure prophylaxis with tixagevimab/cilgavimab (median=49 days [range, 7-102] prior to infection). Twenty-seven patients (30.0%) were hospitalized, 15 (55.6%) of them due to severe/critical Covid-19. The median time from SARS-CoV-2 diagnosis to hospitalization was 9 days (range, 0-36). Fifteen hospitalized patients (55.6%) required oxygen support and 2 (7.4%) eventually needed mechanical ventilation. Nine patients (33.3%, 9/27) were readmitted because of persistent SARS-CoV-2 infection, including 6 patients (66.7%) who were hospitalized twice and 3 patients (33.3%) three times. Four patients with persistent Covid-19 after a course of antiviral therapy were subsequently successfully treated with paxlovid and remdesivir. The overall 30-day mortality due to Covid-19 was 6.7% (6/90, 22.2% [6/27] of the hospitalized patients). In comparison between the 3 different time periods (Figure 1), both the hospitalization and death rates were higher in the period #1 (hospitalization rate of 42.9% [21/49] vs. 20.0% [5/25] vs. 6.3% [1/16] in period #1, #2, and #3, respectively and a mortality rate of 12.2% [6/49] in period #1 compared with 0% [0/25] in period #2 and 0% [0/16] in period #3). In univariate analysis, the independent variables associated with hospitalization included: period #1 (OR=4.4, 95% CI 1.6-12.3; p=0.007), active anti-CLL therapy (OR=3.8, 95% CI 1.3-8.9; p=0.021), and fever (OR=3.7, 95% CI 1.4-9.4; p=0.012). Conclusions: In patients with CLL, the rates of hospitalization and mortality due to Covid-19 were lower during the BA.2 and BA.5 sub-variants dominating period compared to the period dominated by the Omicron (B.1.1.529) and the BA.1 sub-variant. The improved outcomes may be attributed to better clinical management (e.g. pre-exposure prophylaxis and antiviral therapies) and viral strain properties. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Differences in Humoral and Cellular Response to COVID-19 Vaccine Against Different Variants over Time in Chronic Lymphocytic Leukemia

Background Patients with chronic lymphocytic leukemia (CLL) are at an increased risk of adverse clinical outcomes following COVID-19 infection, due to impaired humoral and cellular response to infection and vaccination. Most of the data available focus on humoral responses to SARS-CoV-2 vaccination or T cell responses following 2-dose vaccine series. However, the effect of emerging variants of concern (VoC) on T cell recognition in this population has not been previously reported. Aim of the study To evaluate functional humoral response and functional SARS-CoV-2 spike-specific T cell response in CLL patients after the second, the third dose, and 12-months since the first dose. To determine the effect of treatment on immune outcomes. To investigate T cell response to Omicron (BA.2) and ancestral strains, and the impact of Omicron-defining mutations on total spike-specific functional response. Methods CLL patients from Mayo Clinic, Rochester who submitted a blood sample soon after the second and the third dose, and 12-months after the first dose of an mRNA-based vaccination were included. The samples collected following a documented SARS-CoV-2 infection were excluded. Spike-specific T cell responses were quantified using IFN-γ ELISpot assay (R&D Systems). PBMCs were stimulated with a peptide pool spanning the complete sequence of ancestral SARS-CoV-2 spike and two 68-peptide pools: the BA.2 mutation pool selectively covering the mutated spike regions, and reference pool containing the wild-type sequences for the same regions (Peptivator pools, Miltenyi Biotec). The results were considered positive if at least two of the following three were met: average spot count > 5 SFUs/2x10^5; mean spot count >3-fold higher than in negative control; and statistically significant difference (paired t-test<0.5) between Ag-specific and negative control wells.For evaluation of humoral response, we utilized an assay measuring antibody capable of blocking spike receptor binding domain (RBD)-ACE2 (cPASS GenScript). Statistical analysis was performed using t-test and Mann-Whitney test for continuous variables; Chi-square (or Fisher's Exact test) was used for comparing categorical variables. The Mayo Clinic IRB approved the study. Results Thirty patients with CLL were included in the study. Eight patients received a fourth vaccine dose before the 12-months blood draw. The rate of positivity for receptor blocking activity was significantly higher in the untreated group after the 2ndand 3rd dose (0% vs. 75%, 38.5% vs. 93.3%, p>0.05). This difference was not observed for the cellular response to spike-specific ancestral in all the three timepoints. At 12 months 54.16 % of the patients had positive IFN-γ ELISpot response, with no significant difference between treated and untreated (58.3% vs. 50%, p=1.0), and patients with and without a fourth dose (62.5% vs. 50%, p=0.67). Among treated CLL patients, seven (70%) and five (41.6%) patients without neutralizing antibodies had detectable cellular response after the 2nd and 3rd dose, respectively. On average, less than 25% of the total spike-specific T cell reactivity was directed against the epitopes in the regions mutated in BA.2 subvariant. Moreover, we did not detect statistically significant differences in IFN-γspot counts between the mutational and reference 68-peptide pools at any timepoint (median spots T1: 1.62 vs. 2.33, p=0.4; T2: 5 vs. 4.33, p=0.31; T3: 5 vs. 6, p=0.49). Conclusion Treatment status impacts humoral, but no cellular response to SARS-CoV-2 vaccination CLL patients. However, the overall rate of positive cellular response one year after the first dose is low. This, combined with no boosting of cellular response upon the 4th dose, reflects an impaired response even after additional doses. Suboptimal cellular immunity may put CLL patients at higher risk of severe COVID-infection. We did not observe significant difference in the cellular response between ancestral and Omicron BA.2 strains, and only the smaller fraction of T cell response was directed against regions harboring BA.2-specific mutations. These findings confirm the greater observed cross-reactivity to VoC with cellular compared to humoral immune responses. They also suggest significant cellular immunity may remain in the face of Omicron circulation, at least among patients who have response to the vaccine. Given the small sample size, our findings need to be confirmed. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Seroprevalence of Measles Antibodies in a Highly MMR-Vaccinated Population.

As an extremely contagious pathogen, a high rate of vaccine coverage and the durability of vaccine-induced immunity are key factors to control and eliminate measles. Herein, we assessed the seroprevalence of antibodies specific to measles in a cohort of 1393 adults (20-44 years old). ELISA results showed a nontrivial proportion of 37.6% study subjects being negative for measles immunoglobulin G (IgG). We also found significant influences of sex and age of the study cohort on the IgG level. Our findings suggest that even within a highly vaccinated population, a subset of individuals may still have sub-optimal immunity against measles and potentially be susceptible during any future measles outbreaks.

11.M. Workshop: Vaccination hesitancy in the Western Balkans and inclusive governance

Abstract Vaccine hesitancy has been identified as one of the crucial contributors to the global decline in vaccination coverage for several well-established vaccines in previous decades and is listed by the World Health Organization as one of the top ten threats to global health. In developing countries, the leading reasons for under-vaccination appear to be the lack of access, low education and socio-economic status. In developed countries psychological, social, and contextual factors are defined as main drivers of vaccine hesitancy. With the COVID-19 pandemic the threat of vaccine hesitancy has become more evident and is now in the focus of strategies and efforts to improve and strengthen the interventions to combat vaccine hesitancy and increase vaccination coverage. Despite the availability of multiple effective vaccines against COVID-19, only 40% of population of Wester Balkans in average has been completely vaccinated (with a complete initial protocol), which is far below the world average (56%). Vaccine hesitancy largely jeopardizes the achievement of heard immunity, postponing the end of the pandemic. To explore reasons of vaccine hesitancy, the cross-sectional and quasi-experimental studies were performed from July to September 2021 in five countries of the Western Balkans: Albania, Bosnia-Herzegovina, Montenegro, North Macedonia, and Serbia. The results will be presented and discussed from a policy perspective. The first presentation will introduce to the actual debate around vaccination hesitancy; the second presentation describes the survey design and key results related to societal factors (confidence in political and health authorities, science, and pharmaceutical companies), social responsibility (personal sense of responsibility in achieving collective immunity and contagion prevention) and the credibility of information sources about COVID-19 vaccines; the third presentation will discuss components of credibility (expertise, trustworthiness, and caring/goodwill) after respondents’ exposure to messages with narratives on COVID-19 vaccine decisions. The fourth presentation is going to identify promising policy options. The objective of the workshop is to present and discuss the results of the Western Balkans study, relate them to corresponding studies in Europe and beyond, and propose effective interventions. The audience is invited to discuss the findings and the practicability of strategies to improve the acceptance of qualified information in the population, how to enhance trustworthy, how to improve vaccination rates. The discussion will focus on the following questions: a) What are the main drivers of vaccination hesitancy? b) Which messaging format is most convincing and trustworthy? c) Why is the global dimension essential? Key messages • Vaccine hesitancy is a serious threat and reason for the insufficient vaccination coverage and suboptimal herd immunity in the Western Balkans. • Vaccination policy has to enhance information trustworthy and source credibility at the national level and argue for fair resource distribution in the global dimension.

Patient-Guided Talking Points to Address COVID-19 and General Vaccine Hesitancy.

Vaccination remains one of the most effective ways to limit spread of disease. Waning public confidence in COVID-19 vaccines has resulted in reduced vaccination rates. In fact, despite vaccine availability, many individuals choose to delay COVID-19 vaccination resulting in suboptimal herd immunity and increased viral mutations. A number of qualitative and quantitative studies have been conducted to identify, understand, and address modifiable barriers and factors contributing to COVID-19 vaccine hesitancy among individuals with access to vaccine. Vaccine confidence may be improved through targeted patient–provider discussion. More patients are turning to pharmacists to receive their vaccinations across the lifespan. The primary goal of this commentary is to share evidence-based, patient talking points, tailored by practicing pharmacists, to better communicate and address factors contributing to vaccine hesitancy and reduced vaccine confidence.

Age and respiratory syncytial virus etiology in bronchiolitis clinical outcomes.

Respiratory syncytial virus (RSV) is the most frequent cause of bronchiolitis. Precise and updated information about demographic characteristics, clinical manifestations, and risk factors for severe disease are needed for optimal implementation of upcoming new therapeutic and preventive interventions. The main goals of this study were to define the epidemiology of acute bronchiolitis in hospitalized young children during 5 calendar years in Spain; evaluate the differences in clinical manifestations between children hospitalized with RSV infection and those hospitalized with non-RSV infection; and identify demographic characteristics, clinical parameters, and risk factors associated with disease severity. We performed a retrospective review of the medical records of children younger than 2 years who were hospitalized with bronchiolitis between January 2015 and December 2019. We constructed multivariable models to identify independent predictors of disease severity defined as length of hospital stay (LOS), pediatric intensive care unit (PICU) admission, and need for a high-flow-nasal canula (HFNC). From January 2015 to December 2019, 1437 children were hospitalized with bronchiolitis and met the inclusion criteria. The proportion of children hospitalized with bronchiolitis caused by RSV increased significantly during the study period, from 60% to 65% (P= .03). The children with RSV bronchiolitis were younger than those with non-RSV bronchiolitis (median age= 3 months [interquartile range= 1.5-6.5 months] vs 4 months [interquartile range= 2-7.5 months], respectively (P< .01). The children younger than 6 months with RSV bronchiolitis had enhanced disease severity compared with those with non-RSV bronchiolitis, as defined by an LOS of more than 4 days, severity scores, need for an HFNC, intravenous fluids, enteral feeding, and PICU admissions (P< .01). Age younger than 6 months and RSV-positive etiology were independently associated with greater odds of PICU admission, need for an HFNC, and longer LOS. This study identified differences in disease severity between young children with RSV bronchiolitis and those with non-RSV bronchiolitis. These differences are particularly significant in children younger than 6 months, who comprise a group of infants with suboptimal innate immunity to RSV and may benefit from new preventive strategies.

Immunodeficiency syndromes differentially impact the functional profile of SARS-CoV-2-specific T cells elicited by mRNA vaccination

Many immunocompromised patients mount suboptimal humoral immunity after SARS-CoV-2 mRNA vaccination. Here, we assessed the single-cell profile of SARS-CoV-2-specific T cells post-mRNA vaccination in healthy individuals and patients with various forms of immunodeficiencies. Impaired vaccine-induced cell-mediated immunity was observed in many immunocompromised patients, particularly in solid-organ transplant and chronic lymphocytic leukemia patients. Notably, individuals with an inherited lack of mature B cells, i.e., X-linked agammaglobulinemia (XLA) displayed highly functional spike-specific T cell responses. Single-cell RNA-sequencing further revealed that mRNA vaccination induced a broad functional spectrum of spike-specific CD4+ and CD8+ T cells in healthy individuals and patients with XLA. These responses were founded on polyclonal repertoires of CD4+ T cells and robust expansions of oligoclonal effector-memory CD45RA+ CD8+ T cells with stem-like characteristics. Collectively, our data provide the functional continuum of SARS-CoV-2-specific T cell responses post-mRNA vaccination, highlighting that cell-mediated immunity is of variable functional quality across immunodeficiency syndromes.

Assessment of vaccination service delivery and quality: a cross-sectional survey of over 1300 health facilities from 29 districts in Sindh, Pakistan conducted between 2017–18

BackgroundRoutine childhood immunization coverage in Pakistan remains sub-par, in part, due to suboptimal utilization of existing vaccination services. Quality of vaccine delivery can affect both supply and demand for immunization, but data for immunization center quality in Pakistan is sparse and in Sindh province in Southern Pakistan, no comprehensive health facility assessment has ever been conducted at a provincial level. We assessed health facilities, specifically immunization centers, and their associated health workers throughout the province to summarize quality of immunization centers. MethodsAn exhaustive list of health facilities obtained from Sindh’s provincial government was included in our analysis, comprising a total of 1396 public, private, and public-private health facilities. We adapted a health facility and health worker assessment survey developed by BASICS and EPI-Sindh to record indicators pertaining to health facility infrastructure, processes and human resources. Using expert panel ranking, we developed critical criteria (the presence of a cold box/refrigerator, vaccinator and vaccination equipment at the immunization center) to indicate the bare minimum items required by immunization centers to vaccinate children. We also categorized other infrastructure, process, and human resource items to determine high, low and moderate function requirements to ascertain quality. We evaluated presence of critical criteria, calculated scores for high, moderate and low function requirements, and displayed frequencies of infrastructure, process and human resource indicators for all immunization centers across Sindh. We analyzed results at the division level and utilized a two-sample independent clustered t-test to test differences in average function requirement scores between facilities that met critical criteria and those that did not.ResultsOut of the 1396 health facilities assessed across Sindh province from October 2017 to January 2018, 1236 (88.5%) were operational while 1209 (86.6%) offered vaccination services (immunization centers). Only 793 (65.6%; 793/1209) immunization centers met the critical criteria of having all the following items: vaccinator, a cold box or refrigerator and vaccine supplies. Of the 416 (34.4%; 416/1209) immunization centers that did not meet the critical criteria, most of the centers did not have a cold box or refrigerator (28.3%; 342/1209), followed by lack of vaccines (19.9%; 240/1209), and a vaccinator (13.0%; 157/1209). Of the 2153 healthcare workers interviewed, 1875 (87.1%) were vaccinators, of which 1745 (81.0%; 1745/2153) were male, and had an average of 12.4 years of schooling. A total of 1805 (96.3%; 1805/1875), 1655 (88.3%; 1655/1875) and 1387 (74.0%; 1387/1875) of the vaccinators were trained in vaccination, cold chain and inventory management respectively.ConclusionOne out of three immunization centers in Sindh lack the critical components essential for quality vaccination services. While the majority of health workers (>80%) were trained on vaccination and cold chain management, the proportion trained on inventory management was comparatively low. Our findings therefore suggest that suboptimal immunization center quality is partly due to inadequate infrastructure and inefficient processes contributed to an extent, by low levels of inventory management training among vaccinators. Our study presents critical research findings with high-impact policy implications for identifying and addressing gaps to improve vaccination uptake within a low-middle income country setting.

SARS-CoV-2-specific immune responses in boosted vaccine recipients with breakthrough infections during the Omicron variant surge.

BackgroundBreakthrough SARS-CoV-2 infections in vaccinated individuals have been previously associated with suboptimal humoral immunity. However, less is known about breakthrough infections with the Omicron variant.MethodsWe analyzed SARS-CoV-2–specific antibody and cellular responses in healthy vaccine recipients who experienced breakthrough infections a median of 50 days after receiving a booster mRNA vaccine with an ACE2 binding inhibition assay and an ELISpot assay, respectively.ResultsWe found that high levels of antibodies inhibited vaccine strain spike protein binding to ACE2 but that lower levels inhibited Omicron variant spike protein binding to ACE2 in 4 boosted vaccine recipients prior to infection. The levels of antibodies that inhibited vaccine strain and Omicron spike protein binding after breakthrough in 18 boosted vaccine recipients were similar to levels seen in COVID-19–negative boosted vaccine recipients. In contrast, boosted vaccine recipients had significantly stronger T cell responses to both vaccine strain and Omicron variant spike proteins at the time of breakthrough.ConclusionOur data suggest that breakthrough infections with the Omicron variant can occur despite robust immune responses to the vaccine strain spike protein.FundingThis work was supported by the Johns Hopkins COVID-19 Vaccine-related Research Fund and by funds from the National Institute of Allergy and Infectious Disease intramural program as well as awards from the National Cancer Institute (U54CA260491) and the National Institutes of Allergy and Infectious Disease (K08AI156021 and U01AI138897).

Why Aren't We Achieving High Vaccination Rates for Rotavirus Vaccine in the United States?

Rotavirus vaccine (RV) coverage levels for US infants are <80%. We surveyed nationally representative networks of pediatricians by internet/mail from April to June, 2019. Multivariable regression assessed factors associated with difficulty administering the first RV dose (RV#1) by the maximum age. Response rate was 68% (303/448). Ninety-nine percent of providers reported strongly recommending RV. The most common barriers to RV delivery overall (definite/somewhat of a barrier) were: parental concerns about vaccine safety overall (27%), parents wanting to defer (25%), parents not thinking RV was necessary (12%), and parent concerns about RV safety (6%). The most commonly reported reasons for nonreceipt of RV#1 by 4 to 5 months (often/always) were parental vaccine refusal (9%), hospitals not giving RV at discharge from nursery (7%), infants past the maximum age when discharged from neonatal intensive care unit/nursery (6%), and infant not seen before maximum age for well care visit (3%) or seen but no vaccine given (4%). Among respondents 4% strongly agreed and 25% somewhat agreed that they sometimes have difficulty giving RV#1 before the maximum age. Higher percentage of State Child Health Insurance Program/Medicaid-insured children in the practice and reporting that recommendations for timing of RV doses are too complicated were associated with reporting difficulty delivering the RV#1 by the maximum age. US pediatricians identified multiple, actionable issues that may contribute to suboptimal RV immunization rates including lack of vaccination prior to leaving nurseries after prolonged stays, infants not being seen for well care visits by the maximum age, missed opportunities at visits and parents refusing/deferring.