BCG Vaccination Enhances the Immunogenicity of Subsequent Influenza Vaccination in Healthy Volunteers: A Randomized, Placebo-Controlled Pilot Study

Leentjens, Jenneke; Kox, Matthijs; Stokman, Robin; Gerretsen, Jelle; Diavatopoulos, Dimitri A.; Crevel, Reinout van; Rimmelzwaan, Guus F.; Pickkers, Peter; Netea, Mihai G.

doi:10.1093/infdis/jiv332

Cited by 225 publications

(212 citation statements)

References 29 publications

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“…Protective role of BCG against influenza infections in mice and unintended beneficial effects of BCG vaccinations in humans have been demonstrated by others [12,13]. BCG’s non-specific protections against other diseases are mostly through enhancement of macrophage recruitment and function in the site of infection [14].…”

Section: Discussionmentioning

confidence: 99%

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Boosting efferocytosis in alveolar space using BCG vaccine to protect host against influenza pneumonia

et al. 2017

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Efferocytosis by alveolar phagocytes (APs) is pivotal in maintenance of lung homeostasis. Increased efferocytosis by APs results in protection against lethal acute lung injury due to pulmonary infections whereas defective efferocytosis by APs results in chronic lung inflammation. In this report, we show that pulmonary delivery of Bacillus Calmette-Guerin (BCG) significantly enhances efferocytosis by APs. Increased efferocytosis by APs maintains lung homeostasis and protects mice against lethal influenza pneumonia. Intranasally treated wild type C57Bl/6 (WT) mice with BCG showed significant increase in APs efferocytosis in vivo compared to their PBS-treated counterparts. All BCG-treated WT mice survived lethal influenza A virus (IAV) infection whereas all PBS-treated mice succumbed. BCG-induced resistance was abrogated by depleting AP prior to IAV infection. BCG treatment increased uptake, and digestion/removal of apoptotic cells by APs. BCG significantly increased the expression of TIM4 on APs and increased expression of Rab5 and Rab7. We demonstrated that increased efferocytosis by APs through pulmonary delivery of BCG initiated rapid clearance of apoptotic cells from the alveolar space, maintained lung homeostasis, reduced inflammation and protected host against lethal IAV pneumonia.

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Section: Discussionmentioning

confidence: 99%

“…BCG also confers a non-specific protection against influenza infections in mice [12]. Substantial evidences for nonspecific beneficial effects of BCG vaccination in humans have been provided by a randomized clinical trial [13]. BCG increases non-specific protection against other diseases mostly through enhancement of macrophage functions.…”

Section: Introductionmentioning

confidence: 99%

Boosting efferocytosis in alveolar space using BCG vaccine to protect host against influenza pneumonia

et al. 2017

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“…Thus, while polyclonal stimulation of B cell responses could contribute to sustained antibody responses throughout life, the evidence for this is inconsistent. When given at or around the same time as other vaccines, BCG may enhance the antibody response to those vaccines, acting as or like an adjuvant, although the specific effects/outcomes are a matter of debate 29-31 . In any case, this is not likely to be the main mechanism for the beneficial heterologous effects of BCG or measles vaccine in infants because they often lack pre-existing immunity to most pathogens and durability of antibody responses is more limited than at older ages, perhaps attributable in part to suboptimal support in the bone marrow 32, 33 .…”

Section: Heterologous Lymphocyte Responsesmentioning

confidence: 99%

Harnessing the beneficial heterologous effects of vaccination

et al. 2016

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Clinical evidence strongly suggests that certain live vaccines, in particular Bacille Calmette–Guérin (BCG) and measles vaccines, can reduce all-cause mortality, likely via protection against non-targeted pathogens in addition to the targeted pathogen. The underlying mechanisms are currently unknown. We discuss how heterologous lymphocyte activation and innate immune memory could promote protection beyond the intended target pathogen and consider how vaccinologists could leverage heterologous immunity to improve outcomes in vulnerable populations, in particular the very young and the elderly.

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“…BCG vaccine has been associated in multiple studies with effects beyond protection against tuberculosis, which is the original target of the intervention (1). As such, BCG vaccination has been shown to enhance the protection provided by H1N1 vaccine (2). Another study observed that prior BCG vaccination attenuates yellow fever vaccine associated viremia (3).…”

Section: Introductionmentioning

confidence: 99%

Association Between BCG Policy is Significantly Confounded by Age and is Unlikely to Alter Infection or Mortality Rates

Kirov

2020

Preprint

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Recently a number of publications looked at the association between COVID-19 morbidity and mortality on one hand and countries' policies with respect to BCG vaccination on the other. This connection arises from differences in the rates of infection in countries where BCG vaccination is mandatory compared to countries where mandatory vaccination no longer exists or was never implemented in the first place. In at least 2 preprint publications the authors expressed the view that the "known immunological benefits" of BCG vaccination may be behind the biological mechanism of such observation. One study accounted for different income levels in different groups. Another study did not attempted to do so, instead exploring the differences between countries where a booster shot is given vs others where no such practice exists (finding no connection). Both of these studies did not explore other potential confounding factors. Meanwhile the press has focused on these headlines and pushed the narrative that BCG vaccination is causally linked to infection and mortality rates. This poses a serious challenge, demonstrated by the recently initiated clinical trials on BCG vaccination within the COVID19 context. This study shows that population age is a very significant confounding factor that explains the rates of infections much better and has a solid biology mechanism which explains this correlation. It suggests that BCG vaccination may have little or no causal link to infection rates and advises that any follow up studies should control for several confounding factors, such as population age, ethnicity, rates of certain chronic diseases, time from community spread start date, major public policy decisions and income levels.

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BCG Vaccination Enhances the Immunogenicity of Subsequent Influenza Vaccination in Healthy Volunteers: A Randomized, Placebo-Controlled Pilot Study

Cited by 225 publications

References 29 publications

Boosting efferocytosis in alveolar space using BCG vaccine to protect host against influenza pneumonia

Boosting efferocytosis in alveolar space using BCG vaccine to protect host against influenza pneumonia

Harnessing the beneficial heterologous effects of vaccination

Association Between BCG Policy is Significantly Confounded by Age and is Unlikely to Alter Infection or Mortality Rates

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