Poland, Gregory A.

Abstract Unvetted scientific claims about vaccines can spread rapidly and undermine decades of progress in immunization and public trust. A recent non-peer-reviewed analysis, promoted at political hearings, in the documentary “An Inconvenient Study,” and on social media, has been used to suggest that vaccinated children experience higher rates of chronic illness than unvaccinated peers. Despite standard regression models, critical flaws - uncontrolled confounding, exposure misclassification, unequal follow-up, and outcome multiplicity, invalidate causal inference. An independent group of international experts critically appraises this analysis and contrast its claims with the consistent evidence confirming vaccine safety and effectiveness. We also show how poorly designed studies can distort public discourse, amplify misinformation, and fuel vaccine hesitancy. We outline actions to strengthen research integrity, such as transparent data sharing, labeling of non-peer-reviewed content, and evidence-based communication. Safeguarding public health demands that vaccine evidence be methodologically sound, reviewed, and interpreted by qualified experts.

Abstract Background While immunologic aging impacts immune responses to vaccination, consistent biomarkers associated with aging of the immune system and suboptimal serologic response to influenza vaccination have not been well-studied. Identification of readily measurable biomarkers of immunosenescence may have predictive clinical utility and inform targeted influenza vaccination strategies and future research into aging of the immune system. Methods We quantified multiple serum/plasma and cell-based parameters related to immune aging (CMV serostatus, plasma cytokines/chemokines, TREC, TERT, NK cell functionality, and DNA methylation clock) at baseline in an adult (age range 18-85) cohort of 2019-2020 influenza vaccine recipients (n=337) and evaluated their associations with vaccine-induced HAI response to influenza A/H1N1, A/H3N2 and B/Victoria strains. Results CMV IgG titers were significantly positively correlated with vaccine-induced increases in HAI antibody titers to influenza A/H1N1 ( p= 0.02) and A/H3N2 ( p =0.014). CMV IgG titers ( p= 0.00096) and CMV seropositivity ( p= 0.003) were also associated with Day 28 HAI seropositivity against influenza A/H3N2 in subjects seronegative at baseline. Conversely, plasma MCP-1 levels were negatively associated with HAI responses to the A/H3N2 ( p= 0.04) strain. These findings were significant independent of age, sex or vaccine type received (high vs standard-dose seasonal influenza vaccine) Conclusions Our identification of significant relationships between easily quantifiable immune markers and HAI responses to influenza A vaccine strains across sex and age enhances our knowledge of specific links between immune aging and influenza vaccine-induced immunity. These markers could be leveraged for predicting response to influenza immunization.

Background Measles remains a public health threat in the United States with over 50,000 cases being reported from 1989 through 1991 with continued smaller outbreaks. Measles vaccine failure is in part to blame for these large-scale outbreaks. The human leukocyte antigen (HLA) genes are important determinants of immune response to measles virus and vaccine. To examine the influence that HLA polymorphisms may have on measles vaccine antibody response, we compared the distribution of HLA-DRB1 alleles between measles vaccine nonresponders and hyper-responders. Methods We determined the seroprevalence of measles antibody in 881 school children immunized with measles-mumps-rubella-II at age 15 months using a whole virus IgG EIA. We performed class II HLA-DR typing by PCR with sequence specific primers (PCR-SSP) on 81 nonresponders (IgG seronegative) and 65 hyper-responders (from the upper 10th percentile of IgG levels of all subjects). We then compared the distribution of alleles between nonresponders and hyper-responders. Results The distribution of HLA-DRB1 alleles among nonresponders compared to hyper-responders was significantly different ( p = 0.014). Nonresponders were significantly less likely to carry the HLA-DRB1*13 alleles than were hyper-responders (7.4% vs 16.2%; p = 0.02). Nonresponders also had an excess of HLA-DRB1*07 alleles (15.4% vs 6.2%; p = 0.015). Conclusions The absence of HLA-DRB1*13 alleles is associated with measles vaccine nonresponse. The absence of this allele has also been associated with susceptibility to other infectious diseases. The role of this gene in the immunogenetic response to infectious diseases requires further study.

ImportanceIndia’s goal of measles elimination remains unmet, as evidenced by significant recent outbreaks.ObjectiveTo identify seroprevalence rates among vaccinated children and to examine demographic factors that influence antibody responses.Design, Setting, and ParticipantsThis cross-sectional study included a highly vaccinated cohort of Indian children from the states of Kerala and Tamil Nadu between 2018 and 2023. Eligible children had received at least 2 doses of measles-containing vaccines; their mothers were recruited from various community settings, including local nursery and secondary schools, residential associations, and hospitals.ExposureMeasles-specific antibodies were quantified in serum samples.Main Outcomes and MeasuresMeasles-specific immunoglobulin G (IgG) and neutralizing antibodies were quantified in both children and mothers. Measles-specific IgM was also measured in children.ResultsThe total cohort comprised 684 children (median age, 9 years [range, 4-18 years]; 348 male [50.1%]) and 544 mothers. All children received at least 2 doses of measles-containing vaccines; 435 children (63.6%) received a third dose, and 7 (1.0%) received a fourth dose. Among the children, 621 (90.8%) had positive measles-specific IgG, and 623 (91.5%) had protective neutralizing antibodies titers, with a strong correlation between measles-specific IgG and neutralizing antibodies (r = 0.73; P < .001). Female children exhibited significantly higher titers of both measles-specific IgG and neutralizing antibodies compared with male children. While IgG and neutralizing antibody titers remained stable over time and were not associated with the number of vaccine doses in children, neutralizing antibody titers increased with age in mothers, likely due to repeated viral exposure. Notably, in 20 families with at least 2 children, differential measles-specific IgM profiles were observed between siblings despite high IgG and neutralizing antibody titers, suggesting ongoing breakthrough infections.Conclusions and RelevanceIn this cross-sectional study, substantial measles immunity gaps were found despite high vaccine coverage with evidence of breakthrough infections, posing significant challenges to India’s measles elimination efforts. These results underscore the urgent need to strengthen India’s immunization program and investigate the mechanisms driving suboptimal responses to measles vaccination; without addressing these immune response deficiencies, achieving measles elimination through increased vaccine coverage alone may remain unattainable in India.

Rubella is typically a mild viral illness, but it can lead to severe complications when contracted during pregnancy, such as pregnancy loss or developmental defects in the fetus (congenital rubella syndrome). Therefore, it is crucial to develop and maintain protective immunity in women of childbearing age. In this study, we assessed the transcriptional factors associated with rubella-specific immune outcomes (IgG binding antibody and avidity, neutralizing antibody, and memory B cell ELISpot response) following a third MMR vaccine dose in women of reproductive age to identify key factors/signatures impacting the immune response. We identified baseline (Day 0) and differentially expressed (Day 28–Day 0) genes associated with several RV-specific immune outcomes, including the transferrin receptor 2 (TFR2), which is an important factor regulating iron homeostasis and macrophage functional activity, and a close functional homolog of TFR1, the cellular receptor of the New World hemorrhagic fever arenaviruses. We also identified enriched KEGG pathways, “cell adhesion molecules”, “antigen processing and presentation”, “natural killer cell-mediated cytotoxicity”, and “immune network for IgA production”, relevant to immune response priming and immune activation to be associated with RV-specific immune outcomes. This study provides novel insights into potential biomarkers of rubella-specific immunity in women of childbearing age.

Sustained measles elimination requires high herd immunity, maintained through vaccination and verified by global serosurveillance. Comparing measles neutralizing antibody titres in US and Indian populations, we identified distinct age-specific and country-specific trends. These findings highlight the urgent need for tailored strategies to strengthen population immunity and global measles control efforts.

Abstract Background Antibody responses to MF59-adjuvanted (MF59Flu) and high-dose (HDFlu) influenza vaccines have been well-characterized in older adults, yet corresponding cellular immune response data remain limited. Methods Blood samples were collected from 106 MF59Flu recipients and 112 HDFlu recipients at 4 time points: before vaccination (day 0) and on days 1, 8, and 28 postvaccination. Antibody responses were assessed in serum samples using a hemagglutination inhibition assay. Eight proinflammatory cytokines and chemokines, including IFN-α2a, IFN-γ, IP-10, MCP-1, MIP-1α, IL-1β, IL-6, and IL-8, were quantified from peripheral blood mononuclear cells using a multiplex assay. Associations between cytokine/chemokine secretion levels and antibody responses were examined, along with the effect of sex, age, body mass index (BMI), and cytomegalovirus infection status. Results Age was positively correlated with IL-8 levels on day 1 (r = 0.24, P < .001) and the change in IL-8 levels from day 0 to day 1 (r = 0.16, P = .021). Notably, the change in IL-8 levels was negatively associated with day 28 hemagglutination inhibition titers (r = −0.15, P = .026). Causal mediation analysis demonstrated that IL-8 exerted significant causal mediation effects on antibody responses at both day 8 (P = .046) and day 28 (P = .0045). No significant effects of other cytokines and chemokines, vaccine type, sex, or BMI on antibody responses were observed. Conclusions Our findings underscore IL-8 as a potential mediator of antibody responses to influenza vaccination in older adults, suggesting that IL-8 inhibition could serve as a molecular intervention to improve antibody responses in this high-risk population.

Objectives: This study aims to identify COVID-19 breakthrough infections among people with HIV (PWH) across different phases of the pandemic and explore whether differential immune dysfunctions are associated with breakthrough infections. Design and methods: This retrospective population-based cohort study used data from an integrated electronic health record (EHR) database in South Carolina (SC). Breakthrough infection was defined as the first COVID-19 diagnosis documented in the state agency after the date an individual was fully vaccinated (ie, 2 doses of Pfizer/BNT162b2 or Moderna/mRNA-1273, or 1 dose of Janssen/Ad26.COV2.S) through June 14, 2022. We analyzed the risk and associated factors of the outcome using Cox proportional hazards models. Results: Among 7596 fully vaccinated PWH, the overall rate of breakthrough infections was 118.95 cases per 1000 person-years. When compared with the alpha-dominant period, the breakthrough infection rate was higher during both delta-dominant (HR: 1.50; 95% CI: 1.25 to 1.81) and omicron-dominant (HR: 2.86; 95% CI: 1.73 to 4.73) periods. Individuals who received a booster dose had a lower likelihood of breakthrough infections (HR: 0.19; 95% CI: 0.15 to 0.24). There was no association of breakthrough infections with degree of HIV viral suppression, but a higher CD4 count was significantly associated with fewer breakthroughs among PWH (>500 vs <200 cells/mm3: HR: 0.68; 95% CI: 0.49 to 0.94). Conclusions: In our PWH population, the incidence of breakthrough infections was high (during both delta-dominant and omicron-dominant periods) and mainly associated with the absence of a booster dose in patients older than 50 years, with comorbidities and low CD4 count.

Abstract Pre and post-licensure studies have supported the safety of the intranasally administered live, attenuated influenza vaccine (LAIV). The objective of this study was to measure changes to the nasal microbiome in subjects who received LAIV. We hypothesized that administration would result in only a transient alteration of the nasal microbiome. To test this hypothesis, we swabbed the anterior nares just before vaccination (Day 0), and on Day 7 and Day 28. We performed next-generation sequencing on amplified 16s rRNA genes. There was a significant increase in alpha diversity (Observed, CHAO, and ACE) from Days 0 to 7 (p = 0.02, 0.00, 0.01; respectively) and Days 0 to 28 (p = 0.05, 0.03, 0.05; respectively). When measuring differences in specific observed taxanomic units (OTUs), we identified a significant increase in Flavobacteriaceae and Enterobacteriaceae after vaccination. These data suggest that LAIV may increase the ability of these less abundant OTUs to establish a community niche and, therefore, could be clinically relevant. We have begun to investigate the second objective of this study, which is to correlate microbiome composition with mucosal immunity to influenza virus. To our knowledge, this is the first study to investigate LAIV-induced alterations to the human microbiome. These data may lead to a better understanding of the influences of the host microbiome on the response to vaccine, and perhaps infection.