Non-specific Effects of Vaccines Illustrated Through the BCG Example: From Observations to Demonstrations

Abstract

Epidemiological studies regarding many successful vaccines suggest that vaccination may lead to a reduction in child mortality and morbidity worldwide, on a grander scale than is attributable to protection against the specific target diseases of these vaccines. These non-specific effects (NSEs) of the Bacille Calmette-Guérin (BCG) vaccine, for instance, implicate adaptive and innate immune mechanisms, with recent evidence suggesting that trained immunity might be a key instrument at play. Collectively referring to the memory-like characteristics of innate immune cells, trained immunity stems from epigenetic reprogramming that these innate immune cells undergo following exposure to a primary stimulus like BCG. The epigenetic changes subsequently regulate cytokine production and cell metabolism and in turn, epigenetic changes are regulated by these effects. Novel -omics technologies, combined with in vitro models for trained immunity and other immunological techniques, identify the biological pathways within innate cells that enable training by BCG. Future research should aim to identify biomarkers for vaccine heterologous effects, such that they can be applied to epidemiological studies. Linking biological mechanisms to the reduction in all-cause mortality observed in epidemiological studies will strengthen the evidence in favor of vaccine NSEs. The universal acceptance of these NSEs would demand a re-evaluation of current vaccination policies, such as the childhood vaccination recommendations by the World Health Organization, in order to produce the maximum impact on childhood mortality.

Incidence, clinical profile, and risk factors for serious bacterial infections in children hospitalized with fever in Ujjain, India

“…Another Indian study [7] observed that 60% of the children with bacterial infection were without BCG scar mark. Recent evidence suggests that the effect of BCG vaccine extends beyond the target-disease immunity [32]. These non-specific effects of BCG are due to epigenetic reprogramming of innate immune cells termed "trained immunity".…”

COVID-19 research: promising tracks leading to uro-oncology

“…First of all, we would like to underline the potential protective effect of Bacillus Calmette Guerin (BCG) vaccination against Covid-19 [4]. There has already been evidence showing that the BCG vaccine not only provides protection against tuberculosis, but also has a so-called heterologous immunomodulatory effect, which results in protection against various viral infections as well [5][6][7]. Its exact mechanism is not yet fully understood, but involves the activation of both heterologous lymphocytes and the trained immune system resulting in lower rates of neonatal sepsis and respiratory tract infections [5,6].…”

Dynamics of Neutrophiles Phagocitary Activity after Repeated Vaccinations of Laboratory Animals by Experimental Diphtheriae Bacterial Antigen Drug

“…Розглянута концепція стала підґрунтям для наших досліджень у напрямку конструювання ком-бінованої дифтерійної вакцини нового класу, до складу якої нами запропоновано увести комплекс поверхневих антигенів, одержаних за допомогою дезінтеграції бактеріальної маси C. diphtheriae фізичними чинниками [11,12]. Бактеріальний компонент має, по-перше, замінити собою нейротоксичний ад'ювант гідроксид алюмінію, з яким пов'язують також численні шкірні реакції у щеплених дифтерійними вакцинами [13,14], по-друге, забезпечити антиколонізаційну дію щодо збудника дифтерії та попередження бактеріоносійства, оскільки дифтерійний анатоксин не попереджає колонізацію слизових збудником дифтерії [15], по-третє, через систему уродженого імунітету він може забезпечити ряд цінних гетерологічних ефектів, підсилюючих імунний захист [16][17][18].…”