Poland, Gregory A.

Older adults experience declining influenza vaccine-induced immunity and are at higher risk of influenza and its complications. For this reason, high dose (e.g., Fluzone) and adjuvanted (e.g., Fluad) vaccines are preferentially recommended for people age 65 years and older. However, T cell transcriptional activity shaping the humoral immune responses to Fluzone and Fluad vaccines in older adults is still poorly understood. We designed a study of 234 older adults (≥65 years old) who were randomly allocated to receive Fluzone or Fluad vaccine and provided blood samples at baseline and at Day 28 after immunization. We measured the humoral immune responses (hemagglutination inhibition/HAI antibody titer) to influenza A/H3N2 and performed mRNA-Seq transcriptional profiling in purified CD4+ T cells, in order to identify T cell signatures that might explain differences in humoral immune response by vaccine type. Given the large differences in formulation (higher antigen dose vs adjuvant), our hypothesis was that each vaccine elicited a distinct transcriptomic response after vaccination. Thus, the main focus of our study was to identify the differential gene expression influencing the antibody titer in the two vaccine groups. Our analyses identified three differentially expressed, functionally linked genes/proteins in CD4+ T cells: the calcium/calmodulin dependent serine/threonine kinase IV (CaMKIV); its regulator the TMEM38B/transmembrane protein 38B, involved in maintenance of intracellular Ca2+ release; and the transcriptional coactivator CBP/CREB binding protein, as regulators of transcriptional activity/function in CD4+ T cells that impact differences in immune response by vaccine type. Significantly enriched T cell-specific pathways/biological processes were also identified that point to the importance of genes/proteins involved in Th1/Th2 cell differentiation, IL-17 signaling, calcium signaling, Notch signaling, MAPK signaling, and regulation of TRP cation Ca2+ channels in humoral immunity after influenza vaccination. In summary, we identified the genes/proteins and pathways essential for cell activation and function in CD4+ T cells that are associated with differences in influenza vaccine-induced humoral immunity by vaccine type. These findings provide an additional mechanistic perspective for achieving protective immunity in older adults.

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.

Abstract Over 10 million doses of COVID-19 vaccines based on RNA technology, viral vectors, recombinant protein, and inactivated virus have been administered worldwide. Although generally very safe, post-vaccine myocarditis can result from adaptive humoral and cellular, cardiac-specific inflammation within days and weeks of vaccination. Rates of vaccine-associated myocarditis vary by age and sex with the highest rates in males between 12 and 39 years. The clinical course is generally mild with rare cases of left ventricular dysfunction, heart failure and arrhythmias. Mild cases are likely underdiagnosed as cardiac magnetic resonance imaging (CMR) is not commonly performed even in suspected cases and not at all in asymptomatic and mildly symptomatic patients. Hospitalization of symptomatic patients with electrocardiographic changes and increased plasma troponin levels is considered necessary in the acute phase to monitor for arrhythmias and potential decline in left ventricular function. In addition to evaluation for symptoms, electrocardiographic changes and elevated troponin levels, CMR is the best non-invasive diagnostic tool with endomyocardial biopsy being restricted to severe cases with heart failure and/or arrhythmias. The management beyond guideline-directed treatment of heart failure and arrhythmias includes non-specific measures to control pain. Anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs, and corticosteroids have been used in more severe cases, with only anecdotal evidence for their effectiveness. In all age groups studied, the overall risks of SARS-CoV-2 infection-related hospitalization and death are hugely greater than the risks from post-vaccine myocarditis. This consensus statement serves as a practical resource for physicians in their clinical practice, to understand, diagnose, and manage affected patients. Furthermore, it is intended to stimulate research in this area.

AbstractBackgroundA 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.MethodsSerum 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.ResultsOf 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.ConclusionsMeasles-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.

AbstractWithin 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.

Abstract 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.

Background: COVID-19 vaccines are safe and effective at preventing severe disease. Among the rare complications that may compromise vaccine acceptance are allergic reactions. This study aimed at comparing the incidence and potential triggers of the most commonly reported allergic reactions related to licensed COVID-19 vaccines in Europe and the United States (US) based on data of the two of the world’s largest vaccine adverse event reporting systems, EudraVigilance and VAERS. Methods: Data pertaining to allergic reactions post COVID-19 vaccination reported from week 52/2020 to week 39/2021 were collected from EudraVigilance and VAERS databases and analyzed. Incidence rates were calculated using the corresponding administered vaccine doses as denominators for all licensed vaccines and both platform types (mRNA or vectored). The composition of the novel mRNA and vectored vaccines was examined to identify potential allergic triggers. Results: Anaphylactic reactions and anaphylactic shock were the most common allergic reactions, predominantly reported by females, at estimated incidence rates of 9.91/million and 1.36/million vaccine doses, respectively. A 2- to 5-fold higher incidence of both allergic reactions was found in Europe compared to the US for both vaccine platforms. Most cases were benign. Fatalities were extremely rare and associated with vectored rather than mRNA vaccines. Conclusions: The precise mechanism(s) for allergic reactions after vaccination with COVID-19 vaccines are not fully known. Plausible explanations include exposure to components of the final pharmaceutical product and cross-reactivity to ingredients or unintentional impurities in the final formula. Additional research is warranted to further improve vaccine safety.