Trained immunity-inducing vaccines: Harnessing innate memory for vaccine design and delivery.

While the efficacy of many current vaccines is well-established, various factors can diminish their effectiveness, particularly in vulnerable groups. Amidst emerging pandemic threats, enhancing vaccine responses is critical. Our review synthesizes insights from immunology and epidemiology, focusing on the concept of trained immunity (TRIM) and the non-specific effects (NSEs) of vaccines that confer heterologous protection. We elucidate the mechanisms driving TRIM, emphasizing its regulation through metabolic and epigenetic reprogramming in innate immune cells. Notably, we explore the extended protective scope of vaccines like BCG and COVID-19 vaccines against unrelated infections, underscoring their role in reducing neonatal mortality and combating diseases like malaria and yellow fever. We also highlight novel strategies to boost vaccine efficacy, incorporating TRIM inducers into vaccine formulations to enhance both specific and non-specific immune responses. This approach promises significant advancements in vaccine development, aiming to improve global public health outcomes, especially for the elderly and immunocompromised populations.

Enduring echoes: Post-infectious long-term changes in innate immunity.

Upon encountering pathogens, the immune system typically responds by initiating an acute and self-limiting reaction, with symptoms subsiding after the pathogen has been cleared. However, long-term post-infectious clinical symptoms can manifest months or even years after the initial infection. 'Trained immunity', the functional reprogramming of innate immune cells through epigenetic and metabolic rewiring, has been proposed as a key concept for understanding these long-term effects. Although trained immunity can result in enhanced protection against reinfection with heterologous pathogens, it can also contribute to detrimental outcomes. Persisting and excessive inflammation can cause tissue damage and aggravate immune-mediated conditions and cardiovascular complications. On the other hand, suppression of immune cell effector functions by long-lasting epigenetic changes can result in post-infectious immune paralysis. Distinct stimuli can evoke different trained immunity programs, potentially resulting in different consequences for the host. In this review, we provide an overview of both the adaptive and maladaptive consequences of infectious diseases. We discuss how long-term immune dysregulation in patients can be addressed by tailoring host-directed interventions and identify areas of scientific and therapeutic potential to advance further.

Cardiovascular events after invasive pneumococcal disease: a retrospective cohort study.

OBJECTIVES: This study aims to understand the magnitude of and mechanisms underlying the development of cardiovascular events (CVEs) in patients with invasive pneumococcal disease (IPD). We aimed to identify factors that contribute to the occurrence of CVEs within 1 year after admission and discuss implications for patient care. METHODS: A multicentered cohort study included adult patients from four Dutch hospitals who had a positive blood culture for Streptococcus pneumoniae and any type of clinical manifestation between 2012 and 2020. Disease characteristics and microbiological data were systematically collected from electronic patient files. The main outcome measures were the occurrence of stroke and acute coronary syndromes (ACS). RESULTS: Of 914 eligible patients, 4.2% experienced a CVE within 1 year after admission for IPD. ACS mainly occurred in the first 2 weeks, whereas stroke developed throughout follow-up. Although ACS was positively associated with disease severity, the sole independent predictor was alcohol abuse (odds ratio [OR] 3.840, 95% confidence interval [CI] 1.108-13.303). Although stroke occurred in 6.3% of meningitis cases, the best clinical predictor of stroke was a body temperature >39.5 °C at admission (OR 3.117 [1.154-8.423]). In the adult IPD population aged <70 years, pneumococcal serotypes were the primary predictors of ACS (7F; OR 15.733 [1.812-136.632]) and stroke (22F; OR 7.320 [1.193-44.903]). CONCLUSIONS: Adverse CVEs were not uncommon after IPD diagnosis and deserve attention, especially in the high-risk groups we identified in our study population. Whether specific serotypes play a role in the development of CVE requires substantiation in further research.

Timing and sequence of vaccination against COVID-19 and influenza (TACTIC): a single-blind, placebo-controlled randomized clinical trial.

Background: Novel mRNA-based vaccines have been used to protect against SARS-CoV-2, especially in vulnerable populations who also receive an annual influenza vaccination. The TACTIC study investigated potential immune interference between the mRNA COVID-19 booster vaccine and the quadrivalent influenza vaccine, and determined if concurrent administration would have effects on safety or immunogenicity. Methods: TACTIC was a single-blind, placebo-controlled randomized clinical trial conducted at the Radboud University Medical Centre, the Netherlands. Individuals ≥60 years, fully vaccinated against COVID-19 were eligible for participation and randomized into one of four study groups: 1) 0.5 ml influenza vaccination Vaxigrip Tetra followed by 0.3 ml BNT162b2 COVID-19 booster vaccination 21 days later, (2) COVID-19 booster vaccination followed by influenza vaccination, (3) influenza vaccination concurrent with the COVID-19 booster vaccination, and (4) COVID-19 booster vaccination only (reference group). Primary outcome was the geometric mean concentration (GMC) of IgG against the spike (S)-protein of the SARS-CoV-2 virus, 21 days after booster vaccination. We performed a non-inferiority analysis of concurrent administration compared to booster vaccines alone with a predefined non-inferiority margin of -0.3 on the log10-scale. Findings: 154 individuals participated from October, 4, 2021, until November, 5, 2021. Anti-S IgG GMCs for the co-administration and reference group were 1684 BAU/ml and 2435 BAU/ml, respectively. Concurrent vaccination did not meet the criteria for non-inferiority (estimate -0.1791, 95% CI -0.3680 to -0.009831) and antibodies showed significantly lower neutralization capacity compared to the reference group. Reported side-effects were mild and did not differ between study groups. Interpretation: Concurrent administration of both vaccines is safe, but the quantitative and functional antibody responses were marginally lower compared to booster vaccination alone. Lower protection against COVID-19 with concurrent administration of COVID-19 and influenza vaccination cannot be excluded, although additional larger studies would be required to confirm this. Trial registration number: EudraCT: 2021-002186-17. Funding: The study was supported by the ZonMw COVID-19 Programme.

C-reactive protein to rule out complicated pneumococcal disease manifestations: a retrospective cohort study in adults with pneumococcal bacteraemia.

OBJECTIVES: To explore the negative predictive value (NPV) of C-reactive protein (CRP) at admission to exclude complicated disease manifestations of pneumococcal disease. METHODS: A Dutch multicentre retrospective cohort study was conducted between 01-01-2012 and 30-06-2020. Adults with positive blood cultures for Streptococcus pneumoniae, whose CRP was measured at admission and whose infection focus was known, were included. Electronic medical and microbiological records were reviewed. RESULTS: Of the 832 bacteraemic patients enrolled, 30% had complicated manifestations of pneumococcal disease; most frequent were pleural effusion (8.9%), pleural empyema (5.4%) and meningitis (7.5%). Compared to solitary pneumonia, patients with pleural effusion and empyema presented with higher CRP levels. Although low CRP levels did not exclude complicated disease in general, a CRP level < 114 mg/L at admission could reliably exclude empyema among adult pneumonia patients with an NPV of 93% and a specificity of 26%. However, in cases where pleural fluid was present, CRP levels were mostly > 114 mg/L, such that suspicion of empyema could only be ruled out in a minority of cases (10%). CONCLUSIONS: Complicated manifestations are prevalent in adult pneumococcal bacteraemia. Low blood CRP levels can reliably exclude the development of pulmonary empyema. Practical value may be largest in settings without thoracic imaging at hand.